articles+ search results

LIVER cells, HOMEOSTASIS, NON-alcoholic fatty liver disease, YAP signaling proteins, GENETIC overexpression, NUCLEOTIDE synthesis, and METABOLIC regulation

A primary role of the liver is to regulate whole body glucose homeostasis. Glucokinase (GCK) is the main hexokinase (HK) expressed in hepatocytes and functions to phosphorylate the glucose that enters via GLUT transporters to become glucose-6-phosphate (G6P), which subsequently commits glucose to enter downstream anabolic and catabolic pathways. In the recent years, hexokinase domain-containing-1 (HKDC1), a novel 5th HK, has been characterized by our group and others. Its expression profile varies but has been identified to have low basal expression in normal liver but increases during states of stress including pregnancy, nonalcoholic fatty liver disease (NAFLD), and liver cancer. Here, we have developed a stable overexpression model of hepatic HKDC1 in mice to examine its effect on metabolic regulation. We found that HKDC1 overexpression, over time, causes impaired glucose homeostasis in male mice and shifts glucose metabolism towards anabolic pathways with an increase in nucleotide synthesis. Furthermore, we observed these mice to have larger liver sizes due to greater hepatocyte proliferative potential and cell size, which in part, is mediated via yes-associated protein (YAP) signaling. [ABSTRACT FROM AUTHOR]

AFFECTIVE neuroscience, BITTERNESS (Taste), SWEETNESS (Taste), AFFECT (Psychology), STIMULUS intensity, TRUST, and STIMULUS & response (Psychology)

• Affect misattribution procedure was used to measure implicit responses to tastes. • Both chemosensory quality and intensity contributed to implicit affective responses. • Reaction times were faster for lower intensity positive stimuli. • Reaction times were faster for strong intensity negative stimuli. • Trustworthiness for faces was applied as a proxy for affective responses. Implicit measurements are indirect and could register emotions elicited by tasting without conscious awareness. While we know that some basic tastes such as sweetness and bitterness are innately liked or disliked, little is known about the affective responses to tactile sensations. It is also underexplored in which way the emotional responses to chemosensory stimuli are affected by the intensity of the stimulus. To address these issues an implicit method based on the Affect Misattribution Procedure using the judgment of trustworthiness to neutral faces, a proxy for valence, was developed using real tastes as primes (instead of pictures). Three different implicit measures were compared in an experiment in which 107 Italian PROP (6-n-propylthiouracil) Medium-Tasters were exposed to bitterness, astringency, and sweetness at weak/moderate and moderate/strong intensity. Samples were presented blind in aqueous solution monadically in triplicate. Participants were asked to taste a sample, then a neutral face was briefly presented on a screen, and participants were asked to indicate if they trusted the face (yes/no) and how much (on a 9-point Scale). Reaction times (RTs) for the yes/no responses were also collected. The data indicated that both taste qualities and intensity level influenced the yes/no trustworthiness judgements as well as the ratings and the reaction times. As expected, sweetness elicited the most positive affective responses and bitterness the most negative. Astringency elicited a positive response (but lower than sweetness) when it was presented at low intensity, while it elicited a more negative response when it was presented at higher intensity, and this effect was particularly evident when this was evaluated with the scale. Faster reaction times were observed for lower intensity stimuli that had been evaluated as positive but also for higher intensity stimuli that had been evaluated as negative. The results of the present study represent an advance in methodologies that tap implicit affective reactions to chemosensory qualities found in foods and beverages and that can be used to study food experience. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion To comprehensively assess hyponatraemia in acute heart failure (AHF) regarding prevalence, associations, hospital course, and post‐discharge outcomes.Of 8298 patients in the European Society of Cardiology Heart Failure Long‐Term Registry hospitalized for AHF with any ejection fraction, 20% presented with hyponatraemia (serum sodium <135 mmol/L). Independent predictors included lower systolic blood pressure, estimated glomerular filtration rate (eGFR) and haemoglobin, along with diabetes, hepatic disease, use of thiazide diuretics, mineralocorticoid receptor antagonists, digoxin, higher doses of loop diuretics, and non‐use of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers and beta‐blockers. In‐hospital death occurred in 3.3%. The prevalence of hyponatraemia and in‐hospital mortality with different combinations were: 9% hyponatraemia both at admission and discharge (hyponatraemia Yes/Yes, in‐hospital mortality 6.9%), 11% Yes/No (in‐hospital mortality 4.9%), 8% No/Yes (in‐hospital mortality 4.7%), and 72% No/No (in‐hospital mortality 2.4%). Correction of hyponatraemia was associated with improvement in eGFR. In‐hospital development of hyponatraemia was associated with greater diuretic use and worsening eGFR but also more effective decongestion. Among hospital survivors, 12‐month mortality was 19% and adjusted hazard ratios (95% confidence intervals) were for hyponatraemia Yes/Yes 1.60 (1.35–1.89), Yes/No 1.35 (1.14–1.59), and No/Yes 1.18 (0.96–1.45). For death or heart failure hospitalization they were 1.38 (1.21–1.58), 1.17 (1.02–1.33), and 1.09 (0.93–1.27), respectively.Among patients with AHF, 20% had hyponatraemia at admission, which was associated with more advanced heart failure and normalized in half of patients during hospitalization. Admission hyponatraemia (possibly dilutional), especially if it did not resolve, was associated with worse in‐hospital and post‐discharge outcomes. Hyponatraemia developing during hospitalization (possibly depletional) was associated with lower risk. [ABSTRACT FROM AUTHOR]

RHINOPLASTY, CLEFT lip, PATIENT satisfaction, RESPIRATION, and QUESTIONNAIRES

Secondary rhinoplasty on patients with cleft is a challenging procedure, and the most important criterion for evaluating the surgery success is patient satisfaction even if it's subjective. To evaluate patient satisfaction following secondary cleft rhinoplasty with a specific assessment for patients with Unilateral Cleft Lip and Palate (UCLP). Our retrospective cross-sectional study is composed of 29 patients with UCLP with a mean age of 23 years old, who underwent secondary rhinoplasty between 2010 and 2021 in our department. The survey was conducted postoperatively using a cleft-nose specific custom designed questionnaire based on the Byrne questionnaire, over the phone. This satisfaction questionnaire comprises six questions about physical appearance and one question about functional aspect. Patients were asked to answer "yes" or "no" or to rate from 0 (no improvement) to 10 (perfect result) depending on the question. Twenty out of 29 people responded to the questionnaire, representing an answer rate of 69%. The average score given by the patient for nasolabial scar improvement was 7.2/10, and the one concerning global improvement was 8.2/10. All patients would be ready to undergo the same procedure again, knowing the final result. A functional improvement concerning breathing or snoring was reported in 45% of cases. All dorsum or tip issues were improved after surgery (P = 0,07). Our results demonstrate high patient satisfaction after cleft rhinoplasty, which encourages the continuation of this surgery. We would recommend the use of this simple questionnaire to allow a more accurate evaluation of patient outcomes. [ABSTRACT FROM AUTHOR]

CATALAN language, OPTIMALITY theory (Linguistics), LANGUAGE & languages, ACCOMMODATIONISM, and AUTOSEGMENTAL theory (Linguistics)

This paper aims at contributing to ascertain the principles of intonational grammar that lie behind the realization of nuclear contours and at presenting them in terms of Optimality Theory constraints. In order to do so, we analyse the prosody of the nuclear configuration of Southern Valencian Catalan yes-no questions, with special emphasis on situations where text-tune accommodation phenomena take place. The empirical data, which are analysed according to the principles of the autosegmental-metrical model, show a complex interplay of different phenomena at the text-tune interface, like vowel lengthening, tonal spreading, tonal retraction and intonation-driven schwa epenthesis. We argue that the variation detected in the data can be accounted for by the interaction of nine constraints (i.e., Max-IO(µp), Dep-IO(µs), Anchor(T%,Rt,IP,Rt), Anchor(L*,Rt,ˈσ,Rt), *Anchor(T,C), *Anchor(T,-voice), Share(T*,NC), Dep-IO(Associate), Max-IO(Associate)), whose ranking is established by means of a Stochastic Optimality Theory analysis. [ABSTRACT FROM AUTHOR]

SECOND language acquisition, DOMINANT language, CHINESE language, LANGUAGE & languages, NATIVE language, and NATURAL languages

And even though I do not think that most domain-general models of L SB 1 sb /L SB 2 sb acquisition are going to come under further scrutiny, Mazuka's distinction is likely to be valuable for domain-specific models of acquisition (of phonology). Yes, L SB 2 sb learners do not parse de-RCs in the same way as native speakers do, but that only indicates that they have not achieved ultimate attainment; not that there are fundamental differences in L SB 1 sb and L SB 2 sb processing. Martohardjono, Valian and Klein (MVK) take up the deficit and transfer accounts (d/t) of L SB 2 sb acquisition in their chapter, while looking at acquisition of tense. [Extracted from the article]

ANGIOKERATOMA corporis diffusum, PATIENTS, TREATMENT effectiveness, KIDNEY physiology, and SYMPTOMS

Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop in adulthood. Outcomes of Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes among patients aged 5–30 years at initiation of treatment with agalsidase beta using data from the Fabry Registry (NCT00196742 , sponsor: Sanofi). Reported GLA variants were predicted to be associated with the classic phenotype or not classified in fabry-database.org. Linear mixed models were conducted to assess changes over ≥2-year follow-up in the estimated glomerular filtration rate (eGFR) stratified by low (LRI) and high (HRI) renal involvement (defined by proteinuria/albuminuria levels), and changes in interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) Z -scores stratified by median age at first treatment. Self-reports ('yes'/'no') of abdominal pain, diarrhea, chronic peripheral pain (denoting neuropathic pain), and acute pain crises at baseline were compared with reports after ≥0.5-year and ≥2.5-year follow-up using McNemar's test. Male (n = 117) and female patients (n = 59) with LRI initiated treatment at a median age of 19.9 and 23.6 years, respectively, and were followed for a median of 6.3 and 5.0 years, respectively. The eGFR slopes were −1.18 (P from 0 <0.001) and −0.92 mL/min/1.73 m2/year (P from 0 = 0.040), respectively. Males with HRI (n = 23, median UPCR 1.0 g/g), who started treatment at a median age of 26.7 years, had an eGFR slope of −2.39 mL/min/1.73 m2/year (P from 0 <0.001; P difference = 0.055, as compared with the slope of −1.18 mL/min/1.73 m2/year for LRI males) during a median follow-up of 5.6 years. Echocardiographic variables were stable among males, regardless of age, and among young females (median follow-up >5.5 years and ≥4.5 years, respectively). Older females (treatment initiation at median age 27.5 years) had a slope of LVPWT Z -scores of 0.18/year (n = 12, P from 0 = 0.028), whereas IVST Z -scores remained stable (n = 13, 0.10/year, P from 0 = 0.304) during a median follow-up of ≥3.7 years. These slopes did not significantly differ from slopes of younger females. Reports of chronic peripheral pain and acute pain crises by males, and of diarrhea and acute pain crises by females, significantly reduced after a median follow-up of ≥4.0 years. After a median follow-up of ≥5.4 years, reports of all four symptoms significantly decreased among males, whereas among females only reports of abdominal pain significantly decreased. During sustained treatment with agalsidase beta in young Fabry patients with a predicted classic phenotype or with unclassified GLA variants with similar characteristics, the decline in eGFR was modest among male and female patients with LRI. The greater decline in eGFR among older, proteinuric (i.e., HRI) males may suggest a benefit of earlier treatment. Overall, echocardiographic variables remained stable, particularly among males and younger females. Significant reductions in symptom reports occurred primarily among males after longer follow-up and were less noticeable among females. These observed trends are suggestive of an overall improvement after treatment in young patients, but warrant larger longitudinal studies. • Overall improvement after sustained agalsidase beta treatment in young Fabry patients. • Modest decrease in kidney function in patients with low renal involvement. • Greater decrease in kidney function in older, proteinuric male patients. • Stable echocardiographic variables among male and younger female patients. • Reductions in Fabry disease symptom reports particularly among male patients. [ABSTRACT FROM AUTHOR]

HUMIC acid, COMPLEX matrices, XENOESTROGENS, POLLUTANTS, SEWAGE disposal plants, ENDOCRINE disruptors, and HUMUS

The presence of estrogenic endocrine disruptors in aquatic environments has been a concern and bioassays are recommended tools for their monitoring. However, the physicochemical properties of contaminants and the environmental matrix features may influence the resultant response. This study aimed to assess this influence on the Yeast Estrogen Screen (YES) assay. Mixtures of 17β-estradiol (E2) and humic acid (HA) were evaluated through the Schild approach aiming to investigate the interactions between estrogens and dissolved organic matter (DOM). Moreover, environmental samples from municipal landfill leachate and wastewater treatment plant (WWTP) influents and effluents were screened for (anti)estrogenic activity at both dissolved and particulate phases. Finally, results were statistically confronted with physicochemical parameters through principal component analysis (PCA). The HA test concentrations strongly reduced the E2 response, even at low levels. Humic substances may not only reduce estrogen bioavailability, but also interfere with the assay mechanism through enzymatic inhibition thus masking the sample estrogenic potential. Landfill leachate had total E2-Eq in the range 1282–2591 ng L−1, while WWTP influent and effluent were in the range 12.1–41.4 and L−1, so estrogenicity was reduced 92% in average. Particulate phase was responsible for 33–100% of measured E2-Eq between matrices, though cytotoxicity occurred in some extracts. Antiestrogenic activity was observed in both phases and might also have masked the estrogenicity of samples. PCA did not resulted in positive correlations supporting a multiphase distribution pattern of estrogenic compounds. Nevertheless, the solids and organic matter characteristics supported the data interpretation. In conclusion, the in vitro YES assay is subjected to factors intrinsic to the environmental sample that can influence on the measured estrogenic response. Therefore, results interpretation should be performed together with organic matter characterization parameters, cytotoxicity and antiestrogenic activity evaluation. [Display omitted] • Humic acid induces strong antagonistic effect in the Yeast Estrogen Screen. • Landfill leachate, WWTP influents and effluents were highly estrogenic. • Cytotoxicity was recurrently associated with particles >0.7 μm. • DOM, antiestrogenic activity and phase distribution influenced on estrogenic response. [ABSTRACT FROM AUTHOR]

KINASES, YAP signaling proteins, FIBROBLAST growth factor 2, FIBROBLAST growth factor receptors, HIPPO signaling pathway, DRUG toxicity, and CHOLANGIOCARCINOMA

There is an unmet need to develop novel, effective medical therapies for cholangiocarcinoma (CCA). The Hippo pathway effector, Yes-associated protein (YAP), is oncogenic in CCA, but has historically been difficult to target therapeutically. Recently, we described a novel role for the LCK proto-oncogene, Src family tyrosine kinase (LCK) in activating YAP through tyrosine phosphorylation. This led to the hypothesis that LCK is a viable therapeutic target in CCA via regulation of YAP activity. A novel tyrosine kinase inhibitor with relative selectivity for LCK, NTRC 0652-0, was pharmacodynamically profiled in vitro and in CCA cells. A panel of eight CCA patient-derived organoids were characterized and tested for sensitivity to NTRC 0652-0. Two patient-derived xenograft models bearing fibroblast growth factor receptor 2 (FGFR2)-rearrangements were utilized for in vivo assessment of pharmacokinetics, toxicity, and efficacy. NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in CCA cells. LCK inhibition with NTRC 0652-0 led to decreased tyrosine phosphorylation, nuclear localization, and co-transcriptional activity of YAP, and resulted in apoptotic cell death in CCA cell lines. A subset of tested patient-derived organoids demonstrated sensitivity to NTRC 0652-0. CCAs with FGFR2 fusions were identified as a potentially susceptible and clinically relevant genetic subset. In patient-derived xenograft models of FGFR2 fusion-positive CCA, daily oral treatment with NTRC 0652-0 resulted in stable plasma and tumor drug levels, acceptable toxicity, decreased YAP tyrosine phosphorylation, and significantly decreased tumor growth. A novel LCK inhibitor, NTRC 0652-0, inhibited YAP signaling and demonstrated preclinical efficacy in CCA cell lines, and patient-derived organoid and xenograft models. Although aberrant YAP activation is frequently seen in CCA, YAP targeted therapies are not yet clinically available. Herein we show that a novel LCK-selective tyrosine kinase inhibitor (NTRC 0652-0) effectively inhibits YAP tyrosine phosphorylation and cotranscriptional activity and is well tolerated and cytotoxic in multiple preclinical models. The data suggest this approach may be effective in CCA with YAP dependence or FGFR2 fusions, and these findings warrant further investigation in phase I clinical trials. [Display omitted] • LCK is a novel therapeutic target in cholangiocarcinoma. • Cholangiocarcinoma organoid and xenograft tumor models respond to LCK inhibition. • FGFR2-altered cholangiocarcinomas have enriched YAP activity and are sensitive to LCK inhibition. [ABSTRACT FROM AUTHOR]

Background: Soft tissue sarcoma is a rare but serious side-effect of radiotherapy to treat breast cancer, and rates are increasing in the USA. We evaluated potential co-factors in two complimentary cohorts of US breast cancer survivors.Methods: In this retrospective cohort study, we sourced data from the Kaiser Permanente (KP) cohort and the Surveillance, Epidemiology, and End Results (SEER) 13 registries cohort, both in the USA. The KP cohort included 15 940 women diagnosed with breast cancer from Jan 1, 1990, to Dec 31, 2016, in KP Colorado, KP Northwest (which serves Oregon and Southwest Washington state), or KP Washington, with detailed treatment data and comorbidities (including hypertension and diabetes at or before breast cancer diagnosis) from electronic medical records. The SEER cohort included 457 300 women diagnosed with breast cancer from Jan 1, 1992, to Dec 31, 2016, within the 13 SEER registries across the USA, with initial treatment data (yes vs no or unknown). Eligibility criteria in both cohorts were female breast cancer survivors (stage I-III) aged 20-84 years at diagnosis who had breast cancer surgery, and had survived at least 1 year after breast cancer diagnosis. The outcome of interest was any second thoracic soft tissue sarcoma (angiosarcomas and other subtypes) that developed at least 1 year after breast cancer diagnosis. Risk factors for thoracic soft tissue sarcoma were assessed using multivariable Poisson regression models.Findings: In the KP cohort, median follow-up was 9·3 years (IQR 5·7-13·9) and 19 (0·1%) of 15 940 eligible, evaluable women developed a thoracic soft tissue sarcoma (11 angiosarcomas, eight other subtypes). Most (94·7%; 18 of 19) thoracic soft tissue sarcomas occurred in women treated with radiotherapy; thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma (relative risk [RR] 8·1 [95% CI 1·1-60·4]; p=0·0052), but there was no association with prescribed dose, fractionation, or boost. The RR of angiosarcoma after anthracyclines was 3·6 (95% CI 1·0-13·3; p=0·058). Alkylating agents were associated with an increased risk of developing other sarcomas (RR 7·7 [95% CI 1·2-150·8]; p=0·026). History of hypertension (RR 4·8 [95% CI 1·3-17·6]; p=0·017) and diabetes (5·3 [1·4-20·8]; p=0·036) were each associated with around a five-times increased risk of angiosarcoma. In the SEER cohort, 430 (0·1%) of 457 300 patients had subsequent thoracic soft tissue sarcomas (268 angiosarcomas and 162 other subtypes) after a median follow-up of 8·3 years (IQR 4·3-13·9). Most (77·9%; 335 of 430) cases occurred after radiotherapy; thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma (RR 3·0 [95% CI 2·4-3·8]; p<0·0001) and, for angiosarcomas, the RR for breast-conserving surgery plus radiotherapy versus mastectomy plus radiotherapy was 1·9 (1·1-3·3; p=0·012). By 10 years after radiotherapy, the cumulative incidence of thoracic soft tissue sarcoma was 0·21% (95% CI 0·12-0·34) in the KP cohort and 0·15% (95% CI 0·13-0·17) in SEER.Interpretation: Radiotherapy was the strongest risk factor for thoracic soft tissue sarcoma in both cohorts. This finding, along with the novel findings for diabetes and hypertension as potential risk factors for angiosarcomas, warrant further investigation as potential targets for prevention strategies and increased surveillance.Funding: US National Cancer Institute and National Institutes of Health. [ABSTRACT FROM AUTHOR]

RADIATION exposure, MEDICAL personnel, COMPUTED tomography, RADIATION protection, and CLINICAL indications

Purpose: To obtain clinicians' views of the need to account for radiation exposure from previous CT scans and the advisability of a regulatory mechanism to control the number of CT scans for an individual patient.Methods: A convenience survey was conducted by emailing a link to a three-question electronic survey to clinicians in many countries, mostly through radiology and radiation protection contacts.Results: 505 responses were received from 24 countries. 293 respondents (58%) understand that current regulations do not limit the number of CT scans that can be prescribed for a single patient in a year. When asked whether there should be a regulation to limit the number of CT scans that can be prescribed for a single patient in one year, only a small fraction (143, 28%) answered 'No', 182 (36%) answered 'Maybe' and 166 (33%) answered 'Yes'. Most respondents (337; 67%) think that radiation risk should form part of the consideration when deciding whether to request a CT exam. A minority (138; 27%) think the decision should be based only on the medical indication for the CT exam. Comparison among the 4 countries (South Korea, Hungary, USA and Canada) with the largest number of respondents indicated wide variations in responses.Conclusions: A majority of the surveyed clinicians consider radiation risk, in addition to clinical factors, when prescribing CT exams. Most respondents are in favor of, or would consider, regulation to control the number of CT scans that could be performed on a patient annually. [ABSTRACT FROM AUTHOR]

TALAROMYCES, CACAO, FUNGAL growth, NATURAL resources, SOIL pollution, and SOILS

Inorganic pollutants in Colombian cocoa (Theobroma cacao L.) agrosystems cause problems in the production, quality, and exportation of this raw material worldwide. There has been an increased interest in bioprospecting studies of different fungal species focused on the biosorption of heavy metals. Furthermore, fungi constitute a valuable, profitable, ecological, and efficient natural soil resource that could be considered in the integrated management of cadmium mitigation. This study reports a new species of Talaromyces isolated from a cocoa soil sample collected in San Vicente de Chucurí, Colombia. T. santanderensis is featured by Lemon Yellow (R. Pl. IV) mycelium on CYA, mono-to-biverticillade conidiophores, and acerose phialides. T. santanderensis is distinguished from related species by its growth rate on CYAS and powdery textures on MEA, YES and OA, high acid production on CREA and smaller conidia. It is differentiated from T. lentulus by its growth rate on CYA medium at 37 °C without exudate production, its cream (R. PI. XVI) margin on MEA, and dense sporulation on YES and CYA. Phylogenetic analysis was performed using a polyphasic approach, including different phylogenetic analyses of combined and individual ITS, CaM, BenA, and RPB2 gene sequences that indicate that it is new to science and is named Talaromyces santanderensis sp. nov. This new species belongs to the Talaromyces section and is closely related to T. lentulus, T. soli, T. tumuli, and T. pratensis (inside the T. pinophilus species complex) in the inferred phylogeny. Mycelia growth of the fungal strains was subjected to a range of 0–400 mg/kg Cd and incorporated into malt extract agar (MEA) in triplicates. Fungal radial growth was recorded every three days over a 13-day incubation period and In vitro cadmium tolerance tests showed a high tolerance index (0.81) when the mycelium was exposed to 300 mg/kg of Cd. Results suggest that T. santanderensis showed tolerance to Cd concentrations that exceed the permissible limits for contaminated soils, and it is promising for its use in bioremediation strategies to eliminate Cd from highly contaminated agricultural soils. [ABSTRACT FROM AUTHOR]

AUTISM in children, AUTISTIC children, MEDICAL screening, AUTISM, COMMUNITIES, and TEACHING hospitals

The Indian Autism Screening Questionnaire (IASQ), derived from the Indian Scale for Assessment of Autism ISAA (the mandated tool for autism in India), is an autism screening instrument for use in the general population by minimally trained workers. While ISAA has 40 items with four anchor points, the IASQ is a 10-item questionnaire with yes/no answers. It was initially validated using the ISAA. During its development the ISAA was itself compared to the Childhood Autism Rating Scale version 1 (ISAA Manual). In the present study, we evaluated both the ISAA and the IASQ in relation to the Childhood Autism Rating Scale version 2 (CARS-2). Methods: Participants were recruited from three settings: a referral clinic for neurodevelopmental conditions run by the Department of Paediatrics of a tertiary care teaching hospital (NDC OPD), the outpatient department of an institute for disability and rehabilitation (NIEPID), and from the community (CGOC). Persons between ages 3–18 were recruited following consent or assent (parent and child/adolescent). The IASQ was administered by a minimally trained administrator. It was followed by ISAA and the CARS-2 (in alternating order, by different evaluators blind to each other) (CARS2 SV (Standard Version) and CARS2 HF (High Functioning) as applicable). Sensitivity, specificity and area under the Receiver Operator Characteristics (ROC) curve were calculated for IASQ and CARS2, as well as for ISAA and CARS2. Concordance between CARS2 and ISAA was calculated using kappa coefficient. Results: A total of 285 participants (NIEPD n = 124; NDC OPD, n = 4; CGOC n = 157) (a total of 70 with autism and 215 controls) participated. IASQ and CARS2 were administered on 285 participants, while IASQ and ISAA were administered on 264 participants. When IASQ was compared to CARS2, sensitivity was 97%, specificity 81%, PPV 63%, NPV 99% at cut off 1 while these values were 97%, 92%, 79% and 99% respectively at cut off 2. There was high concordance between CARS2 and ISAA (Kappa 0.907, p<0.0001). Conclusions: IASQ has satisfactory sensitivity, specificity and concordance when compared with CARS2; it can be used for screening children with autism in community. The ISAA also showed a high concordance with CARS2, as it had with the older version of CARS. [ABSTRACT FROM AUTHOR]

The contamination of water sources by pharmaceutically active compounds (PhACs) and their effect on aquatic communities and human health have become an environmental concern worldwide. Membrane bioreactors (MBRs) are an alternative to improve biological removal of recalcitrant organic compounds from municipal sewage. Their efficiency can be increased by using high retention membranes such as forward osmosis (FO) and membrane distillation (MD). Thus, this research aimed to evaluate the performance of an anaerobic osmotic MBR coupled with MD (OMBR-MD) in the treatment of municipal sewage containing PhACs and estrogenic activity. A submerged hybrid FO-MD module was integrated into the bioreactor. PhACs removal was higher than 96% due to biological degradation, biosorption and membrane retention. Biological removal of the PhACs was affected by the salinity build-up in the bioreactor, with reduction in biodegradation after 32 d. However, salinity increment had little or no effect on biosorption removal. The anaerobic OMBR-MD removed >99.9% of estrogenic activity, resulting in a distillate with 0.14 ng L−1 E2-eq, after 22 d, and 0.04 ng L−1 E2-eq, after 32 d. OMBR-MD treatment promoted reduction in environmental and human health risks from high to low, except for ketoprofen, which led to medium acute environmental and human health risks. Carcinogenic risks were reduced from unacceptable to negligible, regarding estrogenic activity. Thus, the hybrid anaerobic OMBR-MD demonstrated strong performance in reducing risks, even when human health is considered. [Display omitted] • Biological removal of estrogenic compounds was governed mainly by biodegradation. • Biological removal of micropollutants (MP) was affected by the salinity build-up. • MgCl 2 as draw solute reduced the negative impacts on biological removal of MP. • Ketoprofen in distillate led to medium acute environmental and human health risks. • Carcinogenic risk, regarding estrogenicity, reduced from unacceptable to negligible. [ABSTRACT FROM AUTHOR]

DRUG discovery, DATA mining, and CHEMINFORMATICS

CLINICAL trials, MAJOR adverse cardiovascular events, SPONDYLOARTHROPATHIES, HERPES zoster, ANTIRHEUMATIC agents, and SACROILIAC joint

Background: Upadacitinib, a Janus kinase inhibitor, has been shown to be effective in patients with ankylosing spondylitis. We aimed to assess the efficacy and safety of upadacitinib in non-radiographic axial spondyloarthritis.Methods: The SELECT-AXIS 2 non-radiographic axial spondyloarthritis study was a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 113 sites across 23 countries (Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, France, Germany, Hungary, Israel, Japan, Mexico, Poland, Russia, Slovakia, South Korea, Spain, Taiwan, Turkey, Ukraine, and the USA). Eligible adults had active non-radiographic axial spondyloarthritis, with objective signs of inflammation based on MRI or elevated C-reactive protein and an inadequate response to non-steroidal anti-inflammatory drugs. Patients were randomly assigned (1:1) to receive oral upadacitinib 15 mg once daily or placebo using interactive response technology. Random treatment assignment was stratified by MRI inflammation in the sacroiliac joints and screening high-sensitivity C-reactive protein status (MRI-positive and C-reactive protein-positive, MRI-positive and C-reactive protein-negative, and MRI-negative and C-reactive protein-positive) and previous exposure to biologic disease-modifying antirheumatic drugs (yes vs no). Treatment assignment was masked from patients, investigators, study site personnel, and the study sponsor. The primary endpoint was the proportion of patients with an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Analyses were performed on the full analysis set of patients, who underwent random allocation and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04169373.Findings: Between Nov 26, 2019, and May 20, 2021, 314 patients with active non-radiographic axial spondyloarthritis were enrolled into the study, and 313 received study drug (156 in the upadacitinib group and 157 in the placebo group); 295 (94%) patients (145 in the upadacitinib group and 150 in the placebo group) received treatment for the full 14 weeks. A significantly higher ASAS40 response rate was achieved with upadacitinib compared with placebo at week 14 (70 [45%] of 156 patients vs 35 [23%] of 157 patients; p<0·0001; treatment difference 22%, 95% CI 12-32). The rate of adverse events up to week 14 was similar in the upadacitinib group (75 [48%] of 156 patients) and placebo group (72 [46%] of 157 patients). Serious adverse events and adverse events leading to discontinuation of study drug occurred in four (3%) of 156 patients in the upadacitinib group and two (1%) of 157 patients in the placebo group. Few patients had serious infections or herpes zoster in either treatment group (each event occurred in two [1%] of 156 patients in the upadacitinib group and one [1%] of 157 patients in the placebo group). Five (3%) of 156 patients in the upadacitinib group had neutropenia; no events of neutropenia occurred in the placebo group. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, or deaths were reported with upadacitinib treatment.Interpretation: Upadacitinib significantly improved the signs and symptoms of non-radiographic axial spondyloarthritis compared with placebo at week 14. These findings support the potential of upadacitinib as a new therapeutic option in patients with active non-radiographic axial spondyloarthritis.Funding: AbbVie. [ABSTRACT FROM AUTHOR]

VAN der Waals forces, LIFE sciences, SCIENCE journalism, MATERIALS at low temperatures, BIOMOLECULES, and LIE detectors & detection

The NASA/ESA Mars Sample Return (MSR) Campaign seeks to establish whether life on Mars existed where and when environmental conditions allowed. Laboratory measurements on the returned samples are useful if what is measured is evidence of phenomena on Mars rather than of the effects of sterilization conditions. This report establishes that there are categories of measurements that can be fruitful despite sample sterilization and other categories that cannot. Sterilization kills living microorganisms and inactivates complex biological structures by breaking chemical bonds. Sterilization has similar effects on chemical bonds in non-biological compounds, including abiotic or pre-biotic reduced carbon compounds, hydrous minerals, and hydrous amorphous solids. We considered the sterilization effects of applying dry heat under two specific temperature-time regimes and the effects of γ-irradiation. Many measurements of volatile-rich materials are sterilization sensitive—they will be compromised by either dehydration or radiolysis upon sterilization. Dry-heat sterilization and γ-irradiation differ somewhat in their effects but affect the same chemical elements. Sterilization-sensitive measurements include the abundances and oxidation-reduction (redox) states of redox-sensitive elements, and isotope abundances and ratios of most of them. All organic molecules, and most minerals and naturally occurring amorphous materials that formed under habitable conditions, contain at least one redox-sensitive element. Thus, sterilization-sensitive evidence about ancient life on Mars and its relationship to its ancient environment will be severely compromised if the samples collected by Mars 2020 rover Perseverance cannot be analyzed in an unsterilized condition. To ensure that sterilization-sensitive measurements can be made even on samples deemed unsafe for unsterilized release from containment, contingency instruments in addition to those required for curation, time-sensitive science, and the Sample Safety Assessment Protocol would need to be added to the Sample Receiving Facility (SRF). Targeted investigations using analogs of MSR Campaign-relevant returned-sample types should be undertaken to fill knowledge gaps about sterilization effects on important scientific measurements, especially if the sterilization regimens eventually chosen are different from those considered in this report. Executive Summary: A high priority of the planned NASA/ESA Mars Sample Return Campaign is to establish whether life on Mars exists or existed where and when allowed by paleoenvironmental conditions. To answer these questions from analyses of the returned samples would require measurement of many different properties and characteristics by multiple and diverse instruments. Planetary Protection requirements may determine that unsterilized subsamples cannot be safely released to non-Biosafety Level-4 (BSL-4) terrestrial laboratories. Consequently, it is necessary to determine what, if any, are the negative effects that sterilization might have on sample integrity, specifically the fidelity of the subsample properties that are to be measured. Sample properties that do not survive sterilization intact should be measured on unsterilized subsamples, and the Sample Receiving Facility (SRF) should support such measurements. This report considers the effects that sterilization of subsamples might have on the science goals of the MSR Campaign. It assesses how the consequences of sterilization affect the scientific usefulness of the subsamples and hence our ability to conduct high-quality science investigations. We consider the sterilization effects of (a) the application of dry heat under two temperature-time regimes (180°C for 3 hours; 250°C for 30 min) and (b) γ-irradiation (1 MGy), as provided to us by the NASA and ESA Planetary Protection Officers (PPOs). Measurements of many properties of volatile-rich materials are sterilization sensitive—they would be compromised by application of either sterilization mode to the subsample. Such materials include organic molecules, hydrous minerals (crystalline solids), and hydrous amorphous (non-crystalline) solids. Either proposed sterilization method would modify the abundances, isotopes, or oxidation-reduction (redox) states of the six most abundant chemical elements in biological molecules (i.e., carbon, hydrogen, nitrogen, oxygen, phosphorus, and sulphur, CHNOPS), and of other key redox-sensitive elements that include iron (Fe), other first-row transition elements (FRTE), and cerium (Ce). As a result of these modifications, such evidence of Mars' life, paleoenvironmental history, potential habitability, and potential biosignatures would be corrupted or destroyed. Modifications of the abundances of some noble gases in samples heated during sterilization would also reset scientifically important radioisotope geochronometers and atmospheric-evolution measurements. Sterilization is designed to render terminally inactive (kill) all living microorganisms and inactivate complex biological structures (including bacterial spores, viruses, and prions). Sterilization processes do so by breaking certain pre-sterilization chemical bonds (including strong C-C, C-O, C-N, and C-H bonds of predominantly covalent character, as well as weaker hydrogen and van der Waals bonds) and forming different bonds and compounds, disabling the biological function of the pre-sterilization chemical compound. The group finds the following: No sterilization process could destroy the viability of cells whilst still retaining molecular structures completely intact. This applies not only to the organic molecules of living organisms, but also to most organic molecular biosignatures of former life (molecular fossils). As a matter of biological principle, any sterilization process would result in the loss of biological and paleobiological information, because this is the mechanism by which sterilization is achieved. Thus, almost all life science investigations would be compromised by sterilizing the subsample by either mode. Sterilization by dry heat at the proposed temperatures would lead to changes in many of the minerals and amorphous solids that are most significant for the study of paleoenvironments, habitability, potential biosignatures, and the geologic context of life-science observations. Gamma-(γ-)irradiation at even sub-MGy doses induces radiolysis of water. The radiolysis products (e.g., free radicals) react with redox-sensitive chemical species of interest for the study of paleoenvironments, habitability, and potential biosignatures, thereby adversely affecting measurements of those species. Heat sterilization and radiation also have a negative effect on CHNOPS and redox-sensitive elements. MSPG2 was unable to identify with confidence any measurement of abundances or oxidation-reduction states of CHNOPS elements, other redox-sensitive elements (e.g., Fe and other FRTE; Ce), or their isotopes that would be affected by only one, but not both, of the considered sterilization methods. Measurements of many attributes of volatile-rich subsamples are sterilization sensitive to both heat and γ-irradiation. Such a measurement is not useful to Mars science if what remains in the subsample is evidence of sterilization conditions and effects instead of evidence of conditions on Mars. Most measurements relating to the detection of evidence for extant or extinct life are sterilization sensitive. Many measurements other than those for life-science seek to retrieve Mars' paleoenvironmental information from the abundances or oxidation-reduction states of CHNOPS elements, other redox-sensitive elements, or their isotopes (and some noble gases) in returned samples. Such measurements inform scientific interpretations of (paleo)atmosphere composition and evolution, (paleo)surface water origin and chemical evolution, potential (paleo)habitability, (paleo)groundwater-porewater solute chemistry, origin and evolution, potential biosignature preservation, metabolic element or isotope fractionation, and the geologic, geochronological, and geomorphic context of life-sciences observations. Most such measurements are also sterilization sensitive. The sterilization-sensitive attributes cannot be meaningfully measured in any such subsample that has been sterilized by heat or γ-irradiation. Unless such subsamples are deemed biohazard-safe for release to external laboratories in unsterilized form, all such measurements must be made on unsterilized samples in biocontainment. An SRF should have the capability to carry out scientific investigations that are sterilization-sensitive to both PPO-provided sterilization methods (Figure SE1). The following findings have been recognized in the Report. Full explanations of the background, scope, and justification precede the presentation of each Finding in the Section identified for that Finding. One or more Findings follow our assessment of previous work on the effects of each provided sterilization method on each of three broad categories of measurement types—biosignatures of extant or ancient life, geological evidence of paleoenvironmental conditions, and gases. Findings are designated Major if they explicitly refer to both PPO-provided sterilization methods or have specific implications for the functionalities that need to be supported within an SRF. FINDING SS-1: More than half of the measurements described by iMOST for investigation into the presence of (mostly molecular) biosignatures (iMOST Objectives 2.1, 2.2 and 2.3) in returned martian samples are sterilization-sensitive and therefore cannot be performed with acceptable analytical precision or sensitivity on subsamples sterilized either by heat or by γ-irradiation at the sterilization parameters supplied to MSPG2. That proportion rises to 86% of the measurements specific to the investigation of extant or recent life (iMOST Objective 2.3) (see Section 2.5). This Finding supersedes Finding #4 of the MSPG Science in Containment report (MSPG, 2019). FINDING SS-2: Almost three quarters (115 out of 160; 72%) of the measurements described by iMOST for science investigations not associated with Objective 2 but associated with Objectives concerning geological phenomena that include past interactions with the hydrosphere (Objectives 1 and 3) and the atmosphere (Objective 4) are sterilization-tolerant and therefore can (generally) be performed with acceptable analytical precision or sensitivity on subsamples sterilized either by heat or by γ-irradiation at the sterilization parameters supplied to MSPG2 (see Section 2.5). This Finding supports Finding #6 of the MSPG Science in Containment report (MSPG, 2019).MSPG2 endorses the previously proposed strategy of conducting as many measurements as possible outside the SRF where the option exists. FINDING SS-3: Suggested strategies for investigating the potential for extant life in returned martian samples lie in understanding biosignatures and, more importantly, the presence of nucleic acid structures (DNA/RNA) and possible agnostic functionally similar information-bearing polymers. A crucial observation is that exposure of microorganisms to temperatures associated with sterilization above those typical of a habitable surface or subsurface environment results in a loss of biological information. If extant life is a target for subsample analysis, sterilization of material via dry heat would likely compromise any such analysis (see Section 3.2). FINDING SS-4: Suggested strategies for investigating the potential for extant life in returned martian samples lie in understanding biosignatures, including the presence of nucleic acid structures (DNA/RNA) and possible agnostic functionally similar information-bearing polymers. A crucial observation is that exposure of microorganisms to γ-radiation results in a loss of biological information through molecular damage and/or destruction. If extant life is a target for subsample analysis, sterilization of material via γ-radiation would likely compromise any such analysis (see Section 3.3). FINDING SS-5: Suggested strategies for investigating biomolecules in returned martian samples lie in detection of a variety of complex molecules, including peptides, proteins, DNA (deoxyribonucleic acid) and RNA (ribonucleic acid), as well as compounds associated with cell membranes such as lipids, sterols, and fatty acids and their geologically stable reaction products (hopanes, steranes, etc.) and possible agnostic functionally similar information-bearing polymers. Exposure to temperatures above MSR Campaign-Level Requirements for sample temperature, up to and including sterilization temperatures, results in a loss of biological information. If the presence of biosignatures is a target for subsample analysis, sterilization of material via dry heat would likely compromise any such analysis (see Section 4.2). FINDING SS-6: Suggested strategies for investigating biomolecules in returned martian samples lie in detection of a variety of complex molecules, including peptides, proteins, DNA (deoxyribonucleic acid) and RNA (ribonucleic acid), and compounds associated with cell membranes such as lipids, sterols and fatty acids and their geologically stable reaction products (hopanes, steranes, etc.) and possible agnostic functionally similar information-bearing polymers. Exposure to radiation results in a loss of biological information. If the presence of biosignatures is a target for subsample analysis, sterilization of material via γ-irradiation would likely compromise any such analysis (see Section 4.3). FIG. SE1. A key SRF strategy is that the SRF is designed to initially accommodate only the measurements and analyses that cannot reasonably be made outside of biocontainment, including those required for initial sample characterization, Sample Safety Assessment Protocol (SSAP) tests, and time-sensitive science. Two scenarios are shown for sterilization-sensitive measurements that are contingent upon SSAP determination that sample is safe for unsterilized release (green YES path to uncontained outside laboratories) or unsafe for unsterilized release (red NO path to uncontained outside laboratories for sterilization tolerant science PLUS contained contingency laboratories enabling sterilization sensitive MSR Campaign measurements on unsterilized samples that cannot be deemed safe for release from containment). From Carrier et al. (2022). MAJOR FINDING SS-7: The use of heat or γ-irradiation sterilization should be avoided for subsamples intended to be used for organic biosignature investigations (for extinct or extant life). Studies of organic molecules from extinct or extant life (either indigenous or contaminants, viable or dead cells) or even some organic molecules derived from abiotic chemistry cannot credibly be done on subsamples that have been sterilized by any means. The concentrations of amino acids and other reduced organic biosignatures in the returned martian samples may also be so low that additional heat and/or γ-irradiation sterilization would reduce their concentrations to undetectable levels. It is a very high priority that these experiments be done on unsterilized subsamples inside containment (see Section 4.4). FINDING SS-8: Solvent extraction and acid hydrolysis at ∼100°C of unsterilized martian samples will inactivate any biopolymers in the extract and would not require additional heat or radiation treatment for the subsamples to be rendered sterile. Hydrolyzed extracts should be safe for analysis of soluble free organic molecules outside containment and may provide useful information about their origin for biohazard assessments; this type of approach, if approved, is strongly preferred and endorsed (see Section 4.4). FINDING SS-9: Minerals and amorphous materials formed by low temperature processes on Mars are highly sensitive to thermal alteration, which leads to irreversible changes in composition and/or structure when heated. Exposure to temperatures above MSR Campaign-Level Requirements for sample temperature, up to and including sterilization temperatures, has the potential to alter them from their as-received state. Sterilization by dry heat at the proposed sterilization temperatures would lead to changes in many of the minerals that are most significant for the study of paleoenvironments, habitability, and potential biosignatures or biosignature hosts. It is crucial that the returned samples are not heated to temperatures above which mineral transitions occur (see Section 5.3). FINDING SS-10: Crystal structure, major and non-volatile minor element abundances, and stoichiometric compositions of minerals are unaffected by γ-irradiation of up to 0.3–1 MGy, but crystal structures are completely destroyed at 130 MGy. Measurements of these specific properties cannot be acquired from subsamples γ-irradiated at the notional 1 MGy dose—they are sterilization-sensitive (see Section 5.4). FINDING SS-11: Sterilization by γ-irradiation (even at sub-MGy doses) results in significant changes to the redox state of elements bound within a mineral lattice. Redox-sensitive elements include Fe and other first-row transition elements (FRTE) as well as C, H, N, O, P and S. Almost all minerals and naturally occurring amorphous materials that formed under habitable conditions, including the ambient paleotemperatures of Mars' surface or shallow subsurface, contain at least one of these redox-sensitive elements. Therefore, measurements and investigations of the listed properties of such geological materials are sterilization sensitive and should not be performed on γ-irradiated subsamples (see Section 5.4). FINDING SS-12: A significant fraction of investigations that focus on high-temperature magmatic and impact-related processes, their chronology, and the chronology of Mars' geophysical evolution are sterilization-tolerant. While there may be a few analyses involved in such investigations that could be affected to some degree by heat sterilization, most of these analyses would not be affected by sterilization involving γ-irradiation (see Section 5.6). MAJOR FINDING SS-13: Scientific investigations of materials containing hydrous or otherwise volatile-rich minerals and/or X-ray amorphous materials that formed or were naturally modified at low (Mars surface-/near-surface) temperature are sterilization-sensitive in that they would be compromised by changes in the abundances, redox states, and isotopes of CHNOPS and other volatiles (e.g., noble gases for chronometry), FRTE, and Ce, and cannot be performed on subsamples that have been sterilized by either dry heat or γ-irradiation (see Section 5.7). MAJOR FINDING SS-14: It would be far preferable to work on sterilized gas samples outside of containment, if the technical issues can all be worked out, than to build and operate a large gas chemistry laboratory inside containment. Depending on their reactivity (or inertness), gases extracted from sample tubes could be sterilized by dry heat or γ-irradiation and analyzed outside containment. Alternatively, gas samples could be filtered through an inert grid and the filtered gas analyzed outside containment (see Section 6.5). MAJOR FINDING SS-15: It is fundamental to the campaign-level science objectives of the Mars Sample Return Campaign that the SRF support characterization of samples returned from Mars that contain organic matter and/or minerals formed under habitable conditions that include the ambient paleotemperatures of Mars' surface or subsurface (<∼200°C)—such as most clays, sulfates, and carbonates—in laboratories on Earth in their as-received-at-the-SRF condition (see Section 7.1). MAJOR FINDING SS-16: The search for any category of potential biosignature would be adversely affected by either of the proposed sterilization methods (see Section 7.1). MAJOR FINDING SS-17: Carbon, hydrogen, nitrogen, oxygen, sulfur, phosphorus, and other volatiles would be released from a subsample during the sterilization step. The heat and γ-ray sterilization chambers should be able to monitor weight loss from the subsample during sterilization. Any gases produced in the sample headspace and sterilization chamber during sterilization should be captured and contained for future analyses of the chemical and stable isotopic compositions of the evolved elements and compounds for all sterilized subsamples to characterize and document fully any sterilization-induced alteration and thereby recover some important information that would otherwise be lost (see Section 7.2). This report shows that most of the sterilization-sensitive iMOST measurement types are among either the iMOST objectives for life detection and life characterization (half or more of the measurements for life-science sub-objectives are critically sterilization sensitive) or the iMOST objectives for inferring paleoenvironments, habitability, preservation of potential biosignatures, and the geologic context of life-science observations (nearly half of the measurements for sub-objectives involving geological environments, habitability, potential biosignature preservation, and gases/volatiles are critically sterilization sensitive) (Table 2; see Beaty et al.,2019 for the full lists of iMOST objectives, goals, investigations, and sample measurement types). Sterilization-sensitive science about ancient life on Mars and its relationship to its ancient environment will be severely impaired or lost if the samples collected by Perseverance cannot be analyzed in an unsterilized condition. Summary: ○ The SRF should have the capability to carry out or otherwise support scientific investigations that are sensitive to both PPO-provided sterilization methods. ○ Measurements of most life-sciences and habitability-related (paleoenvironmental) phenomena are sensitive to both PPO-provided sterilization modes. (Major Finding SS-7, SS-15, SS-16 and Finding SS-1, SS-3, SS-4, SS-5, SS-6, SS-9, SS-11, SS-13) If subsamples for sterilization-sensitive measurement cannot be deemed safe for release, then additional contingency analytical capabilities are needed in the SRF to complete MSR Campaign measurements of sterilization-sensitive sample properties on unsterilized samples in containment (Figure SE1, below). ○ Measurements of high-temperature (low-volatile) phenomena are tolerant of both PPO-provided sterilization modes (Finding SS-12). Subsamples for such measurements may be sterilized and released to laboratories outside containment without compromising the scientific value of the measurements. ○ Capturing, transporting, and analyzing gases is important and will require careful design of apparatus. Doing so for volatiles present as headspace gases and a dedicated atmosphere sample will enable important atmospheric science (Major Finding SS-14). Similarly, capturing and analyzing gases evolved during subsample sterilization (i.e., gas from the sterilization chamber) would compensate for some sterilization-induced loss of science data from volatile-rich solid (geological) subsamples (Finding SS-14, SS-17; other options incl. SS-8). [ABSTRACT FROM AUTHOR]

Endocrine disrupting compounds (EDCs) in the environment are considered a motif of concern, due to the widespread occurrence and potential adverse ecological and human health effects. The natural estrogen, 17β-estradiol (E2), is frequently detected in receiving water bodies after not being efficiently removed in conventional wastewater treatment plants (WWTPs), promoting a negative impact for both the aquatic ecosystem and human health. In this study, the biodegradation of E2 by Rhodococcus sp. ED55, a bacterial strain isolated from sediments of a discharge point of WWTP in Coloane, Macau, was investigated. Rhodococcus sp. ED55 was able to completely degrade 5 mg/L of E2 in 4 h in a synthetic medium. A similar degradation pattern was observed when the bacterial strain was used in wastewater collected from a WWTP, where a significant improvement in the degradation of the compound occurred. The detection and identification of 17 metabolites was achieved by means of UPLC/ESI/HRMS, which proposed a degradation pathway of E2. The acute test with luminescent marine bacterium Aliivibrio fischeri revealed the elimination of the toxicity of the treated effluent and the standardized yeast estrogenic (S-YES) assay with the recombinant strain of Saccharomyces cerevisiae revealed a decrease in the estrogenic activity of wastewater samples after biodegradation. [ABSTRACT FROM AUTHOR]

ELECTRONIC tongues, SALIVA, SUPERVISED learning, MACHINE learning, DIGITAL learning, COMPUTER-aided diagnosis, ELECTRONIC noses, and ARTIFICIAL saliva

The diagnosis of cancer and other diseases using data from non-specific sensors – such as the electronic tongues (e-tongues) - is challenging owing to the lack of selectivity, in addition to the variability of biological samples. In this study, we demonstrate that impedance data obtained with an e-tongue in saliva samples can be used to diagnose cancer in the mouth. Data taken with a single-response microfluidic e-tongue applied to the saliva of 27 individuals were treated with multidimensional projection techniques and non-supervised and supervised machine learning algorithms. The distinction between healthy individuals and patients with cancer on the floor of mouth or oral cavity could only be made with supervised learning. Accuracy above 80% was obtained for the binary classification (YES or NO for cancer) using a Support Vector Machine (SVM) with radial basis function kernel and Random Forest. In the classification considering the type of cancer, the accuracy dropped to ca. 70%. The accuracy tended to increase when clinical information such as alcohol consumption was used in conjunction with the e-tongue data. With the random forest algorithm, the rules to explain the diagnosis could be identified using the concept of Multidimensional Calibration Space. Since the training of the machine learning algorithms is believed to be more efficient when the data of a larger number of patients are employed, the approach presented here is promising for computer-assisted diagnosis. [Display omitted] • First use of an impedimetric electronic tongue (e-tongue) for the diagnosis of cancer. • E-tongue data were used in cancer diagnosis without needing a specific biomarker. • From saliva samples our e-tongue translated information of clinical importance. • Multidimensional calibration space created rules to explain the diagnosis results. [ABSTRACT FROM AUTHOR]

DIABETIC retinopathy, VISUAL acuity, VISION, CAPILLARIES, and RETINAL diseases

Background/Aim. The relationship between the foveal avascular zone (FAV) and visual acuity (VA) in retinal diseases remains a matter of discussion. The aim of this study was to determine the impact of diabetic macular ischemia (DMI) on VA through the analysis of the perifoveal capillary network in various stages of diabetic retinopathy - DR (non-proliferative diabetic retinopathy – NPDR and proliferative diabetic retinopathy – PDR). Methods. Qualitative and quantitative analysis of 143 angiograms of patients with different stages of DR was performed. The degree of macular ischemia was assessed by the analysis of 2 parameters: perifoveal capillary ring, ie, the FAZ outline irregularity, and capillary loss. Finally, a comparison was made between the degree of macular ischemia with the best-corrected VA, depending on macular thickness. Results. In the eyes with mild and moderate NPDR, without significant macular thickening, no statistically significant decrease in VA caused by macular ischemia was noticed (p = 0.81). Opposite, in a subgroup with severe NPDR and PDR, without significant macular thickening, a statistically significant difference was presented among eyes with moderate and severe macular ischemia compared to e yes with l ower g rades of m acular i schemia (p = 0.021 and p = 0.018, respectively). In the eyes with moderate NPDR and mild macular ischemia, the increase in macular thickness resulted in a statistically insignificant decrease in VA compared to eyes with a normal macular thickness (p = 0.088). However, in the eyes with severe NPDR, every pathological increase in macular thickness caused a statistically significant decrease in VA, regardless of the degree of macular ischemia (p = 0.018–0.040). A similar relationship was also found in the eyes with PDR (p = 0.017–0.042). In the eyes with a statistically significant decrease in VA, most of the examined eyes (98%) had the FAZ outline irregularity in the nasal perifoveal subfield. Conclusion. In the absence of significant macular thickening, the destruction of one-half of the perifoveal capillary network, or greater, is associated with reduced VA. The location of macular ischemic changes in the nasal parts of the perifoveal capillary ring plays a crucial role in its effects on visual function. [ABSTRACT FROM AUTHOR]

HUNTINGTON disease, YAP signaling proteins, HIPPO signaling pathway, HUMAN embryonic stem cells, and MEDICAL model

The Hippo pathway, a highly conserved signaling cascade that functions as an integrator of molecular signals and biophysical states, ultimately impinges upon the transcription coactivator Yes-associated protein 1 (YAP). Hippo-YAP signaling has been shown to play key roles both at the early embryonic stages of implantation and gastrulation, and later during neurogenesis. To explore YAP's potential role in neurulation, we used self-organizing neuruloids grown from human embryonic stem cells on micropatterned substrates. We identified YAP activation as a key lineage determinant, first between neuronal ectoderm and nonneuronal ectoderm, and later between epidermis and neural crest, indicating that YAP activity can enhance the effect of BMP4 stimulation and therefore affect ectodermal specification at this developmental stage. Because aberrant Hippo-YAP signaling has been implicated in the pathology of Huntington's Disease (HD), we used isogenic mutant neuruloids to explore the relationship between signaling and the disease. We found that HD neuruloids demonstrate ectopic activation of gene targets of YAP and that pharmacological reduction of YAP's transcriptional activity can partially rescue the HD phenotype. [ABSTRACT FROM AUTHOR]

LUNG transplantation, TRANSPLANTATION of organs, tissues, etc., BIOMARKERS, PERFUSION, and LUNGS

Biomarker-based scoring algorithms have been reported throughout the EVLP literature; however, the role that prediction models play in influencing surgical decision-making is not known. Herein, we sought to assess the impact of biomarker scoring on EVLP-decisions in a retrospective, single center study. A total of n=20 clinical EVLP cases were used in this study. Each case was independently assessed by n=15 study participants that included surgeons, surgical fellows, organ perfusion specialists, and EVLP assistants. Each EVLP case was de-identified and presented alongside an intended recipient. Participants were asked to determine the suitability of the lung for transplant (yes/no) based on standard EVLP assessments alone and their impression of the organ on a scale from 0-10. Biomarker scores were then revealed and participants were then asked to re-answer the transplant and lung suitability questions. There were a total of n=300 transplant decisions in this study with and without biomarker scoring. The use of biomarker scoring greatly increased the recommendation to transplant lungs predicted to result in post-transplant extubation <72h [OR=13; 95%CI:4-45] and significantly increased a participant's lung suitability score [+1.0; 95%CI:0.4-1.5]. For lungs predicted to have excellent recipient outcomes and the historical decision was to transplant the organ, there was a 6.7% increase in transplant recommendation. Importantly, there was a net 13.3% increase in transplant recommendation when the historical decision was to decline an organ likely to result in a good outcome. Conversely, there was a 13.3% decrease in the recommendation to transplant lungs likely to produce poor outcomes (i.e., prolonged ventilation or PGD 3) using biomarker scores (OR=0.4; 95%CI:0.16-0.98). This study demonstrates that the inclusion of biomarker scoring during EVLP can lead to an increase in organ acceptance following EVLP. Furthermore, we demonstrate that organs that were associated with poor patient outcomes are less likely to be transplanted as a result of biomarker scoring being included in EVLP assessments. Taken together, this study provides strong rationale for the adoption of biomarker scoring algorithms during EVLP. [ABSTRACT FROM AUTHOR]

ATTEMPTED suicide, BIPOLAR disorder, LOGISTIC regression analysis, SUICIDAL behavior, and MULTIPLE regression analysis

The purpose of the present study was to detect demographic and clinical factors associated with lifetime suicide attempts in Bipolar Disorder (BD). A total of 1673 bipolar patients from different psychiatric departments were compared according to the lifetime presence of suicide attempts on demographic/clinical variables. Owing to the large number of variables statistically related to the dependent variable (presence of suicide attempts) at the univariate analyses, preliminary multiple logistic regression analyses were realized. A final multivariable logistic regression was then performed, considering the presence of lifetime suicide attempts as the dependent variable and statistically significant demographic/clinical characteristics as independent variables. The final multivariable logistic regression analysis showed that an earlier age at first contact with psychiatric services (odds ratio [OR] = 0.97, p < 0.01), the presence of psychotic symptoms (OR = 1.56, p < 0.01) or hospitalizations (OR = 1.73, p < 0.01) in the last year, the attribution of symptoms to a psychiatric disorder (no versus yes: OR = 0.71, partly versus yes OR = 0.60, p < 0.01), and the administration of psychoeducation in the last year (OR = 1.49, p < 0.01) were all factors associated with lifetime suicide attempts in patients affected by BD. In addition, female patients resulted to have an increased association with life-long suicidal behavior compared to males (OR: 1.02, p < 0.01). Several clinical factors showed complex associations with lifetime suicide attempts in bipolar patients. These patients, therefore, require strict clinical monitoring for their predisposition to a less symptom stabilization. Future research will have to investigate the best management strategies to improve the prognosis of bipolar subjects presenting suicidal behavior. [ABSTRACT FROM AUTHOR]

PATIENTS' attitudes, COVID-19 pandemic, SMALL molecules, and COVID-19

002 No35 (81.4%)23 (65.7%)29 (100%)17 (68%)11 (78.6%) Yes12 (27.9%)12 (34.3%)1 (3.4%)3 (12%)6 (42.9%). Yes8 (18.6%)12 (34.3%)0 (0%)8 (32%)3 (21.4%). 003 No31 (72.1%)23 (65.7%)28 (96.6%)22 (88%)8 (57.1%)

PROGRESSION-free survival, CARCINOMA, CLASSIFICATION, SYMPTOMS, ADRENAL tumors, and ADRENALECTOMY

Objective: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC. Design: This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy. Methods: The S-GRAS score was calculated as a sum of the following points: tumour stage (1-2 = 0; 3=1; 4 = 2), grade (Ki67 index 0-9% = 0; 10-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell's Concordance index (C-index) and Royston-Sauerbrei's R2D statistic. Results: We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01 vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5. Conclusion: The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment). [ABSTRACT FROM AUTHOR]

HELP-seeking behavior, TINNITUS, and HEARING disorders

Knowledge on characteristics of people that seek help for tinnitus is scarce. The primary objective of this study was to describe differences in characteristics between people with tinnitus that seek help compared to those who do not seek help. Next, we described differences in characteristics between those with and without tinnitus. In this cross-sectional study, we sent a questionnaire on characteristics in different domains; demographic, tinnitus-specific, general- and psychological health, auditory and noise- and substance behaviour. We assessed if participants had sought help or planned to seek help for tinnitus. Tinnitus distress was defined with the Tinnitus Functional Index. Differences between groups (help seeking: yes/no, tinnitus: yes/no) were described. 932 people took part in our survey. Two hundred and sixteen participants were defined as having tinnitus (23.2%). Seventy-three of those sought or planned to seek help. A constant tinnitus pattern, a varying tinnitus loudness, and hearing loss, were described more frequently in help seekers. Help seekers reported higher TFI scores. Differences between help seekers and people not seeking help were mainly identified in tinnitus- and audiological characteristics. These outcomes might function as a foundation to explore the heterogeneity in tinnitus patients. [ABSTRACT FROM AUTHOR]

ANDROGEN deprivation therapy, PROSTATECTOMY, PROSTATE-specific antigen, ONCOLOGY, RADIOTHERAPY, and GLEASON grading system

Purpose/objective(s): To determine if hypofractionated post-operative prostate bed radiotherapy (HYPORT) does not increase patient-reported genitourinary (GU) or gastrointestinal (GI) toxicity over conventionally fractionated post-operative radiotherapy (COPORT).Materials/methods: Eligibility criteria were: 1) an undetectable PSA (< 0.1 ng/mL) with either margin negative pT3pN0/X or margin positive pT2pN0/X adenocarcinoma of the prostate or 2) a detectable PSA (≥ 0.1 ng/mL) and pT2/3pN0/X disease. HYPORT was 62.5 Gy to the prostate bed in 25 fractions of 2.5 Gy. COPORT was 66.6 Gy in 37 fractions of 1.8 Gy. Lymph node RT was not allowed. Androgen deprivation therapy (ADT) ≤ 6 months was allowed. Patients were stratified according to baseline Expanded Prostate cancer Index Composite (EPIC) score (four tiers based on GU and GI scores) and ADT use (yes vs. no) then randomized 1:1. The co-primary endpoints were based on change scores (24-month score minus baseline score) from the GU and GI domains of the EPIC. The hypothesis is that the mean change scores at 24 months are no worse for HYPORT than it is for COPORT. The non-inferiority margins were based on 0.5*standard error from NRG Oncology/RTOG 0415: -5 for GU and -6 for GI. Two hundred eighty-two patients provide ≥ 90% power with a one-sided alpha = 0.025 for each domain while inflating for non-compliance/loss to follow-up.Results: Between July 2017 and July 2018, 298 patients were screened and 296 were randomized: 144 to HYPORT and 152 to COPORT. Compliance with the EPIC was 100% at baseline, 83% at the end of RT, 77% at 6 months, 78% at 12 months, and 73% at 24 months. At the end of RT, the HYPORT and COPORT mean GU change scores were neither clinically significant nor significantly different and remained so at 6 and 12 months. The mean GI change scores for HYPORT and COPORT were both clinically significant and significantly different at the end of RT (HYPORT mean GI = -15.0 vs COPORT mean GI = -6.8 P ≤ 0.01). However, both the HYPORT and COPORT mean GI change scores clinically and statistically significant differences were resolved at 6 and 12 months. The 24-month mean GU and GI change scores for HYPORT and COPORT remained neither clinically nor statistically significant (HYPORT mean GU = -5.2 vs COPORT mean GU = -3.0, P = 0.81; HYPORT mean GI = -2.2 vs COPORT mean GI = -1.5, P = 0.12). With a median follow-up for censored patients of 2.1 years, there was no difference between HYPORT versus COPORT for biochemical failure defined as a PSA ≥ 0.4 ng/mL followed by a value higher than the first by any amount (2-yr actuarial, 12% vs 8%, P = 0.29) or local failure (2-yr actuarial, 0.7% vs 0.8%, P = 0.35).Conclusion: HYPORT is non-inferior to COPORT in terms of late patient-reported GU or GI toxicity. More follow-up is needed to appropriately assess disease control endpoints. In some clinic scenarios, HYPORT may be considered an acceptable practice standard. [ABSTRACT FROM AUTHOR]

PLASMONICS, DNA, ZEBRA mussel, DNA sequencing, and ENVIRONMENTAL monitoring

Plasmonic nanosensors for label-free detection of DNA require excellent sensing resolution, which is crucial when monitoring short DNA sequences, as these induce tiny peak shifts, compared to large biomolecules. We report a versatile and simple strategy for plasmonic sensor signal enhancement by assembling multiple (four) plasmonic sensors in series. This approach provided a fourfold signal enhancement, increased signal-to-noise ratio, and improved sensitivity for DNA detection. The response of multiple sensors based on AuNSpheres was also compared with AuNRods, the latter showing better sensing resolution. The amplification system based on AuNR was integrated into a microfluidic sequential injection platform and applied to the monitoring of DNA, specifically from environmental invasive species—zebra mussels. DNA from zebra mussels was log concentration-dependent from 1 to 1 × 106 pM, reaching a detection limit of 2.0 pM. In situ tests were also successfully applied to real samples, within less than 45 min, using DNA extracted from zebra mussel meat. The plasmonic nanosensors' signal can be used as a binary output (yes/no) to assess the presence of those invasive species. Even though these genosensors were applied to the monitoring of DNA in environmental samples, they potentially offer advantage in a wide range of fields, such as disease diagnostics. [ABSTRACT FROM AUTHOR]

DE facto doctrine, ADMINISTRATIVE law, CONSTITUTIONAL law, CHARTERING, and CORPORATION law

Despite over 200 years of deliberation and debate, the United States has not adopted a federal corporate chartering law. Instead, Delaware is the "Federal Option" for corporate law and adjudication. The contemporary federal corporate chartering debate is, in part, a referendum on its role. Although the federal government has regulated other aspects of interstate commerce and has the power to charter corporations and preempt Delaware pursuant to its Commerce Clause power, it has not done so. Despite the rich and robust scholarly discussion of Delaware's jurisdictional dominance, its role as a de facto national regulator remains underdeveloped. This Article addresses a vexing question: Can Delaware, a haven for incorporation and adjudication, serve as an effective national regulator? Following an analysis of federal chartering alternatives, such as the Nader Plan, the Warren Plan, the Sanders Plan, and other modes of regulation, the answer is yes, but with some caveats and qualifications. Delaware's adequate, if imperfect, performance as a surrogate national regulator of corporate internal affairs argues against the upheaval of the existing corporate law framework federal chartering would bring. Even in the contemporary moment where longstanding concerns about corporate power, purpose, accountability, and the uneasy relationship between corporations and society are amplified, Delaware can continue to perform an important agency-like role in collaboration with federal regulators and regulated firms. A deeper examination comparing the merits of federal corporate chartering with Delaware's de facto agency function illuminates the potential of existing and future reforms. This Article concludes that federal chartering proposals have an important impact despite not being adopted for centuries. First, federal chartering proposals encourage policymakers to look beyond the status quo toward greater hybridization in regulatory design. Second, elements of previous federal chartering proposals have historically become successful "à la carte" reforms or part of other successful reform measures. Third, federal chartering proposals provide value as a bargaining tool where the threat of more intrusive federal regulation makes other reform methods more palatable to diverse corporate constituencies. [ABSTRACT FROM AUTHOR]

INTONATION (Phonetics), PROSODIC analysis (Linguistics), CATALAN language, INTERROGATIVE (Grammar), ROMANCE languages, SENTENCES (Grammar), MODALITY (Linguistics), and CORPORA

In this work, the intonation of broad focus statements and information-seeking yes-no questions of Catalan obtained using an induced corpus (ICD) is analyzed. The study is carried out within the framework of the AMPERCAT project (Contini et al., 2002; Fernández Planas, 2005). Data obtained with DCT are compared with those obtained through textual elicitation in AMPER and other prosodic studies of Catalan (Prieto et al., 2015). The majority nuclear contours for the broad focus statements is L*L%, while for the interrogatives there are different contours: two falling contours (H+L*L% and ¡H+L*L%) and two raising patterns (L*H% and H+L*LH%). [ABSTRACT FROM AUTHOR]

COMPUTED tomography, PULMONARY nodules, LUNGS, LUNG diseases, DOGS, and MEDICAL digital radiography

• Sensitivity for lung nodules was similar between radiography and lung ultrasound. • Lung ultrasound was limited by its low specificity and negative predictive value. • Caution should be used when interpreting absence of nodules using ultrasonography. Thoracic radiography (TR), the most common screening test for pulmonary metastases in dogs, can fail to detect small lesions <3 mm. Lung ultrasonography (LUS) is a widely available imaging modality capable of detecting peripheral nodules but is underutilized for this purpose. Thoracic computed tomography (CT) is the criterion standard for diagnosis of lung metastases and nodular disease but is less practical for a variety of reasons. We hypothesized that LUS would be more sensitive but less specific at detecting nodules consistent with metastatic pulmonary disease in dogs compared to TR, using CT as the criterion standard. This was a masked, single-center prospective study of 62 client-owned dogs evaluated for respiratory signs or pulmonary metastatic neoplasia screening using TR, LUS and CT. Dogs were included if metastatic pulmonary disease was a differential. All imaging modalities were scored as having nodules (yes/no) and other types of pathologic lesions were recorded. Sensitivity (Se), specificity (Sp) and positive (LR+) and negative likelihood ratios (LR−) were determined for TR and LUS. For TR, Se and Sp were 64% and 73%, and LR+ and LR− were 2.37 and 0.49, respectively. For LUS, Se and Sp were 60% and 65% and LR+ and LR− were 1.71 and 0.62, respectively. The results of the study indicate that LUS had a similar Se to TR, with both modalities missing nodules when used for screening. The low Sp and LR− suggests caution should be used when assuming TR and LUS rule out the presence of nodules. [ABSTRACT FROM AUTHOR]

CARDIOVASCULAR diseases risk factors, MYELOPEROXIDASE, CORONARY disease, CARDIOVASCULAR diseases, CIRCULATING tumor DNA, and HDL cholesterol

Introduction: Neutrophil extracellular traps (NETs) are DNA scaffolds enriched with antimicrobial proteins. NETs have been implicated in the development of various diseases, such as cardiovascular disease. Here, we investigate the association of demographic and cardiovascular (CVD) risk factors with NETs in the general population. Material and methods: Citrated plasma was collected from 6449 participants, aged ≥55 years, as part of the prospective population-based Rotterdam Study. NETs were quantified by measuring MPO-DNA complex using an ELISA. We used linear regression to determine the associations between MPO-DNA complex and age, sex, cardio-metabolic risk factors, and plasma markers of inflammation and coagulation. Results: MPO-DNA complex levels were weakly associated with age (log difference per 10 year increase: -0.04 mAU/mL, 95% confidence interval [CI] -0.06;-0.02), a history of coronary heart disease (yes versus no: -0.10 mAU/mL, 95% CI -0.17;-0.03), the use of lipid-lowering drugs (yes versus no: -0.06 mAU/mL, 95% CI -0.12;-0.01), and HDL-cholesterol (per mmol/l increase: -0.07 mAU/mL/, 95% CI -0.12;-0.03). Conclusions: Older age, a history of coronary heart disease, the use of lipid-lowering drugs and higher HDL-cholesterol are weakly correlated with lower plasma levels of NETs. These findings show that the effect of CVD risk factors on NETs levels in a general population is only small and may not be of clinical relevance. This supports that NETs may play a more important role in an acute phase of disease than in a steady state situation. [ABSTRACT FROM AUTHOR]

SHEEP breeding, HORSE farms, EWES, SHEEP breeds, ERECTOR spinae muscles, LEG, ANIMAL welfare, and LAMB (Meat)

Context. Brazilian sheep production chain includes farms that raise sheep to produce breeding rams and ewes, i.e. stud farms, and farms that raise sheep to breed lambs for meat. However, there are few studies on sheep welfare in Brazil. Aims. To assess the welfare of sheep in Brazil, comparing ewes on stud and meat farms. Methods. Seven stud (S) and 10 meat (M) farms were assessed in the metropolitan regions of Curitiba and Castro, State of Parana, using the Animal Welfare Indicators protocol for sheep. Results of both groups were compared using Fisher's exact test for yes or no questions, Mann-Whitney test for non-normal data and linear mixed models to check each indicator, with significance level at 0.05. Key results. Main characteristics that reduce sheep welfare were low body condition scores (40.6% on both groups), lesions to the legs (S = 45.9%, M = 56.0%), and pain induced by tail docking, with most ewes having a short tail length (S = 79.1%, M = 85.6%). Comparing both groups, ewes from stud farms presented less light faecal soiling (S = 1.3%, M = 27.0%), less faecal soiling and dags (S = 0%, M = 15.7%), better fleece cleanliness (S = 64.8%, M = 19.8%), fewer lesions to the head and neck (S = 3.2%, M = 12.3%), and higher frequency of panting (S = 28.0%, M = 1.5%). Conclusions. We were able to identify the main welfare restrictions in both stud and meat farms, and the hypothesis that welfare is higher on stud farms was not confirmed. Implications. The identification of on-farm welfare concerns as well as the differences between stud and meat farms allows for readily applicable recommendations, tailored to improve welfare within the prevalent sheep-rearing systems in southern Brazil. This experience with the Animal Welfare Indicators protocol for sheep in the Brazilian context may facilitate further studies and implementation of permanent welfare monitoring and action plans. [ABSTRACT FROM AUTHOR]

MEMBRANE distillation, ANAEROBIC reactors, MICROPOLLUTANTS, SEWAGE, DISSOLVED organic matter, SEWAGE disposal plants, and ENVIRONMENTAL risk

[Display omitted] • Removal of estrogenic activity by the AnOMBR-MD was higher than 99.97%. • Only 17α-ethynylestradiol and fluconazole presented estrogenic activity. • Microbial community change did not affect AnOMBR-MD performance. • Environmental chronic risk was high for estrogenic activity in distillate. • Human health risks were acceptable for estrogenic activity in distillate. Pharmaceutically active compounds (PhACs) may cause harmful effects in living beings, and advanced treatment is required to improve wastewater treatment plant efficiency. In this context, this study aimed to assess the performance of a hybrid anaerobic osmotic membrane bioreactor coupled with a membrane distillation system (AnOMBR-MD) for removing PhACs and estrogenic activity from municipal sewage. Human health and environmental risks of produced water were also assessed. The removal efficiency of dissolved organic carbon and P-PO 4 3- reached 97.2% and 98.0%, respectively. N-NH 4 + accumulated in the bioreactor since anaerobic treatment can not remove it. Salinity increase in the bioreactor caused a great change in the microbial community, with Chao 1 and Shannon indexes higher in the sludge after 50 days of operation than in the sludge used as inoculum. Estrogenic activity of municipal sewage spiked with PhACs was >3 times higher than the expected value calculated by the additive model (2 µg L−1E2-eq.), which indicates that some of the PhACs effects increased in the presence of others. Estrogenicity was not detected in distillate samples, which greatly reduced human health risks to acceptable values. Of the 7 PhACs selected in this study, only betamethasone, fluconazole, and prednisone were detected in the distillate. However, the overall removal of PhACs by the AnOMBR-MD system was higher than 96.4%. The chronic environmental risk considering the estrogenic activity was classified as high because of the detection limit in the yeast estrogen screen (YES), which supports the need for improving bioassay sensibility. The results demonstrated that the use of the YES assay combined with detection and identification of micropollutants allowed an effective assessment of the overall treatment performance. [ABSTRACT FROM AUTHOR]

SELF-deception, COVID-19, PSYCHOLOGICAL well-being, COVID-19 pandemic, SOCIAL attitudes, FEAR, and ATTITUDE (Psychology)

Background: Poland's inhabitants have often expressed disbelief and negative attitudes toward social isolation, combined with restlessness. This is due to a tendency to discount troubling informa tion while facing the unknown and counter-argue against information that causes discomfort and fear. This tendency helps humans to maintain hope and well-being. The study aimed to determine if Polish citizens tend to downplay or even deny danger when faced with a death threat. Material/Methods: The study comprised 58 adults - 46 females 12 males, aged 21 to 49. The participants were asked to answer 12 questions defining their beliefs and attitudes towards the COVID-19 pandemic threat and its consequences. The subjects gave answers on the 5-point Likert scale, from "definitely not" to "de finitely yes". Results: The findings of the present study show that a considerable number of the participants tend to exhibit an optimistic bias. This is reflected in their direct statements and in the lack of congruence of their opinions. They do feel the threat of becoming ill but also seem to believe it need not affect them personally. They are also relatively optimistic about the outcomes of the pandemic. At the same time, they realize that COVID-19 may lead to severe psychological, neurological, and mental disorders. Conclusions: The study confirmed a tendency to deny the threat that can pose a severe risk to health and psychological well-being. This is a manifestation of an optimism bias that has its roots in the way the human brain works. The participants did express concerns about the future but at the same time hoped that life after the pandemic would return to normal. It reflects a benevolent facet of self-deception since it makes it possible to cope with highly threatening and impossible to control events. [ABSTRACT FROM AUTHOR]

Objective: To investigate to what extent promotions in Dutch supermarket sales flyers contribute to a healthy diet and whether there are differences between supermarket types.Design: A cross-sectional study investigating promotions on foods and beverages (n 7825) in supermarket sales flyers from thirteen Dutch supermarket chains (8-week period), including ten traditional, two discount and one organic supermarket chain(s). Promoted products were categorised by food group (e.g. bread), contribution to a healthy diet (yes/no), degree of processing (e.g. ultra-processed), promotion type (temporary reduction in price, volume-based promotions or advertised only) and percentage discount of price promotions. Differences between supermarket chains in the degree of healthiness and processing of products and the types of price promotions were investigated.Results: In total, 70·7 % of all promoted products in supermarket sales flyers did not contribute to a healthy diet and 56·6 % was ultra-processed. The average discount on less healthy products (28·7 %) was similar to that of healthy products (28·9 %). Less healthy products were more frequently promoted via volume-based promotions than healthy products (37·6 % v. 25·4 %, P < 0·001). Discount supermarket chains promoted less healthy (80·3 %) and ultra-processed (65·1 %) products more often than traditional supermarket chains (69·6 % and 56·6 %, respectively).Conclusions: The majority of promoted products via supermarket sales flyers do not contribute to a healthy diet. As promotions are an important determinant of food purchasing decisions, supermarkets do not support healthy choices. Future studies should identify barriers that withhold supermarket chains from promoting more healthy foods in supermarket sales flyers. [ABSTRACT FROM AUTHOR]

LEACHATE, EISENIA, EARTHWORMS, LANDFILLS, RISK assessment, VERMICOMPOSTING, and SOLID waste management

Leachate is difficult to biodegrade, and presents variable physical, chemical and biological characteristics, as well as high toxicological potential for soil, groundwater and water bodies. In this context, untreated leachate toxicity was evaluated through acute and chronic exposures in Eisenia andrei earthworms. Physico-chemical leachate characterizations indicate a complex composition, with high organic matter (COD – 10,634 mg L−1) and ammoniacal nitrogen (2388 mg L−1) concentrations. Metals with carcinogenic potential, such as Cr, As and Pb, were present at 0.60, 0.14 and 0.01 μg L−1, respectively and endocrine disrupting compounds were detected in estradiol equivalents of 660 ± 50 ng L−1. Acute tests with Eisenia andrei indicated an LC 50 (72 h) of 1.3 ± 0.1 μL cm−2 in a filter paper contact test and 53.9 ± 1.3 mL kg−1 in natural soil (14 days). The EC 50 in a behavioral test was estimated as 31.6 ± 6.8 mL kg−1, indicating an escape effect for concentrations ranging from 35.0 to 70.0 mL kg−1 and habitat loss from 87.5 mL kg−1 of leachate exposure. Chronic exposure (56 days) led to reproduction effects, resulting in a 4-fold decreased cocoon production and 7-fold juvenile decrease. This effect was mainly attributed to the possible presence of endocrine disrupting compounds. An estimated NOAEL of 1.7 mL L−1 and LOAEL of 3.5 mL L−1 were estimated for earthworms exposed to the assessed effluent. Extremely high-risk quotients (RQ ≥ 1) were estimated based on leachate application in irrigation. Thus, adequate municipal solid waste management is paramount, especially with regard to generated by-products, which can result in high toxicological risks for terrestrial organisms. [Display omitted] • Thirty metals and high COD and ammoniacal nitrogen were determined in leachate. • Leachate exhibited high estrogenic activity by the YES assay. • Leachate exposure resulted in Eisenia andrei earthworm escape and loss of habitat. • Reproduction effects were noted in leachate-exposed earthworms. • Leachate was considered as high environmental risk (RQ ≥ 1). [ABSTRACT FROM AUTHOR]

MEDICAL care costs, EPIDERMAL growth factor receptors, BREAST cancer, HORMONE receptors, HOSPITAL costs, and CANCER treatment

Objectives: Policy makers increasingly seek to complement data from clinical trials with information from routine care. This study aims to provide a detailed account of the hospital resource use and associated costs of patients with advanced breast cancer in The Netherlands.Methods: Data from 597 patients with advanced breast cancer, diagnosed between 2010 and 2014, were retrieved from the Southeast Netherlands Advanced Breast Cancer Registry. Database lock for this study was in October 2017. We report the observed hospital costs for different resource categories and the lifetime costs per patient, adjusted for censoring using Lin's method. The relationship between patients' characteristics and costs was studied using multivariable regression.Results: The average (SE) lifetime hospital costs of patients with advanced breast cancer were €52 709 (405). Costs differed considerably between patient subgroups, ranging from €29 803 for patients with a triple-negative subtype to €92 272 for patients with hormone receptor positive and human epidermal growth factor receptor 2 positive cancer. Apart from the cancer subtype, several other factors, including age and survival time, were independently associated with patient lifetime costs. Overall, a large share of costs was attributed to systemic therapies (56%), predominantly to a few expensive agents, such as trastuzumab (15%), everolimus (10%), and bevacizumab (9%), as well as to inpatient hospital days (20%).Conclusions: This real-world study shows the high degree of variability in hospital resource use and associated costs in advanced breast cancer care. The presented resource use and costs data provide researchers and policy makers with key figures for economic evaluations and budget impact analyses. [ABSTRACT FROM AUTHOR]

PHYSICAL activity, SKIN diseases, SPANIARDS, CHRONIC diseases, and METABOLIC equivalent

Background: To date there is limited literature on the prevalence of chronic skin conditions and its association with levels of physical activity (PA) in Spain. Aim: To determine the prevalence of chronic skin disease and to compare levels of PA between people with and without chronic skin disease in a large representative sample of Spanish adults aged 15–69 years. Methods: Data from the Spanish National Health Survey 2017 were analysed. Chronic skin disease was assessed using a yes/no question. PA was measured using the short form of the International Physical Activity Questionnaire. Total PA metabolic equivalent of task min/week were calculated, and PA was included in the analyses as a continuous and a five‐category variable. Results: This cross‐sectional study included 17 777 adult participants (52.0% women; mean ± SD age 45.8 ± 14.1 years), of whom 940 (5.3%) had chronic skin disease. After adjusting for several potential confounders, there was a negative association between chronic skin disease and PA (OR = 0.87, 95% CI 0.76–1.00, P = 0.05), which was significant for men (OR = 0.76, 95% CI 0.62–0.93, P = 0.01) but not for women (OR = 0.97, 95% CI 0.81–1.16, P = 0.72). Conclusions: In this large representative sample of Spanish adults, the prevalence of chronic skin disease was low. Levels of PA were lower in men with than in men without chronic skin conditions, but this association was not seen in women. [ABSTRACT FROM AUTHOR]

PSORIASIS, CONFIDENCE intervals, FACTOR analysis, QUALITY of life, RECEIVER operating characteristic curves, and ITCHING

Objective: To generate an operational definition to adequately reflect the construct 'Minimal Disease Activity (MDA)' in psoriasis. Methods: A systematic review of domains included in clinical trials of psoriasis was presented to a panel of dermatologists and patients. Further domains were elicited by panel discussions. Domains (and instruments measuring these) were items of two consecutive Delphi rounds targeting dermatologists from the Psoriasis Group of the Spanish Academy of Dermatology and Venereology and patients from the Acción Psoriasis association. The instruments selected were used to generate 388 patient vignettes. The expert group then classified these vignettes as 'No MDA/MDA/Unclassifiable'. The items were further reduced by factorial analysis. Using the classification variable as gold standard, several operational constructions were tested in regression models and ROC curves and accuracy was evaluated with area under the curve (AUC). Results: The following domains were included: itching, scaling, erythema and visibility by 0–10 scales, extension by BSA, impact on quality of life by DLQI, special location and presence of arthritis as yes/no. The definition with the highest AUC and best balance between sensitivity and specificity was the one including no presence of arthritis plus at least three others below the upper limit of the 95% confidence interval (AUC, 0.897; sensitivity, 95.2%, specificity, 84.1%). Conclusion: This study provides, for the very first time, the construct of 'Minimal Disease Activity' in psoriasis as agreed by dermatologists and patients. MDA is defined as absence of active arthritis plus 3 out of 6: itching ≤ 1/10; scaling ≤ 2/10; redness ≤ 2/10; visibility ≤ 2/10; BSA ≤ 2; DLQI ≤ 2; and no lesions in special locations. By design, domains are representative of disease impact. This MDA definition may be used as a measure of adequate management and replace other subjective or restrictive tools. [ABSTRACT FROM AUTHOR]

Endocrine disruptors, Suspended solids, Rivers, Endocrine glands, and Endocrine system

Endocrine disrupting chemicals (EDC) are exogenous substances that can potentially mimic hormonal substances and cause adverse effects on the endocrine system of living beings. The behavior and fate of these compounds in the environment is directly related to their physical-chemical properties, which indicate great affinity for solid and organic particles and suggest an inherent mechanism of fractionation between dissolved and particulate phases of aqueous matrices. However, few studies have been considering this fact when quantifying these pollutants and their effects through bioassays. In this study, the fractionation of estrogenic substances between dissolved and particulate phases in an urban stream was investigated via estrogenic activity evaluation by the YES assay. Two fractions of suspended solids (< 0.7 µm and between 0.45 and 0.7 µm) and the dissolved phase were considered and two approaches of SPE percolations were applied. Total estradiol equivalent (E2-Eq) values were observed in the 29–65 ng L−1 range, of which 35–62% were associated with the particulate phase. Most of the estrogenicity was associated with particles between 0.45 and 0.7 µm, whereas cytotoxicity was induced by extracts of particles greater than 0.7 µm. Results demonstrated the importance of solid fractions analysis towards the quantification of total estrogenic activity from aqueous environmental matrices and highlights the relevance of controlling fine suspended solids in sewage treatment plant effluents, regarding the control of endocrine disrupters in the environment. ga1 • High level of total estrogenic activity was quantified up to 65 ng L−1. • Phase distribution of estrogenic activity was highly influenced by SPM profile. • Cytotoxicity was recurrently associated with particles > 0.7 µm. • SPM < 0.7 µm in wastewaters might be of great concern due to associated EDC. [ABSTRACT FROM AUTHOR]

SEDENTARY behavior, COVID-19 pandemic, MENTAL health surveys, BRAZILIANS, SADNESS, BEHAVIORAL research, and LONELINESS

Objective: To analyze the associations of physical activity and TV-viewing reported changes during the COVID-19 pandemic quarantine with mental health among Brazilian adults with and without depression.Methods: Data of 43,995 Brazilian adults from a cross-sectional, nationwide behavior research were used. Participants reported the frequency on loneliness, sadness (feel sad, crestfallen or depressed) and anxiety (feel worried, anxious or nervous) feelings during the pandemic period. Frequency and duration of physical activity as well as duration of TV-viewing before and during the pandemic period were also reported. We created four categories of reported changes in physical activity (1-consistently active, 2-become active, 3-become inactive or 4-consistently inactive) and TV-viewing (1-consistently high, 2-become low, 3-become high or 4-consistently high). Participants also reported previous diagnoses of depression [yes (PD) or no (nPD). Logistic regression models separating people with and without depression were created.Results: Compared to consistently active participants, to become inactive during the pandemic was associated with a higher odds for loneliness [nPD:OR:1.32 (95%CI,1.02-1.70); PD:2.22 (1.21-4.06)], sadness [nPD:1.34 (1.01-1.77); PD:2.88 (1.54-5.36)], and anxiety [nPD:1.71 (1.30-2.25); PD:2.55 (1.20-5.42)]. Also, people with depression and consistently physically inactive presented higher odds for loneliness and sadness. Compared to consistently low TV-viewing, participants that become with high TV-viewing showed higher odds for loneliness [nPD:1.59 (1.37-1.86)], sadness [nPD:1.68 (1.44-1.96); PD:1.61 (1.21 to 2.15)] and anxiety [nPD:1.73 (1.48-2.02); PD:1.58 (1.12-2.23)].Conclusions: Reported increases in physical inactivity and TV-viewing during the COVID-19 pandemic were associated with poorer mental health indicators. People with depression and consistently physically inactivity were more likely to present loneliness and sadness. [ABSTRACT FROM AUTHOR]

STUDENT counselors, AUTISM, AUTISTIC people, COMMUNITY health workers, AUTISM in children, PSYCHOMETRICS, and PEOPLE with disabilities

Introduction: Autism is included as a certifiable disability in the Indian Rights of Persons with Disability Act, 2016. The Indian Scale for Assessment of Autism (ISAA), developed by the Government of India and mandated for certifying disability, is a detailed instrument that needs trained mental health experts and takes time to administer. The current project was planned to develop a simple, easy to use screening tool based on the ISAA to identify possible cases in the community. Methods: The project is planned in three phases. During the first phase, data collected during the development of the ISAA (N = 433/436 children with autism) will be used to identify questions answered as frequently, mostly, and always. During the second phase, the psychometric properties of the screening tool based on these items will be evaluated among research participants recruited from hospitals and special schools (n = 100). In the third phase, the screening questionnaire will be administered in the community (n = 500). Results: The most frequently answered questions will be selected for inclusion in the proposed screening tool. The number of items in the screening tool will be kept as few as possible, with yes or no responses Discussion: Indian Autism Screening Questionnaire (IASQ) will be tested as a screening version of ISAA, which can be used by community health workers, teachers, or school counselors. The IASQ will not provide a diagnosis of autism. A positive screening result should be followed by a thorough assessment by a trained specialist. Analyzing the psychometric properties of the test can help ensure cost-effective screening of the community to identify autism. [ABSTRACT FROM AUTHOR]

ATTITUDE (Psychology), CULTURE, EXPERIENTIAL learning, FAMILY psychotherapy, HOSPITAL medical staff, INTERPROFESSIONAL relations, INTERVIEWING, MEDICAL personnel, PROFESSIONS, SELF-efficacy, SUPERVISION of employees, PEER relations, and THEMATIC analysis

This article explores family therapy trainees' subjective experiences of working as cotherapists with a supervisory‐level therapist in a Chinese context, regarding their perceptions of and positioning in it and also their opinions on the benefits and/or pitfalls of cotherapy. Individual interviews with a total of six cotherapists revealed three themes: (1) Cotherapy was perceived as an experiential learning journey that evolved from anxiety and excitement to empowerment and nurturing; (2) a collaborative master–apprentice relationship of openness, trust, and mutual respect was developed with both sides' interactive effort, which included common commitment and concern for the client, the supervisor's awareness and explicit address of the role hierarchy, principle setting prior to the cooperation, and honest pre‐ and‐postsession sharing and discussion; (3) the dual‐purpose supervisor–trainee cotherapy brought direct benefits for all involved parties and for others. The findings have useful implications for integrating treatment and training for optimal training/learning outcomes and for advancing knowledge transfer from senior to junior and from academia to the field, with reference to local cultural characteristics.comment="AUTHOR: Please suggest whether the terms ‘co‐therapy, co‐learning, and cotherapist’ could be changed to ‘cotherapy, colearning, and cotherapist’ throughout the article as per style sheet requirement."comment="Dear Editor,Yes, I think these terms could be changed as suggested according to the style sheet requirement, as the meaning remains the same. Thank you.Best regards,Lily" [ABSTRACT FROM AUTHOR]

Extensive use of endocrine disruptor compounds (EDCs) and their release through various pathways into the environment are emerging environmental concerns. In this context, H 2 O 2 and chlorine UV-based treatments were carried out to evaluate their efficiency in the removal of the bisphenol A (BPA), 17β-estradiol (E2) and 17α-ethinylestradiol (EE2) at 100 μg L−1 from ultrapure water and from wastewater treatment plants (WWTP). Photolysis was performed under different irradiation sources, i.e. UVC and UVA. The effect of H 2 O 2 (3 and 30 mg·L−1), free chlorine concentrations (1 and 2 mg·L−1) and pH (5, 7 and 9) were also investigated. Toxicity (Raphidocelis subcapitata) and estrogenic activity (yeast estrogen screen - YES assay) were assessed during the processes. Compound removal at optimal operating parameters reached 100% after 15 and 2 min for UVC/H 2 O 2 (pH 9 and 3 mg L−1 of H 2 O 2), and UVC/Cl (pH 9 and 2 mg L−1 of chlorine), respectively. Total organic carbon (TOC) removal achieved 37% and 45% for the H 2 O 2 and Cl-UV based process, respectively. The in vitro YES assay indicated that the formed by-products were non-estrogenic compounds, while the toxicity evaluation revealed high cell growth inhibition due to UVC/Cl byproducts. During the UV-based processes, 30 transformation products (TPs) were identified, in which three new chlorinated TPs from E2 and EE2 may be responsible for toxicity effects. EDC degradation by UV/Cl is faster than by UV/H 2 O 2 , although chlorinated toxic byproducts were also formed during the UV/Cl process. Unlabelled Image • The Cl/UV process is more efficient than H 2 O 2 /UV in removing E2, EE2 and BPA. • Both processes are capable of removing WWTP EDCs. • EDC degradation products do not display estrogenic activity. • The Cl/UV process produces high toxicity TPs. • Three new TPs were identified during the Cl/UV process. [ABSTRACT FROM AUTHOR]

SMELL disorders, COVID-19, CENTRAL nervous system viral diseases, ODORS, and OLFACTOMETRY

Anosmia has been recognized as a prevalent and early symptom by many COVID-19 patients. However, most researchers have recorded smell dysfunction solely as present or absent and based on subjective evaluation by patients. We described the results of 57 consecutive COVID-19 patients seen at FIOCRUZ, Rio de Janeiro, Brazil, from April to May 2020. Data about the presence of smell loss, the onset of smell loss and other COVID-19 symptoms such as ageusia and nasal congestion or rhinorrhea were recorded. All patients at the initial consultation and 34 healthy controls underwent the Q-SIT, which is a quick disposable three-item smell identification test, by a trained physician. We compared three groups: healthy controls, COVID+ patients with reported smell loss (COVID w/ SL) and COVID+ patients without smell loss (COVID+ w/o SL). The mean age of patients was 41.4 years (SD ± 10.4), and 54.4% were women. Smell loss was reported by 40.4% of COVID-19 patients. We observed a gradual effect with higher Q-SIT scores in healthy controls, followed by COVID+ w/o SL and COVID+ w/ SL (medians = 3, 2 and 0; respectively, p < 0.001). Anosmia or severe microsmia (Q-SIT≤1) was present in 11.1% (CI: 3.1%–26.1%) of controls, 32.4% (CI: 17.4%–50.5%) of COVID-19 w/o SL and 87% (CI: 66.4%–97.2%) of COVID+ w/ SL (p < 0.001). This study provides evidence that olfactory dysfunction in COVID-19 is common and more prevalent than what is perceived by patients. Q-SIT is a quick and reliable screening test for the detection of smell dysfunction during the pandemics. • Smell dysfunction is frequent in COVID-19 patients. • Subtle olfactory dysfunction is frequently not perceived by patients when inquired during medical visits. • Q-SIT is a quick and reliable screening test for the detection of smell dysfunction during the pandemics. [ABSTRACT FROM AUTHOR]

SOLID phase extraction, LIQUID-liquid extraction, CHROMATOGRAPHIC analysis, NEONICOTINOIDS, COTYLEDONS, LIQUID analysis, and COMPARATIVE studies

• Development of a novel in-syringe dispersive liquid-liquid microextraction method. • Implementation of the experimental design to stablish the best experimental conditions. • Extraction performance evaluation by comparison with a solid phase-based methodology. • Determination of three neonicotinoids in soy cotyledons by liquid chromatography. A novel extraction strategy for the determination of imidacloprid, thiamethoxam and clothianidin in soy cotyledons by liquid chromatography was developed based on the implementation of an in-syringe-dispersive liquid-liquid microextraction system, optimized through successive experimental designs. First, a fractional factorial design was built to screen the influence of five experimental factors: a) aqueous solution (water or ethylenediaminetetraacetic acid 0.20 mol L–1); b) type of solvent (methanol or acetonitrile); c) use of salt (yes or no) for the adjustment of the ionic strength; d) homogenization method (vortex or sonication); and e) extractant solvent (toluene or ethyl acetate). Afterwards, in order to build a response surface model, a central composite design was implemented considering the influencing factors. For the in-syringe-dispersive liquid-liquid microextraction system, optimal conditions resulted in 1140 µL of acetonitrile, 583 µL of ethyl acetate and three successive extractions. Finally, due to fact that the system involves an evaporation step, a simplex-lattice mixture design was built. The optimum composition of the resuspension solution was methanol:water (60:40 v/v). The developed method was compared with a previously reported solid phase extraction methodology taken as reference method. Higher recovery percentages were achieved with the novel procedure, i.e. in the range of 69.5 to 74.2%, for the three considered analytes. [ABSTRACT FROM AUTHOR]

CONTACT angle, SURFACE analysis, WETTING, HYDROPHOBIC surfaces, ELECTROLESS plating, PRINCIPAL components analysis, and POLYMERSOMES

Electroless Ni plating is widely used for its properties such as wear resistance, uniform coating and excellent brazing and solderability. In electronic and mechatronic applications, the chemical composition of the Ni layer and its surface quality still remains elusive and improvisation of Ni layer surface quality is vital. This research work investigates the surface properties of Ni films subjected to Ar-H 2 RF plasma treatment. Plasma treatment parameters are defined by utilizing D-Optimal design of experiments. A precise mapping of the evolution of Ni surface global chemical composition is obtained using an XPS. Principal component analysis on XPS mapping coupled with 3D ToF-SIMS chemical cartography enables precise identification of the different oxidation states of nickel and their distribution in the plasma-treated nickel samples. The nickel surface wettability is then determined using the classical sessile drop technique. The findings of the study enable to define the plasma optimal power and accomplish the best compromise between the positive effects of the surface decontamination and the negative effects of the surface recontamination. The optimized plasma treatment succeeds to modify the surface nature of the nickel from hydrophobic to strongly hydrophilic. It demonstrates that the Ar-H 2 plasma treatment is a very efficient process to increase the Ni surface wettability and thereby to improve the electronic and mechatronic assembly processes. • Nickel surface chemical composition, dependence on argon‑hydrogen plasma treatment settings is established. • Plasma-induced deoxidation efficiency passes through a maximum for a given power optimum value. • Optimum plasma treatment produces a soft argon ballistic effect which limits surface recontamination. • Optimized plasma treatment produces an efficient reduction of nickel hydroxide by hydrogen. • Optimized plasma treatment changes the nickel surface from hydrophobic to strongly hydrophilic. [ABSTRACT FROM AUTHOR]

ACADEMIC medical centers, CANCER genetics, CHI-squared test, CONFIDENCE intervals, EMPLOYMENT, GENETIC counseling, HEALTH services accessibility, HEALTH status indicators, HEALTH insurance, MARITAL status, MEDICAL care use, MEDICAL referrals, METROPOLITAN areas, MULTIVARIATE analysis, RACISM, LOGISTIC regression analysis, ELECTRONIC health records, DESCRIPTIVE statistics, ODDS ratio, and DISEASE risk factors

Purpose: Genetic counseling (GC) provides critical risk prediction information to women at-risk of carrying a genetic alternation; yet racial/ethnic and socioeconomic disparities persist with regard to GC uptake. This study examined patterns of GC uptake after a referral in a racially diverse population. Materials and Methods: In an urban academic medical center, medical records were reviewed between January 2016 and December 2017 for women who were referred to a genetic counselor for hereditary breast and ovarian cancer. Study outcomes were making an appointment (yes/no) and keeping an appointment. We assessed sociodemographic factors and clinical factors. Associations between factors and the outcomes were analyzed using chi square, and logistic regression was used for multivariable analysis. Results: A total of 510 women were referred to GC and most made appointments. More than half were white (55.3%) and employed (53.1%). No significant associations were observed between sociodemographic factors and making an appointment. A total of 425 women made an appointment and 268 kept their appointment. Insurance status ( p = 0.003), marital status ( p = 0.000), and work status ( p = 0.039) were associated with receiving GC. In the logistic model, being married (odds ratio [OR] 2.119 [95% confidence interval, CI 1.341–3.347] p = 0.001) and having insurance (OR 2.203 [95% CI 1.208–4.016] p = 0.021) increased the likelihood of receiving counseling. Conclusions: Racial disparities in GC uptake were not observed in this sample. Unmarried women may need additional support to obtain GC. Financial assistance or other options need to be discussed during navigation as a way to lessen the disparity between women with insurance and those without. [ABSTRACT FROM AUTHOR]

PEOPLE with schizophrenia, BIPOLAR disorder, VISUAL perception, MENTAL illness, and MEDICAL care

Introduction: Reduction in the amplitude of P300, is found more frequently in the auditory mode but has also been reported using visual stimulus in people with schizophrenia. Previous research may imply that visual P300 alterations are specific markers of schizophrenia, but they have small sample sizes, and few make comparisons with other psychiatric disorders. Objectives: To compare the amplitude and latency of visual P300, in people with schizophrenia, bipolar disorder and a control group from Valparaíso, Chile. Methods: Study protocol was approved by the Ethics Committee of the Valparaiso San Antonio Health Service. Sample consisted of 17 controls, 13 subjects with bipolar disorder and 17 with schizophrenia (18-55 years, both genders). Potentials were registered with a 64 -electrode cap, following the standard 10-20 system. Stimulus consisted in the presentation of 3 visual stimuli, triangles containing real contours (infrequent target stimulus), triangles containing illusory contours, and "no figures" images (distractors). Subjects were instructed to give a yes or no answer on a keyboard, depending on whether or not they saw the real triangle. llusory and distractor conditions were presented 60 times each, while the target, real triangle only 30. Series were repeated with a total duration of 20 minutes. Results: There were statistically significant differences in the amplitude of P300 between the clinical population and the controls, but not between people with schizophrenia and bipolar disorder. Conclusions: We found a decrease in the amplitude of visual P300 wave in subjects with a severe psychiatric disorder. However, this alteration was not specific to schizophrenia. [ABSTRACT FROM AUTHOR]

EMPLOYMENT, HEADACHE, INTERVIEWING, LONGITUDINAL method, MUSCULOSKELETAL system diseases, PAIN, RESEARCH funding, SELF-evaluation, SEX distribution, TIME, WELL-being, PAIN measurement, and LIFESTYLES

Background: Pain is a common symptom, often associated with neurological and musculoskeletal conditions, and experienced especially by females and by older people. The aims of this study are to evaluate the temporal variations of pain rates among general populations for the period 1991–2015 and to project 10-year pain rates. Methods: We used the harmonized dataset of ATHLOS project, which included 660,028 valid observations in the period 1990–2015 and we applied Bayesian age–period–cohort modeling to perform projections up to 2025. The harmonized Pain variable covers the content "self-reported pain experienced at the time of the interview", with a dichotomous (yes or no) modality. Results: Pain rates were higher among females, older subjects, in recent periods, and among observations referred to cohorts of subjects born between the 20s and the 60s. The 10-year projections indicate a noteworthy increase in pain rates in both genders and particularly among subjects aged 66 or over, for whom a 10–20% increase in pain rate is foreseen; among females only, a 10–15% increase in pain rates is foreseen for those aged 36–50. Conclusions: Projected increase in pain rates will require specific interventions by health and welfare systems, as pain is responsible for limited quality of subjective well-being, reduced employment rates and hampered work performance. Worksite and lifestyle interventions will therefore be needed to limit the impact of projected higher pain rates. [ABSTRACT FROM AUTHOR]

SELENIUM, MERCURY vapor, MERCURY, THYROID gland, DOPPLER ultrasonography, LOGISTIC regression analysis, and STATISTICAL significance

Introduction: Experiments in animals exposed to mercury (Hg) in different chemical states have shown thyroid parenchymal and hormone alterations. However, these experiments did not allow the establishment of dose–response curves or provide an understanding of whether these Hg effects on the thyroid parenchyma occur in humans. Objective: To evaluate the association between chronic occupational exposure to metallic Hg and alterations in thyroid hormones and gland parenchyma 14 years after the last exposure. Methods: A cross-sectional study including 55 males exposed in the past to metallic Hg and 55 non-exposed males, paired by age, was conducted in the Hospital das Clínicas (Brazil) from 2016 to 2017. Serum concentrations of total and free triiodothyronine (TT3 and FT3), free thyroxine (FT4), thyrotropin (TSH), reverse T3 (RT3), selenium and antithyroid antibody titers were obtained. The Hg and iodine concentrations were measured in urine. The thyroid parenchyma was evaluated by B-mode ultrasonography with Doppler. The nodules with aspects suspicious for malignancy were submitted to aspiration puncture with a thin needle, and the cytology assessment was classified by the Bethesda system. The t test or Mann–Whitney test, Chi-square test and Spearman correlation were used to compare the exposed and non-exposed groups and examine the relationships between the variables. Univariate and multivariate logistic regression models were used to trace determinants of the risk of thyroid hormone alteration. Statistical significance was defined by p < 0.05. Results: The urinary Hg average was significantly higher in the exposed group than in the non-exposed group (p < 0.01). The mean TSH serum concentration in the exposed group was higher, with a statistically significant difference between the groups (p = 0.03). Serum concentrations of TSH exceeded the normality limit (4.20 µIU/ml) in 13 exposed individuals (27.3%) and 4 non-exposed individuals (7.3%), with a statistically significant association between the hormonal increase and exposure to Hg (p = 0.02). In the logistic regression model, exposure to Hg (yes or no) showed an odds ratio = 4.86 associated with an increase of TSH above the normal limit (p = 0.04). The serum concentrations of RT3 showed a statistically borderline difference between the groups (p = 0.06). There was no statistically significant difference between the mean TT3, FT3 and FT4 serum concentrations in the Hg-exposed group compared to the non-exposed group. The proportions of the echogenicity alterations were higher in the exposed group compared to the non-exposed group (27.3% versus 9.1%; p = 0.03). Papillary carcinomas were documented in three exposed individuals and one non-exposed individual. A follicular carcinoma was recorded in one non-exposed individual. Conclusions: Due to the higher serum TSH concentration and the prevalence of parenchymal alterations in the Hg-exposed group, even after cessation of exposure, it is recommended that the thyroid status of exposed workers be followed for a long period. [ABSTRACT FROM AUTHOR]

HENS, EGG quality, AGRICULTURAL egg production, EGG incubation, HATCHABILITY of eggs, MINERALS, and ROOSTERS

This experiment was conducted to evaluate the effects of dietary supplementation with organic micro-minerals on egg production, egg quality, sperm quality and hatching of eggs of laying breeder hens. A total of 144 White Plymouth Rock hens and 36 Red Rhode Island roosters were used. For each treatment, birds were assigned to eight replicates with six hens and 12 replicates with one rooster. Birds were fed a basal diet (BD) containing only inorganic micro-minerals (10 mg Cu, 60 mg Fe, 70 mg Mn, 75 mg Zn and 0.3 mg Se per kg of diet) or a BD +500 g/ton of organic micro-mineral (OMM) product (2.5 mg Cu, 17.5 mg Fe, 20 mg Mn, 27.5 mg Zn and 0.080 mg Se per kg of diet) and BD +800 g/ton of OMM (4 mg Cu, 28 mg Fe, 32 mg Mn, 44 mg Zn and 0.128 mg Se per kg of ration). At 43, 44, 45 and 49 wks, egg production was greater with the BD +800 g OMM treatment than with the BD. Egg quality was not affected as a result of diet. Sperm viability was greater in roosters fed BD +800 g of OMM than those fed the BD. Fertility was greater for eggs from hens fed the BD +500 g OMM compared with BD. In conclusion, addition of organic minerals to the diet resulted in l an increased egg production and viability of rooster spermatozoa and egg fertility were greater with feeding of OMM. [ABSTRACT FROM AUTHOR]

STEM cells, MUSCLE cells, NEMALINE myopathy, NUCLEAR membranes, MUSCULAR dystrophy, and LAMINS

Mutations in the LMNA gene, encoding the nuclear envelope A-type lamins, are responsible for muscular dystrophies, the most severe form being the LMNA-related congenital muscular dystrophy (L-CMD), with severe defects in myonucleus integrity. We previously reported that L-CMD mutations compromise the ability of muscle stem cells to modulate the yes-associated protein (YAP), a pivotal factor in mechanotransduction and myogenesis. Here, we investigated the intrinsic mechanisms by which lamins influence YAP subcellular distribution, by analyzing different conditions affecting the balance between nuclear import and export of YAP. In contrast to wild type (WT) cells, LMNADK32 mutations failed to exclude YAP from the nucleus and to inactivate its transcriptional activity at high cell density, despite activation of the Hippo pathway. Inhibiting nuclear pore import abolished YAP nuclear accumulation in confluent mutant cells, thus showing persistent nuclear import of YAP at cell confluence. YAP deregulation was also present in congenital myopathy related to nesprin-1 KASH mutation, but not in cells expressing the LMNAH222P mutation, the adult form of lamin-related muscle dystrophy with reduced nuclear deformability. In conclusion, our data showed that L-CMD mutations increased YAP nuclear localization via an increased nuclear import and implicated YAP as a pathogenic contributor in muscle dystrophies caused by nuclear envelop defects. [ABSTRACT FROM AUTHOR]

Introduction: The newborn undergoing a surgery is exposed to the development of infections. The serum lactate has been recommended as a diagnostic criterion of sepsis. Objective: To determine the magnitude of association of the value of serum lactate with sepsis in the newborn undergoing a surgery. Methods: Study conducted from 2013 to 2016 in "William Soler" Pediatric Teaching Hospital, to 307 newborns whom underwent surgery. The variables were grouped in: clinical (gestational age, birth weight, cause of surgical intervention, location of the infection) and paraclinical (causative microorganisms, serum lactate). The partial Pearson's test of linear correlation was applied and it was estimated the odds ratio with the control of the variable infection (yes and no) to identify correlation between serum lactate values in the preoperative and postoperative results. Results: Of the newborns, 63 were under weight (20.52%) and 55 were preterm infants (17.92%). In the infected newborns, 20.83% were operated due to digestive conditions (n= 35); systemic infections reached 67.74% (n= 42), caused in 45.24% by Candida sp. The rate of change of the values of serum lactate in infected subjects (p= 0.001) meant that for each unit in mmol/L in which increased the preoperative lactate, the postoperative increased 0.489 mmol/L; and these changes were due in a 16.9% to the values of preoperative lactate. Conclusions: The serum lactate is associated to the infection in newborns that underwent surgery and is a useful biomarker of sepsis in neonatal intensive care. [ABSTRACT FROM AUTHOR]

POLLINATION, AGRICULTURAL productivity, APPLE orchards, CROP yields, FACTORIAL experiment designs, SUSTAINABLE agriculture, POLLINATORS, and ORCHARDS

The alarming loss of pollinator diversity world‐wide can reduce the productivity of pollinator‐dependent crops, which could have economic impacts. However, it is unclear to what extent the loss of a key native pollinator species affects crop production and farmer's profits.By experimentally manipulating the presence of colonies of a native bumblebee species Bombus pauloensis in eight apple orchards in South Argentina, we evaluated the impact of losing natural populations of a key native pollinator group on (a) crop yield, (b) pollination quality, and (c) farmer's profit. To do so, we performed a factorial experiment of pollinator exclusion (yes/no) and hand pollination (yes/no).Our results showed that biotic pollination increased ripe fruit set by 13% when compared to non‐biotic pollination. Additionally, fruit set and the number of fruits per apple tree was reduced by less than a half in those orchards where bumblebees were absent, even when honeybees were present at high densities. Consequently, farmer's profit was 2.4‐fold lower in farms lacking bumblebees than in farms hosting both pollinator species. The pollination experiment further suggested that the benefits of bumblebees could be mediated by improved pollen quality rather than quantity.Synthesis and applications. This study highlights the pervasive consequences of losing key pollinator functional groups, such as bumblebees, for apple production and local economies. Adopting pollinator‐friendly practices such as minimizing the use of synthetic inputs or restoring/maintaining semi‐natural habitats at farm and landscape scales, will have the double advantage of promoting biodiversity conservation, and increasing crop productivity and profitability for local farmers. Yet because the implementation of these practices can take time to deliver results, the management of native pollinator species can be a provisional complementary strategy to increase economic profitability of apple growers in the short term. [ABSTRACT FROM AUTHOR]

METABOLIC bone disorders, OSTEOPOROSIS, CUSHING'S syndrome, TENSILE tests, and STRUCTURAL models

• Mineralized fibrils in healthy mouse bone show strain-rate dependent stiffening. • The fibrillar stiffening is absent in steroid-induced osteoporosis. • Modelling suggests altered collagen-mineral interactions may explain this change. • Changed fibrillar stiffening may be relevant to altered mechanics in osteoporosis. As bone is used in a dynamic mechanical environment, understanding the structural origins of its time-dependent mechanical behaviour – and the alterations in metabolic bone disease – is of interest. However, at the scale of the mineralized fibrillar matrix (nanometre-level), the nature of the strain-rate dependent mechanics is incompletely understood. Here, we investigate the fibrillar- and mineral-deformation behaviour in a murine model of Cushing's syndrome, used to understand steroid induced osteoporosis, using synchrotron small- and wide-angle scattering/diffraction combined with in situ tensile testing at three strain rates ranging from 10-4 to 10-1 s-1. We find that the effective fibril- and mineral-modulus and fibrillar-reorientation show no significant increase with strain-rate in osteoporotic bone, but increase significantly in normal (wild-type) bone. By applying a fibril-lamellar two-level structural model of bone matrix deformation to fit the results, we obtain indications that altered collagen-mineral interactions at the nanoscale – along with altered fibrillar orientation distributions – may be the underlying reason for this altered strain-rate sensitivity. Our results suggest that an altered strain-rate sensitivity of the bone matrix in osteoporosis may be one of the contributing factors to reduced mechanical competence in such metabolic bone disorders, and that increasing this sensitivity may improve biomechanical performance. [ABSTRACT FROM AUTHOR]

EXPERT evidence and PART-time employment

Background First-line afatinib significantly improved median progression-free survival (PFS) in pts with EGFRm+ NSCLC vs chemotherapy (CT) in LUX-Lung (LL) 3/6 (HR [95% CI]: 0.58 [0.43, 0.78]/0.28 [0.20, 0.39]), and vs gefitinib in LL7 (0.73 [0.57, 0.95]). We conducted a phase IIIb study of afatinib in a broader patient population, similar to real-world practice, of treatment-naïve or CT pre-treated pts with EGFRm+ NSCLC. Here we present an interim analysis. Methods EGFR TKI-naïve pts with locally advanced/metastatic EGFRm+ NSCLC and ECOG PS 0–2 received afatinib 40 mg/day; dose reduction was permitted (min. 20 mg/day). Primary endpoint: adverse events (AEs; descriptive fashion). Efficacy was assessed and post-hoc subgroup analysis conducted. Results 479 pts were included (data cut-off: 30/04/18): Caucasian/Asian: 97%/2%; female: 66%; 1st/2nd/≥3rd-line therapy: 78%/17%/5%; ECOG PS 0 or 1/2: 92%/8%; brain metastases: 17%; common/uncommon [C/U] mutations: 87%/13%. Median time on afatinib: 359 days. Objective response rate: 46%. Disease control rate: 86%. Median time to symptomatic progression (TTSP) and PFS were 14.9 (95% CI: 13.8, 17.6) and 13.4 (11.8, 14.5); subgroup analysis is in the table. Most common grade ≥3 afatinib-related AEs were diarrhea (16%) and rash (11%). AEs led to dose reduction in 258 (54%) pts (most frequently diarrhea 25%, rash 11%) and to afatinib discontinuation in 105 (22%) pts (malignant neoplasm progression 3%, diarrhea 3% [rash 0.8%]). Afatinib-related serious AEs occurred in 39 (8%) pts. Conclusions This analysis indicates a predictable and manageable safety profile for afatinib, consistent with the pivotal LL trials, and encouraging efficacy findings in this broad patient population. As expected, TTSP/PFS were longer for pts with ECOG PS 0/1 vs 2, and for pts with Del 19 or L858R mutations, vs those with uncommon mutations, which may be due to the high prevalence (44%) of pts with exon 20 insertions included in this study. Table: 482P   TTSP, mos   PFS, mos   Baseline characteristic (n)  Median  95% CI  Median  95% CI  Line of tx          1 (374)  15.6  14.1, 18.5  13.8  12.6, 15.2  2 (81)  14.7  11.3, 20.6  13.2  8.3, 17.7  ≥3 (24)  8.1  3.7, 14.4  6.6  3.2, 12.6  Mutations a           Del 19 b (232)  19.3  15.6, 21.8  15.9  13.9, 19.1  L858R b (162)  14.5  12.7, 17.9  13.1  11.5, 15.2  U c (84)  7.4  5.7, 9.0  6.0  4.2, 8.1  ECOG PS, inc. mutations          0–1 (442) a   15.8  14.4, 18.8  13.8  12.8, 15.2  C b (364)  18.2  15.5, 19.8  15.2  13.8, 17.7  U (77)  7.4  5.7, 9.7  6.6  4.6, 8.2  2 (36)  8.9  5.7, 13.2  6.2  2.5, 11.6  C b (30)  8.9  5.7, 13.9  7.7  3.9, 13.2  U (6)  7.0  0.9, 13.0  1.4  0.4, 6.0  Brain mets a           No (395)  15.8  14.1, 18.8  13.9  12.7, 15.5  Yes (83)  13.7  9.7, 17.2  10.1  8.2, 13.9    TTSP, mos   PFS, mos   Baseline characteristic (n)  Median  95% CI  Median  95% CI  Line of tx          1 (374)  15.6  14.1, 18.5  13.8  12.6, 15.2  2 (81)  14.7  11.3, 20.6  13.2  8.3, 17.7  ≥3 (24)  8.1  3.7, 14.4  6.6  3.2, 12.6  Mutations a           Del 19 b (232)  19.3  15.6, 21.8  15.9  13.9, 19.1  L858R b (162)  14.5  12.7, 17.9  13.1  11.5, 15.2  U c (84)  7.4  5.7, 9.0  6.0  4.2, 8.1  ECOG PS, inc. mutations          0–1 (442) a   15.8  14.4, 18.8  13.8  12.8, 15.2  C b (364)  18.2  15.5, 19.8  15.2  13.8, 17.7  U (77)  7.4  5.7, 9.7  6.6  4.6, 8.2  2 (36)  8.9  5.7, 13.2  6.2  2.5, 11.6  C b (30)  8.9  5.7, 13.9  7.7  3.9, 13.2  U (6)  7.0  0.9, 13.0  1.4  0.4, 6.0  Brain mets a           No (395)  15.8  14.1, 18.8  13.9  12.7, 15.5  Yes (83)  13.7  9.7, 17.2  10.1  8.2, 13.9  a Missing n = 1. b Del 19/L858R only. c Includes, n (%): ex 20 ins: 37 (44). Table: 482P   TTSP, mos   PFS, mos   Baseline characteristic (n)  Median  95% CI  Median  95% CI  Line of tx          1 (374)  15.6  14.1, 18.5  13.8  12.6, 15.2  2 (81)  14.7  11.3, 20.6  13.2  8.3, 17.7  ≥3 (24)  8.1  3.7, 14.4  6.6  3.2, 12.6  Mutations a           Del 19 b (232)  19.3  15.6, 21.8  15.9  13.9, 19.1  L858R b (162)  14.5  12.7, 17.9  13.1  11.5, 15.2  U c (84)  7.4  5.7, 9.0  6.0  4.2, 8.1  ECOG PS, inc. mutations          0–1 (442) a   15.8  14.4, 18.8  13.8  12.8, 15.2  C b (364)  18.2  15.5, 19.8  15.2  13.8, 17.7  U (77)  7.4  5.7, 9.7  6.6  4.6, 8.2  2 (36)  8.9  5.7, 13.2  6.2  2.5, 11.6  C b (30)  8.9  5.7, 13.9  7.7  3.9, 13.2  U (6)  7.0  0.9, 13.0  1.4  0.4, 6.0  Brain mets a           No (395)  15.8  14.1, 18.8  13.9  12.7, 15.5  Yes (83)  13.7  9.7, 17.2  10.1  8.2, 13.9    TTSP, mos   PFS, mos   Baseline characteristic (n)  Median  95% CI  Median  95% CI  Line of tx          1 (374)  15.6  14.1, 18.5  13.8  12.6, 15.2  2 (81)  14.7  11.3, 20.6  13.2  8.3, 17.7  ≥3 (24)  8.1  3.7, 14.4  6.6  3.2, 12.6  Mutations a           Del 19 b (232)  19.3  15.6, 21.8  15.9  13.9, 19.1  L858R b (162)  14.5  12.7, 17.9  13.1  11.5, 15.2  U c (84)  7.4  5.7, 9.0  6.0  4.2, 8.1  ECOG PS, inc. mutations          0–1 (442) a   15.8  14.4, 18.8  13.8  12.8, 15.2  C b (364)  18.2  15.5, 19.8  15.2  13.8, 17.7  U (77)  7.4  5.7, 9.7  6.6  4.6, 8.2  2 (36)  8.9  5.7, 13.2  6.2  2.5, 11.6  C b (30)  8.9  5.7, 13.9  7.7  3.9, 13.2  U (6)  7.0  0.9, 13.0  1.4  0.4, 6.0  Brain mets a           No (395)  15.8  14.1, 18.8  13.9  12.7, 15.5  Yes (83)  13.7  9.7, 17.2  10.1  8.2, 13.9  a Missing n = 1. b Del 19/L858R only. c Includes, n (%): ex 20 ins: 37 (44). Clinical trial identification NCT01853826. Editorial acknowledgement Christina Jennings of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure F. De Marinis: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Boehringer Ingelheim. M. Hochmair: Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Pfizer. M.R. Migliorino: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: B.I.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: ROCHE; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: PFIZER. G.Z. Mukhametshina: Advisory / Consultancy: Association of oncologists of Russian Federation; Full / Part-time employment: State Autonomous Healthcare Institution «Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Tatarstan». M. Schumacher: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca. S. Novello: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: BI; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda. R. Dziadziuszko: Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self): MSD; Honoraria (self): Bristol-Myers Squibb. W. Tang: Full / Part-time employment: Boehringer Ingelheim. L. Clementi: Full / Part-time employment: Boehringer Ingelheim Italia SpA. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Recent reports suggest that the Hippo signaling pathway influences ovarian follicle development; however, its exact roles remain unknown. Here, we examined the ovarian functions of the Hippo kinases large tumor suppressors (LATS)1 and 2, which serve to inactivate the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Inactivation of Lats1/2 in murine granulosa cells either in vitro or in vivo resulted in a loss of granulosa cell morphology, function, and gene expression. Mutant cells further underwent changes in structure and gene expression suggestive of epithelial-to-mesenchymal transition and transdifferentiation into multiple lineages. In vivo, granulosa cell-specific loss of Lats1/2 caused the ovarian parenchyma to be mostly replaced by bone tissue and seminiferous tubule-like structures. Transdifferentiation into Sertoli-like cells and osteoblasts was attributed in part to the increased recruitment of YAP and TAZ to the promoters of sex-determining region Y box 9 and bone γ-carboxyglutamate protein, key mediators of male sex determination and osteogenesis, respectively. Together, these results demonstrate for the first time a critical role for Lats1/2 in the maintenance of the granulosa cell genetic program and further highlight the remarkable plasticity of granulosa cells. [ABSTRACT FROM AUTHOR]

SEDENTARY behavior, SEXUAL intercourse, ALCOHOL drinking, HUMAN sexuality, TEENAGERS' sexual behavior, and TEENAGERS

The association between sedentary behavior and sexual behavior has not been investigated among adolescents. The aim of this study was to: (i) investigate the association between leisure-time sedentary behavior and sexual intercourse, and (ii) test for mediation by alcohol consumption, drug use, physical activity, bullying victimization, parental support/monitoring, loneliness, and depressive symptoms in a large global sample of young adolescents. Data were analyzed from 34,674 adolescents aged 12−15 years participating in the Global School-based Student Health Survey. Participants reported the number of hours spent in leisure-time sedentary behavior on a typical day (<1, 1−2, 3−4, 5−8, and >8 hours). Data on alcohol consumption, drug use, physical activity, bullying victimization, parental support/monitoring, loneliness, and depressive symptoms were considered as potential mediators. Participants reported whether or not they had sexual intercourse in the past 12 months (yes/no). The prevalence of past 12-month sexual intercourse was 11.9%, whereas the prevalence of <1, 1−2, 3−4, 5−8, and >8 hours per day of leisure-time sedentary behavior were 26.7%, 35.6%, 21.4%, 11.5%, and 4.9%, respectively. There was a dose-dependent relationship between sedentary behavior and odds of reporting sexual intercourse: compared with <1 hour/day of sedentary behavior, the odds ratio (95% CI) of sexual intercourse associated with 1−2, 3−4, 5−8, and >8 hours/day of sedentary behavior were 1.12 (0.94−1.33), 1.22 (1.01−1.48), 1.34 (1.08−1.66), and 1.76 (1.37−2.27), respectively. There was no significant interaction by sex. The largest proportion of the association between sedentary behavior and sexual intercourse was explained by alcohol use (% mediated 21.2%), with other factors explaining an additional 11.2%. Interventions to reduce leisure-time sedentary and/or alcohol consumption may contribute to a reduction in the proportion of adolescents engaging in sexual intercourse at a young age. The strengths and limitations of this study are the large, representative sample of adolescents from 19 countries. However, the cross-sectional design means causality or temporal associations could not be established. In young adolescents, leisure-time sedentary behavior is positively associated with odds of having sexual intercourse in both boys and girls, in a dose-dependent manner. Alcohol consumption seems to be a key mediator of this relationship. Smith L, Jackson SE, Jacob L, et al. Leisure-Time Sedentary Behavior, Alcohol Consumption, and Sexual Intercourse Among Adolescents Aged 12-15 Years in 19 Countries From Africa, the Americas, and Asia. J Sex Med 2019;16:1355–1363. [ABSTRACT FROM AUTHOR]

ONCOLOGY, TUMORS, CANCER, AGE, and TUMORS in children

Background: To enhance risk stratification for Wilms tumour (WT) in a pre-operative chemotherapy setting, we explored the prognostic significance and optimal age cutoffs in patients treated according to International Society of Paediatric Oncology Renal Tumour Study Group (SIOP-RTSG) protocols. Methods: Patients(6 months-18 years) with unilateral WT were selected from prospective SIOP 93–01 and 2001 studies(1993–2016). Martingale residual analysis was used to explore optimal age cutoffs. Outcome according to age was analyzed by uni- and multivariable analysis, adjusted for sex, biopsy(yes/no), stage, histology and tumour volume at surgery. Results: 5631 patients were included; median age was 3.4 years(IQR: 2–5.1). Estimated 5-year event-free survival (EFS) and overall survival (OS) were 85%(95%CI 83.5–85.5) and 93%(95%CI 92.0–93.4). Martingale residual plots detected no optimal age cutoffs. Multivariable analysis showed lower EFS with increasing age(linear trend P<0.001). Using previously described age categories, EFS was lower for patients aged 2-4(HR 1.34, P = 0.02), 4-10(HR 1.83, P<0.0001) and 10–18 years(HR 1.74, P = 0.01) as compared to patients aged 6 months-2 years. OS was lower for patients 4–10 years(HR 1.67, P = 0.01) and 10–18 years(HR 1.87, P = 0.04), but not for 2–4 years(HR 1.29, P = 0.23). Higher stage, histological risk group and tumour volume were independent adverse prognostic factors. Conclusion: Although optimal age cutoffs could not be identified, we demonstrated the prognostic significance of age as well as previously described cutoffs for EFS (2 and 4 years) and OS (4 years) in children with WT treated with pre-operative chemotherapy. These findings encourage the consideration of age in the design of future SIOP-RTSG protocols. [ABSTRACT FROM AUTHOR]

GAIT disorders, ANATOMICAL planes, CEREBRAL palsy, THERAPEUTICS, and INTER-observer reliability

Aim: To assess interobserver reliability in the interpretation of three-dimensional gait analysis (3DGA) of children with gait disorders within a single institution.Method: Seven experienced interpreters in our institution participated in a quality-assurance program reviewing one unique patient's 3DGA data every 3 months. Between 2014 and 2017, 15 patients' data were interpreted (14 with spastic cerebral palsy, 1 with myelodysplasia). Interpreters were asked to select 'yes', 'no', or 'indeterminate' from a list of problems and treatment recommendations. Kappa and percent agreement calculations were performed to evaluate consistency.Results: Average percentage agreement in problem identification and treatment recommendation was greater than 84 percent and 90 percent for all interpreters respectively. Average kappa for the 10 most consistently identified problems and recommended treatments were 0.69 and 0.59 respectively. Interpreter consistency was moderate or better for the most commonly performed operations at our institution (0.44-0.59). Sagittal plane abnormalities of the hip and knee had the highest consistency.Interpretation: When institutional differences in data collection and regional variations in management philosophies are removed, interobserver consistency in 3DGA interpretation is moderate to substantial for many commonly selected items. Identification of areas with poor consistency may help address underlying causes and improve data processes.What This Paper Adds: Consistency in three-dimensional gait analysis interpretation and treatment recommendation is high within a single institution. There is moderate or better consistency for most commonly identified problems and recommended treatments. Sagittal plane problem identification of the hip and knee have the highest consistency. Lower consistency is seen in areas with poor objective measures, such as dystonia and balance. [ABSTRACT FROM AUTHOR]

EDUCATORS, SEX discrimination, ROLE models, GYNECOLOGY, and GENDER stereotypes

Objective: To examine the relationship between gender and a career in academic medicine. Design: Mixed‐methods study. Setting: Obstetrics–gynaecology postgraduate training programme in Paris, France. Sample: Postgraduate trainees in obstetrics–gynaecology (n = 204). Methods: Statistical analysis of quantitative survey data, thematic analysis of qualitative interview data and integrative analysis. Main outcome measures: Women's aspirations and obstacles related to their decision about a career in academic medicine. Results: A career in academic medicine was envisaged by 13% of the women residents and 27% of the men (P = 0.01). Women reported receiving advice from a mentor less often than men (38.8% versus 52.9%, P = 0.002). Overall, 40.6% of women and 2.9% of men reported experiencing gender discrimination (P < 0.001). In response to the question 'Do you have doubts about your ability to pursue or succeed at an academic career?', 62.4% of the women and only 17.7% of the men answered yes (P < 0.001). The global analysis identified the following obstacles: persistent gender stereotypes that produce everyday sexism, lack of identification with male role models, lack of mentors, perceived discrimination, an ideal of professional excellence that is difficult to attain, constraining professional organisational norms, inequality between men and women in the domestic and family spheres, and finally self‐censorship and important doubts about their ability to combine a demanding career and a fulfilling personal life. Conclusions: Women reported the desire to follow a career in academic medicine half as often as men. Improving the presence and visibility of role models for residents and combating workplace discrimination will address some of the barriers to women choosing a career in academic medicine. Women obstetric trainees in France are only half as likely as men to envisage following an academic path. Women obstetric trainees in France are only half as likely as men to envisage following an academic path. [ABSTRACT FROM AUTHOR]

Background and purpose: Hemorrhagic transformation (HT) is a complication of stroke that can occur spontaneously or after treatment. We aimed to assess the inter‐ and intrarater reliability of HT diagnosis. Methods: Studies assessing the reliability of the European Cooperative Acute Stroke Study (ECASS) classification of HT or of the presence (yes/no) of HT were systematically reviewed. A total of 18 raters independently examined 30 post‐thrombectomy computed tomography scans selected from the Aspiration versus STEnt‐Retriever (ASTER) trial. They were asked whether there was HT (yes/no), what the ECASS classification of the particular scan (0/HI1/HI2/PH1/PH2) (HI indicates hemorrhagic infarctions and PH indicates parenchymal hematomas) was and whether they would prescribe an antiplatelet agent if it was otherwise indicated. Agreement was measured with Fleiss' and Cohen's κ statistics. Results: The systematic review yielded four studies involving few (≤3) raters with heterogeneous results. In our 18‐rater study, agreement for the presence of HT was moderate [κ = 0.55; 95% confidence interval (CI), 0.41–0.68]. Agreement for ECASS classification was only fair for all five categories, but agreement improved to substantial (κ = 0.72; 95% CI, 0.69–0.75) after dichotomizing the ECASS classification into 0/HI1/HI2/PH1 versus PH2. The inter‐rater agreement for the decision to reintroduce antiplatelet therapy was moderate for all raters, but substantial among vascular neurologists (κ = 0.70; 95% CI, 0.57–0.84). Conclusion: The ECASS classification may involve too many categories and the diagnosis of HT may not be easily replicable, except in the presence of a large parenchymal hematoma. [ABSTRACT FROM AUTHOR]

RELIGIOUSNESS, SUICIDAL ideation, SUICIDAL behavior, SOCIODEMOGRAPHIC factors, and LOGISTIC regression analysis

Objective: The goal was to analyze the association of religiosity with suicidal ideation and suicide attempts in a UK nationally representative sample. Methods: This study used cross‐sectional data from 7403 people who participated in the 2007 Adult Psychiatric Morbidity Survey (APMS). Religion was assessed with the question 'Do you have a specific religion?' with 'yes' and 'no' answer options. Lifetime and past 12‐month suicidal ideation and suicide attempts were assessed. The association between religiosity and suicidality was studied in multivariable logistic regression models adjusted for sociodemographic, behavioural, and psychopathological factors. Results: Compared to those without a religion, the prevalence of past 12‐month suicidal ideation (3.2% vs. 5.4%), past 12‐month suicide attempts (0.4% vs. 0.9%), lifetime suicidal ideation (11.2% vs. 16.4%), and lifetime suicide attempts (3.6% vs. 6.0%) was lower among those with a religion. In the fully adjusted model, having a religion was significantly associated with lower odds for all types of suicidality except past 12‐month suicide attempts: suicidal ideation (past 12‐month: OR = 0.71, 95% CI = 0.51–0.99; lifetime: OR = 0.83, 95% CI = 0.69–0.99) and suicide attempts (past 12‐month: OR = 0.71, 95% CI = 0.35–1.45; lifetime: OR = 0.69, 95% CI = 0.53–0.90). Conclusion: There is a negative association between religiosity and suicidality in the UK. Future studies should focus on the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Objective: To examine the relationship between gender and a career in academic medicine.Design: Mixed-methods study.Setting: Obstetrics-gynaecology postgraduate training programme in Paris, France.Sample: Postgraduate trainees in obstetrics-gynaecology (n = 204).Methods: Statistical analysis of quantitative survey data, thematic analysis of qualitative interview data and integrative analysis.Main Outcome Measures: Women's aspirations and obstacles related to their decision about a career in academic medicine.Results: A career in academic medicine was envisaged by 13% of the women residents and 27% of the men (P = 0.01). Women reported receiving advice from a mentor less often than men (38.8% versus 52.9%, P = 0.002). Overall, 40.6% of women and 2.9% of men reported experiencing gender discrimination (P < 0.001). In response to the question 'Do you have doubts about your ability to pursue or succeed at an academic career?', 62.4% of the women and only 17.7% of the men answered yes (P < 0.001). The global analysis identified the following obstacles: persistent gender stereotypes that produce everyday sexism, lack of identification with male role models, lack of mentors, perceived discrimination, an ideal of professional excellence that is difficult to attain, constraining professional organisational norms, inequality between men and women in the domestic and family spheres, and finally self-censorship and important doubts about their ability to combine a demanding career and a fulfilling personal life.Conclusions: Women reported the desire to follow a career in academic medicine half as often as men. Improving the presence and visibility of role models for residents and combating workplace discrimination will address some of the barriers to women choosing a career in academic medicine.Tweetable Abstract: Women obstetric trainees in France are only half as likely as men to envisage following an academic path. [ABSTRACT FROM AUTHOR]

THERAPEUTIC use of monoclonal antibodies, CARDIOVASCULAR diseases, CONFIDENCE intervals, DIABETES, INJECTIONS, MONOCLONAL antibodies, PATIENT safety, PROTEOLYTIC enzymes, RANDOMIZED controlled trials, TREATMENT effectiveness, PROPORTIONAL hazards models, DESCRIPTIVE statistics, ODDS ratio, and THERAPEUTICS

Aim: To evaluate the safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab according to diabetes mellitus status. Methods: Safety data from 14 trials (8–104‐week durations) were analysed by treatment (alirocumab or placebo/ezetimibe control) and diabetes status (yes/no, defined by medical history). Adverse event data were assessed using descriptive statistics and Cox models. Results: Of the 5234 trial participants, 1554 (29.7%) had diabetes. Overall, treatment‐emergent adverse events were similar in the alirocumab and control groups, except for more frequent local injection site reactions with alirocumab. Fewer people with diabetes experienced local injection site reactions [alirocumab, 3.5%, control, 2.9%; hazard ratio 1.24 (95% CI 0.68–2.25)] than those without diabetes [alirocumab, 7.5%; control, 4.9%; hazard ratio 1.51 (95% CI 1.13–2.01)]. Those with diabetes reported a greater number of serious adverse events (alirocumab, 19.4%; control, 19.7%) than those without diabetes (alirocumab, 14.5%; control, 13.5%). In people with diabetes, major adverse cardiac events occurred in 2.7% of alirocumab‐treated people [control, 3.3%; hazard ratio 0.74 (95% CI 0.41–1.35)]; in those without diabetes, 1.8% of alirocumab‐treated people had major adverse cardiac events [control, 1.7%; hazard ratio 0.95 (95% CI 0.56–1.62)]. Overall, no increase in HbA1c or fasting plasma glucose vs control treatment groups was observed, regardless of diabetes status. Conclusion: This pooled analysis across 14 trials demonstrated similar safety for alirocumab vs control treatment, irrespective of diabetes status, except for more frequent local injection site reactions with alirocumab. People with diabetes reported fewer local injection site reactions than those without diabetes. What's new?: People with diabetes are at high cardiovascular risk and may require additional lipid‐lowering beyond statins. PCSK9 inhibitors provide additional LDL cholesterol reductions, but their safety has not been fully evaluated by diabetes status.Our pooled analysis of 14 phase 2/3 trials is the largest safety assessment of the PCSK9 inhibitor alirocumab in terms of study participant numbers (n = 5234), comparing those with vs without diabetes at baseline over 8–104 weeks of treatment.Our findings show comparable safety for alirocumab vs control, irrespective of diabetes status, except for more frequent local injection site reactions with alirocumab; people with diabetes reported fewer local injection site reactions than those without. No clinically significant changes in glycaemic variables (fasting plasma glucose and HbA1c) were observed in people with or without diabetes, regardless of treatment with alirocumab or control. [ABSTRACT FROM AUTHOR]

NEPHROLOGISTS, CHRONICALLY ill, KIDNEY diseases, NEPHROLOGY, KIDNEYS, and CHRONIC diseases

Hyperkalaemia burden in non-dialysis chronic kidney disease (CKD) under nephrology care is undefined. We prospectively followed 2443 patients with two visits (referral and control with 12-month interval) in 46 nephrology clinics. Patients were stratified in four categories of hyperkalaemia (serum potassium, sK ≥ 5.0 mEq/L) by sK at visit 1 and 2: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). We assessed competing risks of end stage kidney disease (ESKD) and death after visit 2. Age was 65 ± 15 years, eGFR 35 ± 17 mL/min/1.73 m2, proteinuria 0.40 (0.14–1.21) g/24 h. In the two visits sK was 4.8 ± 0.6 and levels ≥6 mEq/L were observed in 4%. Hyperkalaemia was absent in 46%, resolving 17%, new onset 15% and persistent 22%. Renin-angiotensin-system inhibitors (RASI) were prescribed in 79% patients. During 3.6-year follow-up, 567 patients reached ESKD and 349 died. Multivariable competing risk analysis (sub-hazard ratio-sHR, 95% Confidence Interval-CI) evidenced that new onset (sHR 1.34, 95% CI 1.05–1.72) and persistent (sHR 1.27, 95% CI 1.02–1.58) hyperkalaemia predicted higher ESKD risk versus absent, independently from main determinants of outcome including eGFR change. Conversely, no effect on mortality was observed. Results were confirmed by testing sK as continuous variable. Therefore, in CKD under nephrology care, mild-to-moderate hyperkalaemia status is common (37%) and predicts per se higher ESKD risk but not mortality. [ABSTRACT FROM AUTHOR]

CADMIUM & the environment, PHYSIOLOGICAL effects of cadmium, ATOMIC absorption spectroscopy, BLOOD testing, and INDUSTRIAL toxicology

Background Mexico City has air, water and food pollution problems; however, human exposure to cadmium and its sources have not been described. Objectives To determine the blood cadmium (BCd) level and its main exposure sources among males aged 40 years or older living in different areas of Mexico City. Methods After receiving informed consent, we interviewed 702 males aged ≥40 years to collect data on their sociodemographic characteristics, lifetime occupation, smoking history, and dietary habits, using a validated questionnaire. The BCd level (μg/L) was determined by atomic absorption spectrophotometry. Results The BCd mean level ± SD was 2.61 ± 0.82 μg/L, and 20% of men reported a potential cadmium occupational exposure. After adjusting for age and other potential confounders, the main determinants of the BCd level were the current smoking status at interview, with low (β ≤8.5packs/year vs. non-smoker  = 0.46; 95% CI: 0.28–0.64 μg/L; p < 0.01) and high (β > 8.5 packs/year vs. non-smoker  = 0.71; 95% CI: 0.56–0.87 μg/L; p < 0.01) smoking intensity, and living in the Center (β Center vs. South  = 0.20; 95% CI: 0.02–0.37 μg/L; p = 0.02) or West area of the city (β West vs. South  = 0.40, 95% CI: 0.21–0.58 μg/L; p < 0.001). Moreover, the potential dietary sources of BCd included: liver (β Yes vs. No  = 0.13, 95% CI: 0.03–0.23 μg/L; p = 0.01), “ Chorizo” (β >1–3servings/month vs. No  = 0.14, 95% CI: 0.01–0.26 μg/L; p < 0.001), sausage and ham. Conclusions The BCd levels observed in this population are high and only similar to those observed in workers from a sanitary landfill area in Southern Thailand. Potential environmental Cd exposure sources, such as industrial activity and previous land use, in the West and Center areas of the city should be explored in detail, especially in vulnerable population groups, such as children. [ABSTRACT FROM AUTHOR]

MESOPOROUS silica and DISTRIBUTION isotherms (Chromatography)

Since the emergence of deferiprone as an iron(iii) chelating drug, hydroxypyridinones have been intensively explored due to their high affinity for trivalent metal ions and ability to form complexes at physiological pH with low toxicity. For instance, they have been employed as carriers of La(iii) in therapy for bone diseases and to remove Gd(iii) from Gd-based contrast agents. We believe that a pyridinone-based sensor can be useful for iron(iii) monitoring. Herein, we present a novel chelating solid-phase, resulting from the functionalization of a mesoporous silica MCM-41, with the hydroxypyridinone N(3′-aminopropyl)-3-hydroxy-2-methyl-4-pyridinone (AHP) as the active site. The physico-chemical characterization of the new solid-state device, named AHP-MCM41@, demonstrates that the AHP moiety is covalently anchored on the silica surface; the active site concentration was found to be around 0.4 mmol g−1. Furthermore, its sorption of Fe(iii) from aqueous solution is rather rapid. The soluble AHP forms a rich variety of complexes with iron(iii), which is typical of all analogous O,O donor ligands, and is dominated by M : L = 1 : 3 complexes. Could complexes with such high stoichiometry can be retained in the solid phase? The answer is yes. The existence of these different species in the solid phase is evidenced by the sorption isotherm results and from sorption experiments as a function of solution pH and also in the presence of a competitive ligand. Furthermore, the existence of complexes in the solid phase was demonstrated via solid vis-spectrophotometry, where these species showed identical colour variations to those formed in solution. Such complexes in the solid phase have never been reported in the literature. Additionally, the intense colour of the solid phase in the presence of iron(iii) is promising for naked eye detection. [ABSTRACT FROM AUTHOR]

BODY mass index, CLINICAL trials, REGULATION of body weight, OVERWEIGHT persons, and WEIGHT loss

Aims: To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once‐weekly glucagon‐like peptide 1 analogue for the treatment of type 2 diabetes. Semaglutide demonstrated superior reductions in HbA1c and superior weight loss (by 2.3‐6.3 kg) versus different comparators across the SUSTAIN 1 to 5 trials; the contributing factors to weight loss are not established. Materials and Methods: Subjects with inadequately controlled type 2 diabetes (drug‐naïve or on background treatment) were randomized to subcutaneous semaglutide 0.5 mg (excluding SUSTAIN 3), 1.0 mg (all trials), or comparator (placebo, sitagliptin, exenatide extended release or insulin glargine). Subjects were subdivided by baseline BMI and reporting (yes/no) of any nausea and/or vomiting. Change from baseline in body weight was assessed within each trial and subgroup. A mediation analysis separated weight loss into direct or indirect (mediated by nausea or vomiting) effects. Results: Clinically relevant weight‐loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. Overall, 15.2% to 24.0% and 21.5% to 27.2% of subjects experienced nausea or vomiting with semaglutide 0.5 and 1.0 mg, respectively, versus 6.0% to 14.1% with comparators. Only 0.07 to 0.5 kg of the treatment difference between semaglutide and comparators was mediated by nausea or vomiting (indirect effects). Conclusions: In SUSTAIN 1 to 5, semaglutide‐induced weight loss was consistently greater versus comparators, regardless of baseline BMI. The contribution of nausea or vomiting to this weight loss was minor. [ABSTRACT FROM AUTHOR]

ELECTRONIC health records, ACUTE leukemia, HEMORRHAGE, HEMOGLOBINS, and BLOOD transfusion

Introduction: Electronic health care data offers the opportunity to study rare events, although detecting these events in large datasets remains difficult. We aimed to develop a model to identify leukemia patients with major hemorrhages within routinely recorded health records. Methods: The model was developed using routinely recorded health records of a cohort of leukemia patients admitted to an academic hospital in the Netherlands between June 2011 and December 2015. Major hemorrhage was assessed by chart review. The model comprised CT-brain, hemoglobin drop, and transfusion need within 24 hours for which the best discriminating cut off values were taken. External validation was performed within a cohort of two other academic hospitals. Results: The derivation cohort consisted of 255 patients, 10,638 hospitalization days, of which chart review was performed for 353 days. The incidence of major hemorrhage was 0.22 per 100 days in hospital. The model consisted of CT-brain (yes/no), hemoglobin drop of ≥0.8 g/dl and transfusion of ≥6 units. The C-statistic was 0.988 (CI 0.981–0.995). In the external validation cohort of 436 patients (19,188 days), the incidence of major hemorrhage was 0.46 per 100 hospitalization days and the C-statistic was 0.975 (CI 0.970–0.980). Presence of at least one indicator had a sensitivity of 100% (CI 95.8–100) and a specificity of 90.7% (CI 90.2–91.1). The number of days to screen to find one case decreased from 217.4 to 23.6. Interpretation: A model based on information on CT-brain, hemoglobin drop and need of transfusions can accurately identify cases of major hemorrhage within routinely recorded health records. [ABSTRACT FROM AUTHOR]

SPINAL surgery, SPINE abnormalities, MEDICAL decision making, HEALTH counseling, and QUALITY of life

BACKGROUND CONTEXT Adult spinal deformity (ASD) surgery is costly with variable outcomes; in some series only 50% of patients achieve clinically important (MCID) improvements. Predictive modeling with machine learning is a relatively unexplored area of patient-reported outcomes research. These methods may be useful in shared-decision making, surgical planning, and postoperative patient counseling. PURPOSE To use predictive analytics to model health-related quality of life (HRQOL) outcomes at 1 year and 2 years after ASD surgery; including predicting the likelihood of achieving MCID. STUDY DESIGN/SETTING Data from two unique, multicenter, prospective observational cohort studies PATIENT SAMPLE Patients 18 years or older and treated for ASD with surgery. OUTCOME MEASURES Scoliosis Research Society-22, Oswestry Disability Index, Short Form-36v2. METHODS Two multi-center, prospective observational cohorts of ASD patients were queried to identify patients with complete enrollment, 1 and 2-year follow-up SRS-22, ODI and SF-36v2 data. Standard demographic and radiographic variables were collected. Modifiable surgical data (eg, 3-Column Osteotomy Yes or No), intraoperative and postoperative complications were collected. A total of 75 variables were used in the training of the models. Eight different prediction algorithms were trained with 3-time horizons: baseline to 1 year, baseline to 2 years, and 1 year to 2 years. External validation was accomplished via an 80/20 data split for training and testing each model, respectively. Five-fold cross validation within the training sample was performed. Accuracy was measured as the mean average error (MAE; smaller is better) and R² values. Models were created to predict HRQOL values at 2 years and to predict the likelihood of achieving MCID thresholds at 2 years postoperatively. RESULTS A total of 570 patients were included in the analysis. Models with the lowest MAE for each of the 5-time points were selected, achieving 82.4% predictive power. Patients with lower enrollment HRQOL were likely to achieve the greatest improvements and enrollment HRQOL values were the most important variables included. Age at enrollment was the most important demographic variable. Addition of surgeon and site to preoperative data increased the predictive power 1.8%. Site and surgeon fixed-effects played a crucial role in explaining outcome variance. Levels fused and enrollment curve magnitude were less important. CONCLUSIONS Predictive modeling from a large cohort of ASD patients was able to model 2-year outcomes scores, including the likelihood of achieving clinically relevant improvements. Patients with the lowest HRQOL scores were likely to appreciate the greatest improvements at 2 years postoperatively. Surgeon and site were important covariates, explaining variance in outcomes measures. These data may be used in informed decision making and patient counseling before and after ASD surgery. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs. [ABSTRACT FROM AUTHOR]

ELECTROENCEPHALOGRAPHY, MAGNETOENCEPHALOGRAPHY, SIGNAL detection, STIMULUS & response (Biology), and THETA rhythm

Introduction Analyzing the influence of pre-stimulus EEG/MEG-oscillations on stimulus detection is typically performed by calculating the oscillatory power in each individual EEG/MEG sensor and a single frequency band and correlating it to the parameters of standard Signal Detection Theory (SDT). In the visual domain, this classical approach revealed an effect of widely distributed alpha activity on the perception bias (i.e., how conservative or liberal subjects decide) but not on the overall sensitivity (i.e., the ability to discriminate between stimulus presence and absence). However, sensor-space EEG/MEG data is spatially non-specific and highly susceptible to far-field activity and noise sources. Moreover, classical equal-variances SDT analysis might lead to spurious results. Here, we extract sources of alpha and theta activity using spatio-spectral decomposition (SSD) and model their collective effect on visual detection effectivity using heterogeneous choice models. Methods 64-multichannel EEG of 30 subjects was recorded during a visual yes/no detection task with 60% stimulus present trials and 40% stimulus absent trials. The stimuli consisted of low-contrast Gabor patches displayed at 10 degrees of visual angle in the left or right hemifield. The two strongest alpha and theta sources common for all subjects were identified by SSD applied at group-level. The rank-normalized alpha and theta powers at stimulus presentation ( t  = 0 ms) were used as regressors in a heterogeneous choice model. Results The heterogeneous choice model replicated the finding that oscillatory alpha power influences the perceptual bias. Additionally, strong occipital alpha power was found to increase the variability in the detection model. Furthermore, the power of a bipolar theta source, tentatively attributable to a deeper origin, was found to be negatively correlated to the overall sensitivity of the visual detection task. Discussion and significance SSD effectively extracted collectively strongest sources of alpha and theta activity across subjects, hereby increasing the spatial specificity of the data and the signal-to-noise ratio. The heterogeneous choice model revealed that alpha oscillations not only influence perceptual bias but also the variability in the model and that strong regional theta oscillations are correlated with less effective visual detection, potentially due to drowsiness. However, further studies are needed to characterize the neurophysiological underpinnings of these observations. [ABSTRACT FROM AUTHOR]

The ability to communicate in English is often associated with the condition of social class, gender and other factors of cultural identity. In this early 21st century, it has become one of the main constraints to participate in study and research programs in universities with top academic rankings. However, in many countries with too many educational inequalities, namely in Portugal and Brazil, the hegemony of the English language is a worrying factor for the internationalisation policies aimed at the high qualification of researchers in several scientific areas, especially those that lead to innovation and bring added value to the knowledge economy. From a comparative perspective, and taking into account some assumptions of postcolonial critical theories, this article presents a critical reflection on how English language teaching policies in the countries mentioned have acted to reinforce inequalities in terms of international student mobility. [ABSTRACT FROM AUTHOR]

ENGLISH as a foreign language and EDUCATIONAL equalization

The ability to communicate in English is often associated with the condition of social class, gender and other factors of cultural identity. In this early 21st century, it has become one of the main constraints to participate in study and research programs in universities with top academic rankings. However, in many countries with too many educational inequalities, namely in Portugal and Brazil, the hegemony of the English language is a worrying factor for the internationalisation policies aimed at the high qualification of researchers in several scientific areas, especially those that lead to innovation and bring added value to the knowledge economy. From a comparative perspective, and taking into account some assumptions of postcolonial critical theories, this article presents a critical reflection on how English language teaching policies in the countries mentioned have acted to reinforce inequalities in terms of international student mobility. [ABSTRACT FROM AUTHOR]

ATHEROSCLEROSIS, LUNG diseases, VITAMIN D deficiency, COMPUTED tomography, ARTERIOSCLEROSIS, COMPARATIVE studies, ETHNIC groups, INTERSTITIAL lung diseases, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, RESEARCH, RESEARCH funding, VITAMIN D, and EVALUATION research

Background: Activated vitamin D has anti-inflammatory properties. 25-Hydroxyvitamin D [25(OH)D] deficiency might contribute to subclinical interstitial lung disease (ILD).Objective: We examined associations between serum 25(OH)D concentrations and subclinical ILD among middle-aged to older adults who were free of cardiovascular disease at baseline.Methods: We studied 6302 Multi-Ethnic Study of Atherosclerosis (MESA) participants who had baseline serum 25(OH)D concentrations and computed tomography (CT) imaging spanning ≤ 10 y. Baseline cardiac CT scans (2000-2002) included partial lung fields. Some participants had follow-up cardiac CT scans at exams 2-5 and a full-lung CT scan at exam 5 (2010-2012), with a mean ± SD of 2.1 ± 1.0 scans. Subclinical ILD was defined quantitatively as high-attenuation areas (HAAs) between -600 and -250 Hounsfield units. We assessed associations of 25(OH)D with adjusted HAA volumes and HAA progression. We also examined associations between baseline 25(OH)D and the presence of interstitial lung abnormalities (ILAs) assessed qualitatively (yes or no) from full-lung CT scans at exam 5. Models were adjusted for sociodemographic characteristics, lifestyle factors (including smoking), and lung volumes.Results: The cohort's mean ± SD characteristics were 62.2 ± 10 y for age, 25.8 ± 10.9 ng/mL for 25(OH)D concentrations, and 28.3 ± 5.4 for body mass index (kg/m2); 53% were women, with 39% white, 27% black, 22% Hispanic, and 12% Chinese race/ethnicities. Thirty-three percent had replete (≥30 ng/mL), 35% intermediate (20 to <30 ng/mL), and 32% deficient (<20 ng/mL) 25(OH)D concentrations. Compared with those with replete concentrations, participants with 25(OH)D deficiency had greater adjusted HAA volume at baseline (2.7 cm3; 95% CI: 0.9, 4.5 cm3) and increased progression over a median of 4.3 y of follow-up (2.7 cm3; 95% CI: 0.9, 4.4 cm3) (P < 0.05). 25(OH)D deficiency was also associated with increased prevalence of ILAs 10 y later (OR: 1.5; 95% CI: 1.1, 2.2).Conclusions: Vitamin D deficiency is independently associated with subclinical ILD and its progression, based on both increased HAAs and ILAs, in a community-based population. Further studies are needed to examine whether vitamin D repletion can prevent ILD or slow its progression. The MESA cohort design is registered at www.clinicaltrials.gov as NCT00005487. [ABSTRACT FROM AUTHOR]

OVERWEIGHT persons, NUCLEOTIDE sequence, DNA damage, LYMPHOCYTES, and DNA repair

Health authorities are alarmed worldwide about the increase of obesity and overweight in the last decades which lead to adverse health effects including inflammation, cancer, accelerated aging and infertility. We evaluated the state of knowledge concerning the impact of elevated body mass on genomic instability. Results of investigations with humans (39 studies) in which DNA damage was monitored in lymphocytes and sperm cells, are conflicting and probably as a consequence of heterogeneous study designs and confounding factors ( e.g. uncontrolled intake of vitamins and minerals and consumption of different food types). Results of animal studies with defined diets (23 studies) are more consistent and show that excess body fat causes DNA damage in multiple organs including brain, liver, colon and testes. Different molecular mechanisms may cause genetic instability in overweight/obese individuals. ROS formation and lipid peroxidation were found in several investigations and may be caused by increased insulin, fatty acid and glucose levels or indirectly via inflammation. Also reduced DNA repair and formation of advanced glycation end products may play a role but more data are required to draw firm conclusions. Reduction of telomere lengths and hormonal imbalances are characteristic for overweight/obesity but the former effects are delayed and moderate and hormonal effects were not investigated in regard to genomic instability in obese individuals. Increased BMI values affect also the activities of drug metabolizing enzymes which activate/detoxify genotoxic carcinogens, but no studies concerning the impact of these alterations of DNA damage in obese individuals are available. Overall, the knowledge concerning the impact of increased body weight and DNA damage is poor and further research is warranted to shed light on this important issue. [ABSTRACT FROM AUTHOR]

LIPODYSTROPHY, HIV infections, BODY composition, WAIST circumference, ADVERSE health care events, and DIAGNOSIS

Background: Body composition alterations, or lipodystrophy, can lead to serious health problems in people living with HIV/AIDS (PLWHA). The objectives of this study are to predict and validate sex-specific anthropometric predictive models for the diagnosis of lipodystrophy in PLWHA.Methods: A cross-sectional design was employed to recruit 106 PLWHA (men = 65 and women = 41) in Brazil during 2013-2014. They were evaluated using dual-energy X-ray absorptiometry, and 19 regions of body perimeters and 6 skinfold thicknesses were taken. Sex-specific predictive models for lipodystrophy diagnosis were developed through stepwise linear regression analysis. Cross-validations using predicted residual error sum of squares was performed to validate each predictive model.Results: Results support the use of anthropometry for the diagnosis of lipodystrophy in men and women living with HIV/AIDS. A high power of determination with a small degree of error was observed for lipodystrophy diagnosis for men in model six (r2 = 0.77, SEE = 0.14, r2PRESS = 0.73, SEE PRESS = 0.15), that included ratio of skinfold thickness of subscapular to medial calf, skinfold thickness of thigh, body circumference of waist, formal education years, time of diagnosis to HIV months, and type of combined antiretroviral therapy (cART) (with protease inhibitor "WI/PI = 1" or without protease inhibitor "WO/PI = 0"); and model five for women (r2 = 0.78, SEE = 0.11, r2PRESS = 0.71, SEE PRESS = 0.12), that included skinfold thickness of thigh, skinfold thickness of subscapular, time of exposure to cART months, body circumference of chest, and race (Asian) ("Yes" for Asian race = 1; "No" = 0).Conclusions: The proposed anthropometric models advance the field of public health by facilitating early diagnosis and better management of lipodystrophy, a serious adverse health effect experienced by PLWHA. [ABSTRACT FROM AUTHOR]

GENETICS of disease susceptibility, BIOLOGICAL assay, BIOLOGICAL models, GENE expression, GENETIC polymorphisms, META-analysis, PROBABILITY theory, PULMONARY hypertension, SYSTEMIC scleroderma, TRANSCRIPTION factors, EVIDENCE-based medicine, PROFESSIONAL practice, FIBROSIS, IN vitro studies, VASCULAR remodeling, and DISEASE complications

Objective: NKX2‐5 is a homeobox transcription factor that is required for the formation of the heart and vessels during development, with significant postnatal down‐regulation and reactivation in disease states, characterized by vascular remodeling. The purpose of this study was to investigate mechanisms that activate NKX2‐5 expression in diseased vessels, such as systemic sclerosis (scleroderma; SSc)–associated pulmonary hypertension (PH), and to identify genetic variability that potentially underlies susceptibility to specific vascular complications. Methods: We explored NKX2‐5 expression in biopsy samples from patients with SSc‐associated PH and in pulmonary artery smooth muscle cells (PASMCs) from patients with scleroderma. Disease‐associated putative functional single‐nucleotide polymorphisms (SNPs) at the NKX2-5 locus were cloned and studied in reporter gene assays. SNP function was further examined through protein–DNA binding assays, chromatin immunoprecipitation assays, and RNA silencing analyses. Results: Increased NKX2‐5 expression in biopsy samples from patients with SSc‐associated PH was localized to remodeled vessels and PASMCs. Meta‐analysis of 2 independent scleroderma cohorts revealed an association of rs3131917 with scleroderma (P = 0.029). We demonstrated that disease‐associated SNPs are located in a novel functional enhancer, which increases NKX2-5 transcriptional activity through the binding of GATA‐6, c‐Jun, and myocyte‐specific enhancer factor 2C. We also characterized an activator/coactivator transcription‐enhancer factor domain 1 (TEAD1)/Yes‐associated protein 1 (YAP1) complex, which was bound at rs3095870, another functional SNP, with TEAD1 binding the risk allele and activating the transcription of NKX2-5. Conclusion: NKX2-5 is genetically associated with scleroderma, pulmonary hypertension, and fibrosis. Functional evidence revealed a regulatory mechanism that results in NKX2-5 transcriptional activation in PASMCs through the interaction of an upstream promoter and a novel downstream enhancer. This mechanism can act as a model for NKX2‐5 activation in cardiovascular disease characterized by vascular remodeling. [ABSTRACT FROM AUTHOR]

CONFERENCES & conventions, COCHLEAR implants, DECISION making, and HEARING disorders

Objective:To assess speech perception skills in Open Set and the benefit acquired through the use of the second CI and Bilateral CI(BICI) that was sequentially delayed. Material and Method: Evaluation of 25 patients who had received a Sequential CI with an interval of over 7yrs between both surgeries. The speech recognition acquired through the use of CI1, CI2 and BICI benefit was carried out by applying two-syllable words in Open Set. The perceptual subjective benefit obtained with the CI2 was made using Questionnaire of Anecdotal Report . The evaluation was made after 12 month use of CI2. Results: The results were analyzed in three different groups: 1) 1stCI made before the age 3 and with consistent use of contralateral hearing aid(HA). 2) The same condition but without the use of HA and 3) 1stCI made in patients older than 3 yrs old. G1: were included 9 children with an interval from 11 to 16yrs(10.7), all perform in Open Set with their CI2, G2: 4 children with an interval from 7 to 15yrs(10.5), 50% perform in Open Set, G3 11 patients, interval from 8 to 15 yrs(10.4), 7 were users of contralateral HA, 55% perform in Open Set. The average indicates that, there was an improvement of 18% benefit with the use of both CI. Regarding the use of the CI2 throughout the whole day and the preference for the use of BICI, 92 % of the patients answered Yes. Regarding the fact of feeling comfortable with BICI, the 100% answered Yes. Regarding similar hearing in both ears, 44% answered that hearing was similar. Conclusion: The best results in speech perception skills were in patients with contralateral residual hearing who used hearing aids consistently before CI2. All the patients said that they felt subjetively better in the BICI condition. The delayed sequential CI, in youth and young adults that were implanted at an early stage, provides an additional benefit in the general performance. [ABSTRACT FROM AUTHOR]

RETIREMENT -- Psychological aspects, ANALYSIS of covariance, AUTONOMY (Psychology), CHRONIC diseases, LONGITUDINAL method, PROBABILITY theory, PROFESSIONS, LOGISTIC regression analysis, and MIDDLE age

Aim: The ageing society and recent policy changes may lead to an increase of older workers with chronic diseases in the workforce. To date, it is unclear whether workers with chronic diseases have specific needs while employed. The aim of this study is to explore the differences in determinants of working until retirement compared to a reference group who have transitioned to early retirement among workers with and without chronic diseases. Methods: Dutch workers aged 57-62 years (n = 2445) were selected from an existing prospective cohort study, 'STREAM'. The potential determinants were categorized into: individual, health, work-related and social factors. logistic regression analyses were performed to determine the associations between these determinants and working until retirement - once for workers with and once for those without chronic diseases. To test differences, we included an interaction term between the determinant and the covariate 'having a chronic disease yes/no' in the analyses of the total population. Results: In total, 1652 (68%) persons were employed from 2011 to 2013. The majority of the determinants appeared to be similar for workers with or without a chronic disease; the interaction terms for these determinants and the covariate 'having a chronic disease' showed a p-value higher than 0.05, except for one individual factor (i.e. mastery) and one work-related factor (i.e. autonomy), which showed a p-value below 0.05. Higher mastery and higher autonomy were statistically significantly associated with working until retirement for those with chronic diseases, whereas they were not for those without chronic diseases. Conclusions: Differences between workers with and without chronic diseases may exist for working until a statutory retirement age. Interventions aimed at encouraging work participation of older workers should make a distinction between the two groups. Autonomy at work and mastery were found to be factors that may promote work participation until higher age, specifically for older workers with chronic diseases. [ABSTRACT FROM AUTHOR]

ENDOCRINE disruptors, BOTTLED water, BISPHENOL A, POLYETHYLENE terephthalate, and HEALTH risk assessment

Potential endocrine disrupting chemicals (EDCs) are present in bottled water from various countries. In South Africa (SA), increased bottled water consumption and concomitant increases in plastic packaging create important consequences for public health. This study aimed to screen SA bottled water for estrogenic activity, selected target chemicals and assessing potential health risks. Ten bottled water brands were exposed to 20 C and 40 C over 10 days. Estrogenic activity was assessed using the recombinant yeast estrogen screen (YES) and the T47D-KBluc reporter gene assay. Solid phase extracts of samples were analyzed for bis(2-ethylhexyl) adipate (DEHA), selected phthalates, bisphenol-A (BPA), 4-nonylphenol (4-NP), 17β-estradiol (E2), estrone (E1), and ethynylestradiol (EE2) using gas chromatography-mass spectrophotometry. Using a scenario-based health risk assessment, human health risks associated with bottled water consumption were evaluated. Estrogenic activity was detected at 20 C (n = 2) and at 40 C (n = 8). Estradiol equivalent (EEq) values ranged from 0.001 to 0.003 ng/L. BPA concentrations ranged from 0.9 ng/L to 10.06 ng/L. Although EEqs and BPA concentrations were higher in bottled water stored at 40 C compared to 20 C, samples posed an acceptable risk for a lifetime of exposure. Irrespective of temperature, bottled water from SA contained chemicals with acceptable health risks. [ABSTRACT FROM AUTHOR]

ACTINOMYCETALES, COMMON bean, RHIZOCTONIA solani, CORTICIUM sasakii, and GREENHOUSES

The effect of seed treatment with the actinomycetes strains EA2 and CB14, and their combination, on damping-off incidence caused by Rhizoctonia solani Kühn in Phaseolus vulgaris L. cv. Velasco largo was evaluated under greenhouse conditions. These strains were compared with Trichoderma harzianum A-34, Celest®Top 312 FS and two controls (positive and negative). Inceptisol sterile and non-sterile soil was used under a completely randomized design. The coating seeds with strains were made using 8 % cassava starch. The incidence of R. solani was determined 21 days after sowing. In non-sterile soil, the lowest incidences caused by R. solani were found with Celest®Top 312 FS, which did not significantly differ from the combination of actinomycete strains CB14 + EA2, but yes with the rest of the treatments. In the sterile soil, the lowest percentages of incidences were obtained with the combination of actinomycete strains (CB14 + EA2). [ABSTRACT FROM AUTHOR]

IMMUNOTHERAPY, ALLERGENS, CLINICAL immunology, and PHYSICIANS

Abstract: Background: Since 1988, numerous allergen immunotherapy guidelines (AIT‐GLs) have been developed by national and international organizations to guide physicians in AIT. Even so, AIT is still severely underused. Objective: To evaluate AIT‐GLs with AGREE‐II, developed in 2010 by McMaster University methodologists to comprehensively evaluate GL quality. Methods: Allergist, from different continents, knowledgeable in AIT and AGREE‐II trained were selected into the project team. The project received methodologists’ guidance. AIT‐GLs in any language were sought from 1980 to 2016; AIT‐GLs were AGREE II‐evaluated by at least 2 team members, independently; discrepancies were resolved in a second round, by team discussion or methodologists’ consulting. Results: We found 31 AIT‐GLs (15 post‐2010), ranging from local consensus reports to international position papers (EAACI, AAAAI‐ACAAI, WAO). Pre‐2010 GLs scored 1.6‐4.6 (23%‐67%) and post‐2010 GLs scored 2.1‐6 (30%‐86%), on a 7‐point Likert scale. The highest scores went to: German‐Austrian‐Swiss (6.0), Mexican (5.1), and the AAAAI/ACAAI AIT‐GL (4.7). These were also the only 3 GLs that received “yes” of both evaluators to the item: “I would recommend this GL for use.” The domains of “Stakeholder involvement” and “Rigor of Development” only scored 3/7, and “Applicability” scored the lowest. Strikingly, newer GLs only scored clearly better in “Editorial independence” and “Global evaluation.” Conclusions: In AIT‐GLs, there is still a lot of room for improvement, especially in domains crucial for the dissemination. For some GLs, the “Scientific rigor” domain flawed. When resources are limited, transculturizing a high‐quality GL might be preferable over developing a GL from zero. Our study and AGREE‐II could help to select the best candidate. Clinical Implications: We here evaluate allergen immunotherapy guideline (AIT‐GL) quality. Only high‐quality AIT‐GLs should be consulted for AIT management decisions. In low‐resource settings, transculturization of these is preferred over developing low‐quality guidelines. [ABSTRACT FROM AUTHOR]

ARTHRITIS, GOUT, PREDICTIVE tests, CROSS-sectional method, RECEIVER operating characteristic curves, DESCRIPTIVE statistics, and RESEARCH evaluation

Objective: To perform external validation of a provisional definition of disease flare in patients with gout. Methods: Five hundred nine patients with gout were enrolled in a cross‐sectional study during a routine clinical care visit at 17 international sites. Data were collected to classify patients as experiencing or not experiencing a gout flare, according to a provisional definition. A local expert rheumatologist performed the final independent adjudication of gout flare status. Sensitivity, specificity, predictive values, and receiver operating characteristic (ROC) curves were used to determine the diagnostic performance of gout flare definitions. Results: The mean ± SD age of the patients was 57.5 ± 13.9 years, and 89% were male. The definition requiring fulfillment of at least 3 of 4 criteria (patient‐defined gout flare, pain at rest score of >3 on a 0–10‐point numerical rating scale, presence of at least 1 swollen joint, and presence of at least 1 warm joint) was 85% sensitive and 95% specific in confirming the presence of a gout flare, with an accuracy of 92%. The ROC area under the curve was 0.97. The definition based on a classification and regression tree algorithm (entry point, pain at rest score >3, followed by patient‐defined flare “yes”) was 73% sensitive and 96% specific. Conclusion: The definition of gout flare that requires fulfillment of at least 3 of 4 patient‐reported criteria is now validated to be sensitive, specific, and accurate for gout flares, as demonstrated using an independent large international patient sample. The availability of a validated gout flare definition will improve the ascertainment of an important clinical outcome in studies of gout. [ABSTRACT FROM AUTHOR]

Water quality, Endocrine disruptors, Marine pollution, and Sewage disposal plants

Endocrine disrupting compounds (EDCs) can be found in domestic sewage, wastewater treatment plant effluents, natural water, rivers, lakes and in the marine environment. Jurujuba Sound, located in the state of Rio de Janeiro, Southeastern Brazil, receives untreated sewage into its waters, one the main sources of aquatic contamination in this area. In this context, the aim of the present study was to evaluate the estrogenic potential of water sampled from different depths and from areas with differential contamination levels throughout Jurujuba Sound. Water quality was evaluated and acute toxicity assays using Allviibrio fischeri were conducted, while estrogenic activity of the water samples was determined by a Yeast Estrogen Screening assay (YES). Water quality was mostly within the limits established for marine waters by the Brazilian legislation, with only DOC and ammoniacal nitrogen levels above the maximum permissible limits. No acute toxicity effects were observed in the Allivibrio fisheri assay. The YES assay detected moderate estrogenic activity in bottom water samples from 3 sampling stations, ranging from 0.5 to 3.2 ng L −1 , as well as in one surface water sample. Estrogenic activity was most frequently observed in samples from the bottom of the water column, indicating adsorption of estrogenic compounds to the sediment. [ABSTRACT FROM AUTHOR]

COMPOSITE materials, SISAL (Fiber), CHEMICAL decomposition kinetics, THERMAL stability, THERMOGRAVIMETRY, and CHEMICAL reactions

The decomposition behaviours of composites made of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and sisal were assessed in terms of thermal stability and decomposition kinetics, under inert and oxidative conditions, by means of multi-rate linear non-isothermal thermogravimetric experiments. A statistical design of experiments was applied to study the influence of the addition of sisal (0–10–20–30%wt), the presence coupling agent (Yes/No) and the applied conditions of work (inert or oxidative). An improvement of the thermal and thermo-oxidative stability of PHBV with the addition of sisal was observed for all cases. An accurate methodology based on iso-conversional methods was applied to simulate the potential of thermal recovery technologies, such as pyrolysis and controlled combustion, to use these biocomposites after the end of their service life. The mathematical descriptions of both thermo-chemical reactions were helpful in the evaluation of the eventual optimal operational conditions to carry out a suitable energetic valorisation. A minimum of 240°C and 137 kJ/mol of activation energy in inert conditions and 236°C and 118 kJ/mol in oxidative conditions ensured the feasibility of the reactions regardless the composition of the PHBV/sisal biocomposites, which may ease the operability of further energy valorisation with the aim to turn biowaste into new fuels. [ABSTRACT FROM AUTHOR]

YOUTH health, MENTORING, SOCIAL anxiety, MOOD (Psychology), and SELF-esteem

Background: Youth with chronic physical health problems often experience social and emotional problems. We investigate the relationship between participation in the Big Brothers Big Sisters of Canada community-based mentoring programs (BBBS) and youth social and mood outcomes by youth health status. Methods: Youth newly enrolled in BBBS were classified by health status (one or more chronic physical health problems without activity limitation, n = 191; one or more chronic physical health problems with activity limitation, n = 94; no chronic health problem or activity limitation, n = 536) and mentoring status (yes/no) at 18 month follow-up. Youth outcomes measured at follow-up were social anxiety, depressed mood, and peer self-esteem. Results: Youth with chronic health problems and activity limitation were more likely to live with two biological parents, use mental health or social services, and have parents who reported difficulties with depressed mood, social anxiety, family functioning and neighbourhood problems. At 18 month follow-up, mentored youth in this health status group experienced fewer symptoms of social anxiety and higher peer self-esteem compared to non-mentored youth. Mentored youth with chronic health problems without activity limitation and mentored youth with no health problems or limitations did not show significant improvements in social anxiety and peer self-esteem. Regardless of their health status, mentored youth reported fewer symptoms of depressed mood than non-mentored youth. Conclusions: Youth with chronic health problems, particularly those with activity limitation as well, demonstrate a capacity to experience social and mood benefits associated with mentoring. [ABSTRACT FROM AUTHOR]

For the development of the subject we first need the concept of constitutional state -aluding to its substantive distancing with the old rule of law-, and seeking its direct entanglement with a broad democratic order, yes, in Colombia, impaired with the continuity of the everlasting reformist custom of the Political Charter, basically along the way of art. 375 constitutional (and mainly on initiative or with the endorsement of the executive in office), which, for that task, the referred rule empowers the Congress of the Republic through the figure of legislative acts. Next (point 2), we alluded to tht' theme of the different constitutional reforms that have cracked the text of the Charter, and on them we need and develop (point 3), in our opinion, one of the most reactionary reforms, if not the most, altering the precarious state legitimacy achieved with the issuance of the Constitution itself. We refer here to the detriment that, by different legal paths, the democratic figure of the administrative career has suffered. In this last aspect we specify the obstinacy of the Uribe Velez period for depreciating and despising the importance of the institution of merit in the public service; inheritance received by the Santos government, trying to give continuity. [ABSTRACT FROM AUTHOR]

TWINS, INTERNET pharmacies, DOPAMINE receptors, SCHIZOPHRENIA, GLUTAMIC acid, GLUTAMATE receptors, DOPAMINE, and GENES

publisher‐imprint‐name Springer volume‐issue‐count 1 issue‐article‐count 0 issue‐toc‐levels 0 issue‐pricelist‐year 2017 issue‐copyright‐holder The Author(s) issue‐copyright‐year 2017 article‐contains‐esm Yes article‐numbering‐style Unnumbered article‐registration‐date‐year 2017 article‐registration‐date‐month 11 article‐registration‐date‐day 6 article‐toc‐levels 0 toc‐levels 0 volume‐type Regular journal‐product ArchiveJournal numbering‐style Unnumbered article‐grants‐type OpenChoice metadata‐grant OpenAccess abstract‐grant OpenAccess bodypdf‐grant OpenAccess bodyhtml‐grant OpenAccess bibliography‐grant OpenAccess esm‐grant OpenAccess online‐first false pdf‐file‐reference BodyRef/PDF/40169_2017_Article_174.pdf pdf‐type Typeset target‐type OnlinePDF issue‐type Regular article‐type OriginalPaper journal‐subject‐primary Medicine & Public Health journal‐subject‐secondary Medicine/Public Health, general journal‐subject‐collection Medicine open‐access true --> Background: Monozygotic twins are valuable in assessing the genetic vs environmental contribution to diseases. In the era of complete genome sequences, they allow identification of mutational mechanisms and specific genes and pathways that offer predisposition to the development of complex diseases including schizophrenia. Methods: We sequenced the complete genomes of two pairs of monozygotic twins discordant for schizophrenia (MZD), including one representing a family tetrad. The family specific complete sequences have allowed identification of post zygotic mutations between MZD genomes. It allows identification of affected genes including relevant network and pathways that may account for the diseased state in pair specific patient. Results: We found multiple twin specific sequence differences between co‐twins that included small nucleotides [single nucleotide variants (SNV), small indels and block substitutions], copy number variations (CNVs) and structural variations. The genes affected by these changes belonged to a number of canonical pathways, the most prominent ones are implicated in schizophrenia and related disorders. Although these changes were found in both twins, they were more frequent in the affected twin in both pairs. Two specific pathway defects, glutamate receptor signaling and dopamine feedback in cAMP signaling pathways, were uniquely affected in the two patients representing two unrelated families. Conclusions: We have identified genome‐wide post zygotic mutations in two MZD pairs affected with schizophrenia. It has allowed us to use the threshold model and propose the most likely cause of this disease in the two patients studied. The results support the proposition that each schizophrenia patient may be unique and heterogeneous somatic de novo events may contribute to schizophrenia threshold and discordance of the disease in monozygotic twins. [ABSTRACT FROM AUTHOR]

FACTOR analysis, JOINT diseases, LONGITUDINAL method, MEDICAL cooperation, MENTAL health, HEALTH outcome assessment, POSTOPERATIVE period, QUESTIONNAIRES, RESEARCH, STATISTICS, TOTAL knee replacement, PAIN measurement, PATIENTS' attitudes, and FUNCTIONAL assessment

Background There is conflicting evidence about what factors influence outcomes after total knee replacement (TKR). The objective is to identify baseline factors that differentiate patients who achieve both, minimal clinically important difference (MCID) and a patient acceptable symptom state (PASS) in pain and function, measured by WOMAC, after TKR from those who do not attain scores above the cutoff in either of these dimensions. Methods One-year prospective multicentre study. Patients completed WOMAC, SF-12, EQ-5D, expectations, other joint problems and sociodemographic data while in the waiting list, and 1-year post-TKR. Dependent variable was a combination of MCID and PASS in both dimensions (yes/no). Univariate analysis was performed to identify variables associated. Exploratory factor analysis (EFA) was performed to study how these variables grouped into different factors. Results Total sample comprised 492 patients. Mean (SD) age was 71.3 (6.9), and there were a 69.7% of women. Of the total, 106 patients did not attain either MCID or PASS in either dimension, and 230 exceeded both thresholds in both dimensions. In the univariate analysis, 13 variables were associated with belonging to one group or another. These 13 variables were included in EFA; 3 factors were extracted: expectations, mental health, and other joints problems. The percentage of variance explained by the 3 factors was 80.4%. Conclusion We have found 2 modifiable baseline factors, expectations and mental health, that should be properly managed by different specialist. Indication of TKR should take into account these modifiable factors for improving outcomes after TKR. [ABSTRACT FROM AUTHOR]

PLURALISM, ABORIGINAL Canadians, INDIGENOUS peoples, MARRIAGE, and HUMAN rights

In the case of Connolly v Woolrich, decided by the Québec Superior Court within ten days of Canadian Confederation in 1867, a judge upheld the validity of a marriage conducted according to Cree customary law in what is now northern Alberta. In doing so, the judge advanced a complex and far-reaching theory of legal pluralism and multi-layered governance within territories under the "joint occupation" of Europeans and Aboriginal peoples -- territories that would soon become part of the new Dominion of Canada. Canada thus began its life with a constitutional vision that was inclusive and respectful of Indigenous legal traditions. However, that vision was quickly lost. For over one hundred years, the case of Connolly v Woolrich was forgotten. Only in recent years has the case found its way back into mainstream legal discourse. Indeed, it is now often feted as a model for a multijuridical legal reality in Canada. But could this old case really provide a way forward for acknowledging Indigenous legal traditions in Canada today? There are good reasons to doubt this possibility, given the colonial legal sensibilities that informed the reasoning that the judge employed. However, after considering three readings of Connolly v Woolrich, the incorporative, assimilationist, and reconciliatory readings, the author argues that, yes, properly interpreted, Connolly v Woolrich may indeed provide eff ective insights into the status of Indigenous legal traditions in Canadian law today. The case of Connolly v Woolrich may well be worth celebrating 150 years or so after it was decided. [ABSTRACT FROM AUTHOR]

HEALTH risk assessment, ENDOCRINE disruptors, DRINKING water quality, WATER purification, and WATER supply

Endocrine disrupting chemicals (EDCs) are ubiquitous in the environment and have been detected in drinking water from various countries. Although various water treatment processes can remove EDCs, chemicals can also migrate from pipes that transport water and contaminate drinking water. This study investigated the estrogenic activity in drinking water from various distribution points in Pretoria (City of Tshwane) (n = 40) and Cape Town (n = 40), South Africa, using the recombinant yeast estrogen screen (YES) and the T47D-KBluc reporter gene assay. The samples were collected seasonally over four sampling periods. The samples were also analysed for bisphenol A (BPA), nonylphenol (NP), di(2-ethylhexyl) adipate (DEHA), dibutyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP), diisononylphthalate (DINP), 17β-estradiol (E 2 ), estrone (E 1 ) and ethynylestradiol (EE 2 ) using ultra-performance liquid chromatography-tandem mass spectrophotometry (UPLC-MS/MS). This was followed by a scenario based health risk assessment to assess the carcinogenic and toxic human health risks associated with the consumption of distribution point water. None of the water extracts from the distribution points were above the detection limit in the YES bioassay, but the EEq values ranged from 0.002 to 0.114 ng/L using the T47D-KBluc bioassay. BPA, DEHA, DBP, DEHP, DINP E 1 , E 2, and EE 2 were detected in distribution point water samples. NP was below the detection limit for all the samples. The estrogenic activity and levels of target chemicals were comparable to the levels found in other countries. Overall the health risk assessment revealed acceptable health and carcinogenic risks associated with the consumption of distribution point water. [ABSTRACT FROM AUTHOR]

SPINAL surgery, BACKACHE, LOGISTIC regression analysis, SOMATIZATION disorder, HOSPITAL records, CHRONIC pain, LONGITUDINAL method, MEDICAL referrals, SELF-evaluation, and LUMBAR pain

Purpose: It is unknown which chronic low back pain (CLBP) patients are typically referred to spinal surgery. The present study, therefore, aimed to explore which patient-reported factors are predictive of spinal surgery referral among CLBP patients.Methods: CLBP patients were consecutively recruited from a Dutch orthopedic hospital specialized in spine care (n = 4987). The outcome of this study was referral to spinal surgery (yes/no), and was assessed using hospital records. Possible predictive factors were assessed using a screening questionnaire. A prediction model was constructed using logistic regression, with backwards selection and p < 0.10 for keeping variables in the model. The model was internally validated and evaluated using discrimination and calibration measures.Results: Female gender, previous back surgery, high intensity leg pain, somatization, and positive treatment expectations increased the odds of being referred to spinal surgery, while being obese, having comorbidities, pain in the thoracic spine, increased walking distance, and consultation location decreased the odds. The model's fit was good (X 2 = 10.5; p = 0.23), its discriminative ability was poor (AUC = 0.671), and its explained variance was low (5.5%). A post hoc analysis indicated that consultation location was significantly associated with spinal surgery referral, even after correcting for case-mix variables.Conclusion: Some patient-reported factors could be identified that are predictive of spinal surgery referral. Although the identified factors are known as common predictive factors of surgery outcome, they could only partly predict spinal surgery referral. [ABSTRACT FROM AUTHOR]

MALNUTRITION, PERMANENT dentition, ENAMEL & enameling, HELMINTHIASIS, and TEENAGERS

Objectives We investigated the relationship between early childhood malnutrition-related measures and subsequent enamel defects in the permanent dentition. Materials and Methods This cohort study included 349 Amerindian adolescents (10-17 years, 52% male) from the Bolivian Amazon. Exposures included: stunted growth (height-for-age z-scores), underweight (weight-for-age z-scores), anemia (hemoglobin), acute inflammation (C-reactive protein) and parasitic infection (hookworm). We measured the occurrence (no/yes) and extent (<1/3, 1/3-2/3, >2/3) of enamel defects. We estimated associations between childhood exposures and enamel defect measures using log-binomial and multinomial logistic regression. Results The prevalence of an enamel defect characterized by an orange peel texture on a large central depression on the labial surface of the central maxillary incisors was 92.3%. During childhood (1-4 years), participants had a high prevalence of stunted growth (75.2%), anemia (56.9%), acute inflammation (39.1%), and hookworm infection (49.6%). We observed associations between childhood height-for-age (OR = 0.65; P = 0.028 for >2/3 extent vs. no EH) and gastrointestinal hookworm infection (OR = 3.43; P = 0.035 for >2/3 extent vs. no defects or <1/3 extent) with enamel defects. Discussion The study describes a possibly novel form of enamel hypoplasia and provides evidence for associations of malnutrition-related measures in early childhood, including stunted growth and parasitic helminth infection, with the observed enamel defects. [ABSTRACT FROM AUTHOR]

PERMANENT dentition, DENTAL enamel, LONGITUDINAL method, STUNTED growth, and CHILDREN

Objectives: We investigated the relationship between early childhood malnutrition-related measures and subsequent enamel defects in the permanent dentition. Materials and Methods: This cohort study included 349 Amerindian adolescents (10-17 years, 52% male) from the Bolivian Amazon. Exposures included: stunted growth (height-for-age zscores), underweight (weight-for-age z-scores), anemia (hemoglobin), acute inflammation (C-reactive protein) and parasitic infection (hookworm). We measured the occurrence (no/yes) and extent (<1/3, 1/3-2/3, >2/3) of enamel defects. We estimated associations between childhood exposures and enamel defect measures using log-binomial and multinomial logistic regression. Results: The prevalence of an enamel defect characterized by an orange peel texture on a large central depression on the labial surface of the central maxillary incisors was 92.3%. During childhood (1-4 years), participants had a high prevalence of stunted growth (75.2%), anemia (56.9%), acute inflammation (39.1%), and hookworm infection (49.6%). We observed associations between childhood height-for-age (OR=0.65; P=0.028 for >2/3 extent vs. no EH) and gastrointestinal hookworm infection (OR=3.43; P=0.035 for >2/3 extent vs. no defects or <1/3 extent) with enamel defects. Discussion: The study describes a possibly novel form of enamel hypoplasia and provides evidence for associations of malnutrition-related measures in early childhood, including stunted growth and parasitic helminth infection, with the observed enamel defects. [ABSTRACT FROM AUTHOR]

RILPIVIRINE, ANTIRETROVIRAL agents, HIV infections, ABACAVIR-lamivudine (Drug), NONSENSE suppression (Genetics), LAMIVUDINE, PYRIDINE, ANTI-HIV agents, REVERSE transcriptase inhibitors, DEOXYRIBONUCLEOSIDES, COMBINATION drug therapy, HIV, INTRAMUSCULAR injections, WORLD health, VIRAL load, RANDOMIZED controlled trials, and THERAPEUTICS

Background: Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks.Methods: In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir-lamivudine 600-300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir-lamivudine. After a 20-week induction period on oral cabotegravir plus abacavir-lamivudine, patients with viral suppression (plasma HIV-1 RNA <50 copies per mL) were randomly assigned (2:2:1) to intramuscular long-acting cabotegravir plus rilpivirine at 4-week intervals (long-acting cabotegravir 400 mg plus rilpivirine 600 mg; two 2 mL injections) or 8-week intervals (long-acting cabotegravir 600 mg plus rilpivirine 900 mg; two 3 mL injections) or continued oral cabotegravir plus abacavir-lamivudine. Randomisation was computer-generated with stratification by HIV-1 RNA (<50 copies per mL, yes or no) during the first 12 weeks of the induction period. The primary endpoints were the proportion of patients with viral suppression at week 32 (as defined by the US Food and Drug Administration snapshot algorithm), protocol-defined virological failures, and safety events through 96 weeks. All randomly assigned patients who received at least one dose of study drug during the maintenance period were included in the primary efficacy and safety analyses. The primary analysis used a Bayesian approach to evaluate the hypothesis that the proportion with viral suppression for each long-acting regimen is not worse than the oral regimen proportion by more than 10% (denoted comparable) according to a prespecified decision rule (ie, posterior probability for comparability >90%). Difference in proportions and associated 95% CIs were supportive to the primary analysis. The trial is registered at ClinicalTrials.gov, number NCT02120352.Findings: Among 309 enrolled patients, 286 were randomly assigned to the maintenance period (115 to each of the 4-week and 8-week groups and 56 to the oral treatment group). This study is currently ongoing. At 32 weeks following randomisation, both long-acting regimens met primary criteria for comparability in viral suppression relative to the oral comparator group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group (difference 2·8% [95% CI -5·8 to 11·5] vs oral treatment), and 109 (95%) of 115 patients in the 8-week group (difference 3·7% [-4·8 to 12·2] vs oral treatment). At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. Three patients (1%) experienced protocol-defined virological failure (two in the 8-week group; one in the oral treatment group). Injection-site reactions were mild (3648 [84%] of 4360 injections) or moderate (673 [15%] of 4360 injections) in intensity and rarely resulted in discontinuation (two [<1%] of 230 patients); injection-site pain was reported most frequently. Serious adverse events during maintenance were reported in 22 (10%) of 230 patients in the intramuscular groups (4-week and 8-week groups) and seven (13%) of 56 patients in the oral treatment group; none were drug related.Interpretation: The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated.Funding: ViiV Healthcare and Janssen R&D. [ABSTRACT FROM AUTHOR]

COMPOSITION of feeds, INSECT proteins, FOOD chains, SUSTAINABILITY, FEED utilization efficiency, ANIMAL feeds, and SAFETY

In the framework of sustainability and a circular economy, new ingredients for feed are desired and, to this end, initiatives for implementing such novel ingredients have been started. The initiatives include a range of different sources, of which insects are of particular interest. Within the European Union, generally, a new feed ingredient should comply with legal constraints in terms of ‘yes, provided that’ its safety commits to a range of legal limits for heavy metals, mycotoxins, pesticides, contaminants, pathogens etc. In the case of animal proteins, however, a second legal framework applies which is based on the principle ‘no, unless’. This legislation for eradicating transmissible spongiform encephalopathy consists of prohibitions with a set of derogations applying to specific situations. Insects are currently considered animal proteins. The use of insect proteins is a good case to illustrate this difference between a positive, although restricted, modus and a negative modus for allowing animal proteins. This overview presents aspects in the areas of legislation, feed safety, environmental issues, efficiency and detection of the identity of insects. Use of insects as an extra step in the feed production chain costs extra energy and this results in a higher footprint. A measure for energy conversion should be used to facilitate the comparison between production systems based on cold- versus warm-blooded animals. Added value can be found by applying new commodities for rearing, including but not limited to category 2 animal by-products, catering and household waste including meat, and manure. Furthermore, monitoring of a correct use of insects is one possible approach for label control, traceability and prevention of fraud. The link between legislation and enforcement is strong. A principle called WISE (Witful, Indicative, Societal demands, Enforceable) is launched for governing the relationship between the above-mentioned aspects. [ABSTRACT FROM AUTHOR]

This work aims at describing differences between the dialectal varieties of Portuguese spoken at Salvador, Fortaleza and Rio de Janeiro, Brazil, in both the declarative and interrogative modalities. Analyses of prosodic parameters (fundamental frequency, duration, intensity) are made on the final nucleus of oxytonic, paroxytonic and proparoxytonic sentences. There are systematic prosodic changes between modalities - with a higher / rising F0 in interrogative nucleus where it is lower / decreasing for declaratives. The interrogative nucleus are also longer and stronger than the declaratives. Dialectal variations are also observed. The accentual patterns H + L*L% for declaratives and L + H*L% for interrogatives proposed by Moraes (2008) are observed in Rio de Janeiro speakers - the latter being truncated or compressed in oxytonic sentences due to lack of post-tonic material. Meanwhile, in the Salvador and Fortaleza varieties, interrogatives may also be performed with a L + H*H% pattern. More syllable elisions are also observed in Fortaleza speakers. [ABSTRACT FROM AUTHOR]