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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]

Water treatment plants, Ozonization, Estrogen, Hydrological research, and Yeast

The estrogenicity of waters collected from an important hydrological system in Brazil (Paraiba do Sul and Guandu Rivers) was assessed using the yeast estrogen screen (YES) assay. Sampling was performed in rivers and at the outlets of conventional water treatment plants (WTP). The removal of estrogenic activity by ozonation and chlorination after conventional water treatment (clarification and sand filtration) was investigated employing samples of the Guandu River spiked with estrogens and bisphenol A (BPA). The results revealed a preoccupying incidence of estrogenic activity at levels higher than 1 ng L −1 along some points of the rivers. Another matter of concern was the number of samples from WTPs presenting estrogenicity surpassing 1 ng L −1 . The oxidation techniques (ozonation and chlorination) were effective for the removal of estrogenic activity and the combination of both techniques led to good results using less amounts of oxidants. [ABSTRACT FROM AUTHOR]

Pollination, Agricultural productivity, Crop yields, Sustainable agriculture, Pollinators, Apple orchards, Factorial experiment designs, 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]

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]

ATHLETES, FATIGUE (Physiology), PHYSICAL education, QUESTIONNAIRES, and SPORTS medicine

Abstract: Objective. – The group of consensus of the French Society of Sport Medicine prepared a questionnaire in order to detect early stage of overtraining. This questionnaire includes 54 items which the subjects have to answer by “yes” or by “not”. A score is then established by summing the “yes”. Taking into account the formulation of the questions, this score will increase with the training load. The aim of our study is to propose a score of overtraining, and also to highlight the importance of some items or groups of items. Methods. – Our population consisted of French sportsmen of both sexes, from different geographical origins, age, sporting practice and level. A multicentric analysis was carried out on the basis of 1984 collected questionnaires. We analysed the evolution of the percentage of subjects, the weight of various parameters (age, overtraining) and the evolution of the frequency of each item as a function of the score. Results. – A score of 20 was proposed as an overtraining state threshold, which has to be confirmed on the basis of correlations with biological indices, in particular with a state of clinically established overtraining. Sixteen items present a linear evolution traducing an increase of tiredness according to the overload. Six items have a logarithmic increase, traducing a kind of “background noise”. The others items (N =32) presenting a non-linear increase are sign of a decompensation phenomenon. Conclusion. – This analysis by item make possible an improve of the questionnaire, by selecting items groups which may give an orientation on the type of tiredness. It also confirms the usefulness of this questionnaire as a tool for the follow-up of the training state of sportsmen, a score equal to or higher than 20 constituting the overtraining threshold. [Copyright &y& Elsevier]

Wastewater treatment, Sewage purification, Sewage disposal plants, Yeast-free diet, Leavening agents, and Fire assay

Effluents from wastewater treatment plants (WWTPs) are responsible for the input of estrogenic contaminants into aquatic ecosystems, leading to widespread effects in wildlife. In the present work, levels of estrone (E1), 17α- and 17β-estradiol (E2), 17α-ethinylestradiol (EE2), bisphenol A (BPA), and nonylphenol (NP) were quantified in effluents from WWTPs located in Ria de Aveiro (NW Portugal), as well as in the final effluent discharged into the Atlantic Ocean through the S. Jacinto submarine outfall. Reference sites, located at the entrance of the estuarine system and at the seaside, were also included. Samples were collected under summer (June 2005) and winter (February 2006) conditions. For the summer survey samples, estrogenicity and androgenicity were evaluated using the yeast estrogen screen (YES) and the yeast androgen screen (YAS) assay. Estrone levels varied from 0.5 to 85 ng/L in the summer survey and between L in winter; estradiol levels ranged from L in summer and were always L up to 2,350 ng/L in summer and from 10 to 2,410 ng/L in winter; BPA levels varied from 2.8 to 897 ng/L in summer and from 2.6 up to 316 ng/L in winter. Biological assays disclosed estrogenic levels at reference sites lower than the ones reported to pose risk for wildlife. However, the S. Jacinto outfall effluent released high concentrations of NP and BPA into the marine environment. [ABSTRACT FROM AUTHOR]

BIPOLAR disorder, MENTAL depression, DEPRESSED persons, ANTIPSYCHOTIC agents, and MENTAL health

Abstract: Introduction: Although depressive moods are recognised as a very broad condition, there is still only one definition in international classifications for describing a major depressive episode (MDE). However, there is currently some controversy surround the treatment of depressive states. This includes SSRIs and suicide in adolescents, and more specifically in bipolar disorders where some depressions are made worse by antidepressants. New data has suggested that depressive states in BP patients can be improved by atypical antipsychotics. Aim: We aimed to assess 1) whether it is possible to distinguish different forms of bipolar depression using a dimensional approach, and 2) if, yes, whether there are different patterns of treatment response. Method: We characterised 60 bipolar patients with a Major Depressive Episode (DSM-IV) using a new tool (MATHYS: Multidimensional Assessment of Thymic States) assessing five fundamental dimensions (emotional reactivity, cognitive speed, psycho-motricity, motivation and senses perception) of mood states (full description elsewhere). Results: A cluster analysis using the items of the dimensional scale revealed two types of depressive states. One group (G1; N =38), which had a low score, is characterised by an inhibition in all dimensions, whereas the other group (G2; N =22) is characterised by an over-activation. Emotional reactivity is a useful dimension for discriminating these two types of depression (G1: hyporeactivity; G2: hyperreactivity) whereas sadness is not. A lower score on the MAThyS scale at day 1 was associated with a good response to antidepressant treatment, whereas higher scores were linked to a good response to a mood stabilizers alone or in combination with an antipsychotic. Conclusion: Bipolar depressive states are not homogeneous and this heterogeneity can explain various patterns of treatment response. A dimensional approach could be useful for discriminating the different forms of bipolar depression and to help manage treatment. [Copyright &y& Elsevier]

ETHICS, PSYCHIATRISTS, MENTAL health personnel, PSYCHIATRY, and PSYCHOTHERAPISTS

Abstract: In legal proceedings the expert witness testimony may be considered a medical act only if the expert conducts his clinical observations within the limits established by the medical code of ethics. This will then allow the psychiatrist to help the judge reach a more informed legal decision. The difficulty inherent in this process is for the expert to give an exact answer (“yes” or “no”) to the questions formulated in order for the judge to arrive at an accurate decision. To better understand the evidence presented, the judge may ask empirical questions that require the expert witness to give testimony going beyond the information directly gathered through clinical observations. It is the expert witness'' responsibility to determine what amount of interpretation of material drawn from a clinical observation is appropriate to help the judge make a legal decision. This requires defining legal standards such as credibility, truth, and suggestibility. One must also recognize that the clinical observation of a victim is often the person''s first contact with a psychiatrist. [Copyright &y& Elsevier]

Health risk assessment, Endocrine disruptors, Water purification, Water supply, and Drinking water quality

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]

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]

Environmental monitoring, Water pollution measurement, Water quality monitoring, Biological assay, Xenoestrogens, Analytical chemistry techniques, In vitro toxicity testing, and Evaluation

Bioassays are well established in the pharmaceutical industry and single compound analysis, but there is still uncertainty about their usefulness in environmental monitoring. We compared the responses of five bioassays designed to measure estrogenic activity (the yeast estrogen screen, ER-CALUX, MELN, T47D-KBluc, and E-SCREEN assays) and chemical analysis on extracts from four different water sources (groundwater, raw sewage, treated sewage, and river water). All five bioassays displayed similar trends and there was good agreement with analytical chemistry results. The data from the ER-CALUX and E-SCREEN bioassays were robust and predictable, and well-correlated with predictions from chemical analysis. The T47D-KBluc appeared likewise promising, but with a more limited sample size it was less compelling. The YES assay was less sensitive than the other assays by an order of magnitude, which resulted in a larger number of nondetects. The MELN assay was less predictable, although the possibility that this was due to laboratory-specific difficulties cannot be discounted. With standardized bioassay data analysis and consistency of operating protocols, bioanalytical tools are a promising advance in the development of a tiered approach to environmental water quality monitoring. [ABSTRACT FROM AUTHOR]

Sewage disposal plants, Sewage purification, Refuse disposal facilities, Environmental impact charges, Water quality management, Water utilities, Hospitals, Steroids, and Hormones

Influent and effluent samples originating from two wastewater treatment plants (WWTPs) (treating hospital wastewater and domestic wastewater, Belgium) have been analyzed in order to estimate their steroid hormone content. The natural estrogens estrone (E1), 17β-estradiol (E2), and the synthetic 17α-ethinylestradiol (EE2) together with other steroid hormones progesterone (P) and testosterone (T) metabolites were detected in these samples. The hormone concentrations in both the hospital and the domestic WWTP samples were not significantly different and ranged from <0.2 ng EE2/L to 114 ng EE2/L, from <0.2 ng E1/L to 58 ng E1/L and from <0.2 ng P/L to >100 ng P/L. E2 was detected once at a concentration of 17 ng/L. In the domestic WWTP which comprises a conventional activated sludge treatment in parallel with a membrane bioreactor, no differences in estrogen removal efficiency could be observed for both treatments. In comparison to chemical analysis data, the Yeast Estrogen Screen (YES) appears to underestimate the influent estrogen concentrations, probably due to influent toxicity for the YES. Effluent estrogen concentrations, on the other hand, were overestimated by the YES test, probably due to the presence of other estrogenic compounds in the effluent. [ABSTRACT FROM AUTHOR]

Organic water pollutants, Particulate matter, Endocrine disruptors, Sewage disposal plants, and Estrogen

Trace emerging contaminants (ECs) occur in both waste and surface waters that are rich in particulates that have been found to sorb several organic contaminants. An analytical method based on off-line solid-phase extraction (SPE) followed by liquid chromatography-mass spectrometry (LC-MS) analysis was developed for the detection and quantification of 31 ECs from surface water, wastewater, suspended particulate matter (SPM) as well as sediments. Lyophilized sediments and air-dried SPM were subjected to ultrasonic extraction. Water samples and extracts were then concentrated and cleaned-up by off-line SPE. Quantification was realized using a Q Exactive mass spectrometer in both full scan (FS) and MS 2 modes. These two modes were optimized and compared to determine which one was the most suitable for each matrix studied. Yeast estrogen screen assay (YES-assay) adapted from the direct measurement of estrogenic activity without sample extraction was tested on filtered wastewater samples. An endocrine disrupting effect was detected in all effluent samples analyzed with estradiol equivalent concentrations ranging from 4.4 to 720 ng eq E2 L −1 for the WWTP-1 and 6.5–42 ng eq E2 L −1 for the WWTP-2. The analytical methods were also applied on six samples of surface water, the corresponding SPM, the sediments and thirty-nine effluent samples from two wastewater treatment plants (WWTPs) sampled over a period of five months (February to June 2014). [ABSTRACT FROM AUTHOR]

ANESTHESIA, PLACEBOS, ETOMIDATE, and HEART beat

Abstract: Objective: Various drugs including hydroxyzine are preoperatively administered to facilitate the induction of general anaesthesia. We investigated the effect of hydroxyzine premedication on BIS-based etomidate induction of general anaesthesia. Patients and methods: Sixty-seven ASA I–II consecutive patients were randomly allocated to receive oral hydroxyzine 1.5 mg/kg or placebo, 90 min prior to inducing general anaesthesia using intravenous etomidate alone 0.3 mg/kg. BIS values were continuously recorded. The times for the BIS to decrease to 50 and to loss of eyelid reflex; the evolution of arterial pressure and heart rate; and myoclonia rate and grade were investigated and compared. Results: The results for the hydroxyzine and placebo groups were similar with respect to: a) time [median (range) (seconds)] to a BIS decrease to 50 [100 (21–266) versus 113 (30–510), P =0.1] and to loss of eyelid reflex [83 (21–210) versus 97 (30–300), P =0.1]; b) myoclonia frequency (yes/no) (9/26 versus 4/28, P =0.2) and grade (P =0.3); the evolution of mean arterial pressure and heart rate (P =0.3). Conclusion: Oral weight-related hydroxyzine premedication does not alter BIS-based etomidate induction of GA. [Copyright &y& Elsevier]

Corbicula fluminea, Caffeine, Ibuprofen, Carbamazepine, Novobiocin, Tamoxifen, DNA damage, and Oxidative stress

Reports indicating the presence of pharmaceutical in fresh water environment in the ng L −1 to µg L −1 range are occurring with increasing frequency. It is also a fact that pharmaceuticals may produce adverse effects on aquatic organisms. Nevertheless, there is still a lack of knowledge regarding how these emergent contaminants may affect aquatic biota. The goal of this research was to evaluate the sublethal responses in Corbicula fluminea such as, general stress (lysosomal membrane stability [LMS]), biomarkers of phase I and II (etoxyresorufin O-deethylase [EROD], dibenzylfluorescein dealkylase [DBF], gluthathione-S-transferase [GST]), oxidative stress (gluthathione reductase [GR], gluthathione peroxidase [GPX], lipid peroxidation [LPO]), and biomarkers of effect (DNA damage) after 21 days of exposure to caffeine, ibuprofen, carbamazepine, novobiocin and tamoxifen at 0.1, 1, 5, 10, 15, 50 µg L −1 . Environmental concentrations tested in this study caused general stress and produced changes on biomarkers tested. LMS, responses from phase I and II enzymatic activity, oxidative stress, and biomarker of effect represent important ecotoxicological information, and will provide a useful reference for the assessment of selected drugs and the effects which these compounds may have on aquatic invertebrates, using C. fluminea as a bioindicator species. [ABSTRACT FROM AUTHOR]

Humic acid, Pollutants, Sewage disposal plants, Endocrine disruptors, Humus, Complex matrices, and Xenoestrogens

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]

Environmental monitoring, Environmental quality, Sediments, Extraction (Chemistry), Atmospheric chemistry, and Mixtures

Aquatic environments are often contaminated with complex mixtures of chemicals that may pose a risk to ecosystems and human health. This contamination cannot be addressed with target analysis alone but tools are required to reduce this complexity and identify those chemicals that might cause adverse effects. Effect-directed analysis (EDA) is designed to meet this challenge and faces increasing interest in water and sediment quality monitoring. Thus, the present paper summarizes current experience with the EDA approach and the tools required, and provides practical advice on their application. The paper highlights the need for proper problem formulation and gives general advice for study design. As the EDA approach is directed by toxicity, basic principles for the selection of bioassays are given as well as a comprehensive compilation of appropriate assays, including their strengths and weaknesses. A specific focus is given to strategies for sampling, extraction and bioassay dosing since they strongly impact prioritization of toxicants in EDA. Reduction of sample complexity mainly relies on fractionation procedures, which are discussed in this paper, including quality assurance and quality control. Automated combinations of fractionation, biotesting and chemical analysis using so-called hyphenated tools can enhance the throughput and might reduce the risk of artifacts in laboratory work. The key to determining the chemical structures causing effects is analytical toxicant identification. The latest approaches, tools, software and databases for target-, suspect and non-target screening as well as unknown identification are discussed together with analytical and toxicological confirmation approaches. A better understanding of optimal use and combination of EDA tools will help to design efficient and successful toxicant identification studies in the context of quality monitoring in multiply stressed environments. [ABSTRACT FROM AUTHOR]

ANTIBIOTICS, MOLECULES, PHARMACEUTICAL industry, SCIENCE, and CLINICAL trials

Abstract: The golden age of antibacterial antibiotics extend from year 1941 to the 1990s decade. At that time, something like an earth quake occurred: from the thirty molecules or so whose development was being achieved or was already marketed, only three were put on the French market, and faced the greatest difficulties to be prescribed by practicians, because: [-] the knights of good practice want a strict limitation of their use to precise indications; [-] the pharmaceutical companies find that the return on investment is almost impossible; [-] the prescribers are stunned by the inconsistency between the MAs, the advances in science and the health economic authorities advices which claim that these products are not very interesting; [-] the research for new antibiotics is stalling; [-] thus, for the first time in 60 years, an iconoclastic question arises: do we need new antibiotics? However, while the debate is raging, many of us think “yes we do”, as it is a duty to anticipate today the consequences of tomorrow''s bacterial resistances. This paper presents three types of propositions to optimise the development of future molecules: [-] sharpening of the data concerning preclinical security for a better predicting both the activity and the toxicity; [-] improvement in performances and organization of clinical trials, which implicates to reconsider some of the present methodological rules; [-] inclusion in the evaluation data of some relevant and new features measuring the anti-bacterial activity while taking into account the present and future bacterial resistances. The development of new concepts to develop new drugs which would be active against tomorrow''s bacteria compels us to manage in a new fashion today''s systems, which have reached their own limits. [Copyright &y& Elsevier]

DRUG discovery, DATA mining, and CHEMINFORMATICS

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]

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]

Cadmium & the environment, Physiological effects of cadmium, Industrial toxicology, Atomic absorption spectroscopy, and Blood testing

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]

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]

ULCER treatment, COMBINATORIAL optimization, SURGICAL emergencies, ORAL diseases, HOSPITAL care, and PHYSICIAN practice patterns

Résumé: La prise en charge chirurgicale de l’escarre en France demeure très coûteuse même si les mesures de prévention et l’amélioration du parcours de soins ont permis de limiter les dépenses dans ce domaine ces dernières années. Depuis 2004, le mode de financement des établissements de santé français par la tarification à l’acte (TAA) et la maîtrise médicalisée des dépenses de soins hospitaliers nous obligent forcément à nous intéresser à ces considérations purement économiques et parfois à nuancer nos besoins en durée d’hospitalisation ou en soins spécialisés pour optimiser le groupe homogène de séjour (GHS) d’un patient. Cela ne risque-t-il pas à l’avenir d’obliger le chirurgien à biaiser les réels besoins du patient au profit de l’établissement hospitalier ? Au travers d’une analyse médico-économique de nos pratiques, réalisée dans le service de chirurgie plastique du CHU de Toulouse, nous avons tenté d’identifier comment optimiser la prise en charge chirurgicale de l’escarre en termes de valorisation de séjour. L’objectif étant néanmoins de rester critique sur les dérives que cela pourrait instaurer à l’avenir pour notre activité clinique. [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]

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]

Colorrectal adenocarcinoma it's a common entity, but the vulvar metastasis from it, it's very rare, they can be metachronous. The vulvar metastasis it's only 5 to 8 % of all of the site tumors. W e present a case of a 35 years old woman, who was diagnosed with a poorly differentiated, infiltrating and ulcerated colorrectal adenocarcinoma by colonoscopy biopsy, latter a surgical resection it's taken so Dukes C2 stratification it's made. After 14 months a skin injury appears in vulvar and perirectal area, the next step skin biopsy is realized, the histopathological findings are a metastasic disease from invasive adenocarcinoma, an immunohistochemical cytokeratin (Cl<) 20 reactive shows positivity therefore the origin its colorrectal adenocarcinoma. The most frequent metastasis from colon adenocarcinoma is the liver, the female genital tract is rare, but within this system the ovary is the most common. Metastasis to skin is exceptional, but when it happens periumbilical area is the most frequent site, that means our case presentation has low incidence so the importance of it and the bad prognosis of it. [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]

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]

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]

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]

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]

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]

Introduction: the Danish questionnaire entitled The Copenhagen Neck Functional Disability Scale(CNFDS) is a tool for self-assessment of cervical complaints,originally developed in English, of which there is, so far, no translation into Brazilian Portuguese. The process involvedin this researchproved to be relevant for the exploration of the questionnaire and the realization of adjustments necessary for it to be functiona l and applicable in Portuguese Language and Brazilian Culture settings. Thus, once this has been carried out, many health professionals will benefit from this version in their clinical practice. Objective: To perform the translation and cultural adaptation to Brazilian Portuguese of the Escala funcional de incapacidade do pescoço de Copenhagen (The Copenhagen Neck Functional Disability Scale -- CNFDS). Methods: The questionnaire was translated into Brazilian Portuguese by two bilingual, Brazilian physiotherapists who were aware of the objective of this research. The back-translation was performed by a third person, a Brazilian, bilingual English teacher, who had not participated in the previous step. After comparing the resulting translations, a single translated version was produced named the Escala Funcional de Incapacidade do Pescoço de Copenhagen (EFIPC) and in each question the option "not applicable" was added to the answer key. During the translation and cultural adaptation process there were no changes and/or eliminations of any questions. Result: The composition of the Escala Funcional de Incapacidade do Pescoço de Copenhagen reflects the original English version, with a total of 15 questions, with the questions numbered 1 to 5 presenting a positive direction response (a "yes" answer indicates good cervical condition), and questions numbered 6 to 15 presenting a negative direction response (a "yes" answer indicates poor cervical condition). Conclusion: The process involved in this research allowed the achievement of thedesired goal, and thus it was possible totranslate and culturally adapt to Brazilian Portuguese the content of the CNFDS questionnaire, giving riseto the Escala funcional de incapacidade do pescoço de Copenhagen. [ABSTRACT FROM AUTHOR]

CROP genetics, SOYBEAN, SWEETPOTATO whitefly, DISEASE resistance of plants, BIOLOGICAL control of plant parasites, ANTIBIOSIS, OVIPARITY, GREENHOUSE plants, and TRICHOMES

Since it was first reported in Brazil in the 1990s, the B biotype of silverleaf whitefly (Bemisia tabaci [Genn.], Hemiptera Aleyrodidae) has been recognized as an important pest in soybeans (Glycine max L.), reducing the productivity of this legume species in some areas of the country. As an alternative to chemical control, the use of resistant genotypes represents an important tool for integrated pest management (IPM). This study evaluated the performance of 10 soybean genotypes prior to whitefly infestation, by testing attractiveness and preference for oviposition in the greenhouse and antibiosis in the laboratory. In a multiple-choice test, 'IAC-17' was the least attractive to insects. In a no-choice test, 'IAC-17' was the least attractive for egg deposition, indicating the occurrence of non-preference for oviposition on this genotype. Trichome density was positively correlated with the oviposition site and may be associated with the resistance of 'IAC-17' to infestation. The genotypes 'IAC-PLI', 'IAC-19', 'Conquista', 'IAC-24' and 'IAC-17' extended the insect's life cycle, indicating occurrence of a small degree of antibiosis and/or non-preference for feeding. [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]

SYMMETRY (Physics), INVARIANT measures, DE Bruijn graph, ENTROPY, and LATTICE constants

We investigate the following questions: Given a measure $$\mu _\Lambda $$ on configurations on a subset $$\Lambda $$ of a lattice $$\mathbb {L}$$ , where a configuration is an element of $$\Omega ^\Lambda $$ for some fixed set $$\Omega $$ , does there exist a measure $$\mu $$ on configurations on all of $$\mathbb {L}$$ , invariant under some specified symmetry group of $$\mathbb {L}$$ , such that $$\mu _\Lambda $$ is its marginal on configurations on $$\Lambda $$ ? When the answer is yes, what are the properties, e.g., the entropies, of such measures? Our primary focus is the case in which $$\mathbb {L}=\mathbb {Z}^d$$ and the symmetries are the translations. For the case in which $$\Lambda $$ is an interval in $$\mathbb {Z}$$ we give a simple necessary and sufficient condition, local translation invariance ( LTI), for extendibility. For LTI measures we construct extensions having maximal entropy, which we show are Gibbs measures; this construction extends to the case in which $$\mathbb {L}$$ is the Bethe lattice. On $$\mathbb {Z}$$ we also consider extensions supported on periodic configurations, which are analyzed using de Bruijn graphs and which include the extensions with minimal entropy. When $$\Lambda \subset \mathbb {Z}$$ is not an interval, or when $$\Lambda \subset \mathbb {Z}^d$$ with $$d>1$$ , the LTI condition is necessary but not sufficient for extendibility. For $$\mathbb {Z}^d$$ with $$d>1$$ , extendibility is in some sense undecidable. [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]

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]

CANCER treatment, SMALL cell lung cancer, OLDER patients, CANCER chemotherapy, POPULATION health, and DRUG toxicity

Background: Twenty percent of all newly diagnosed patients with small-cell lung cancer (SCLC) are >75 years. Elderly patients may show more toxicity due to co-morbidity. We evaluated motives for adherence to treatment guidelines, completion of treatment and toxicity.Patients and methods: Population-based data from patients aged ≥75 years and diagnosed with SCLC in 1997–2004 in The Netherlands were used (368 limited disease and 577 extensive disease). Additional data on co-morbidity (Adult Co-morbidity Evaluation 27), World Health Organisation performance status (PS), treatment, motive for no chemotherapy, adaptations and underlying motive and grade 3 or 4 toxicity were gathered from the medical records.Results: Forty-eight percent did not receive chemotherapy. The most common motives were refusal by the patient or family, short life expectancy or a combination of high age, co-morbidity and poor PS. Although only relatively fit elderly were selected for chemotherapy, 60%–75% developed serious toxicity, and two-thirds of all patients could not complete the full chemotherapy.Conclusions: We hypothesise that a better selection by proper geriatric assessments is needed to achieve a more favourable balance between benefit and harm. [ABSTRACT FROM AUTHOR]

The waltz of Afrikaans "a" with "l" The present study is a follow-up of previous ones on the rounding of the long low /a/ vowel in Afrikaans, a relatively new sound variation. Against the background of existing descriptions I report a similar tendency of rounding of short /a/ vowel, specifically when followed by the lateral consonant /l/. I suggest an explanation of such rounding as being the result of a process of coarticulation, specifically under the influence of a distinct dark, retroflex quality of this lateral. A post hoc investigation with an ultrasound scanner and lip video camera confirmed this to be the case. The vowel productions of a single speaker, known to be a clear rounding of long /a/ was explored in an extensively designed case study. The phenomenon of /a/-rounding implies a qualitative change of the /a/ to [ɒ] as in [jɒ] (ja; "yes") and in [snɒks (snaaks; "funny"). Apart from superficial references to its existence in linguistic handbooks, such as De Villiers and Ponelis (1987:100), the first systematic study was done by Wissing (2006), followed-up by more recent other studies (Wissing 2010; 2013). Rounding is currently seemingly limited to the speech of young adult female speakers of Afrikaans, but it appears as if it has lately been spreading to the broader Afrikaans speaking community at a rather noticeable pace. It is provoking extremely negative reactions in especially the case of older, or more conservative Afrikaans speaking persons. On the other hand, younger users of Afrikaans do not even seem to notice the existence of this phenomenon, especially in their own language use. Such a vowel change is apparently part of a larger vowel shift which has recently been taking place, viz. the lowering of the front-mid vowel /ε/ to almost the position of the short low /a/, or the shifting of /u/ from a back to a more centralised position (cf. Wissing 2010). Broadly defined, language change is a topic that integrates the social as well as the cognitive aspects of what it means to be human. A central feature of a language in the process of change is variation. During a period of change, there is variation in the language between forms that represent the current/previous stage and forms that represent the innovative/new stage of the language. Consequently, the rounding of /a/ could be of linguistic significance when considered against this general linguistic backdrop. The present investigation aims in particular at both broadening, developing and understanding of /a/-rounding to [ɒ] in modern Afrikaans. In order to achieve this, firstly the existing knowledge concerning this phenomenon was summarised, whereafter a variety of carefully constructed stimuli were used in an in-depth case study of the pronunciation of a young female radio presenter at Radio Sonder Grense, the leading Afrikaans public broadcaster (hence referred to as C). The testing material was created with a view to obtaining a fuller understanding of /a/- rounding to [ɒ] in Afrikaans in two respects. Firstly, the stimulus series concerning the degree to which long /a/ vowels are subjected to such rounding was expanded considerably. Secondly, stimuli were included with the aim of examining the possible co-articulatory influence of the rounding of /a/ followed by the lateral consonant /l/ (characterised as a dark l in the case of English pronunciation) on especially the short /ɑ/-vowel, as in wals ("waltz"). Dark /l/ has received much attention in literature. Moreover, word frequency also has been shown (Lin, Beddor & Coetzee 2013) to influence the magnitude of the tongue tip gesture in laterals, especially with regard to /l/ vocalization. It might be applicable on the case of /l/-velarisation as well. Degree of darkness, differences in articulatory closure, dorsopalatal contact size, closure duration, relative timing of events and formant frequency (cf. Recasens & Espinosa 2005) are some of the important factors to take into account when studying this consonant and its co-articulatory effects on phonetic environment. Up until now none of these have been mentioned in Afrikaans phonetic literature. In the present article I superficially touch on some of them. Obviously these facets deserve fundamental attention. I utilised three different types of recording tasks, namely firstly the reading of carrier phrases containing a focus form with the structure /sVs/ (eg. among others, saas and sas); secondly, the naming of the letters of the alphabet (with an interest in a, h, k; all pronounced with a long [a]), and thirdly, the reading of a variety of isolated words and phrases, mostly containing words relevant to this study. In some cases C was prompted to orally complete a task, for example, a noun like val was to be read, but its diminutive (valletjie) and plural forms (valle) were to be completed without visual stimulus. Syllable structure was controlled systematically. In the case of val, /a/ appears in a closed syllable, but in valletjie and valle the syllables are open. These tasks had to be carried out twice. Recordings were done with high quality equipment, in use by RSG. Processing and acoustic analyses of the recordings were performed by means of standard procedures. As is conventional in studies of this nature, acoustic characteristics of the production of long /a/ and short /Q/ were investigated via vowel formant frequencies, F1 as well as F2. F1, the first formant, corresponds to vowel openness (vowel height). An open vowel, such as /a/, has high F1 frequencies, while close vowels, like /i/, have low F1 frequencies. The second formant, F2, corresponds to the front positions of a vowel. Back vowels, which are normally at the same time also rounded, have low F2 frequencies, in contrast to front vowels, which have high F2 frequencies. Generally the results clearly confirm the audible perception that C is a strong rounder of the long /a/. There is a very positive correlation between C's acoustic measurements and that previously found for another young female individual (Wissing 2006) as well as that of twenty others of about the same age (Wissing 2013). This finding strongly suggests a restriction on the number of participants as well as the range of required stimuli in instances of experiments of this kind, especially in the case of pilot studies. The role of syllable structure was found to be of limited importance. The short /a / was rounded to a significant degree when followed by /l/ in open as well as closed syllables, but to a small degree as in the case of open syllables. Of special importance is the finding that F1 also plays a significant role in the expression of degree of roundedness of the /a/ vowel, albeit not quite to the same extent as is the case with F2, generally considered to be the sole carrier of roundedness. The fact that the rounded [594;] is frequently misinterpreted (as the rounded vowel [ɔ] (in kom "come")), from a perceptual angle supports the current results of the analysis of the rounded [594;] in Afrikaans. Of course, [ɔ] is characterised inter alia by a higher F1 than that of the unrounded [a]. In many languages the existence of dark /l/ ([ɫ]) is well-known (cf. Hamann 2003; also Lin, Beddor & Coetzee 2014 and references cited by them). With regard to Afrikaans, a co-articulatory effect of this lateral was found to be clearly manifested in the present study on the rounding to [...] of the short /a/, but also of the long /a/. In a broader linguistic perspective the present findings should be of distinctive importance to those interested in language change in general, and more specifically in sound variation. [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]

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]

ACUTE otitis media, ANTIBIOTICS, DISEASE relapse, DRUG efficacy, DRUG prescribing, and THERAPEUTICS

Objective: Antibiotic treatment of acute otitis media (AOM) has been suggested to increase the risk of future AOM episodes by causing unfavorable shifts in microbial flora. Because current evidence on this topic is inconclusive and long-term follow-up data are scarce, we wanted to estimate the effect of antibiotic treatment for a first AOM episode occurring during infancy on AOM recurrences and AOM-related health care utilization later in life. Methods: We obtained demographic information and risk factors from data of the Wheezing Illnesses Study Leidsche Rijn, a prospective birth cohort study in which all healthy newborns born in Leidsche Rijn (between 2001 and 2012), The Netherlands, were enrolled. These data were linked to children’s primary care electronic health records up to the age of four. Children with at least one family physician-diagnosed AOM episode before the age of two were included in analyses. The exposure of interest was the prescription of oral antibiotics (yes vs no) for a child’s first AOM episode before the age of two years. Results: 848 children were included in analyses and 512 (60%) children were prescribed antibiotics for their first AOM episode. Antibiotic treatment was not associated with an increased risk of total AOM recurrences (adjusted rate ratio: 0.94, 95% CI: 0.78–1.13), recurrent AOM (≥3 episodes in 6 months or ≥4 in one year; adjusted risk ratio: 0.79, 95% CI: 0.57–1.11), or with increased AOM-related health care utilization during children’s first four years of life. Conclusions: Oral antibiotic treatment of a first AOM episode occurring during infancy does not affect the number of AOM recurrences and AOM-related health care utilization later in life. This information can be used when weighing the pros and cons of various AOM treatment options. [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]

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]