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LAMOTRIGINE, BIPOLAR disorder, GLOMERULAR filtration rate, and BODY mass index

Monitoring of lamotrigine levels is recommended in epilepsy. However, in bipolar disorders (BD), no study has described the therapeutic range in daily practice and factors being associated to it. We used retrospective data of individuals with BD, treated with lamotrigine, and included in the FondaMental Advanced Centers of Expertise for Bipolar Disorders cohort. We extracted clinical and biological data and explored associations between these variables and lamotrigine concentration/dose (C/D) ratio. The database included 675 individuals who received lamotrigine at inclusion, whose main characteristics were female sex (68.3%) and BD type 2 (52.1%). Data about lamotrigine C/D ratio were available for 205 individuals. Lamotrigine C/D ratio was significantly associated with: Body Mass Index (BMI) (r =-0.159), estimated GFR (glomerular filtration rate) (r =-0.228), total bilirubin (r = 0.241) and at a trend level, antidepressant co-prescription (U = 3169). The model obtained was: lamotrigine C/D ratio = 1.736 - 0.013*BMI + 0.095*total bilirubin (UI/L) - 0.007*eGFR (ml/min) + 0.210*AST/ALT – 0.004*GGT (UI/L) + 0.014*age (year) + 0.303*currently smoking (yes or no) – 0.588*antidepressant co-prescription (yes or no) – 0.357*gender (F = 1.899, p = 0.057, adjusted R2 = 0.11) Information about plasma lamotrigine C/D ratio were available for only 205 out of the 675 individuals in the database and has been obtained from different laboratories. The representativeness of the included sample may be questionable. This is the first study providing information on a large sample of individuals with BD regarding factors associated with lamotrigine C/D ratio. This study allows to propose a model of lamotrigine C/D ratio that would deserve further replication. [ABSTRACT FROM AUTHOR]

GALVANIC skin response, PERSONALITY, AFFECTIVE neuroscience, STIMULUS & response (Psychology), TASTE perception, TASTE receptors, and SYMPATHETIC nervous system

• Skin conductance responses to oral stimuli primarily reflect surprisingness. • Individual differences modulate skin conductance responses to oral stimuli. • Skin conductance reflects higher stimulus intensity only in some individuals. • High skin conductance bitter responders are more anxious and less emotionally stable. • Lower skin conductance responses are associated with a heightened taste perception. Measuring emotional responses to tastes and foods, using both self-reports and also implicit and physiological measurements is gaining attention. Among physiological measurements, skin conductance response (SCR) is one the most commonly used indicators of emotional activation but it has been rarely applied to taste and other oral stimuli and its interpretation is not yet clear. Furthermore, the effect of individual differences in SCR to tastes has been rarely taken into account. To address these issues, SCR to bitter, astringent, and sweet samples presented both at weak/moderate and moderate/strong intensity was recorded while eighty Italians, selected based on PROP (6-n-propylthiouracil) status (only Medium-Tasters), performed an implicit affective test. Samples were presented blind in aqueous solutions monadically in triplicate. Subjects (Ss) were asked to taste a sample, then a neutral face was briefly presented on a screen, and Ss were asked to indicate if they trusted the face (yes/no) and how much (on a 9-point Scale). Data on Ss' psychological traits (anxiety, sensation seeking, food neophobia, emotional stability) was also collected. Two clusters were identified based individual SCR. These clusters differed in their SCR mainly to strong bitterness, and partially to astringency, while they did not differ for their response to the sweet samples. The High bitter responders were more anxious and neurotic than Low bitter responders. For this cluster higher intensities induced higher SCR, but this was not found in the Low bitter responders cluster that tended to have higher SCR to the least intense samples. No differences in the implicit affective responses to samples were found between clusters. These results indicate that SCR to tastes reflect mainly different sources of arousal, such as novelty/surprisingness, quality and intensity of the stimuli, and this may change at an individual level. This suggests that measurement of SC can contribute to a better understanding of individual differences in taste and oral experience and could provide a link between taste responsiveness and sympathetic nervous system activity. [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]

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]

SPANISH language, CORPORA, DISCOURSE, and CONVERSATION

The aim of this paper is to describe the prosodic features --nuclear pitch configurations and pitch range-- of neutral and oriented interrogative utterances in the Spanish of Mexico City. We carried out a study of polar and wh- questions recorded in the free conversation module of the Corpus Norma Lingüística Culta (Lope Blanch 1971) and Habla Popular de la Ciudad de México (Lope Blanch 1976). The findings of the qualitative analysis show: i) the nuclear pitch configuration L* (L)H% --with the variants L* (L)H%, L* ¡H%, !H* ¡H%-- in information-seeking yes-no questions and confirmation questions, ii) the nuclear configuration L* L% documented in neutral wh- questions, and the boundary tone H% produced in the non-neutral condition --hypothetical or confirmative-- of the utterance; iii) the use of the pitch range as a potential prosodic resource for the expression of lesser or greater knowledge about the expected answer. The spontaneous speech data partially confirm the descriptions based on discourse completion tasks for this variety of Spanish (de-la-Mota et al. 2010). [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]