Circulating pancreatic enzyme levels are a causal biomarker of type 1 diabetes.

Novel biomarkers of type 1 diabetes (T1D) are needed for earlier detection of disease and identifying therapeutic targets. We identified biomarkers of T1D by combining plasma cis and trans protein QTLs (pQTLs) for 2,922 proteins in the UK Biobank with a T1D genome-wide association study (GWAS) in 157k samples. T1D risk variants at over 20% of known loci colocalized with cis or trans pQTLs, and distinct sets of T1D loci colocalized with immune, pancreatic secretion, or gut-related proteins. We identified 23 proteins with evidence for a causal role in using pQTLs as genetic instruments in Mendelian Randomization which included multiple sensitivity analyses. Proteins increasing T1D risk were involved in immune processes (e.g. HLA-DRA) and, more surprisingly, T1D protective proteins were enriched in pancreatic secretions (e.g. CPA1), cholesterol metabolism (e.g. APOA1), and gut homeostasis. Genetic variants associated with plasma levels of T1D-protective pancreatic enzymes such as CPA1 were enriched in cis-regulatory elements in pancreatic exocrine and gut enteroendocrine cells, and the protective effects of CPA1 and other enzymes on T1D were consistent when using instruments specific to acinar cells. Finally, pancreatic enzymes had decreased acinar expression in T1D, including CPA1 which was altered prior to onset. Together, these results reveal causal biomarkers and highlight processes in the exocrine pancreas, immune system, and gut that modulate T1D risk.

Inter-and intrarater agreement of Computed Tomographic brain calcification scoring in Primary Familial Brain Calcification.

BACKGROUND AND PURPOSE: The Total Calcification Score (TCS) is a visual rating scale to measure Primary Familial Brain Calcification (PFBC) related calcification severity on Computed Tomography (CT). We investigated the inter-and intrarater agreement of a modified TCS. MATERIALS AND METHODS: Patients aged ≥18 years with PFBC or Fahr's syndrome who visited the outpatient clinic of a Dutch academic hospital were included. The TCS was modified, for example by adding hippocampal calcification, and ranged from 0 to 95 points. Fifteen raters evaluated all CTs, of whom three evaluated the CTs twice. Their Entrustable Professional Activity (EPA) level ranged from II (medical student) to V (neuroradiologist). Agreement was assessed using the intraclass correlation coefficient (ICC) for the total score. Kendall's W and weighted Cohen's Kappa were used to determine the inter- and intrarater agreement for individual locations, respectively. RESULTS: Forty patients were included (mean age 60 years, 53% female). The median modified TCS was 34 (range 4-76). For all EPA levels, the interrater agreement of the modified TCS was excellent (ICC=0.97 (95% CI 0.95-0.98)). Kendall's W's were good to excellent for commonly affected locations, but poor to moderate for less commonly affected locations for raters with lower levels of expertise. The intrarater agreement of the modified TCS was excellent. Kappa's of most locations were substantial to almost perfect. CONCLUSIONS: The modified TCS can be used with excellent reproducibility of the overall amount of brain calcifications and with limited training, although for some individual calcification locations more expertise is needed. ABBREVIATIONS: CI, Confidence Interval; CT, Computed Tomography; EPA, Entrustable Professional Activity; IBGC, Idiopathic Basal Ganglia Calcification; ICC, Intraclass Correlation Coefficient; IQR, Interquartile Range; PFBC, Primary Familial Brain Calcification; SD, Standard Deviation, TCS, Total Calcification Score; UMCU, University Medical Center Utrecht.

Insomnia and the effect of zolpidem-extended-release on the sleep items of the Hamilton Rating Scale for Depression in outpatients with depression, insomnia, and suicidal ideation: Relationship to patient age.

BACKGROUND: There are limited data regarding gamma-aminobutyric acid (GABA) allosteric modulator sleep-aid medications in persons with depression, insomnia, and suicidal ideation (SI). AIMS: This secondary analysis examined the relationship of age to insomnia and the impact of age on the treatment of insomnia with zolpidem extended-release (zolpidem-ER) in depressed suicidal patients. A prior report found that the addition of zolpidem-ER promoted significantly superior reductions in global severity of insomnia in depressed outpatients with insomnia and SI over 8 weeks, but here we report the differences among early, middle, and late insomnia. METHODS: This secondary analysis examined the three early, middle, and late insomnia items of the Hamilton Rating Scale for Depression (HRSD) and their relationship to age and responsiveness to treatment with zolpidem-ER. One hundred and three patients with major depression, SI, and insomnia received open-label serotonin reuptake inhibitors and were randomly allocated 1:1 to receive zolpidem-ER or placebo at bedtime. Results: Older age at baseline was associated with worse middle and late insomnia, but not with early insomnia. Subsequent treatment with zolpidem-ER produced superior improvement in early and middle insomnia, but not late insomnia. CONCLUSIONS: These findings are consistent with the known age-related advancement of sleep timing in the general population and depressed outpatients and with the expected effects of a short half-life GABA allosteric modulator sleep aid. By implication, prescribers of pharmacologic treatment of insomnia in depressed patients should consider an alternative to zolpidem-ER when late insomnia is a concern.Trial registration number: ClinicalTrials.gov Identifier: NCT01689909.

Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor-Positive Breast Cancer.

Importance: Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking. Objective: To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer. Design, Setting, and Participants: This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022. Main Outcomes and Measures: Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses. Results: Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively. Conclusions and Relevance: In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

Ambient ultraviolet A, ultraviolet B and risk of melanoma in a nationwide United States cohort, 1984-2014.

BACKGROUND: Ultraviolet radiation (UVR) exposure is the primary risk factor for melanoma although the relationship is complex. Compared to radiation from UVB wavelengths, UVA makes up a majority of the surface solar UVR, penetrates the skin more deeply, is the principal range emitted by tanning beds, and is less filtered by sunscreens and window glass. Few studies have examined the relationship between ambient UVA and UVB and melanoma risk. METHODS: Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated for the association between satellite-based ambient (based on residential history) UVA, UVB and melanoma in non-Hispanic White participants using data from the United States Radiologic Technologists study, a large, nationwide prospective cohort. Associations of UVA and UVB quartile (Q) were examined in mutually adjusted and stratified models, additionally adjusted for demographic and sun sensitivity characteristics. RESULTS: There were 837 incident melanoma cases among 62,785 participants. Incidence of melanoma was statistically significantly increased for the highest quartile of childhood UVA exposure after adjustment for UVB (IRR = 2.82; 95%CI:1.46,5.44), but not for higher childhood UVB after adjustment for UVA. Childhood UVA was associated with increased melanoma risk within strata of UVB. Childhood UVB was not associated with melanoma after adjustment for UVA, but there was some evidence of lower risk with increased lifetime ambient UVB after UVA adjustment. CONCLUSIONS: Melanoma risk was elevated among participants living in locations with high annual childhood and lifetime UVA after controlling for UVB. With confirmation, these findings support increased protection from solar UVA for melanoma prevention.

Liquid Ammonia: More than an Innocent Solvent for Zintl Anions.

Liquid ammonia as the original solvent for Zintl anions has been replaced by easier to handle or more versatile solvents in most recent Zintl chemistry. However, methodological advances have made it possible to structurally investigate the anions in ammoniate crystals via crystallography or in the solutions themselves via nuclear magnetic resonance. While in some cases liquid ammonia acts as an innocent solvent, it also provides different possibilities of direct involvement in chemical reactions. In addition to simple dissolution without changes to the anions observed in the solid starting materials, protonation of the anion, incongruent dissolution involving redox processes, and further oxidation and reduction products have been observed. The use of the solvent liquid ammonia under ambient pressure is limited to low temperatures, which in turn allows the monitoring of kinetically stabilized species, some of which cannot be accessed at higher temperatures. In this work, the available literature reports are summarized or referenced, and compounds that have been characterized as new ammoniate crystals are presented and contextualized. Innocent dissolution is observed for clusters involved in K2.9Rb5.1[Si4][Si9]·15NH3, Cs4Sn9·12NH3, Cs4Pb9·5NH3, and [Rb@[18]crown-6]2[Rb@[2.2.2]crypt]Rb[Ge9]·4NH3. Formal protonation of [Ge4]4- results in the crystallization of [Na@[2.2.2]crypt]2[H2Ge4]·3NH3. Tt52- (Tt = Sn or Pb) and HSi93- cannot be accessed in a binary solid state material but can be crystallized in co-crystals of PPh3 in [Rb@[2.2.2]crypt]2[Sn5][PPh3]2·NH3, [Rb@[2.2.2]crypt]2[Pb5][PPh3]2·NH3, and [K@[2.2.2]crypt]3[HSi9][PPh3]·5NH3.

PET/CT targeted tissue sampling reveals intravenously administered HGN194 IgG1 affects HIV distribution after rectal exposure.

Neutralizing monoclonal antibodies hold great potential for prevention of human immunodeficiency virus (HIV) acquisition. IgG is the most abundant antibody in human serum, has a long half-life, and potent effector functions, making it a prime candidate for an HIV prevention therapeutic. We combined Positron Emission Tomography (PET) imaging and fluorescent microscopy of 64Cu-labeled, photoactivatable-GFP HIV (PA-GFP-BaL) and fluorescently labeled HGN194 IgG1 to determine whether intravenously instilled IgG influences viral interaction with mucosal barriers and viral penetration in colorectal tissue two hours after rectal viral challenge. Our results show that IgG1 did not alter the number of virions found throughout the colon or viral penetration into the epithelium of the rectum or descending colon. A minor increase in virions was observed in the transverse colon of IgG1 treated animals. Overall, the number of viral particles found in the mesenteric lymph nodes was low. However, IgG1 administration resulted in a significant reduction of virions found in mesenteric lymph nodes. Taken together, our results show that HGN194 IgG1 does not prevent virions from penetrating into the colorectal mucosa but may perturb HIV virion access to the lymphatic system.

Cognitive and psychiatric symptom trajectories 2-3 years after hospital admission for COVID-19: a longitudinal, prospective cohort study in the UK.

BACKGROUND: COVID-19 is known to be associated with increased risks of cognitive and psychiatric outcomes after the acute phase of disease. We aimed to assess whether these symptoms can emerge or persist more than 1 year after hospitalisation for COVID-19, to identify which early aspects of COVID-19 illness predict longer-term symptoms, and to establish how these symptoms relate to occupational functioning. METHODS: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study of adults (aged ≥18 years) who were hospitalised with a clinical diagnosis of COVID-19 at participating National Health Service hospitals across the UK. In the C-Fog study, a subset of PHOSP-COVID participants who consented to be recontacted for other research were invited to complete a computerised cognitive assessment and clinical scales between 2 years and 3 years after hospital admission. Participants completed eight cognitive tasks, covering eight cognitive domains, from the Cognitron battery, in addition to the 9-item Patient Health Questionnaire for depression, the Generalised Anxiety Disorder 7-item scale, the Functional Assessment of Chronic Illness Therapy Fatigue Scale, and the 20-item Cognitive Change Index (CCI-20) questionnaire to assess subjective cognitive decline. We evaluated how the absolute risks of symptoms evolved between follow-ups at 6 months, 12 months, and 2-3 years, and whether symptoms at 2-3 years were predicted by earlier aspects of COVID-19 illness. Participants completed an occupation change questionnaire to establish whether their occupation or working status had changed and, if so, why. We assessed which symptoms at 2-3 years were associated with occupation change. People with lived experience were involved in the study. FINDINGS: 2469 PHOSP-COVID participants were invited to participate in the C-Fog study, and 475 participants (191 [40·2%] females and 284 [59·8%] males; mean age 58·26 [SD 11·13] years) who were discharged from one of 83 hospitals provided data at the 2-3-year follow-up. Participants had worse cognitive scores than would be expected on the basis of their sociodemographic characteristics across all cognitive domains tested (average score 0·71 SD below the mean [IQR 0·16-1·04]; p<0·0001). Most participants reported at least mild depression (263 [74·5%] of 353), anxiety (189 [53·5%] of 353), fatigue (220 [62·3%] of 353), or subjective cognitive decline (184 [52·1%] of 353), and more than a fifth reported severe depression (79 [22·4%] of 353), fatigue (87 [24·6%] of 353), or subjective cognitive decline (88 [24·9%] of 353). Depression, anxiety, and fatigue were worse at 2-3 years than at 6 months or 12 months, with evidence of both worsening of existing symptoms and emergence of new symptoms. Symptoms at 2-3 years were not predicted by the severity of acute COVID-19 illness, but were strongly predicted by the degree of recovery at 6 months (explaining 35·0-48·8% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); by a biocognitive profile linking acutely raised D-dimer relative to C-reactive protein with subjective cognitive deficits at 6 months (explaining 7·0-17·2% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); and by anxiety, depression, fatigue, and subjective cognitive deficit at 6 months. Objective cognitive deficits at 2-3 years were not predicted by any of the factors tested, except for cognitive deficits at 6 months, explaining 10·6% of their variance. 95 of 353 participants (26·9% [95% CI 22·6-31·8]) reported occupational change, with poor health being the most common reason for this change. Occupation change was strongly and specifically associated with objective cognitive deficits (odds ratio [OR] 1·51 [95% CI 1·04-2·22] for every SD decrease in overall cognitive score) and subjective cognitive decline (OR 1·54 [1·21-1·98] for every point increase in CCI-20). INTERPRETATION: Psychiatric and cognitive symptoms appear to increase over the first 2-3 years post-hospitalisation due to both worsening of symptoms already present at 6 months and emergence of new symptoms. New symptoms occur mostly in people with other symptoms already present at 6 months. Early identification and management of symptoms might therefore be an effective strategy to prevent later onset of a complex syndrome. Occupation change is common and associated mainly with objective and subjective cognitive deficits. Interventions to promote cognitive recovery or to prevent cognitive decline are therefore needed to limit the functional and economic impacts of COVID-19. FUNDING: National Institute for Health and Care Research Oxford Health Biomedical Research Centre, Wolfson Foundation, MQ Mental Health Research, MRC-UK Research and Innovation, and National Institute for Health and Care Research.

Sociodemographic Differences in Perspectives on Postpartum Symptom Reporting.

OBJECTIVE: The overall goal of this work is to create a patient-reported outcome (PRO) and decision support system to help postpartum patients determine when to seek care for concerning symptoms. In this case study, we assessed differences in perspectives for application design needs based on race, ethnicity, and preferred language. METHODS: A sample of 446 participants who reported giving birth in the past 12 months was recruited from an existing survey panel. We sampled participants from four self-reported demographic groups: (1) English-speaking panel, Black/African American race, non-Hispanic ethnicity; (2) Spanish-speaking panel, Hispanic-ethnicity; (3) English-speaking panel, Hispanic ethnicity; (4) English-speaking panel, non-Black race, non-Hispanic ethnicity. Participants provided survey-based feedback regarding interest in using the application, comfort reporting symptoms, desired frequency of reporting, reporting tool features, and preferred outreach pathway for concerning symptoms. RESULTS: Fewer Black participants, compared with all other groups, stated that they had used an app for reporting symptoms (p = 0.02), were least interested in downloading the described application (p < 0.05), and found a feature for sharing warning sign information with friends and family least important (p < 0.01). Black and non-Hispanic Black participants also preferred reporting symptoms less frequently as compared with Hispanic participants (English and Spanish-speaking; all p < 0.05). Spanish-speaking Hispanic participants tended to prefer calling their professional regarding urgent warning signs, while Black and English-speaking Hispanic groups tended to express interest in using an online chat or patient portal (all p < 0.05) CONCLUSION: Different participant groups described distinct preferences for postpartum symptom reporting based on race, ethnicity, and preferred languages. Tools used to elicit PROs should consider how to be flexible for different preferences or tailored toward different groups.

The multiple mediating effects of vision-specific factors and depression on the association between visual impairment severity and fatigue: a path analysis study.

BACKGROUND: Severe fatigue is a common symptom for people with visual impairment, with a detrimental effect on emotional functioning, cognition, work capacity and activities of daily living. A previous study found that depression was one of the most important determinants of fatigue, but less is known about disease-specific factors in this patient population. This study aimed to explore the association between visual impairment severity and fatigue in adults with low vision, both directly and indirectly, with vision-specific factors and depression as potential mediators. METHODS: Cross-sectional data were collected from 220 Dutch low vision service patients by telephone interviews. Fatigue was defined as a latent variable by severity and impact on daily life. Potential mediators included vision-related symptoms, adaptation to vision loss and depression. Hypothesized structural equation models were constructed in Mplus to test (in)direct effects of visual impairment severity (mild/moderate, severe, blindness) on fatigue through above mentioned variables. RESULTS: The final model explained 60% of fatigue variance and revealed a significant total effect of visual impairment severity on fatigue. Patients with severe visual impairment (reference group) had significantly higher fatigue symptoms compared to those with mild/moderate visual impairment (ß = -0.50, 95% bias-corrected confidence interval [BC CI] [-0.86, -0.16]) and those with blindness (ß = -0.44, 95% BC CI [-0.80, -0.07]). Eye strain & light disturbance, depression and vision-related mobility mediated the fatigue difference between the severe and mild/moderate visual impairment categories. The fatigue difference between the severe visual impairment and blindness categories was solely explained by eye strain & light disturbance. Moreover, depressive symptoms (ß = 0.65, p < 0.001) and eye strain & light disturbance (ß = 0.19, p = 0.023) were directly associated with fatigue independent of visual impairment severity. CONCLUSIONS: Our findings indicate an inverted-U shaped relationship between visual impairment severity and fatigue in patients with low vision. The complexity of this relationship is likely explained by the consequences of visual impairment, in particular by strained eyes and depressive mood, rather than by severity of the disability itself.

Single cell multiome profiling of pancreatic islets reveals physiological changes in cell type-specific regulation associated with diabetes risk.

Physiological variability in pancreatic cell type gene regulation and the impact on diabetes risk is poorly understood. In this study we mapped gene regulation in pancreatic cell types using single cell multiomic (joint RNA-seq and ATAC-seq) profiling in 28 non-diabetic donors in combination with single cell data from 35 non-diabetic donors in the Human Pancreas Analysis Program. We identified widespread associations with age, sex, BMI, and HbA1c, where gene regulatory responses were highly cell type- and phenotype-specific. In beta cells, donor age associated with hypoxia, apoptosis, unfolded protein response, and external signal-dependent transcriptional regulators, while HbA1c associated with inflammatory responses and gender with chromatin organization. We identified 10.8K loci where genetic variants were QTLs for cis regulatory element (cRE) accessibility, including 20% with lineage- or cell type-specific effects which disrupted distinct transcription factor motifs. Type 2 diabetes and glycemic trait associated variants were enriched in both phenotype- and QTL-associated beta cell cREs, whereas type 1 diabetes showed limited enrichment. Variants at 226 diabetes and glycemic trait loci were QTLs in beta and other cell types, including 40 that were statistically colocalized, and annotating target genes of colocalized QTLs revealed genes with putatively novel roles in disease. Our findings reveal diverse responses of pancreatic cell types to phenotype and genotype in physiology, and identify pathways, networks, and genes through which physiology impacts diabetes risk.

Identifying Strategies to Improve Shared Decision Making for Pregnant Patients' Decisions about Prenatal Genetic Screens and Diagnostic Tests.

PURPOSE: Prenatal genetic screens and diagnostic tests are vital components of prenatal care. The first prenatal visit is a critical time in the decision-making process when patients decide whether to use these tests in addition to address a series of other essential prenatal care aspects. We conducted this study to examine the role of a shared decision-making (SDM) instrument to support these discussions. METHODS: We conducted a cluster randomized controlled trial of patients allocated to an SDM tool or usual care at their first prenatal visit. Participants completed a baseline survey to measure decision-making needs and preferences. Direct observation was conducted and analyzed using the OPTION scale to measure SDM during prenatal genetic testing discussions. RESULTS: Levels of SDM were similar across groups (P = 0.081). The highest levels of SDM were observed during screening test discussions (NEST 2.4 ± 0.9 v. control 2.6 ± 1.0). Lowest levels were observed in discussions about patients' preference for risk versus diagnostic information (NEST 1.0 ± 1.1 v. control 1.2 ± 1.3). CONCLUSION: Study findings demonstrate the need for targeted patient-focused and provider-focused efforts to improve SDM to enhance patients' informed decision making about these options. Importantly, patients' baseline knowledge and attitudes need to be considered given that patients with less knowledge may need more carefully crafted communication. HIGHLIGHTS: Choices about whether, when, and how to use prenatal genetic tests are highly preference-based decisions, with patients' baseline attitudes about these options as a major driver in health care discussions.The decision-making process is also shaped by patient preferences regarding a shared or informed decision-making process for medical decisions that are highly personal and have significant ramifications for obstetric outcomes.There is a need to develop targeted efforts to improve decision making and enhance patients' ability to make informed decisions about prenatal genetic tests in early pregnancy.

Unravelling White Phosphorus: Experimental and Computational Studies Reveal the Mechanisms of P4 Hydrostannylation.

The hydrostannylation of white phosphorus (P4) allows this crucial industrial precursor to be easily transformed into useful P1 products via direct, 'one pot' (or even catalytic) procedures. However, a thorough mechanistic understanding of this transformation has remained elusive, hindering attempts to use this rare example of successful, direct P4 functionalization as a model for further reaction development. Here, we provide a deep and generalizable mechanistic picture for P4 hydrostannylation by combining DFT calculations with in situ31P NMR reaction monitoring and kinetic trapping of previously unobservable reaction intermediates using bulky tin hydrides. The results offer important insights into both how this reaction proceeds and why it is successful and provide implicit guidelines for future research in the field of P4 activation.

Single cell regulatory architecture of human pancreatic islets suggests sex differences in ß cell function and the pathogenesis of type 2 diabetes.

Type 2 and type 1 diabetes (T2D, T1D) exhibit sex differences in insulin secretion, the mechanisms of which are unknown. We examined sex differences in human pancreatic islets from 52 donors with and without T2D combining single cell RNA-seq (scRNA-seq), single nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), hormone secretion, and bioenergetics. In nondiabetic (ND) donors, sex differences in islet cells gene accessibility and expression predominantly involved sex chromosomes. Islets from T2D donors exhibited similar sex differences in sex chromosomes differentially expressed genes (DEGs), but also exhibited sex differences in autosomal genes. Comparing ß cells from T2D vs. ND donors, gene enrichment of female ß cells showed suppression in mitochondrial respiration, while male ß cells exhibited suppressed insulin secretion. Thus, although sex differences in gene accessibility and expression of ND ß cells predominantly affect sex chromosomes, the transition to T2D reveals sex differences in autosomes highlighting mitochondrial failure in females.

Measuring progress on health and well-being in the Eastern Mediterranean Region via voluntary national reviews, 2016-2021: What does the data reveal?

BACKGROUND: Country submission of Voluntary National Reviews is the formal mechanism to report on progress of the Sustainable Development Goals (SDGs). Despite strong political commitment to strong information systems, large data gaps exist in the Eastern Mediterranean Region. METHODS: This study aims to review reports submitted by countries in the region to assess the comprehensiveness of reporting on the health-reported SDG targets and indicators. We conducted a content analysis of reports submitted between 2016 and 2021 of 18 countries of the region. The review focused on progress on the SDGs by assessing i) the reporting on the 50 health-related targets and indicators ii) data availability using the WHO reporting framework, and iii) data availability based on source of information. Spreadsheets were developed and used to extract data and facilitate content analysis. RESULTS: All reports confirmed that SDG monitoring and reporting mechanisms have been established, however, only 11 reported on all 17 SDGs and 8 explicitly mentioned country specific 2030 targets. Many reports identified data availability as a key challenge to SDG monitoring; for the health SDG, data availability ranged from 48% to 93% among the five countries reporting this figure. Comprehensiveness of reporting varied by type of indicator (maternal, child and infant mortality were the most common) and by country income level (greater reporting by high income countries). CONCLUSIONS: Significant work remains to enhance information systems across the region to monitor progress and guide actions to achieve the health-related SDGs. Strengthening health information systems regulatory frameworks, data collection capacities including strengthening civil registration and vital statistics and population-based surveys are key steps to enhancing access to quality data which in turn can contribute to achieving the health-related SDGs.

Differences in Objective Physical Activity Between Children With Visual Impairment and Those With Normal Sight.

Purpose: To compare objective physical activity (PA) levels of children with visual impairment (VI) and children with normal sight. Methods: One hundred children with VI and 100 age- and gender-matched normal-sighted peers 7 to 17 years of age wore an ActiGraph for 1 week. Activity count per minute (cpm) was modeled using a series of generalized linear mixed-effects models including vision, age, sex, time of day, and vision by time of day interaction. PA outcomes included mean counts per minute and proportion of time spent on sedentary, light, moderate, and vigorous intensity PA. Results: Data of 83 children with VI and 77 normal-sighted peers were included. Mean counts per minute were lower in children with VI (P < 0.001), especially during and after school. Children with VI were less sedentary (55%; 95% confidence interval [CI], 53-57) than children with normal sight before school (62%; 95% CI, 60-64) and over weekends: children with VI, 41% (95% CI, 39-43); children with normal sight, 45% (95% CI, 43-47). Yet, children with VI were more sedentary during school (36%; 95% CI, 34-37) compared with children with normal sight (30%; 95% CI, 29-32). They also spent more time performing light PA and less time performing moderate PA at school and vigorous PA across all periods of day (P < 0.001). Conclusions: Children with VI participated in light and moderate PA but did not perform as much vigorous PA as children with normal sight, especially during school hours. Translational Relevance: There is a need to promote more intense PA programs in schools tailored for children with VI.

A global survey of the attitudes and perspectives of cognitive bias in forensic anthropology.

It is now well established that decision making can be susceptible to cognitive bias in a broad range of fields, with forensic science being no exception. Previously published research has revealed a bias blind spot in forensic science where examiners do not recognise bias within their own domain. A survey of 101 forensic anthropology practitioners (n = 52) and students (n = 38) was undertaken to assess their level of awareness of cognitive bias and investigate their attitudes towards cognitive bias within forensic anthropology. The results revealed that the forensic anthropology community (∼90%) had a high level of awareness of cognitive bias. Overall ∼89% expressed concerns about cognitive bias in the broad discipline of forensic science, their own domain of forensic anthropology, and in the evaluative judgments they made in reconstruction activities, identifying a significant reduction in the bias blind spot. However, more than half of the participants believed that bias can be reduced by sheer force of will, and there was a lack of consensus about implementing blinding procedures or context management. These findings highlight the need to investigate empirically the feasibility of proposed mitigating strategies within the workflow of forensic anthropologists and their capabilities for increasing the transparency in decision making.

Short-term high fat diet impairs memory, exacerbates the neuroimmune response, and evokes synaptic degradation via a complement-dependent mechanism in a mouse model of Alzheimer's disease.

Alzheimer's Disease (AD) is a neurodegenerative disease characterized by profound memory impairments, synaptic loss, neuroinflammation, and hallmark pathological markers. High-fat diet (HFD) consumption increases the risk of developing AD even after controlling for metabolic syndrome, pointing to a role of the diet itself in increasing risk. In AD, the complement system, an arm of the immune system which normally tags redundant or damaged synapses for pruning, becomes pathologically overactivated leading to tagging of healthy synapses. While the unhealthy diet to AD link is strong, the underlying mechanisms are not well understood in part due to confounding variables associated with long-term HFD which can independently influence the brain. Therefore, we experimented with a short-term diet regimen to isolate the diet's impact on brain function without causing obesity. This project investigated the effect of short-term HFD on 1) memory, 2) neuroinflammation including complement, 3) AD pathology markers, 4) synaptic markers, and 5) in vitro microglial synaptic phagocytosis in the 3xTg-AD mouse model. Following the consumption of either standard chow or HFD, 3xTg-AD and non-Tg mice were tested for memory impairments. In a separate cohort of mice, levels of hippocampal inflammatory markers, complement proteins, AD pathology markers, and synaptic markers were measured. For the last set of experiments, BV2 microglial phagocytosis of synapses was evaluated. Synaptoneurosomes isolated from the hippocampus of 3xTg-AD mice fed chow or HFD were incubated with equal numbers of BV2 microglia. The number of BV2 microglia that phagocytosed synaptoneurosomes was tracked over time with a live-cell imaging assay. Finally, we incubated BV2 microglia with a complement receptor inhibitor (NIF) and repeated the assay. Behavioral analysis showed 3xTg-AD mice had significantly impaired long-term contextual and cued fear memory compared to non-Tg mice that was further impaired by HFD. HFD significantly increased inflammatory markers and complement expression while decreasing synaptic marker expression only in 3xTg-AD mice, without altering AD pathology markers. Synaptoneurosomes from HFD-fed 3xTg-AD mice were phagocytosed at a significantly higher rate than those from chow-fed mice, suggesting the synapses were altered by HFD. The complement receptor inhibitor blocked this effect in a dose-dependent manner, demonstrating the HFD-mediated increase in phagocytosis was complement dependent. This study indicates HFD consumption increases neuroinflammation and over-activates the complement cascade in 3xTg-AD mice, resulting in poorer memory. The in vitro data point to complement as a potential mechanistic culprit and therapeutic target underlying HFD's influence in increasing cognitive vulnerability to AD.

Integrating health across the Sustainable Development Goals in the Eastern Mediterranean Region: Assessment of Voluntary National Reviews from 18 countries.

Voluntary National Reviews are the formal mechanism for countries to report on progress and share lessons learned on SDG implementation. We assessed the Voluntary National Reviews submitted by countries in the WHO Eastern Mediterranean Region to note the reported progress on Sustainable Development Goal (SDG) implementation, the review preparation process and how health is positioned and framed to identify priorities for accelerating progress on the health-related SDGs. We extracted quantitative and qualitative data from 26 Voluntary National Reviews from 18 countries submitted during the period 2016 to January 2022. We focused on three areas: SDG implementation, the review preparation process and the positioning of health in the reviews. Three assessors conducted the data extraction based on the agreed framework according to their language of expertise (Arabic, English and French). One assessor supervised the whole process for consistency. If there was a doubt in interpretation, it was discussed and agreed among the assessors. Countries have established a mechanism for SDG implementation under high-level leadership, engaged in multistakeholder consultations, aligned and mainstreamed SDGs to national plans, and created a monitoring and review mechanism. Countries reported use of national participatory approach for the report preparation. The prioritization of both health and well-being (SDG3) and economic growth (SDG8) in the reports is unique compared to other regional and global assessments. Health was often framed around disease and health care provision without linkages to societal inequities and structural challenges. The reports indicated good progress in SDG implementation. Addressing upstream issues and the determinants of health requires the health sector to take a more strategic approach in advocating for health and well-being. Further research is needed to demonstrate how to address synergies and trade-offs of policy choices and identify the co-benefits of addressing health in the context of fiscal instability and widening inequities in the region.

Early intermediates in bacterial RNA polymerase promoter melting visualized by time-resolved cryo-electron microscopy.

During formation of the transcription-competent open complex (RPo) by bacterial RNA polymerases (RNAPs), transient intermediates pile up before overcoming a rate-limiting step. Structural descriptions of these interconversions in real time are unavailable. To address this gap, here we use time-resolved cryogenic electron microscopy (cryo-EM) to capture four intermediates populated 120 ms or 500 ms after mixing Escherichia coli σ70-RNAP and the λPR promoter. Cryo-EM snapshots revealed that the upstream edge of the transcription bubble unpairs rapidly, followed by stepwise insertion of two conserved nontemplate strand (nt-strand) bases into RNAP pockets. As the nt-strand 'read-out' extends, the RNAP clamp closes, expelling an inhibitory σ70 domain from the active-site cleft. The template strand is fully unpaired by 120 ms but remains dynamic, indicating that yet unknown conformational changes complete RPo formation in subsequent steps. Given that these events likely describe DNA opening at many bacterial promoters, this study provides insights into how DNA sequence regulates steps of RPo formation.