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BackgroundWe previously developed a prediction score for MRI-quantified abdominal visceral adipose tissue (VAT) based on concurrent measurements of height, body mass index (BMI), and nine blood biomarkers, for optimal performance in five racial/ethnic groups. Here we evaluated the VAT score for prediction of future VAT and examined if enhancement with additional biomarkers, lifestyle behavior information, and medical history improves the prediction.MethodsWe examined 500 participants from the Multiethnic Cohort (MEC) with detailed data (age 50-66) collected 10 years prior to their MRI assessment of VAT. We generated three forecasted VAT prediction models: first by applying the original VAT equation to the past data on the predictors ("original"), second by refitting the past data on anthropometry and biomarkers ("refit"), and third by building a new prediction model based on the past data enhanced with lifestyle and medical history ("enhanced"). We compared the forecasted prediction scores to future VAT using the coefficient of determination (R2). In independent nested case-control data in MEC, we applied the concurrent and forecasted VAT models to assess association of the scores with subsequent incident breast cancer (950 pairs) and colorectal cancer (831 pairs).ResultsCompared to the VAT prediction by the concurrent VAT score (R2 = 0.70 in men, 0.68 in women), the forecasted original VAT score (R2 = 0.54, 0.48) performed better than past anthropometry alone (R2 = 0.47, 0.40) or two published scores (VAI, METS-VF). The forecasted refit (R2 = 0.61, 0.51) and enhanced (R2 = 0.62, 0.55) VAT scores each showed slight improvements. Similar to the concurrent VAT score, the forecasted VAT scores were associated with breast cancer, but not colorectal cancer. Both the refit score (adjusted OR for tertile 3 vs. 1 = 1.27; 95% CI: 1.00-1.62) and enhanced score (1.27; 0.99-1.62) were associated with breast cancer independently of BMI.ConclusionsPredicted VAT from midlife data can be used as a surrogate to assess the effect of VAT on incident diseases associated with obesity, as illustrated for postmenopausal breast cancer.

Health assessments have potential to improve health of older people. This study compares long-term health care utilisation, physical functioning, and mortality for women aged 75 years or over who have had a health assessment and those who have not. Prospective data on health service use, physical functioning, and deaths among a large cohort of women born 1921-26 were analysed. Propensity score matching was used to produce comparable groups of women according to whether they had a health assessment or not. The study population included 6128 (67.3%) women who had an assessment, and 2971 (32.7%) women who had no assessment. Propensity matching produced 2101 pairs. Women who had an assessment had more use of other health services, longer survival, and were more likely to survive with high physical functioning compared to women with no assessment. Among women who had good baseline physcial functioning scores, women who had an assessment had significantly lower odds of poor outcomes at 1000 days follow-up compared to women who had no assessment (OR: 0.67, 95%CI: 0.52, 0.85). This large observational study shows the real-world potential for assessments to improve health outcomes for older women. However, they also increased health service use. This increased healthcare is likely to be an important mechanism in improving the women's health outcomes.

BackgroundThe gut microbiome may play a role in inflammation associated with type 2 diabetes (T2D) development. This cross-sectional study examined its relation with glycemic status within a subset of the Multiethnic Cohort (MEC) and estimated the association of circulating bacterial endotoxin (measured as plasma lipopolysaccharide-binding protein (LBP)) with T2D, which may be mediated by C-reactive protein (CRP).MethodsIn 2013-16, cohort members from five ethnic groups completed clinic visits, questionnaires, and stool and blood collections. Participants with self-reported T2D and/or taking medication were considered T2D cases. Those with fasting glucose >125 and 100-125 mg/dL were classified as undiagnosed (UT2D) and pre-diabetes (PT2D) cases, respectively. We characterized the gut microbiome through 16S rRNA gene sequencing and measured plasma LBP and CRP by standard assays. Linear regression was applied to estimate associations of the gut microbiome community structure and LBP with T2D status adjusting for relevant confounders.ResultsAmong 1,702 participants (59.9-77.4 years), 735 (43%) were normoglycemic (NG), 506 (30%) PT2D, 154 (9%) UT2D, and 307 (18%) T2D. The Shannon diversity index decreased (ptrend = 0.05), while endotoxin, measured as LBP, increased (ptrend = 0.0003) from NG to T2D. Of 10 phyla, Actinobacteria (ptrend = 0.007), Firmicutes (ptrend = 0.003), and Synergistetes (ptrend = 0.02) were inversely associated and Lentisphaerae (ptrend = 0.01) was positively associated with T2D status. Clostridium sensu stricto 1, Lachnospira, and Peptostreptococcaceae were less, while Escherichia-Shigella and Lachnospiraceae were more abundant among T2D patients, but the associations with Actinobacteria, Clostridium sensu stricto 1, and Escherichia-Shigella may be due metformin use. PT2D/UT2D values were closer to NG than T2D. No indication was detected that CRP mediated the association of LBP with T2D.ConclusionsT2D but not PT2D/UT2D status was associated with lower abundance of SCFA-producing genera and a higher abundance of gram-negative endotoxin-producing bacteria suggesting that the gut microbiome may contribute to chronic systemic inflammation and T2D through bacterial translocation.

Breast ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC). It is still unclear which DCIS will become invasive and which will remain indolent. Patients often receive surgery and radiotherapy, but this early intervention has not produced substantial decreases in late-stage disease. Sprouty proteins are important regulators of ERK/MAPK signaling and have been studied in various cancers. We hypothesized that Sprouty4 is an endogenous inhibitor of ERK/MAPK signaling and that its loss/reduced expression is a mechanism by which DCIS lesions progress toward IDC, including triple-negative disease. Using immunohistochemistry, we found reduced Sprouty4 expression in IDC patient samples compared to DCIS, and that ERK/MAPK phosphorylation had an inverse relationship to Sprouty4 expression. These observations were reproduced using a 3D culture model of disease progression. Knockdown of Sprouty4 in MCF10.DCIS cells increased ERK/MAPK phosphorylation as well as their invasive capability, while overexpression of Sprouty4 in MCF10.CA1d IDC cells reduced ERK/MAPK phosphorylation, invasion, and the aggressive phenotype exhibited by these cells. Immunofluorescence experiments revealed reorganization of the actin cytoskeleton and relocation of E-cadherin back to the cell surface, consistent with the restoration of adherens junctions. To determine whether these effects were due to changes in ERK/MAPK signaling, MEK1/2 was pharmacologically inhibited in IDC cells. Nanomolar concentrations of MEK162/binimetinib restored an epithelial-like phenotype and reduced pericellular proteolysis, similar to Sprouty4 overexpression. From these data we conclude that Sprouty4 acts to control ERK/MAPK signaling in DCIS, thus limiting the progression of these premalignant breast lesions.

IntroductionFunding and staff formerly dedicated to routine public health tasks (e.g., responding to communicable and non-communicable diseases, investigating foodborne outbreaks, conducting routine surveillance) and services (e.g., environmental health, substance abuse, maternal-child health) may no longer be available in many public health departments due to the COVID-19 response. The objective of this study was to assess the extent to which staffing for essential public health services has been redirected to the COVID-19 response.Materials and methodsThis is a cross-sectional study using a survey distributed through the Qualtrics platform. Individuals (N = 298) working in public health across governmental and academic public health departments in the U.S. during the ongoing COVID-19 pandemic response were surveyed. Survey items measured multiple domains including professional experience (i.e., training, years of experience, content expertise, job functions, hours worked), mental and physical health status (i.e., generalized anxiety, depression, burnout), and career plans (i.e., pre-pandemic vs. current career plans).ResultsThe total number of content expertise areas and programmatic functions covered by individual public health workers increased between January and September of 2020, with 26% (73 of 282) of respondents reporting an increase in both. The total number of respondents working in infectious disease and preparedness remained constant, while declines were reported in program evaluation (-36%) and health education (-27%) and increases were reported in disease investigation (+35%).ConclusionsThe provision of many essential public health functions and tasks have been limited or eliminated while the U.S. public health workforce responds to the COVID-19 pandemic. These findings highlight opportunities for funding and professional development of public health systems, both during and after the COVID-19 response, to help ensure the continuity of essential public health services, staffing sustainability, and preparedness for future public health emergencies in the U.S.

Zika virus infection during pregnancy is associated with miscarriage and with a broad spectrum of fetal and neonatal developmental abnormalities collectively known as congenital Zika syndrome (CZS). Symptomology of CZS includes malformations of the brain and skull, neurodevelopmental delay, seizures, joint contractures, hearing loss and visual impairment. Previous studies of Zika virus in pregnant rhesus macaques (Macaca mulatta) have described injury to the developing fetus and pregnancy loss, but neonatal outcomes following fetal Zika virus exposure have yet to be characterized in nonhuman primates. Herein we describe the presentation of rhesus macaque neonates with a spectrum of clinical outcomes, including one infant with CZS-like symptoms including cardiomyopathy, motor delay and seizure activity following maternal infection with Zika virus during the first trimester of pregnancy. Further characterization of this neonatal nonhuman primate model of gestational Zika virus infection will provide opportunities to evaluate the efficacy of pre- and postnatal therapeutics for gestational Zika virus infection and CZS.

BACKGROUND:Cardiovascular disease is common in patients with systemic lupus erythematosis (SLE) and lupus nephritis (LN). Up to 80% of children with SLE develop kidney disease, which is also associated with increased risk for cardiovascular disease and death compared to those without renal involvement. Hepcidin is an iron-regulatory protein which may contribute to atherosclerosis and is elevated in autoimmune disease. Pulse wave velocity (PWV) is a validated indicator of arterial stiffness, an early marker of cardiovascular risk, and is increased in children with SLE versus healthy controls. Our objective was to quantify hepcidin and PWV in children with SLE and investigate if those with biopsy-proven LN have higher hepcidin levels and higher PWV compared to those without kidney disease. METHODS:Cross-sectional analysis with hepcidin was measured via ELISA assay in 16 children aged 10-21 years with SLE recruited from a single center. Subjects were classified as having LN if histologic evidence of the disease was documented on a clinical renal biopsy. Serum hepcidin was quantified using a validated competitive enzyme-linked immunoassay. Carotid-femoral PWV was measured using applanation tonometry. Wilcoxon rank sum testing was used to compare median levels of hepcidin, PWV, and other continuous variables by nephritis status. RESULTS:The cohort (n = 16) was 93.8% female and 68.8% African-American with mean (SD) 16 (3.6) years. 37.5% (n = 6) had LN. Overall median (IQR) hepcidin was 34.4 (18.9, 91.9) ng/ml, and PWV 4.4 (4, 4.6) meters/second. Although significance was limited by small sample size, both hepcidin and PWV were higher in the subjects with LN. Median (IQR) hepcidin in subjects with LN was 71.5 (26.4, 116.4) ng/ml compared to 27.9 (18.7, 59.7) ng/ml in those with SLE(p = 0.19). Similarly, median (IQR) PWV in those with LN was 4.4 (4.4, 4.9) meters/second compared to 3 (3.75, 4.55) meters/second in those with without kidney involvement (p = 0.10). CONCLUSION:PWV and serum hepcidin were higher in subjects with LN compared to those with SLE alone, suggesting that elevated hepcidin levels may be associated with morbid CV changes in children with LN. This association, along with identification of additional predictors of arterial stiffness in patients with LN, warrants further investigation.

Intestinal failure-associated liver disease (IFALD) is a risk of parenteral nutrition (PN)-dependence. Intravenous soybean oil-based parenteral fat can exacerbate the risk of IFALD while intravenous fish oil can minimize its progression, yet the mechanisms by which soybean oil harms and fish oil protects the liver are uncertain. Properties that differentiate soybean and fish oils include α-tocopherol and phytosterol content. Soybean oil is rich in phytosterols and contains little α-tocopherol. Fish oil contains abundant α-tocopherol and little phytosterols. This study tested whether α-tocopherol confers hepatoprotective properties while phytosterols confer hepatotoxicity to intravenous fat emulsions. Utilizing emulsions formulated in the laboratory, a soybean oil emulsion (SO) failed to protect from hepatosteatosis in mice administered a PN solution enterally. An emulsion of soybean oil containing α-tocopherol (SO+AT) preserved normal hepatic architecture. A fish oil emulsion (FO) and an emulsion of fish oil containing phytosterols (FO+P) protected from steatosis in this model. Expression of hepatic acetyl CoA carboxylase (ACC) and peroxisome proliferator-activated receptor gamma (PPARγ), was increased in animals administered SO. ACC and PPARγ levels were comparable to chow-fed controls in animals receiving SO+AT, FO, and FO+P. This study suggests a hepatoprotective role for α-tocopherol in liver injury induced by the enteral administration of a parenteral nutrition solution. Phytosterols do not appear to compromise the hepatoprotective effects of fish oil.

Nature exposure has been linked to a plethora of health benefits, but the mechanism for this effect is not well understood. We conducted two studies to test a new model linking the health benefits of nature exposure to reduced impulsivity in decision-making (as measured by delay discounting) via psychologically expanding space perception. In study 1 we collected a nationwide U.S. sample (n = 609) to determine whether nature exposure was predictive of health outcomes and whether impulsive decision-making mediated the effect. Results indicated that Nature Accessibility and Nature Exposure From Home significantly predicted reduced scores on the Depression, Anxiety, Stress Scales (DASS) (p < .001, p = .03, respectively) and improved general health and wellbeing (p < .001, p < .01, respectively). Nature Accessibility also predicted reduced impulsive decision-making (p < .01), and Nature Accessibility showed significant indirect effects through impulsive decision-making on both the DASS (p = .02) and general health and wellbeing (p = .04). In Study 2, a lab-based paradigm found that nature exposure expanded space perception (p < .001), and while the indirect effect of nature exposure through space perception on impulsive decision-making did not meet conventional standards of significance (p < .10), the pattern was consistent with hypotheses. This combination of ecologically-valid and experimental methods offers promising support for an impulsivity-focused model explaining the nature-health relationship.

Exogenous vascular endothelial growth factor (VEGF) accelerates compensatory lung growth (CLG) in mice after unilateral pneumonectomy. In this study, we unexpectedly discovered a method to enhance CLG with a VEGF inhibitor, soluble VEGFR1. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily intraperitoneal (ip) injection of either saline (control) or 20 μg/kg of VEGFR1-Fc. On post-operative day (POD) 4, mice underwent pulmonary function tests (PFT) and lungs were harvested for volume measurement and analyses of the VEGF signaling pathway. To investigate the role of hypoxia in mediating the effects of VEGFR1, experiments were repeated with concurrent administration of PT-2385, an inhibitor of hypoxia-induced factor (HIF)2α, via orogastric gavage at 10 mg/kg every 12 hours for 4 days. We found that VEGFR1-treated mice had increased total lung capacity (P = 0.006), pulmonary compliance (P = 0.03), and post-euthanasia lung volume (P = 0.049) compared to control mice. VEGFR1 treatment increased pulmonary levels of VEGF (P = 0.008) and VEGFR2 (P = 0.01). It also stimulated endothelial proliferation (P < 0.0001) and enhanced pulmonary surfactant production (P = 0.03). The addition of PT-2385 abolished the increase in lung volume and endothelial proliferation in response to VEGFR1. By paradoxically stimulating angiogenesis and enhancing lung growth, VEGFR1 could represent a new treatment strategy for neonatal lung diseases characterized by dysfunction of the HIF-VEGF pathway.

Vascular endothelial growth factor (VEGF) has previously been demonstrated to accelerate compensatory lung growth (CLG) in mice and may be a useful therapy for pulmonary hypoplasia. Systemic administration of VEGF can result in side effects such as hypotension and edema. The aim of this study was to explore nasal delivery as a route for intrapulmonary VEGF administration. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily nasal instillation of VEGF at 0.5 mg/kg or isovolumetric saline. Lung volume measurement, morphometric analysis, and protein expression studies were performed on lung tissues harvested on postoperative day (POD) 4. To understand the mechanism by which VEGF accelerates lung growth, proliferation of human bronchial epithelial cells (HBEC) was assessed in a co-culture model with lung microvascular endothelial cells (HMVEC-L) treated with and without VEGF (10 ng/mL). The assay was then repeated with a heparin-binding EGF-like growth factor (HB-EGF) neutralizing antibody ranging from 0.5-50 μg/mL. Compared to control mice, the VEGF-treated group displayed significantly higher lung volume (P = 0.001) and alveolar count (P = 0.005) on POD 4. VEGF treatment resulted in increased pulmonary expression of HB-EGF (P = 0.02). VEGF-treated HMVEC-L increased HBEC proliferation (P = 0.002) while the addition of an HB-EGF neutralizing antibody at 5 and 50 μg/mL abolished this effect (P = 0.01 and 0.002, respectively). These findings demonstrate that nasal delivery of VEGF enhanced CLG. These effects could be mediated by a paracrine mechanism through upregulation of HB-EGF, an epithelial cell mitogen.

BACKGROUND:Large and giant dog breeds have a high risk for gastric dilatation-volvulus (GDV) which is an acute, life-threatening condition. Previous work by our group identified a strong risk of GDV linked to specific alleles in innate and adaptive immune genes. We hypothesize that variation in the genes of the immune system act through modulation of the gut microbiome, or through autoimmune mechanisms, or both, to predispose dogs to this condition. Here, we investigate whether differences in the canine fecal microbiome are associated with GDV and are linked to previously identified risk alleles. METHODOLOGY/PRINCIPLE FINDINGS:Fecal samples from healthy Great Danes (n = 38), and dogs with at least one occurrence of GDV (n = 37) were collected and analyzed by paired-end sequencing of the 16S rRNA gene. Dietary intake and temperament were estimated from a study-specific dietary and temperament questionnaire. Dogs with GDV had significantly more diverse fecal microbiomes than healthy control dogs. Alpha diversity was significantly increased in dogs with GDV, as well as dogs with at least one risk allele for DRB1 and TRL5. We found no significant association of dietary intake and GDV. Dogs with GDV showed a significant expansion of the rare lineage Actinobacteria (p = 0.004), as well as a significantly greater abundance of Firmicutes (p = 0.004) and a significantly lower abundance of Bacteroidetes (p

The transcriptome can reveal insights into precancer biology. We recently conducted RNA-Seq analysis on liver RNA from male rats exposed to the carcinogen, aflatoxin B1 (AFB1), for 90 days prior to liver tumor onset. Among >1,000 differentially expressed transcripts, several novel, unannotated Cufflinks-assembled transcripts, or HAfTs (Hepatic Aflatoxin Transcripts) were found. We hypothesized PCR-cloning and RACE (rapid amplification of cDNA ends) could further HAfT identification. Sanger data was obtained for 6 transcripts by PCR and 16 transcripts by 5'- and 3'-RACE. BLAST alignments showed, with two exceptions, HAfT transcripts were lncRNAs, >200nt without apparent long open reading frames. Six rat HAfT transcripts were classified as 'novel' without RefSeq annotation. Sequence alignment and genomic synteny showed each rat lncRNA had a homologous locus in the mouse genome and over half had homologous loci in the human genome, including at least two loci (and possibly three others) that were previously unannotated. While HAfT functions are not yet clear, coregulatory roles may be possible from their adjacent orientation to known coding genes with altered expression that include 8 HAfT-gene pairs. For example, a unique rat HAfT, homologous to Pvt1, was adjacent to known genes controlling cell proliferation. Additionally, PCR and RACE Sanger sequencing showed many alternative splice variants and refinements of exon sequences compared to Cufflinks assembled transcripts and gene prediction algorithms. Presence of multiple splice variants and short tandem repeats found in some HAfTs may be consequential for secondary structure, transcriptional regulation, and function. In summary, we report novel, differentially expressed lncRNAs after exposure to the genotoxicant, AFB1, prior to neoplastic lesions. Complete cloning and sequencing of such transcripts could pave the way for a new set of sensitive and early prediction markers for chemical hepatocarcinogens.

Impulsivity in delay discounting is associated with maladaptive behaviors such as overeating and drug and alcohol abuse. Researchers have recently noted that delay discounting, even when measured by a brief laboratory task, may be the best predictor of human health related behaviors (e.g., exercise) currently available. Identifying techniques to decrease impulsivity in delay discounting, therefore, could help improve decision-making on a global scale. Visual exposure to natural environments is one recent approach shown to decrease impulsive decision-making in a delay discounting task, although the mechanism driving this result is currently unknown. The present experiment was thus designed to evaluate not only whether visual exposure to natural (mountains, lakes) relative to built (buildings, cities) environments resulted in less impulsivity, but also whether this exposure influenced time perception. Participants were randomly assigned to either a natural environment condition or a built environment condition. Participants viewed photographs of either natural scenes or built scenes before and during a delay discounting task in which they made choices about receiving immediate or delayed hypothetical monetary outcomes. Participants also completed an interval bisection task in which natural or built stimuli were judged as relatively longer or shorter presentation durations. Following the delay discounting and interval bisection tasks, additional measures of time perception were administered, including how many minutes participants thought had passed during the session and a scale measurement of whether time "flew" or "dragged" during the session. Participants exposed to natural as opposed to built scenes were less impulsive and also reported longer subjective session times, although no differences across groups were revealed with the interval bisection task. These results are the first to suggest that decreased impulsivity from exposure to natural as opposed to built environments may be related to lengthened time perception.

The purpose of the present study was to investigate the relations between posttraumatic stress disorder's (PTSD) dysphoria and reexperiencing factors and underlying dimensions of rumination. 304 trauma-exposed primary care patients were administered the Stressful Life Events Screening Questionnaire, PTSD Symptom Scale based on their worst traumatic event, and Ruminative Thought Style Questionnaire (RTSQ). Confirmatory factor analyses (CFAs) were conducted to determine the dysphoria and reexperiencing factors' relationships with the four factors of rumination. Results revealed that both the dysphoria and reexperiencing factors related more to problem-focused thinking and anticipatory thoughts than counterfactual thinking. Additionally, the reexperiencing factor related more to anticipatory thinking than repetitive thinking. Clinical and theoretical implications are discussed.

Bladder fibrosis is an undesired end point of injury of obstruction and often renders the smooth muscle layer noncompliant. In many cases, the long-term effect of bladder fibrosis is renal failure. Despite our understanding of the progression of this disease, little is known about the cellular mechanisms that lead to a remodeled bladder wall. Resident stem (progenitor) cells have been identified in various organs such as the brain, heart and lung. These cells function normally during organ homeostasis, but become dysregulated after organ injury. Here, we aimed to characterize a mesenchymal progenitor cell population as a first step in understanding its role in bladder fibrosis. Using fluorescence activated cell sorting (FACS), we identified a Sca-1+/ CD34+/ lin- (PECAM-: CD45-: Ter119-) population in the adult murine bladder. These cells were localized to the stromal layer of the adult bladder and appeared by postnatal day 1. Cultured Sca-1+/ CD34+/ lin- bladder cells self-renewed, formed colonies and spontaneously differentiated into cells expressing smooth muscle genes. These cells differentiated into other mesenchymal lineages (chondrocytes, adipocytes and osteocytes) upon culture in induction medium. Both acute and partial obstruction of the bladder reduced expression of CD34 and changed localization of Sca-1 to the urothelium. Partial obstruction resulted in upregulation of fibrosis genes within the Sca-1+/CD34+/lin- population. Our data indicate a resident, mesenchymal stem cell population in the bladder that is altered by bladder obstruction. These findings provide new information about the cellular changes in the bladder that may be associated with bladder fibrosis.

TLR7 enhances germinal center maturation and migration of B cells to the dark zone where proliferation and somatic hypermutation occur. Our goal was to determine how Tlr7 dose influences selection of the autoreactive B cell repertoire in NZW/BXSB. Yaa mice bearing the site-directed heavy chain transgene 3H9 that encodes for the TLR7 regulated anti-CL response. To create a physiologic setting in which autoreactive B cells compete for survival with non-autoreactive B cells, we generated bone marrow chimeras in which disease onset occurred with similar kinetics and the transferred 3H9+ female non-Yaa, male Yaa or male TLR7(-/Yaa) cells could be easily identified by positivity for GFP. Deletion of 3H9 B cells occurred in the bone marrow and the remaining 3H9 follicular B cells manifested a decrease in surface IgM. Although there were differences in the naïve repertoire between the chimeras it was not possible to distinguish a clear pattern of selection against lupus related autoreactivity in TLR7(-/Yaa) or female chimeras. By contrast, preferential expansion of 3H9+ B cells occurred in the germinal centers of male Yaa chimeras. In addition, although all chimeras preferentially selected 3H9/Vκ5 encoded B cells into the germinal center and plasma cell compartments, 3H9 male Yaa chimeras had a more diverse repertoire and positively selected the 3H9/Vκ5-48/Jκ4 pair that confers high affinity anti-cardiolipin activity. We were unable to demonstrate a consistent effect of Tlr7 dose or Yaa on somatic mutations. Our data show that TLR7 excess influences the selection, expansion and diversification of B cells in the germinal center, independent of other genes in the Yaa locus.

The NIMH-funded Multilevel Community-Based Mental Health Intervention to Address Structural Inequities and Adverse Disparate Consequences of COVID-19 Pandemic on Latinx Immigrants and African Refugees study aims to advance the science of multilevel interventions to reduce the disparate, adverse mental health, behavioral, and socioeconomic consequences of the COVID-19 pandemic that are a result of complex interactions between underlying structural inequities and barriers to health care. The study tests three nested levels of intervention: 1) an efficacious 4-month advocacy and mutual learning model (Refugee and Immigrant Well-being Project, RIWP); 2) engagement with community-based organizations (CBOs); and 3) structural policy changes enacted in response to the pandemic. This community-based participatory research (CBPR) study builds on long-standing collaboration with five CBOs. By including 240 Latinx immigrants and 60 African refugees recruited from CBO partners who are randomly assigned to treatment-as-usual CBO involvement or the RIWP intervention and a comparison group comprised of a random sample of 300 Latinx immigrants, this mixed methods longitudinal waitlist control group design study with seven time points over 36 months tests the effectiveness of the RIWP intervention and engagement with CBOs to reduce psychological distress, daily stressors, and economic precarity and increase protective factors (social support, access to resources, English proficiency, cultural connectedness). The study also tests the ability of the RIWP intervention and engagement with CBOs to increase access to the direct benefits of structural interventions. This paper reports on the theoretical basis, design, qualitative and quantitative analysis plan, and power for the study. [ABSTRACT FROM AUTHOR]

The World Health Organization recommends that all blood donations be screened for transfusion transmissible infections; these data are currently not incorporated into national disease surveillance efforts. We set out to use routinely collected data from blood donors in Blantyre district, Malawi to explore HIV and syphilis prevalence and identify sero-conversions among repeat donors. We conducted a retrospective cohort analysis of blood donation data collected by the Malawi Blood Transfusion Service from 2015 to 2021. All blood donations were routinely screened for HIV and syphilis. We characterized donor demographics as well as screening outcomes, including identifying sero-conversions among repeat donors who previously tested negative on their last donation. A total of 23,280 donations from 5,051 donors were recorded, with a median frequency of donations of 3 (IQR:2–6). Most donors were male (4,294; 85%) and students (3,262; 64.6%). Prevalence of HIV at first donation was 1.0% (52/5,051) and prevalence of syphilis was 1.6% (80/5,051); 52 HIV sero-conversions and 126 syphilis sero-conversions were identified, indicating an incidence rate per 1,000 person-years of 5.9 (95% CI: 4.7, 7.4) and 13.3 (95% CI:11.4, 15.4) respectively. Students had a lower prevalence of HIV and syphilis but higher risk of syphilis seroconversion. While blood donors are generally considered a low-risk population for HIV and syphilis, we were able to identify relatively high rates of undiagnosed HIV and syphilis infections among donors. Routinely collected data from national blood donation services may be used to better understand local HIV and syphilis epidemiology, with the potential to enhance disease surveillance systems. These findings may be used to identify priority prevention areas and populations in Blantyre district that can inform targeted interventions for improved disease prevention, testing and treatment. [ABSTRACT FROM AUTHOR]

Objectives: To determine how pre-existing conditions contribute to racial disparities in adverse maternal outcomes and incorporate these conditions into models to improve risk prediction for racial minority subgroups. Study design: We used data from the "Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b)" observational cohort study. We defined multimorbidity as the co-occurrence of two or more pre-pregnancy conditions. The primary outcomes of interest were severe preeclampsia, postpartum readmission, and blood transfusion during pregnancy or up to 14 days postpartum. We used weighted Poisson regression with robust variance to estimate adjusted risk ratios and 95% confidence intervals, and we used mediation analysis to evaluate the contribution of the combined effects of pre-pregnancy conditions to racial/ethnic disparities. We also evaluated the predictive performance of our regression models by racial subgroup using the area under the receiver operating characteristic curve (AUC) metric. Results: In the nuMoM2b cohort (n = 8729), accounting for pre-existing conditions attenuated the association between non-Hispanic Black race/ethnicity and risk of severe preeclampsia. Cardiovascular and kidney conditions were associated with risk for severe preeclampsia among all women (aRR, 1.77; CI, 1.61–1.96, and aRR, 1.27; CI, 1.03–1.56 respectively). The mediation analysis results were not statistically significant; however, cardiovascular conditions explained 36.6% of the association between non-Hispanic Black race/ethnicity and severe preeclampsia (p = 0.07). The addition of pre-pregnancy conditions increased model performance for the prediction of severe preeclampsia. Conclusions: Pre-existing conditions may explain some of the association between non-Hispanic Black race/ethnicity and severe preeclampsia. Specific pre-pregnancy conditions were associated with adverse maternal outcomes and the incorporation of comorbidities improved the performance of most risk prediction models. [ABSTRACT FROM AUTHOR]

Introduction: The J9 Plus (J9) maternal-child accompaniment program is based on four pillars: group antenatal care (GANC), group pediatric care, psychosocial support, and community-based care. We aimed to evaluate the impact of the J9 model of care on perinatal outcomes. Methodology: We conducted a convergent mixed methods study of maternal-newborn dyads born in 2019 at Hôpital Universitaire de Mirebalais. Quantitative data was collected retrospectively to compare dyads receiving J9 care to usual care. A secondary analysis of qualitative data described patient perspectives of J9 care. Results: Antenatal care attendance was significantly higher among women in J9 (n = 524) compared to usual care (n = 523), with 490(93%) and 189(36%) having >4 visits, respectively; p <0.001, as was post-partum visit attendance [271(52%) compared to 84(16%), p<0.001] and use of post-partum family planning methods [98(19%) compared to 47(9%), p = 0.003]. Incidence of pre-eclampsia with severe features was significantly lower in the J9 group [44(9%)] compared to the usual care group [73(14%)], p <0.001. Maternal and neonatal mortality and low birth weight did not differ across groups. Cesarean delivery [103(20%) and 82(16%), p<0.001] and preterm birth [118 (24%)] and 80 (17%), p <0.001] were higher in the J9 group compared to usual care, respectively. In the qualitative analysis, ease of access to high-quality care, meaningful social support, and maternal empowerment through education were identified as key contributors to these outcomes. Conclusion: Compared to usual care, the J9 Plus maternal-child accompaniment model of care is associated with increased engagement in antenatal and postpartum care, increased utilization of post-partum family planning, and lower incidence of pre-eclampsia with severe features, which remains a leading cause of maternal mortality in Haiti. The J9 accompaniment approach to care is an empowering model that has the potential to be replicated in similar settings to improve quality of care and outcomes globally. [ABSTRACT FROM AUTHOR]

Social media data provide unprecedented access to discussions of active, naturalistic, and often real-time cannabis use in an era of cannabis policy liberalization. The aim of this study was to explore psychological and environmental correlates of cannabis effects by applying computational social science approaches to a large dataset of unprompted reports of naturalistic cannabis use with corresponding self-reported numerical ratings of subjective highness. Post title text was extracted via the Pushshift dataset from N = 328,865 posts to the r/trees Reddit community, where posters self-assess and disclose how high they feel on a scale from 1 to 10 (M = 6.9, SD = 1.8). Structural topic modelling and Linguistic Inquiry and Word Count (LIWC) dictionary-based approaches were applied to identify (1) frequently discussed topics and (2) text indicative of 5 psychological processes (affective, social, cognitive, perceptual, biological), respectively, as well as to examine relationships between subjective highness and (1) topic prevalence and (2) psychological process word counts. A 40-topic model was selected for interpretation based on semantic coherence and exclusivity. The most discussed topics in a 40-topic model were characterized by references to smoking places, social contexts, positive affect, cognitive states, as well as food and media consumed. In LIWC dictionary analyses, words mentioning affective, social, and cognitive processes were referenced more often than perceptual or body processes. Posters reported greater subjective highness when using language that referred to in-person social environments and lower subjective highness when using language that referred to online social environments and positive affect psychological states. This examination of unprompted online reports of naturalistic cannabis use identified textual content referring to affect and to other people as being associated with perceived effects of cannabis. These affective and social aspects of the cannabis use experience were salient to active posters in this online community and should be integrated into experience sampling methods and behavioral pharmacology research, as well as public health messaging. [ABSTRACT FROM AUTHOR]

Hyperthyroidism is the most common feline endocrinopathy. In hyperthyroid humans, untargeted metabolomic analysis identified persistent metabolic derangements despite achieving a euthyroid state. Therefore, we sought to define the metabolome of hyperthyroid cats and identify ongoing metabolic changes after treatment. We prospectively compared privately-owned hyperthyroid cats (n = 7) admitted for radioactive iodine (I-131) treatment and euthyroid privately-owned control (CON) cats (n = 12). Serum samples were collected before (T0), 1-month (T1), and three months after (T3) I-131 therapy for untargeted metabolomic analysis by MS/MS. Hyperthyroid cats (T0) had a distinct metabolic signature with 277 significantly different metabolites than controls (70 increased, 207 decreased). After treatment, 66 (T1 vs. CON) and 64 (T3 vs. CON) metabolite differences persisted. Clustering and data reduction analysis revealed separate clustering of hyperthyroid (T0) and CON cats with intermediate phenotypes after treatment (T1 & T3). Mevalonate/mevalonolactone and creatine phosphate were candidate biomarkers with excellent discrimination between hyperthyroid and healthy cats. We found several metabolic derangements (e.g., decreased carnitine and α-tocopherol) do not entirely resolve after achieving a euthyroid state after treating hyperthyroid cats with I-131. Further investigation is warranted to determine diagnostic and therapeutic implications for candidate biomarkers and persistent metabolic abnormalities. [ABSTRACT FROM AUTHOR]

Both sexually selected traits and mate preferences for these traits can be context dependent, yet how variation in preferred traits could select for context dependent preferences has rarely been examined. The signal reliability hypothesis predicts that mate preferences vary across contexts (e.g., environments) in relation to the reliability of the information preferred traits provide in those contexts. Extensive variation in copy number of mc4r B alleles on the Y-chromosome that associates with male size in Xiphophorus multilineatus allowed us to use a split-sibling design to determine if male size is more likely to provide information about male genotype (i.e., dam) when males were reared in a warm as compared to a cold environment. We then examined strength of preference for male size by females reared in the same two environments. We found that males were larger in the cold environment, but male size was more variable across dams in the warm environment, and therefore male size would be a more reliable indicator of dam (i.e., genetics) in the warm environment. Females reared in the warm environment had stronger mate preferences based on male size than cold reared females, with a significant influence of dam on strength of preference. Therefore, strength of female preference for male size was influenced by the temperature in which they were reared, with the direction of the difference across treatments supporting the signal reliability hypothesis. Understanding how the reliability of male traits can select for contextual variation in the strength of the female mate preferences will further our discovery of adaptive mate preferences. For example, a relationship between the strength of a female's mate preference and their growth rates was detected in the context where females had a preference based on male size, supporting a hypothesis from previous work with this species of disassortative mating in relation to growth rates to mitigate a documented growth-mortality tradeoff. [ABSTRACT FROM AUTHOR]

Objective: Investigate the cross-sectional association between the psychosocial status of mothers and fathers and the BMI z-scores of their 10 to 12-year-old children. Explore whether this association is mediated by children's diet, physical activity, screen time and sleep. Analyze the moderating effect of the educational levels of both the mother and father on the association. Design: In a cross-sectional study design, children's height and weight were measured following a standardized protocol. Parents completed the validated Depression Anxiety and Stress questionnaire, while diet quality, sports participation, time spent in bed and screen time were assessed through child-report using previously validated questions. Participants: The data for this study were obtained from the Amsterdam Born Children and their Development study, involving children aged 10 to 12 years and both of their parents (N = 1315). Results: The majority, 80%, of the parents were highly educated and born in the Netherlands, and 68% of the children had a healthy BMI. Maternal or paternal psychosocial status was not significantly associated with children's BMI z-score (maternal β -0.0037; 95% CI: -0.008 to 0.0007, paternal β 0.0028; 95% CI: -0.007 to 0.002). Screen time mediated the association between paternal psychosocial status and children's BMI z-score (β = 0.010, 95% CI: 0.002; 0.020). Children's diet, physical activity, and sleep did not mediate the association between paternal psychosocial status and children's BMI z-score. Parental educational level was not a moderator. Conclusions: This research is unique in including four energy balance behaviors and including both mothers and fathers' psychosocial status. Children withfathers experiencing poorer psychosocial status engaged in more screen time which partly explained their higher BMI z-score. [ABSTRACT FROM AUTHOR]

Background: Despite conflicting findings in the current literature regarding the correlation between contraceptives and maternal health consequences, statistical analyses indicate that family planning may decrease the occurrence of such outcomes. Consequently, it is crucial to assess the capability of family planning to mitigate adverse maternal health outcomes. Objectives: This review investigates the effects of modern contraceptive use on maternal health. Search methods: This systematic review is registered on Prospero (CRD42022332783). We searched numerous databases with an upper date limit of February 2022 and no geographical boundaries. Selection criteria: We included observational studies, including cross-sectional, cohort, case-control studies, and non-RCT with a comparison group. We excluded systematic reviews, scoping reviews, narrative reviews, and meta-analyses from the body of this review. Main results: The review included nineteen studies, with five studies reporting a reduction in maternal mortality linked to increased access to family planning resources and contraceptive use. Another three studies examined the impact of contraception on the risk of preeclampsia and our analysis found that preeclampsia risk was lower by approximately 6% among contraceptive users (95% CI 0.82–1.13) compared to non-users. Two studies assessed the effect of hormonal contraceptives on postpartum glucose tolerance and found that low-androgen contraception was associated with a reduced risk of gestational diabetes (OR 0.84, 95% CI 0.58–1.22), while DMPA injection was possibly linked to a higher risk of falling glucose status postpartum (OR 1.42, 95% CI 0.85–2.36). Two studies evaluated high-risk pregnancies and births in contraceptive users versus non-users, with the risk ratio being 30% lower among contraceptive users of any form (95% CI 0.61, 0.80). None of these results were statistically significant except the latter. In terms of adverse maternal health outcomes, certain contraceptives were found to be associated with ectopic pregnancy and pregnancy-related venous thromboembolism through additional analysis. [ABSTRACT FROM AUTHOR]

Background: Cash transfers are a promising but understudied intervention that may protect cognitive function in adults. Although South Africa has a rapidly ageing population, little is known about the nature of association between cash transfers and cognitive function in this setting. Objectives: We leveraged age-eligibility expansions to South Africa's Child Support Grant (CSG) to investigate the association between duration of CSG eligibility and cognitive function of biological mothers of child beneficiaries in South Africa. Methods: We analysed 2014/2015 baseline data from 944 women, aged 40–59 years with at least one CSG-eligible child, enrolled in the population-representative HAALSI cohort in Agincourt, South Africa. Duration of CSG eligibility for each mother was calculated based on the birth dates of all their children and the CSG age-eligibility expansion years (2003–2012). Cognitive function was measured using a cognitive battery administered at the HAALSI baseline interview. Linear regression was used to estimate the association between duration of CSG eligibility, dichotomized as low (≤10 years) and high (>10 years) eligibility, and cognitive function z-scores of the mothers. Results: High vs. low duration of CSG eligibility, was associated with higher cognitive function z-scores in the full sample [β: 0.15 SD units; 95% CI: 0.04, 0.26; p-value = 0.01]. In mothers with one to four lifetime children, but not five or more, high vs. low duration of CSG eligibility, was associated with higher cognitive function z-scores [β: 0.19 SD units; 95% CI: 0.05, 0.34, p-value = 0.02]. Conclusion: Government cash transfers given to support raising children may confer substantial protective effects on the subsequent cognitive function of mothers. Further studies are needed to understand how parity may influence this relationship. Our findings bring evidence to policymakers for designing income supplementation programmes to promote healthy cognitive ageing in low-income settings. [ABSTRACT FROM AUTHOR]

Introduction: Early in the COVID-19 pandemic, Canadian primary care practices rapidly adapted to provide care virtually. Most family physicians lacked prior training or expertise with virtual care. In the absence of formal guidance, they made individual decisions about in-person versus remote care based on clinical judgement, their longitudinal relationships with patients, and personal risk assessments. Our objective was to explore Canadian family physicians' perspectives on the strengths and limitations of virtual care implementation for their patient populations during the COVID-19 pandemic and implications for the integration of virtual care into broader primary care practice. Methods: We conducted semi-structured qualitative interviews with family physicians working in four Canadian jurisdictions (Vancouver Coastal health region, British Columbia; Southwestern Ontario; the province of Nova Scotia; and Eastern Health region, Newfoundland and Labrador). We analyzed interview data using a structured applied thematic approach. Results: We interviewed 68 family physicians and identified four distinct themes during our analysis related to experiences with and perspectives on virtual care: (1) changes in access to primary care; (2) quality and efficacy of care provided virtually; (3) patient and provider comfort with virtual modalities; and (4) necessary supports for virtual care moving forward. Conclusions: The move to virtual care enhanced access to care for select patients and was helpful for family physicians to better manage their panels. However, virtual care also created access challenges for some patients (e.g., people who are underhoused or living in areas without good phone or internet access) and for some types of care (e.g., care that required access to medical devices). Family physicians are optimistic about the ongoing integration of virtual care into broader primary care delivery, but guidance, regulations, and infrastructure investments are needed to ensure equitable access and to maximize quality of care. [ABSTRACT FROM AUTHOR]

We established consensus on practice-based metrics that characterize quality of care for older primary care patients and can be examined using secondary health administrative data. We conducted a two-round RAND/UCLA Appropriateness Method (RAM) study and recruited 10 Canadian clinicians and researchers with expertise relevant to the primary care of elderly patients. Informed by a literature review, the first RAM round evaluated the appropriateness and importance of candidate quality measures in an online questionnaire. Technical definitions were developed for each endorsed indicator to specify how the indicator could be operationalized using health administrative data. In a virtual synchronous meeting, the expert panel offered feedback on the technical specifications for the endorsed indicators. Panelists then completed a second (final) questionnaire to rate each indicator and corresponding technical definition on the same criteria (appropriateness and importance). We used statistical integration to combine technical expert panelists' judgements and content analysis of open-ended survey responses. Our literature search and internal screening resulted in 61 practice-based quality indicators for rating. We developed technical definitions for indicators endorsed in the first questionnaire (n = 55). Following the virtual synchronous meeting and second questionnaire, we achieved consensus on 12 practice-based quality measures across four Priority Topics in Care of the Elderly. The endorsed indicators provide a framework to characterize practice- and population-level encounters of family physicians delivering care to older patients and will offer insights into the outcomes of their care provision. This study presented a case of soliciting expert feedback to develop measurable practice-based quality indicators that can be examined using administrative data to understand quality of care within population-based data holdings. Future work will refine and operationalize the technical definitions established through this process to examine primary care provision for older adults in a particular context (Ontario, Canada). [ABSTRACT FROM AUTHOR]

Evidence to date indicates that compassion and empathy are health-enhancing qualities. Research points to interventions and practices involving compassion and empathy being beneficial, as well as being salient outcomes of contemplative practices such as mindfulness. Advancing the science of compassion and empathy requires that we select measures best suited to evaluating effectiveness of training and answering research questions. The objective of this scoping review was to 1) determine what instruments are currently available for measuring empathy and compassion, 2) assess how and to what extent they have been validated, and 3) provide an online tool to assist researchers and program evaluators in selecting appropriate measures for their settings and populations. A scoping review and broad evidence map were employed to systematically search and present an overview of the large and diverse body of literature pertaining to measuring compassion and empathy. A search string yielded 19,446 articles, and screening resulted in 559 measure development or validation articles reporting on 503 measures focusing on or containing subscales designed to measure empathy and/or compassion. For each measure, we identified the type of measure, construct being measured, in what context or population it was validated, response set, sample items, and how many different types of psychometrics had been assessed for that measure. We provide tables summarizing these data, as well as an open-source online interactive data visualization allowing viewers to search for measures of empathy and compassion, review their basic qualities, and access original citations containing more detail. Finally, we provide a rubric to help readers determine which measure(s) might best fit their context. [ABSTRACT FROM AUTHOR]

Tardigrades, commonly known as 'waterbears', are eight-legged microscopic invertebrates renowned for their ability to withstand extreme stressors, including high osmotic pressure, freezing temperatures, and complete desiccation. Limb retraction and substantial decreases to their internal water stores results in the tun state, greatly increasing their ability to survive. Emergence from the tun state and/or activity regain follows stress removal, where resumption of life cycle occurs as if stasis never occurred. However, the mechanism(s) through which tardigrades initiate tun formation is yet to be uncovered. Herein, we use chemobiosis to demonstrate that tardigrade tun formation is mediated by reactive oxygen species (ROS). We further reveal that tuns are dependent on reversible cysteine oxidation, and that this reversible cysteine oxidation is facilitated by the release of intracellular reactive oxygen species (ROS). We provide the first empirical evidence of chemobiosis and map the initiation and survival of tardigrades via osmobiosis, chemobiosis, and cryobiosis. In vivo electron paramagnetic spectrometry suggests an intracellular release of reactive oxygen species following stress induction; when this release is quenched through the application of exogenous antioxidants, the tardigrades can no longer survive osmotic stress. Together, this work suggests a conserved dependence of reversible cysteine oxidation across distinct tardigrade cryptobioses. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article about shell midden formation in the Farasan Islands, Saudi Arabia. It acknowledges errors in Tables 1 and 2 of the article and provides the correct tables and captions. The document also includes a graph and a table showing radiocarbon dates used to calculate time depth and accumulation rates at different sites. The radiocarbon dates for marine shell samples from the species C. fasciatus range from 4701 to 5698 years before present. The document also presents dates for other species and shows that shell accumulation rates vary between sites, with shoreline sites having faster rates than post-shore sites. [Extracted from the article]

Background: The validated Incremental Shuttle Walk Test (ISWT) is widely used for evaluating maximal exercise capacity, with the distance-walked (IWSD) as the primary outcome. However, there are no normative reference values (NRV) and reference equations to predict ISWD for the Singaporean population. Objectives: This study aims to establish the NRV and reference equations for ISWD in healthy Singaporeans aged 21 to 80 and investigate the determining variables during ISWT. Methods: This cross-sectional study recruited community-dwelling healthy subjects aged 21–80 from the community via convenience sampling. Each subject completed two trials of the ISWT according to the standard protocol. Variables measured during the trials included ISWD, pre-and post-test heart rate (HR), oxygen saturation, blood pressure (BP), modified Borg's dyspnoea score and Borg's rate of perceived exertion (RPE). Results: 199 healthy Singaporean (females = 114, males = 85) participated in the study. The overall median ISWD was 660.0 metres (m) [interquartile range (IQR):440.0–850.0]. The age-stratified mean ISWD ranged from 430.0 m (IQR:350.0–450.0) (aged 60–80) to 480.0 m (IQR:438.0–650.0) (aged 40–59) to 780.0 m (IQR:670.0–960.0) (aged 21–39). Gender, age, weight, height and HR change (highest post-test HR minus pre-test HR) were the most significant variables (p < 0.001). IWSD (m) = 651.4(Height, m) +89.7(Gender, male = 1; female = 0) –6.31(Age, years) –3.61(Weight, kilograms) +2.54(HR change, beats per minute); R2 = 0.741. Previously published ISWT reference equations cannot accurately predict the ISWD in the Singaporean population. Conclusions: This study investigated the ISWD NRV and established reference equations for healthy Singaporeans aged 21–80. The information would be beneficial in setting performance benchmarks to guide physical assessment, intervention and rehabilitation. [ABSTRACT FROM AUTHOR]

Exosomes are emerging as potent and safe delivery carriers for use in vaccinology and therapeutics. A better vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to provide improved, broader, longer lasting neutralization of SARS-CoV-2, a more robust T cell response, enable widespread global usage, and further enhance the safety profile of vaccines given the likelihood of repeated booster vaccinations. Here, we use Capricor's StealthXTM platform to engineer exosomes to express native SARS-CoV-2 spike Delta variant (STX-S) protein on the surface for the delivery of a protein-based vaccine for immunization against SARS-CoV-2 infection. The STX-S vaccine induced a strong immunization with the production of a potent humoral immune response as demonstrated by high levels of neutralizing antibody not only against the delta SARS-CoV-2 virus but also two Omicron variants (BA.1 and BA.5), providing broader protection than current mRNA vaccines. Additionally, both CD4+ and CD8+ T cell responses were increased significantly after treatment. Quantification of spike protein by ELISA showed that only nanograms of protein were needed to induce a potent immune response. This is a significantly lower dose than traditional recombinant protein vaccines with no adjuvant required, which makes the StealthXTM exosome platform ideal for the development of multivalent vaccines with a better safety profile. Importantly, our exosome platform allows novel proteins, or variants in the case of SARS-CoV-2, to be engineered onto the surface of exosomes in a matter of weeks, comparable with mRNA vaccine technology, but without the cold storage requirements necessary for mRNA vaccines. The ability to utilize exosomes for cellular delivery of proteins, as demonstrated by STX-S, has enormous potential to revolutionize vaccinology by rapidly facilitating antigen presentation at an extremely low dose resulting in a potent, broad antibody response. [ABSTRACT FROM AUTHOR]

Introduction: Pregnant people have a higher risk of severe COVID-19 disease. They have been disproportionately impacted by COVID-19 infection control policies, which exacerbated conditions resulting in intimate partner violence, healthcare access, and mental health distress. This project examines the impact of accumulated individual health decisions and describes how perinatal care and health outcomes changed during the COVID-19 pandemic. Objectives: Quantitative strand: Describe differences between 2019, 2021, and 2022 birth groups related to maternal vaccination, perinatal care, and mental health care. Examine the differential impacts on racialized and low-income pregnant people. Qualitative strand: Understand how pregnant people's perceptions of COVID-19 risk influenced their decision-making about vaccination, perinatal care, social support, and mental health. Methods and analysis: This is a Canadian convergent parallel mixed-methods study. The quantitative strand uses a retrospective cohort design to assess birth group differences in rates of Tdap and COVID-19 vaccination, gestational diabetes screening, length of post-partum hospital stay, and onset of depression, anxiety, and adjustment disorder, using administrative data from ICES, formerly the Institute for Clinical Evaluative Sciences (Ontario) and PopulationData BC (PopData) (British Columbia). Differences by socioeconomic and ethnocultural status will also be examined. The qualitative strand employs qualitative description to interview people who gave birth between May 2020- December 2021 about their COVID-19 risk perception and health decision-making process. Data integration will occur during design and interpretation. Ethics and dissemination: This study received ethical approval from McMaster University and the University of British Columbia. Findings will be disseminated via manuscripts, presentations, and patient-facing infographics. Trial registration: Registration: Clinicaltrials.gov registration number: NCT05663762. [ABSTRACT FROM AUTHOR]

Background: To fully leverage the potential of the early care and education (ECE) setting for childhood obesity prevention, initiatives must not intervene solely at the organizational level, but rather they should also address the health needs of the ECE workers. Workers suffer disproportionately high rates of obesity, and have reported low confidence in modeling and promoting healthy eating and activity behaviors. However, information regarding the effectiveness of improving ECE workers' health behaviors or whether such improvements elicit meaningful change in the ECE environment and/or the children in their care is limited. Method: The proposed study will integrate a staff wellness intervention into a nationally recognized, ECE obesity prevention initiative (Go NAPSACC). Go NAPSACC+ Staff Wellness program will be assessed using a clustered randomized controlled trial including 84 ECE centers, 168 workers, and 672 2–5-year-old children. Centers will be randomly assigned to 1) standard "Go NAPSACC" or 2) Go NAPSACC+ Staff Wellness. Outcome measures will assess impact on dietary intake and PA behaviors of 2-5-year-old children at 6 months (primary aim) and 12 months. Secondarily, we will compare the impact of the intervention on centers' implementation of healthy weight practices and the effect on ECE workers' diet quality and PA at 6- and 12 months. Discussion: This trial expects to increase our understanding of how ECE worker's personal health behaviors impact the health behaviors of the children in their care and the ECE environment. Trial registration: ClinicalTrials.gov: NCT05656807, registered on 19 December 2022. Protocol version 1.0, 22 March 2023. [ABSTRACT FROM AUTHOR]

The extent to which mate preferences are adaptive requires a better understanding of the factors that influence variation in mate preferences. Xiphophorus multilineatus is a live-bearing fish with males that exhibit alternative reproductive tactics (courter/sneaker). We examined the influence of a female's genotype (courter vs sneaker lineage), growth rate, and social experience on mate preference for courter as compared to sneaker males. We found that females with a sneaker genotype and slower growth rates had stronger mate preferences for the faster growing courter males than females with a courter genotype, regardless of mating experience with one or both types of males. In addition, the relationship between strength of preference and growth rate depended on a females' genotype; females with sneaker genotypes decreased their preference as their growth rates increased, a pattern that trended in the opposite direction for females from the courter genotypes. Disassortative mating preferences are predicted to evolve when heterozygous offspring benefit from increased fitness. Given male tactical dimorphism in growth rates and a mortality-growth rate tradeoff previously detected in this species, the variation in mating preferences for the male tactics we detected may be under selection to optimize the mortality-growth rate tradeoff for offspring. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the impact and exposure of COVID-19 on parent mental health (e.g., depression, anxiety, and post-traumatic stress disorder (PTSD), for parents of children with hearing loss. The survey was distributed via an electronic survey to families subscribed to a pediatric program listserv as part of a university medical center. Fifty-five percent of parents reported elevated symptoms of anxiety, while 16% scored in the clinically significant range for depression. In addition, 20% of parents reported elevated symptoms of PTSD. Liner regressions found that impact of COVID-19 predicted anxiety symptoms, while both impact and exposure predicted depression and PTSD symptoms. In addition, both impact and exposure predicted COVID related parental distress. Exposure and impact of COVID-19 has had negative consequences on parents of children with hearing loss. Although exposure influenced parental mental health, impact uniquely affected depression and PTSD. Results highlight the need for mental health screening, as well implementation of psychological interventions using telehealth or in-person consultations. Future work should focus on post-pandemic challenges, including long-term psychological functioning due to the established relationship between parental mental health and pediatric outcomes. [ABSTRACT FROM AUTHOR]

Background: The basis of Age-related macular degeneration (AMD) genetic risk has been well documented; however, few studies have looked at genetic biomarkers of disease progression or treatment response within advanced AMD patients. Here we report the first genome-wide analysis of genetic determinants of low-luminance vision deficit (LLD), which is seen as predictive of visual acuity loss and anti-VEGF treatment response in neovascular AMD patients. Methods: AMD patients were separated into small- and large-LLD groups for comparison and whole genome sequencing was performed. Genetic determinants of LLD were assessed by common and rare variant genetic analysis. Follow-up functional analysis of rare coding variants identified by the burden test was then performed in vitro. Results: We identified four coding variants in the CIDEC gene. These rare variants were only present in patients with a small LLD, which has been previously shown to indicate better prognosis and better anti-VEGF treatment response. Our in vitro functional characterization of these CIDEC alleles revealed that all decrease the binding affinity between CIDEC and the lipid droplet fusion effectors PLIN1, RAB8A and AS160. The rare CIDEC alleles all cause a hypomorphic defect in lipid droplet fusion and enlargement, resulting in a decreased fat storage capability in adipocytes. Conclusions: As we did not detect CIDEC expression in the ocular tissue affected by AMD, our results suggest that the CIDEC variants do not play a direct role in the eye and influence low-luminance vision deficit via an indirect and systemic effect related to fat storage capacity. [ABSTRACT FROM AUTHOR]

Throughout the COVID-19 pandemic, valuable datasets have been collected on the effects of the virus SARS-CoV-2. In this study, we combined whole genome sequencing data with clinical data (including clinical outcomes, demographics, comorbidity, treatment information) for 929 patient cases seen at a large UK hospital Trust between March 2020 and May 2021. We identified associations between acute physiological status and three measures of disease severity; admission to the intensive care unit (ICU), requirement for intubation, and mortality. Whilst the maximum National Early Warning Score (NEWS2) was moderately associated with severe COVID-19 (A = 0.48), the admission NEWS2 was only weakly associated (A = 0.17), suggesting it is ineffective as an early predictor of severity. Patient outcome was weakly associated with myriad factors linked to acute physiological status and human genetics, including age, sex and pre-existing conditions. Overall, we found no significant links between viral genomics and severe outcomes, but saw evidence that variant subtype may impact relative risk for certain sub-populations. Specific mutations of SARS-CoV-2 appear to have little impact on overall severity risk in these data, suggesting that emerging SARS-CoV-2 variants do not result in more severe patient outcomes. However, our results show that determining a causal relationship between mutations and severe COVID-19 in the viral genome is challenging. Whilst improved understanding of the evolution of SARS-CoV-2 has been achieved through genomics, few studies on how these evolutionary changes impact on clinical outcomes have been seen due to complexities associated with data linkage. By combining viral genomics with patient records in a large acute UK hospital, this study represents a significant resource for understanding risk factors associated with COVID-19 severity. However, further understanding will likely arise from studies of the role of host genetics on disease progression. [ABSTRACT FROM AUTHOR]

Background: Reductions in hemoglobin A1c (HbA1C) have been associated with improved cardiovascular outcomes and savings in medical expenditures. One public health approach has involved pharmacists within primary care settings. The objective was to assess change in HbA1C from baseline after 3–5 months of follow up in pharmacist-managed cardiovascular risk reduction (CVRR) clinics. Methods: This retrospective cohort chart review occurred in eight pharmacist-managed CVRR federally qualified health clinics (FQHC) in Indiana, United States. Data were collected from patients seen by a CVRR pharmacist within the timeframe of January 1, 2015 through February 28, 2020. Data collected include: demographic characteristics and clinical markers between baseline and follow-up. HbA1C from baseline after 3 to 5 months was assessed with pared t-tests analysis. Other clinical variables were assessed and additional analysis were performed at 6–8 months. Additional results are reported between 9 months and 36 months of follow up. Results: The primary outcome evaluation included 445 patients. Over 36 months of evaluation, 3,803 encounters were described. Compared to baseline, HbA1C was reduced by 1.6% (95%CI -1.8, -1.4, p<0.01) after 3–5 months of CVRR care. Reductions in HbA1C persisted at 6–8 months with a reduction of 1.8% ([95%CI -2.0, -1.5] p<0.01). The follow-up losses were 29.5% at 3–5 months and 93.2% at 33–36 months. Conclusions: Our study augments the existing literature by demonstrating the health improvement of pharmacist-managed CVRR clinics. The great proportion of loss to follow-up is a limitation of this study to be considered. Additional studies exploring the expansion of similar models may amplify the public health impact of pharmacist-managed CVRR services in primary care sites. [ABSTRACT FROM AUTHOR]

The number of new cases of cancer is increasing each year, and rates of diabetes mellitus are also increasing dramatically over time. It is not an unusual occurrence for an individual to have both cancer and diabetes at the same time, given they are both individually common, and that one condition can increase the risk of the other. In this manuscript, we use national-level diabetes (Virtual Diabetes Register) and cancer (New Zealand Cancer Registry) data on nearly five million individuals over 44 million person-years of follow-up to examine the occurrence of cancer amongst a national prevalent cohort of patients with diabetes. We completed this analysis separately by cancer for the 24 most commonly diagnosed cancers in Aotearoa New Zealand, and then compared the occurrence of cancer among those with diabetes to those without diabetes. We found that the rate of cancer was highest amongst those with diabetes for 21 of the 24 most common cancers diagnosed over our study period, with excess risk among those with diabetes ranging between 11% (non-Hodgkin's lymphoma) and 236% (liver cancer). The cancers with the greatest difference in incidence between those with diabetes and those without diabetes tended to be within the endocrine or gastrointestinal system, and/or had a strong relationship with obesity. However, in an absolute sense, due to the volume of breast, colorectal and lung cancers, prevention of the more modest excess cancer risk among those with diabetes (16%, 22% and 48%, respectively) would lead to a substantial overall reduction in the total burden of cancer in the population. Our findings reinforce the fact that diabetes prevention activities are also cancer prevention activities, and must therefore be prioritised and resourced in tandem. [ABSTRACT FROM AUTHOR]

Predicting 30-day procedure-related mortality risk and 30-day unplanned readmission in patients undergoing lower extremity endovascular interventions for peripheral artery disease (PAD) may assist in improving patient outcomes. Risk prediction of 30-day mortality can help clinicians identify treatment plans to reduce the risk of death, and prediction of 30-day unplanned readmission may improve outcomes by identifying patients who may benefit from readmission prevention strategies. The goal of this study is to develop machine learning models to stratify risk of 30-day procedure-related mortality and 30-day unplanned readmission in patients undergoing lower extremity infra-inguinal endovascular interventions. We used a cohort of 14,444 cases from the American College of Surgeons National Surgical Quality Improvement Program database. For each outcome, we developed and evaluated multiple machine learning models, including Support Vector Machines, Multilayer Perceptrons, and Gradient Boosting Machines, and selected a random forest as the best-performing model for both outcomes. Our 30-day procedure-related mortality model achieved an AUC of 0.75 (95% CI: 0.71–0.79) and our 30-day unplanned readmission model achieved an AUC of 0.68 (95% CI: 0.67–0.71). Stratification of the test set by race (white and non-white), sex (male and female), and age (≥65 years and <65 years) and subsequent evaluation of demographic parity by AUC shows that both models perform equally well across race, sex, and age groups. We interpret the model globally and locally using Gini impurity and SHapley Additive exPlanations (SHAP). Using the top five predictors for death and mortality, we demonstrate differences in survival for subgroups stratified by these predictors, which underscores the utility of our model. [ABSTRACT FROM AUTHOR]

With Antarctic expeditioners popularly portrayed in the media during the pandemic as both heroic stalwarts better equipped than any other people to deal with the rigours of isolation and, paradoxically, the only people untouched by the virus, it was all too easy to ignore the actual experiences of those working in the continent. Drawing on the experiences of expeditioners in the Australian Antarctic Program from 2019–21, this article provides a counter to popular media perspective by exploring how COVID-19 protocols–including quarantine and social distancing–affected expeditioners' individual well-being and their experiences of the social environment. We argue that Antarctic life during COVID-19 has not been as detached from the rest of the world nor as heroic as the popular media has suggested, but nonetheless provides important insights for survival in isolated, confined, and extreme environments (ICE) and non-ICE environments at a time of pandemic. [ABSTRACT FROM AUTHOR]

Amanzi Springs is a series of inactive thermal springs located near Kariega in the Eastern Cape of South Africa. Excavations in the 1960s exposed rare, stratified Acheulian-bearing deposits that were not further investigated over the next 50 years. Reanalysis of the site and its legacy collection has led to a redefined stratigraphic context for the archaeology, a confirmed direct association between Acheulian artefacts and wood, as well as the first reliable age estimates for the site. Thermally transferred optically stimulated luminescence and post-infrared infrared stimulated luminescence dating indicates that the Acheulian deposits from the Amanzi Springs Area 1 spring eye formed during Marine Isotope Stage (MIS) 11 at ~ 404–390 ka. At this time, higher sea levels of ~13-14m would have placed Amanzi Springs around 7 km from a ria that would have formed along what is today the Swartkops River, and which likely led to spring reactivation. This makes the Amanzi Springs Area 1 assemblage an unusual occurrence of a verified late occurring, seaward, open-air Acheulian occupation. The Acheulian levels do not contain any Middle Stone Age (MSA) elements such as blades and points that have been documented in the interior of South Africa at this time. However, a small number of stone tools from the upper layers of the artefact zone, and originally thought of as intrusive, have been dated to ~190 ka, at the transition between MIS 7 to 6, and represent the first potential MSA identified at the site. [ABSTRACT FROM AUTHOR]

Multipurpose prevention technologies (MPTs), which prevent sexually transmitted infection(s) and unintended pregnancy, are highly desirable to women. In this randomized, placebo-controlled, phase I study, women used a placebo or tenofovir (TFV) and levonorgestrel (LNG) intravaginal ring (IVR), either continuously or cyclically (three, 28-day cycles with a 3 day interruption in between each cycle), for 90 days. Sixty-eight women were screened; 47 were randomized to 4 arms: TFV/LNG or placebo IVRs used continuously or cyclically (4:4:1:1). Safety was assessed by adverse events and changes from baseline in mucosal histology and immune mediators. TFV concentrations were evaluated in multiple compartments. LNG concentration was determined in serum. Modeled TFV pharmacodynamic antiviral activity was evaluated in vaginal and rectal fluids and cervicovaginal tissue ex vivo. LNG pharmacodynamics was assessed with cervical mucus quality and anovulation. All IVRs were safe with no serious adverse events nor significant changes in genital tract histology, immune cell density or secreted soluble proteins from baseline. Median vaginal fluid TFV concentrations were >500 ng/mg throughout 90d. TFV-diphosphate tissue concentrations exceeded 1,000 fmol/mg within 72hrs of IVR insertion. Mean serum LNG concentrations exceeded 200 pg/mL within 2h of TFV/LNG use, decreasing quickly after IVR removal. Vaginal fluid of women using TFV-containing IVRs had significantly greater inhibitory activity (87–98% versus 10% at baseline; p<0.01) against HIV replication in vitro. There was a >10-fold reduction in HIV p24 antigen production from ectocervical tissues after TFV/LNG exposure. TFV/LNG IVR users had significantly higher rates of anovulation, lower Insler scores and poorer/abnormal cervical mucus sperm penetration. Most TFV/LNG IVR users reported no change in menstrual cycles or fewer days of and/or lighter bleeding. All IVRs were safe. Active rings delivered high TFV concentrations locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. Trial registration: ClinicalTrials.gov #NCT03279120. [ABSTRACT FROM AUTHOR]