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BACKGROUND: The COVID-19 pandemic has caused over 68.7 million infections and 1.35 million deaths in South America. There are limited data on SARS-CoV-2 seropositivity and its determinants from Andean countries prior to mass vaccinations against COVID-19. OBJECTIVE: To estimate SARS-CoV-2 seropositivity and its determinants before vaccination in occupational groups of adults presumed to have different levels of exposure and associations with potential symptomatology. METHODS: We measured seropositivity of anti-SARS-CoV-2 IgG antibodies in a cross-sectional study of vaccine-naïve adults aged 18 years and older, recruited within three occupational risk groups (defined as low [LR], moderate [MR], and high [HR]) between January and September 2021 in two Andean cities in Ecuador. Associations with risk factors were estimated using logistic regression. RESULTS: In a sample of 882 adults, IgG seropositivity for the three different occupational risk groups was 39.9% (CI 95% 35.3-44.6), 74.6% (CI 95% 66.4-81.4), and 39.0% (CI 95% 34.0-44.4) for the HR, MR, and LR groups, respectively. History of an illness with loss of taste and/or smell was significantly associated with seropositivity in all occupational groups, with adjusted ORs of 14.31 (95%CI, 5.83-35.12; p

BACKGROUND: Benfotiamine provides an important novel therapeutic direction in Alzheimers disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. OBJECTIVE: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. METHODS: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. CONCLUSION: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

[This corrects the article DOI: 10.1371/journal.pone.0265254.].

BACKGROUND: Foeniculum vulgare, F. vulgare, commonly known as fennel, is believed to be one of the worlds oldest medicinal herbs and has been exploited by people for centuries as a nutritional aid for digestive disorders. In many southeast Asian countries, it is ingested as an after-meal snack, mukhvas, due to its breath-freshening and digestive aid properties. F. vulgare is used in some countries, such as Iran, as a complementary and alternative treatment for inflammatory bowel disease (IBD). METHODS: This study investigated the effects of fennel seed extract on intestinal epithelium barrier function and the Signal Transducer and Activator of Transcription (STAT) pathway. This pathway is active in inflammatory bowel disease. To study the protective effects of fennel seed extract in vitro, monolayers derived from the T84 colonic cell line were challenged with interferon-gamma (IFN-γ) and monitored with and without fennel seed extract. To complement our in vitro studies, the dextran sodium sulfate induced murine colitis model was employed to ascertain whether the protective effect of fennel seed extract can be recapitulated in vivo. RESULTS: Fennel seed extract was shown to exert a protective effect on transepithelial electrical resistance (TEER) in both T84 and murine models and showed increases in tight junction-associated mRNA in T84 cell monolayers. Both models demonstrated significant decreases in phosphorylated STAT1 (pSTAT1), indicating reduced activation of the STAT pathway. Additionally, mice treated with fennel seed showed significantly lower ulcer indices than control mice. CONCLUSIONS: We conclude barrier function of the gastrointestinal tract is improved by fennel seed extract, suggesting the potential utility of this agent as an alternative or adjunctive therapy in IBD.

The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency differences and population-specific risk alleles identified. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals as well as 2435 Black and African American individuals. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have utilized the differing linkage disequilibrium patterns inherent to these populations to identify an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus with a decrease of ~5.5% in Hispanics and ~0.4% in African Americans. We have identified several susceptibility variants, including within the MICB gene region, which show global ancestry risk modification and indicate ancestral differences which may be due in part to correlated environmental factors. We have also identified several susceptibility variants for which MS risk is modified by local ancestry and indicate true ancestral genetic differences; including HLA-DQB1*06:02 for which MS risk for European allele carriers is almost two times the risk for African allele carriers. These results validate the importance of investigating MS susceptibility at an ancestral level and offer insight into the epidemiology of MS phenotypic diversity.

IntroductionThe NIH All of Us Research Program will have the scale and scope to enable research for a wide range of diseases, including cancer. The program's focus on diversity and inclusion promises a better understanding of the unequal burden of cancer. Preliminary cancer ascertainment in the All of Us cohort from two data sources (self-reported versus electronic health records (EHR)) is considered.Materials and methodsThis work was performed on data collected from the All of Us Research Program's 315,297 enrolled participants to date using the Researcher Workbench, where approved researchers can access and analyze All of Us data on cancer and other diseases. Cancer case ascertainment was performed using data from EHR and self-reported surveys across key factors. Distribution of cancer types and concordance of data sources by cancer site and demographics is analyzed.Results and discussionData collected from 315,297 participants resulted in 13,298 cancer cases detected in the survey (in 89,261 participants), 23,520 cancer cases detected in the EHR (in 203,813 participants), and 7,123 cancer cases detected across both sources (in 62,497 participants). Key differences in survey completion by race/ethnicity impacted the makeup of cohorts when compared to cancer in the EHR and national NCI SEER data.ConclusionsThis study provides key insight into cancer detection in the All of Us Research Program and points to the existing strengths and limitations of All of Us as a platform for cancer research now and in the future.

Artificial intelligence and machine learning (AI/ML) is becoming increasingly more accessible to biomedical researchers with significant potential to transform biomedicine through optimization of highly-accurate predictive models and enabling better understanding of disease biology. Automated machine learning (AutoML) in particular is positioned to democratize artificial intelligence (AI) by reducing the amount of human input and ML expertise needed. However, successful translation of AI/ML in biomedicine requires moving beyond optimizing only for prediction accuracy and towards establishing reproducible clinical and biological inferences. This is especially challenging for clinical studies on rare disorders where the smaller patient cohorts and corresponding sample size is an obstacle for reproducible modeling results. Here, we present a model-agnostic framework to reinforce AutoML using strategies and tools of explainable and reproducible AI, including novel metrics to assess model reproducibility. The framework enables clinicians to interpret AutoML-generated models for clinical and biological verifiability and consequently integrate domain expertise during model development. We applied the framework towards spinal cord injury prognostication to optimize the intraoperative hemodynamic range during injury-related surgery and additionally identified a strong detrimental relationship between intraoperative hypertension and patient outcome. Furthermore, our analysis captured how evolving clinical practices such as faster time-to-surgery and blood pressure management affect clinical model development. Altogether, we illustrate how expert-augmented AutoML improves inferential reproducibility for biomedical discovery and can ultimately build trust in AI processes towards effective clinical integration.

BackgroundThe HEALing Communities Study (HCS) included health campaigns as part of a community-engaged intervention to reduce opioid-related overdose deaths in 67 highly impacted communities across Kentucky, Massachusetts, New York, and Ohio. Five campaigns were developed with community input to provide information on opioid use disorder (OUD) and overdose prevention, reduce stigma, and build demand for evidence-based practices (EBPs). An evaluation examined the recognition of campaign messages about naloxone and whether stigma and efficacy beliefs regarding OUD treatment and naloxone changed in HCS intervention communities.MethodsData were collected through surveys offered on Facebook/Instagram to members of communities participating in the HCS intervention and wait-list control communities.ResultsParticipants in HCS intervention communities reported a reduction in stigma regarding OUD and increased efficacy beliefs regarding naloxone associated with recognition of campaign messages. However, this finding is cautiously interpreted as there was no clear evidence for recognition differences between the treatment/control conditions.ConclusionStudy findings indicate associations between campaign message recognition and positive outcomes. Results also highlight possible challenges concerning evaluations of social media campaigns using conventional evaluation techniques.Trial registrationClinicalTrials.gov NCT04111939.

[This corrects the article DOI: 10.1371/journal.pone.0280014.].

The emergence of SARS-CoV-2 variants presents challenges to vaccine effectiveness, underlining the necessity for next-generation vaccines with multiple antigens beyond the spike protein. Here, we investigated a multiantigenic booster containing spike and a chimeric construct composed of nucleoprotein (N) and membrane (M) proteins, comparing its efficacy to a spike-only booster against Omicron BA.5 in K18-hACE2 mice. Initially, mice were primed and boosted with Beta (B.1.351) spike-only mRNA, showing strong spike-specific T cell responses and neutralizing antibodies, albeit with limited cross-neutralization to Omicron variants. Subsequently, a spike-NM multiantigenic vaccine was then examined as a second booster dose for protection in hACE2-transgenic mice. Mice receiving either homologous spike-only or heterologous spike-NM booster had nearly complete inhibition of infectious virus shedding in oral swabs and reduced viral burdens in both lung and nasal tissues following BA.5 challenge. Examination of lung pathology further revealed that both spike-only and spike-NM boosters provided comparable protection against inflammatory infiltrates and fibrosis. Moreover, the spike-NM booster demonstrated neutralization efficacy in a pseudovirus assay against Wuhan-Hu-1, Beta, and Omicron variants akin to the spike-only booster. These findings indicate that supplementing spike with additional SARS-CoV-2 targets in a booster immunization confers equivalent immunity and protection against Omicron BA.5. This work highlights a promising strategy for individuals previously vaccinated with spike-only vaccines, potentially offering enhanced protection against emerging coronaviruses.

[This corrects the article DOI: 10.1371/journal.pone.0264956.].

BackgroundRoutine health check-ups may improve adolescent health, but global guidelines are lacking. Phase 1 of the WHO-coordinated Y-Check Research Programme involved three African cities to co-produce a programme of adolescent health check-ups. We describe a systematic approach to developing a routine adolescent health check-ups and wellbeing programme (Y-Check) to contribute evidence on whether adolescent health check-ups should be part of routine health services in Ghana.MethodsY-Check Phase 1 was conducted in four communities in Cape Coast Ghana, over two stages using a variety of methods: (a) needs assessment and landscape analysis on the health of adolescents (existing policies/programmes, school system, adolescent health conditions) was conducted through desk-review and interviews with key informants to identify the potential content, delivery strategy and settings for adolescent health check-ups in this context; (b) co-designing the Y-Check intervention framework through person-centred participatory workshops and a consensus-building workshop with multiple stakeholders, including adolescents (10-19 years) and their parents. The study was conducted between January 2020 and October 2020.ResultsThe Y-Check intervention consists of two check-ups with content that is tailored to the needs of younger adolescents and older adolescents; delivered at both school and community settings by a team of trained staff in multiple steps involving up to four stations. Y-Check includes a referral system for adolescents with any problems that cannot be investigated or treated on-the-spot.ConclusionsOur systematic approach to co-producing Y-Check has resulted in an intervention whose content and structure is determined by the local context, and which was adjudged by multiple stakeholders to be likely to be both useful and acceptable, and which builds on best practice. As a logical next step, the Y-Check will be subjected to pilot testing and implementation research to rigorously evaluate the feasibility, acceptability, coverage, yield of previously undiagnosed conditions and cost of these health check-ups.

Dementia is characterized by a decline in memory and thinking that is significant enough to impair function in activities of daily living. Patients seen in dementia specialty clinics are highly heterogenous with a variety of different symptoms that progress at different rates. Recent research has focused on finding data-driven subtypes for revealing new insights into dementia's underlying heterogeneity, rather than assuming that the cohort is homogenous. However, current studies on dementia subtyping have the following limitations: (i) focusing on AD-related dementia only and not examining heterogeneity within dementia as a whole, (ii) using only cross-sectional baseline visit information for clustering and (iii) predominantly relying on expensive imaging biomarkers as features for clustering. In this study, we seek to overcome such limitations, using a data-driven unsupervised clustering algorithm named SillyPutty, in combination with hierarchical clustering on cognitive assessment scores to estimate subtypes within a real-world clinical dementia cohort. We use a longitudinal patient data set for our clustering analysis, instead of relying only on baseline visits, allowing us to explore the ongoing temporal relationship between subtypes and disease progression over time. Results showed that subtypes with very mild or mild dementia were more heterogenous in their cognitive profiles and risk of disease progression.

ObjectiveHypoglycemia is a major concern in type 2 diabetes (T2DM), but little is known about its likelihood compared across common therapies. We compared the likelihood of hypoglycemia among metformin-treated patients with T2DM randomized to the addition of one of 4 common therapies.Research design & methodsRandomized, controlled trial of 5,047 participants with T2DM of 7.5% (>58.5 mmol/mol) was confirmed, rescue glargine and/or aspart insulin was added. We conducted a per-protocol analysis of 4,830, who attended at least one post-baseline visit and took at least one dose of assigned study medication. We assessed severe hypoglycemia events reported throughout the entire study. At quarterly visits, all participants were asked about hypoglycemic symptoms within the last 30 days, and those in the glargine and glimepiride groups were asked for any measured glucose ResultsWhile participants were taking their assigned medications, severe hypoglycemia occurred in 10 (0.8%), 16 (1.3%), 6 (0.5%), and 4 (0.3%), (pConclusionsIn metformin-treated patients with T2DM who add a second medication, hypoglycemia is most likely with addition of glimepiride, less with glargine, and least likely with liraglutide and sitagliptin.Trial registrationClinicalTrials.gov Identifier: NCT01794143.

[This corrects the article DOI: 10.1371/journal.pone.0277267.].

Immune literacy garnered significant attention in recent years due to the threat posed by emerging infectious diseases. The pace of immunological discoveries and their relevance to society are substantial yet coordinated educational efforts have been rare. This motivated us to create a task force of educators to reflect on pedagogical approaches to teaching immunology and to draft, develop, and evaluate key competencies for undergraduate immunology education. The research questions addressed include: 1) Which competencies are considered important by educators? 2) Are the illustrative skills clear, accurate and well aligned with the core competencies listed in the Vision and Change report?; 3) What are the concerns of immunology educators about competencies and skills? We collected data on the draft competencies using surveys, focus groups, and interviews. The iterative revision phase followed the community review phase before finalizing the framework. Here, we report a hierarchical learning framework, with six core competencies, twenty illustrative skills, and companion immunology-specific example learning outcomes. Predominant themes from interviews and focus groups, which informed revisions of this framework are shared. With the growing need for immunology education across the sciences, the ImmunoSkills Guide and accompanying discussion can be used as a resource for educators, administrators and policymakers.

People with an intellectual disability face inequality accessing healthcare that extends to end-of-life care. Furthermore, end-of-life care for people with an intellectual disability is more complex than that for the general population. This protocol sets out how our review will explore the available evidence and identify the key characteristics of care that are required for people with an intellectual disability to have a good end-of-life experience. A critical interpretive synthesis approach will be adopted, combining some elements of a systematic review with interpretive synthesis. This approach has been selected as it allows a diverse body of literature to be considered. Furthermore, it is compatible with theory generation allowing new insights to emerge in an iterative process. Electronic databases and grey literature sources will be searched using pre-defined search terms. Following initial title and abstract screening, eligible papers will undergo full text screening. Papers that are deemed to be 'fatally flawed' will be excluded and remaining papers appraised for relevance. Resultant papers will be included in the sampling frame from which data extraction will occur. An existing framework outlining key factors in the provision of excellent end-of-life care to people with an intellectual disability will be used to support data extraction and synthesis. Data extracted will be integrated into a synthesising argument in the form of a theoretical framework. This will identify the key characteristics in the provision of care that are required for people with an intellectual disability to have a good end-of-life experience. The developing theoretical framework will guide further selection of relevant literature to fill any conceptual gaps until saturation is reached. Our review will add to the existing body of evidence, shedding light on the key factors necessary in the provision of care to ensure that people with an intellectual disability have a good end-of-life experience.

Environmental exposure to cold is increasingly being associated with changes in metabolism. We developed and tested the hypothesis that exposure to cold drives systemic effects in lipid metabolism. Specifically, (i) that energy storage and provision adapts to the cold by altering triglyceride distribution and (ii) that membranes adapt to cold conditions by becoming more unsaturated. These hypotheses were designed to identify the underlying mechanisms that govern the response of mammalian systems to cold. To test these hypotheses, we used a metabolic network analysis. An established model of cold exposure was used, from which lipidomics data that represents the system was collected. The network analysis showed that triglyceride metabolism is altered on exposure to cold, with several smaller effects that are not straightforward, such as changes to the abundance and distribution of odd chain fatty acids. The range and profile of phosphatidylcholine and phosphatidylinositol were modified, but there was little change in phosphatidylethanolamine or sphingomyelin. These results support the hypothesis, and show that exposure to cold is a system-wide phenomenon that requires or drives changes across a range of metabolic pathways.

Stress responses play a vital role in cellular survival against environmental challenges, often exploited by cancer cells to proliferate, counteract genomic instability, and resist therapeutic stress. Heat shock factor protein 1 (HSF1), a central transcription factor in stress response pathways, exhibits markedly elevated activity in cancer. Despite extensive research into the transcriptional role of HSF1, the mechanisms underlying its activation remain elusive. Upon exposure to conditions that induce protein damage, monomeric HSF1 undergoes rapid conformational changes and assembles into trimers, a key step for DNA binding and transactivation of target genes. This study investigates the role of HSF1 as a sensor of proteotoxic stress conditions. Our findings reveal that purified HSF1 maintains a stable monomeric conformation independent of molecular chaperones in vitro. Moreover, while it is known that heat stress triggers HSF1 trimerization, a notable increase in trimerization and DNA binding was observed in the presence of protein-based crowders. Conditions inducing protein misfolding and increased protein crowding in cells directly trigger HSF1 trimerization. In contrast, proteosynthesis inhibition, by reducing denatured proteins in the cell, prevents HSF1 activation. Surprisingly, HSF1 remains activated under proteotoxic stress conditions even when bound to Hsp70 and Hsp90. This finding suggests that the negative feedback regulation between HSF1 and chaperones is not directly driven by their interaction but is realized indirectly through chaperone-mediated restoration of cytoplasmic proteostasis. In summary, our study suggests that HSF1 serves as a molecular crowding sensor, trimerizing to initiate protective responses that enhance chaperone activities to restore homeostasis.

BackgroundHailey-Hailey disease (HHD) is a rare autosomal dominant skin disease caused by mutations in the ATP2C1 gene, which encodes the secretory Ca2+/Mn2+-ATPase (SPCA1) pump in the Golgi apparatus. Although ATP2C1 is ubiquitously expressed in the body, possible extracutaneous manifestations of HHD are unknown. However, dysfunction of the Golgi apparatus not specifically coupled to ATP2C1 has been associated with heart disease.ObjectiveTo investigate the association between HHD and common heart disease in a Swedish, population-based cohort.MethodsWe conducted a population-based cohort study based on a linkage of Swedish nationwide registers to investigate the relationship between HHD and heart disease. We have been granted ethical approval from the Swedish Ethical Review Authority to conduct this study. The patients in this manuscript have given written informed consent to the publication of their case details. A total of 342 individuals with an ICD-10 diagnosis of HHD (Q82.8E) were identified and matched with randomly selected comparison individuals without HHD on a 1:100 ratio. Furthermore, in a separate clinical cohort we matched 23 HHD patients for age, sex, and BMI with control subjects to examine electrocardiogram parameters, electrolytes, and cardiovascular biomarkers.ResultsCompared with individuals without HHD, individuals with HHD had an excess risk of arrhythmia (RR 1.4, CI 1.0-2.0), whereas no increased risks of myocardial infarction (RR 1.1, CI 0.6-1.7) or heart failure (RR 1.0, CI 0.6-1.6; Table 1) were found. We found no difference in ECG parameters, cardiovascular biomarkers, and electrolytes in the clinical subset.ConclusionThis study reveals that HHD is associated with an increased risk of arrhythmia and represents the first data of any extracutaneous comorbidity in HHD. Thus, HHD may be a systemic disease. Our findings also shed light on the importance of the Golgi apparatus' Ca2+/Mn2+ homeostasis in common heart disease.

Stable isotope data have made pivotal contributions to nearly every discipline of the physical and natural sciences. As the generation and application of stable isotope data continues to grow exponentially, so does the need for a unifying data repository to improve accessibility and promote collaborative engagement. This paper provides an overview of the design, development, and implementation of IsoBank (www.isobank.org), a community-driven initiative to create an open-access repository for stable isotope data implemented online in 2021. A central goal of IsoBank is to provide a web-accessible database supporting interdisciplinary stable isotope research and educational opportunities. To achieve this goal, we convened a multi-disciplinary group of over 40 analytical experts, stable isotope researchers, database managers, and web developers to collaboratively design the database. This paper outlines the main features of IsoBank and provides a focused description of the core metadata structure. We present plans for future database and tool development and engagement across the scientific community. These efforts will help facilitate interdisciplinary collaboration among the many users of stable isotopic data while also offering useful data resources and standardization of metadata reporting across eco-geoinformatics landscapes.

Endometriosis and provoked vestibulodynia (PVD) are prevalent pain conditions among women of reproductive age, significantly impacting their quality of life and psychological well-being. However, comprehensive evidence regarding the lifelong health and socioeconomic outcomes for these individuals remains scarce. Additionally, many prior studies rely on limited and sometimes unrepresentative samples. This study aims to inform on the long-term consequences of these disorders by examining health, fertility, and employment outcomes in a cohort of women diagnosed with endometriosis and/or PVD, tracing their experiences from childhood to their 40s. Leveraging nationwide administrative data from Sweden and employing a matched case-control design, we investigate both similarities and differences between women with these diagnoses and those without. Our findings indicate that women diagnosed with endometriosis and/or PVD demonstrate elevated healthcare utilization patterns, commencing in their early teenage years and progressively increasing over time. Notably, disparities in labor market outcomes emerge in their 20s, showcasing lower labor earnings and a rise in sickness benefit receipt. Moreover, our results show a higher likelihood among these women to experience mental health disorders and concurrent chronic pain diseases, as well as infertility. While the association between endometriosis and infertility is well-documented, this study offers novel insights into a potential similar link between PVD and infertility. Our study informs healthcare professionals and policymakers about the considerable burden of compromised health, adverse psychosocial well-being, and reduced productivity in the labor market faced by young women with these common pain conditions. These findings underscore the urgency of addressing the multifaceted challenges encountered by individuals diagnosed with endometriosis and PVD across their lifespan.

BackgroundMild stroke affects more than half the stroke population, yet there is limited evidence characterizing cognition over time in this population, especially with predictive approaches applicable at the individual-level. We aimed to identify patterns of recovery and the best combination of demographic, clinical, and lifestyle factors predicting individual-level cognitive state at 3- and 12-months after mild stroke.MethodsIn this prospective cohort study, the Montreal Cognitive Assessment (MoCA) was administered at 3-7 days, 3- and 12-months post-stroke. Raw changes in MoCA and impairment rates (defined as MoCAResultsParticipants' (n = 119) MoCA scores improved from baseline to 3-months (pConclusionMore than half of mild-stroke survivors are at risk of cognitive decline one year after stroke, even when preceded by a significantly improving pattern in the first 3-months of recovery. Physical activity was the only modifiable factor independently associated with cognitive recovery. Individual-level prediction methods may inform the timing and personalized application of future interventions to maximize cognitive recovery post-stroke.

BackgroundThe COVID-19 pandemic has caused over 68.7 million infections and 1.35 million deaths in South America. There are limited data on SARS-CoV-2 seropositivity and its determinants from Andean countries prior to mass vaccinations against COVID-19.ObjectiveTo estimate SARS-CoV-2 seropositivity and its determinants before vaccination in occupational groups of adults presumed to have different levels of exposure and associations with potential symptomatology.MethodsWe measured seropositivity of anti-SARS-CoV-2 IgG antibodies in a cross-sectional study of vaccine-naïve adults aged 18 years and older, recruited within three occupational risk groups (defined as low [LR], moderate [MR], and high [HR]) between January and September 2021 in two Andean cities in Ecuador. Associations with risk factors were estimated using logistic regression.ResultsIn a sample of 882 adults, IgG seropositivity for the three different occupational risk groups was 39.9% (CI 95% 35.3-44.6), 74.6% (CI 95% 66.4-81.4), and 39.0% (CI 95% 34.0-44.4) for the HR, MR, and LR groups, respectively. History of an illness with loss of taste and/or smell was significantly associated with seropositivity in all occupational groups, with adjusted ORs of 14.31 (95%CI, 5.83-35.12; pConclusionNotable proportions of seropositivity were seen in all occupational groups between January and September 2021 prior to mass vaccination. Loss of taste and/or smell was strongly associated with presence of anti-SARS-CoV-2 IgG antibodies irrespective of presumed occupational exposure risk.

Cholera continues to cause many outbreaks in low and middle-income countries due to inadequate water, sanitation, and hygiene services. We describe a protracted cholera outbreak in Nairobi City County, Kenya in 2017. We reviewed the cholera outbreak line lists from Nairobi City County in 2017 to determine its extent and factors associated with death. A suspected case of cholera was any person aged >2 years old who had acute watery diarrhea, nausea, or vomiting, whereas a confirmed case was where Vibrio cholerae was isolated from the stool specimen. We summarized cases using means for continuous variables and proportions for categorical variables. Associations between admission status, sex, age, residence, time to care seeking, and outbreak settings; and cholera associated deaths were assessed using odds ratio (OR) with 95% confidence interval (CI). Of the 2,737 cholera cases reported, we analyzed 2,347 (85.7%) cases including 1,364 (58.1%) outpatients, 1,724 (73.5%) not associated with mass gathering events, 1,356 (57.8%) male and 2,202 (93.8%) aged ≥5 years, and 35 deaths (case fatality rate: 1.5%). Cases were reported from all the Sub Counties of Nairobi City County with an overall county attack rate of 50 per 100,000 people. Vibrio cholerae Ogawa serotype was isolated from 78 (34.8%) of the 224 specimens tested and all isolates were sensitive to tetracycline and levofloxacin but resistant to amikacin. The odds of cholera-related deaths was lower among outpatient cases (aOR: 0.35; [95% CI: 0.17-0.72]), age ≥5 years old (aOR: 0.21 [95% CI: 0.09-0.55]), and mass gathering events (aOR: 0.26 [95% CI: 0.07-0.91]) while threefold higher odds among male (aOR: 3.04 [95% CI: 1.30-7.13]). Nairobi City County experienced a protracted and widespread cholera outbreak with a high case fatality rate in 2017.

People with severe mental illness engage in considerably less physical activity than those without. They also experience premature mortality of around 10-25 years. A large proportion of these premature deaths are attributed to modifiable behaviours, including physical activity. The inpatient environment provides an opportunity to support people to become more physically active; however, there is limited evidence on which interventions are most successful and what contextual factors affect their delivery. A scoping review was conducted to help understand the extent and type of evidence in this area and identify research gaps. We included studies of physical activity correlates and interventions in adult inpatient mental health services published in peer-reviewed journals. Reviews, meta-analyses, and papers focusing on eating disorder populations were excluded. We searched the MEDLINE, CINAHL, PsycINFO, ASSIA and Web of Science databases for relevant studies published in English. We extracted data on study design, participant characteristics, intervention and control conditions, key findings, and research recommendations. We used a descriptive analytical approach and results are presented in tables and figures. Of 27,286 unique records screened, 210 reports from 182 studies were included. Sixty-one studies reported on correlates of physical activity, and 139 studies reported on physical activity interventions. Most intervention studies used a single-group, pre-post design (40%) and included fewer than 100 participants (86%). Ninety percent of interventions delivered physical activity directly to participants, and 50% included group-based sessions. The duration, type, frequency and intensity of sessions varied. Mental health was the most commonly reported outcome (64%), whereas physical activity was rarely an outcome (13%). Overall, there is a modest but growing body of research on physical activity in adult users of inpatient mental health services. More high-quality trials are needed to advance the field, and future research should target neglected intervention types, outcomes, populations and settings.

Tart cherries have low glycemic index, antioxidant and anti-inflammatory properties, and therefore may benefit performance and recovery from exercise. We determined the effects of consuming tart cherry juice versus a high-glycemic index sports drink on cycling performance, substrate oxidation, and recovery of low-frequency fatigue. Using a randomized, counter-balanced cross-over design, with one-month washout, 12 recreational cyclists (8 males and 4 females; 35±16y; VO2peak 38.2±7.4 ml/kg/min) consumed cherry juice or sports drink twice a day (300mL/d) for 4d before and 2d after exercise. On the exercise day, beverages (providing 1g/kg carbohydrate) were consumed 45min before 90min of cycling at 65%VO2peak, followed by a 10km time trial. Blood glucose, lactate, carbohydrate and fat oxidation, respiratory exchange ratio (RER), O2 cost of cycling, and rating of perceived exertion (RPE) were measured during the initial 90min of cycling. Muscle soreness, maximal voluntary contraction (MVC) and low-frequency fatigue were determined at baseline and after the time trial on the exercise day, and 30min after beverage consumption 24 and 48h later. There were no differences for time trial performance (17±3min cherry juice vs. 17±2min sports drink, p = 0.27) or any other measures between drink conditions. There were time main effects (p

BackgroundInappropriate utilization of higher-level health facilities and ineffective management of referral processes in resource-limited settings are becoming increasingly a concern in health care management in developing countries. This is characterized by self-referral and frequent bypassing of the nearest health facilities coupled with low formal referral mechanisms. This scenario lends itself to a situation where uncomplicated medical conditions are unnecessarily managed in a high-cost health facility. On July 1, 2021, Kenyatta National Hospital (KNH) enforced the Kenya Health Sector Referral Implementation Guidelines, 2014, which required patients to receive approval from the KNH referral office and a formal referral letter to be admitted at KNH to reduce the number of walk-ins and allow KNH to function as a referral facility as envisioned by the Kenya 2010 Constitution and KNH legal statue of 1987.ObjectiveTo determine the effect of enforcing the national referral guidelines on patterns of orthopaedic admissions to the KNH. This was a pre-post intervention study. Data abstraction was done for 459 and 446 charts before and after the enforcement of the national referral guidelines, respectively.ResultsEnforcement of the national referral guidelines reduced the proportion of walk-in admissions from 54.9% to 45.1%, while the proportion of facility referrals increased from 46.6% to 53.4% (p = 0.013). The percentage of non-trauma orthopaedic admissions doubled from 12.0% to 22.4% (pConclusionThe enforcement of the national referral guidelines reduced the proportion of walk-ins' admissions to KNH. While the enforcement of the national referral guidelines had no effect on the use of official formal written referral letters, it did limit access and utilization of inpatient orthopedic services for young male patients with no active insurance cover and in need of emergency orthopedic care.

Lactate and glucose are widely used biochemical parameters in current predictive risk scores for cardiogenic shock. Data regarding the relationship between lactate and glucose levels in cardiogenic shock are limited. Thus, we aimed to analyze glucose and lactate as early markers for in-hospital mortality in cardiogenic shock. In this retrospective cohort study, 312 patients presenting with cardiogenic shock to a tertiary-care hospital between 2016 and 2018 were included. Apparent cardiogenic shock was defined as hypoperfusion with hemodynamic compromise and biochemical marker increase due to diminished tissue perfusion, corresponding to SCAI shock stages. In-hospital mortality was assessed as the primary endpoint. The median age of the study population was 71 (60-79) years and the etiology of cardiogenic shock was acute myocardial infarction in 45.8%. Overall in-hospital mortality was 67.6%. In the receiver operating curve analysis, the area under the receiver-operating curve (AUC) for prediction of in-hospital mortality was higher for lactate (AUC: 0.757) than for glucose (AUC: 0.652). Both values were significantly associated with outcome (groups created with best cutoff values obtained from the Youden index). Correlation analysis showed a significant non-linear association of both values. In a multivariable stepwise Cox regression analysis, lactate remained an independent predictor for in-hospital mortality, whilst glucose, despite being implicated in energy metabolism, was not independently predictive for mortality. Together, these data suggest that lactate at admission is superior for mortality prediction in patients with apparent cardiogenic shock. Glucose was not independently predictive for mortality.

BackgroundThere is a growing epidemic of chronic non-communicable diseases in low and middle-income countries, often attributed to urbanization, although there are limited data from marginalized rural populations. This study aimed to estimate prevalence of cardiometabolic diseases and associated risk factors in transitional rural communities.MethodsA cross-sectional study of Montubio adults aged 18-94 years living in agricultural communities in a tropical coastal region of Ecuador. Data were collected by questionnaires and anthropometry, and fasting blood was analyzed for glucose, glycosylated hemoglobin, insulin, and lipid profiles. Population-weighted prevalences of diabetes, hypertension, and metabolic syndrome were estimated. Associations between potential risk factors and outcomes were estimated using multilevel regression techniques adjusted for age and sex.ResultsOut of 1,010 adults recruited, 931 were included in the analysis. Weighted prevalences were estimated for diabetes (20.4%, 95% CI 18.3-22.5%), hypertension (35.6%, 95% CI 29.0-42.1%), and metabolic syndrome (54.2%. 95% CI 47.0-61.5%) with higher prevalence observed in women. Hypertension prevalence increased with age while diabetes and metabolic syndrome peaked in the 6th and 7th decades of life, declining thereafter. Adiposity indicators were associated with diabetes, hypertension, and metabolic syndrome.ConclusionWe observed an unexpectedly high prevalence of diabetes, hypertension, and metabolic syndrome in these marginalized agricultural communities. Transitional rural communities are increasingly vulnerable to the development of cardiometabolic risk factors and diseases. There is a need for targeted primary health strategies to reduce the burden of premature disability and death in these communities.

[This corrects the article DOI: 10.1371/journal.pone.0273455.].

This experimental study investigates the influence of indoor plants on three aspects of air quality in office spaces: relative humidity, indoor air temperature, and carbon dioxide concentration. Employing a Latin square design, we rotated three different treatments across three offices over six time periods. These treatments included a control (no plants), a low-volume treatment (five plants), and a high-volume treatment (eighteen plants) of Nephrolepis exaltata (Boston fern). Air quality parameters were continuously monitored at five-minute intervals using Trace Gas Analyzers. Generalised linear mixed modelling (GLMM) was employed to examine the effect of each treatment on relative humidity, indoor air temperature and CO2 concentration. We observed a significant positive correlation between the number of indoor plants and relative humidity levels. In offices without any plants, the median relative humidity was 29.1%. This increased to 38.9% in offices with 5 plants and further to 49.2% in offices with 18 plants. However, we did not find significant associations between the number of indoor plants and indoor air temperature or corrected CO2 concentration. Our research provides support for the use of indoor plants to increase relative humidity, which can have health benefits in dry climates, but does not provide support for using indoor plants to regulate indoor air temperatures or CO2 concentration in office environments.

BackgroundBenfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches.ObjectiveTo conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD.MethodsThis is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA.ConclusionThe BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose.Trial registrationClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

The handaxe is an iconic stone tool form used to define and symbolise both the Acheulean and the wider Palaeolithic. There has long been debate around the extent of its morphological variability between sites, and the role that extrinsic factors (especially raw material, blank type, and the extent of resharpening) have played in driving this variability, but there has been a lack of high-resolution examinations of these factors in the same study. In this paper, we present a 2D geometric morphometric analysis of 1097 handaxes from across Africa, the Levant, and western Europe to examine the patterning of this variability and what it can tell us about hominin behaviour. We replicate the findings of previous studies, that handaxe shape varies significantly between sites and entire continental regions, but we find no evidence for raw material, blank type, or resharpening in determining this pattern. What we do find, however, is that markers of reduction trajectory vary substantially between sites, suggesting that handaxes were deployed differently according to hominin need at a given site. We argue this is reflective of a continuum of reduction strategies, from those focused on the maintenance of a sharp cutting edge (i.e. direct use in cutting activities), to those focused on maintaining tip shapes, and perhaps a corresponding production of flakes. Implications for hominin behavioural flexibility are discussed.

IntroductionAntenatal care (ANC) is crucial for positive pregnancy outcomes, but it is underutilised in Nigeria, suggesting unmet needs, and potentially contributing to the country's high burden of maternal and neonatal mortalities. This study comprehensively assesses ANC utilisation and receipt of its components in Nigeria, focusing on disparities between rural and urban areas.MethodsWe used the data disaggregation approach to analyse the Nigeria Demographic and Health Survey 2018. We estimated ANC utilisation, assessed the receipt of ANC components, and identified factors associated with eight or more (≥ 8) ANC contacts nationally and across rural and urban residences.ResultsNationwide, only 20.3% of women had ≥ 8 ANC contacts, with a significant disparity (P < 0.001) between urban (35.5%) and rural (10.4%) areas in Nigeria. The North-East region had the lowest ANC utilisation nationally (3.7%) and in urban areas (3.0%), while the North-West had the lowest in rural areas (2.7%). Nationally, 69% of mothers received iron supplements, 70% had tetanus injections, and 16% received medicines for intestinal parasites, with urban residents having higher proportions across all ANC components. Maternal and husband education, health insurance, and maternal autonomy were associated with increased ANC odds at the national, rural, and urban residences. However, differences exist, with all ethnicities having higher ANC odds than the Hausa/Fulanis in urban areas and the Yorubas demonstrating greater odds than other ethnicities in rural settings. Internet use was significant only in the national context, watching television only in urban settings, while maternal working status, wealth, birth type, religion, and radio listenership were significant in rural areas.ConclusionOur study reveals significant disparities in ANC utilisation and components across Nigeria, with rural residents, particularly in northern regions, as well as socioeconomically disadvantaged and teenage mothers facing notable challenges. A multifaceted approach prioritising the interplay of intersectional factors like geography, socioeconomic status, education, religion, ethnicity, and gender dynamics is essential. Key strategies should include targeted interventions to promote educational opportunities, expand health insurance coverage, leverage internet and context-specific media, and foster socioeconomic empowerment, with priority for underserved populations.

BackgroundEmerging evidence suggests newborn screening analytes may yield insights into the etiologies of birth defects, yet no effort has evaluated associations between a range of newborn screening analytes and birth defects.MethodsThis population-based study pooled statewide data on birth defects, birth certificates, and newborn screening analytes from Texas occurring between January 1, 2007 and December 31, 2009. Associations between a panel of thirty-six newborn screening analytes, collected by the statewide Texas Newborn Screening Program, and the presence of a birth defect, defined as at least one of 39 birth defects diagnoses recorded by the Texas Birth Defects Registry, were assessed using regression analysis.FindingsOf the 27,643 births identified, 20,205 had at least one of the 39 birth defects of interest (cases) as identified by the Texas Birth Defects Registry, while 7,438 did not have a birth defect (controls). Among 1,404 analyte-birth defect associations evaluated, 377 were significant in replication analysis. Analytes most consistently associated with birth defects included the phenylalanine/tyrosine ratio (N = 29 birth defects), tyrosine (N = 28 birth defects), and thyroxine (N = 25 birth defects). Birth defects most frequently associated with a range of analytes included gastroschisis (N = 29 analytes), several cardiovascular defects (N = 26 analytes), and spina bifida (N = 23 analytes).ConclusionsSeveral significant and novel associations were observed between newborn screening analytes and birth defects. While some findings could be consequences of the defects themselves or to the care provided to infants with these defects, these findings could help to elucidate mechanisms underlying the etiology of some birth defects.

BackgroundObesity is associated with locality and alcohol use; however, less is known about how the interaction of these two factors may compound the risk of obesity among adolescents.ObjectivesThis study examines the relationship between alcohol use and obesity among adolescents from rural and urban areas in the United States.MethodsData came from a sample of American adolescents aged 12-17 years from the National Survey on Drug Use and Health (2015-2019; n = 39,489). Obesity was regressed on age, sex, race/ethnicity, income, cigarette smoking, locality, and alcohol use, with an interaction term to examine locality x alcohol use. Predicted probabilities were plotted to assess the interaction.ResultsCompared to adolescents from urban areas, those from rural areas had 1.35 times higher odds of being obese (95% CI 1.25, 1.47). Predicted probabilities indicated that the probability of being obese was higher for rural adolescents at lower levels of drinking, up to about 40 drinks in the past 12 months.ConclusionsFindings suggest rural-urban differences at the intersection of alcohol use and obesity could depend on the frequency of use, but overall adolescents from rural areas may be more at risk.

With a view to developing a much-needed non-invasive method for monitoring the healthy pluripotent state of human stem cells in culture, we undertook proteomic analysis of the waste medium from cultured embryonic (Man-13) and induced (Rebl.PAT) human pluripotent stem cells (hPSCs). Cells were grown in E8 medium to maintain pluripotency, and then transferred to FGF2 and TGFβ deficient E6 media for 48 hours to replicate an early, undirected dissolution of pluripotency. We identified a distinct proteomic footprint associated with early loss of pluripotency in both hPSC lines, and a strong correlation with changes in the transcriptome. We demonstrate that multiplexing of four E8- against four E6- enriched secretome biomarkers provides a robust, diagnostic metric for the pluripotent state. These biomarkers were further confirmed by Western blotting which demonstrated consistent correlation with the pluripotent state across cell lines, and in response to a recovery assay.

We propose a fold change transform that demonstrates a combination of visualization properties exhibited by log and linear plots of fold change. A fold change visualization should ideally exhibit: (1) readability, where fold change values are recoverable from datapoint position; (2) proportionality, where fold change values of the same direction are proportionally distant from the point of no change; (3) symmetry, where positive and negative fold changes of the same magnitude are equidistant to the point of no change; and (4) high dynamic range, where datapoint values are distinguishable across orders of magnitude within a fixed plot area and pixel resolution. A linear visualization has readability and partial proportionality but lacks high dynamic range and symmetry (because negative direction fold changes are bound between [0, 1] while positive are between (1, ∞)). Log plots of fold change have partial readability, high dynamic range, and symmetry, but lack proportionality because of the log transform. We outline a new transform, named mirrored axis distortion of fold change (MAD-FC), that extends a linear visualization of fold change data to exhibit readability, proportionality, and symmetry (but still has the limited dynamic range of linear plots). We illustrate the use of MAD-FC with biomedical data using various fold change plots. We argue that MAD plots may be a more useful visualization than log or linear plots for applications that do not require a high dynamic range (less than 8 units in log2 space).

Fibrotic remodeling is the primary driver of functional loss in chronic kidney disease, with no specific anti-fibrotic agent available for clinical use. Transglutaminase 2 (TG2), a wound response enzyme that irreversibly crosslinks extracellular matrix proteins causing dysregulation of extracellular matrix turnover, is a well-characterized anti-fibrotic target in the kidney. We describe the humanization and characterization of two anti-TG2 monoclonal antibodies (zampilimab [hDC1/UCB7858] and BB7) that inhibit crosslinking by TG2 in human in vitro and rabbit/cynomolgus monkey in vivo models of chronic kidney disease. Determination of zampilimab half-maximal inhibitory concentration (IC50) against recombinant human TG2 was undertaken using the KxD assay and determination of dissociation constant (Kd) by surface plasmon resonance. Efficacy in vitro was established using a primary human renal epithelial cell model of tubulointerstitial fibrosis, to assess mature deposited extracellular matrix proteins. Proof of concept in vivo used a cynomolgus monkey unilateral ureteral obstruction model of chronic kidney disease. Zampilimab inhibited TG2 crosslinking transamidation activity with an IC50 of 0.25 nM and Kd of 50%, with no safety signals. Our data support the clinical investigation of zampilimab for the treatment of kidney fibrosis.

BackgroundMental disorders account for nine percent of the overall global burden of disease and are among the top ten leading causes of disability. Mental illness and tuberculosis share risk factors including poverty, overcrowding, stigma, poor nutrition, substance use and retro-viral disease co-infection. Presence of mental illness in tuberculosis delays health-seeking, affects drug adherence, increases cost of treatment, prolongs disease duration, lowers quality of life, and increases mortality. Early diagnosis, linkage, and treatment of psychiatric morbidity among patients with tuberculosis would improve outcomes for both. This study thus aimed to determine the prevalence and factors associated with psychiatric morbidity among patients on treatment for tuberculosis at a low- middle- income country.MethodsA cross-sectional study carried out at the tuberculosis clinic at Moi Teaching and Referral Hospital (MTRH), Eldoret, Kenya. 367 participants on TB treatment were interviewed using Mini-International Neuropsychiatric Interview (MINI) tool. The key outcome was presence of psychiatric illness. Pearson's Chi-square and logistic regression were used to assess relationships at bivariate and multivariate level respectively.ResultsMajority of the respondents were male (61.3%) and overall median age was 33 years. About half of participants (48.5%) had at least one psychiatric illness. Common disorders were alcohol use disorder (30.3%), depression (23.4%), substance use disorder (12.8%) and suicidality (8.2%). Odds of 'any psychiatric illness' were increased by being male (aOR = 1.92; P = 0.04), being separated or divorced (aOR = 6.86; P = 0.002), using alcohol (aOR = 3.2; PConclusionAlmost half of the patients on treatment for tuberculosis had at least one psychiatric illness. Introduction of protocols for screening for mental illness and integration of mental health services with tuberculosis care would aid prompt diagnosis, referral, and quality of care.

[This corrects the article DOI: 10.1371/journal.pone.0150206.].

BackgroundContraceptive use has complex effects on sexual behaviour and mood, including those related to reduced concerns about unintended pregnancy, direct hormonal effects and effects on endogenous sex hormones. We set out to obtain robust evidence on the relative effects of three contraceptive methods on sex behaviours, which is important for guiding contraceptive choice and future contraceptive developments.MethodsThis is a secondary analysis of data from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) randomized trial in which 7,829 HIV-uninfected women from 12 sites in Eswatini, Kenya, South Africa and Zambia seeking contraception were randomly assigned to intramuscular depot-medroxyprogesterone acetate (DMPA-IM), the copper intrauterine device (Cu-IUD) or the levonorgestrel (LNG) implant. Data collected for 12 to 18 months using 3-monthly behavioural questionnaires that relied on recall from the preceding 3 months, were used to estimate relative risk of post-baseline sex behaviours, as well as sexual desire and menstrual bleeding between randomized groups using modified Poisson regression.ResultsWe observed small but generally consistent effects wherein DMPA-IM users reported lower prevalence of specified high risk sexual behaviours than implant users than Cu-IUD users (the '>' and ' Cu-IUD); partner has sex with others 10% < 11%, 11%. The one exception was having any sex partner 96.5%, 96.9% < 97.4% (DMPA-IM < Cu-IUD). Decrease in sexual desire was reported by 1.6% > 1.1% >0.5%; amenorrhoea by 49% > 41% >12% and regular menstrual pattern by 26% ConclusionsThese findings suggest that women assigned to DMPA-IM may have a modest decrease in libido and sexual activity relative to the implant, and the implant relative to the Cu-IUD. We found more menstrual disturbance with DMPA-IM than with the implant (and as expected, both more than the Cu-IUD). These findings are important for informing the contraceptive choices of women and policymakers and highlight the need for robust comparison of the effects of other contraceptive methods as well.

Somatic Y chromosome loss in hematopoietic cells is associated with higher mortality in men. However, the status of the Y chromosome in cancer tissue is not fully known due to technical limitations, such as difficulties in labelling and sequencing DNA from the Y chromosome. We have developed a system to quantify Y chromosome gain or loss in patient-derived prostate cancer organoids. Using our system, we observed Y chromosome loss in 4 of the 13 (31%) patient-derived metastatic castration-resistant prostate cancer (mCRPC) organoids; interestingly, loss of Yq (long arm of the Y chromosome) was seen in 38% of patient-derived organoids. Additionally, potential associations were observed between mCRPC and Y chromosome nullisomy. The prevalence of Y chromosome loss was similar in primary and metastatic tissue, suggesting that Y chromosome loss is an early event in prostate cancer evolution and may not a result of drug resistance or organoid derivation. This study reports quantification of Y chromosome loss and gain in primary and metastatic prostate cancer tissue and lays the groundwork for further studies investigating the clinical relevance of Y chromosome loss or gain in mCRPC.