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Abstract Background Patient autonomy is central to the provision of respectful maternity care. Enabling women to make decisions free of discrimination and coercion, and respecting their privacy and confidentiality can contribute to positive childbirth experiences. This study aimed to deepen the understanding of how patient autonomy is reflected through social practices during intrapartum care in Benin. Methods Semi-structured interviews with women and midwives, a focus-group discussion with women’s birth companions, and non-participant observations in the delivery room were conducted within the frame of the ALERT research project. This study analysed data through a reflexive thematic analysis approach, in line with Braun and Clarke. Results We identified two themes and five sub-themes. Patient autonomy was systemically suppressed over the course of birth as a result of the conditions of care provision, various forms of coercion and women’s surrendering of their autonomy. Women used other care practices, such as alternative medicine and spiritual care, to counteract experiences of limited autonomy during intrapartum care. Conclusions The results pointed to women’s experiences of limited patient autonomy and their use of alternative and spiritual care practices to reclaim their patient autonomy. This study identified spiritual autonomy as an emergent dimension of patient autonomy. Increasing women’s autonomy during childbirth may improve their experiences of childbirth, and the provision of quality and respectful maternity care.

Abstract Background Serum creatinine is used as initial test to derive eGFR and confirmatory testing with serum cystatin C is recommended when creatinine‐based eGFR is considered less accurate due to deviant muscle mass. Low muscle mass is associated with increased risk of premature mortality. However, the associations of serum creatinine and cystatin C with muscle mass and mortality remain unclear and require further investigation to better inform clinical decision‐making. Methods We included 8437 community‐dwelling adults enrolled in the Dutch PREVEND study and 5033 in the US NHANES replication cohort. Associations of serum creatinine and/or cystatin C with muscle mass surrogates and mortality were quantified with linear and Cox proportional hazards regression, respectively. Missing observations in covariates were multiply imputed using Substantive Model Compatible Fully Conditional Specification. Results Mean (SD) age of PREVEND and NHANES participants (50% and 48% male) were 49.8 (12.6) and 48.7 (18.7) years, respectively. Median (Q1–Q3) serum creatinine and cystatin C were 71 (61–80) and 80 (62–88) μmol/L and 0.87 (0.78–0.98) and 0.91 (0.80–1.10) mg/L, respectively. Higher serum creatinine was associated with greater muscle mass, while serum cystatin C was not associated with muscle mass. Adjusting both markers for each other strengthened the positive relationship between serum creatinine and muscle mass and revealed an inverse association between serum cystatin C and muscle mass. In the PREVEND cohort, 1636 (19%) deaths were registered over a median follow‐up of 12.9 (5.8–16.3) years with a 10‐year mortality rate (95% CI) of 7.6% (7.1–8.2%). In the NHANES, 1273 (25%) deaths were registered over a median follow‐up of 17.9 (17.3–18.5) years with a 10‐year mortality rate of 13.8% (12.8–14.7%). Both markers were associated with increased mortality. Notably, when adjusted for each other, higher serum creatinine was associated with decreased mortality, while the association between serum cystatin C and increased mortality strengthened. The shapes of the associations in the PREVEND study and NHANES were almost identical. Conclusions The strong association between serum creatinine and muscle mass challenges its reliability as GFR marker, necessitating a more cautious approach in its clinical use. The minimal association between serum cystatin C and muscle mass supports its increased use as a more reliable alternative in routine clinical practice.

Abstract Background Genome-wide functional screening using the CRISPR-Cas9 system is a powerful tool to uncover tumor-specific and common genetic dependencies across cancer cell lines. Current CRISPR-Cas9 knockout libraries, however, primarily target protein-coding genes. This limits functional genomics-based investigations of miRNA function. Methods We designed a novel CRISPR-Cas9 knockout library (lentiG-miR) of 8107 distinct sgRNAs targeting a total of 1769 human miRNAs and benchmarked its single guide RNA (sgRNA) composition, predicted on- and off-target activity, and screening performance against previous libraries. Using a total of 45 human cancer cell lines, representing 16 different tumor entities, we performed negative selection screens to identify miRNA fitness genes. Fitness miRNAs in each cell line were scored using a combination of supervised and unsupervised essentiality classifiers. Common essential miRNAs across distinct cancer cell lines were determined using the 90th percentile method. For subsequent validation, we performed knockout experiments for selected common essential miRNAs in distinct cancer cell lines and gene expression profiling. Results We found significantly lower off-target activity for protein-coding genes and a higher miRNA gene coverage for lentiG-miR as compared to previously described miRNA-targeting libraries, while preserving high on-target activity. A minor fraction of miRNAs displayed robust depletion of targeting sgRNAs, and we observed a high level of consistency between redundant sgRNAs targeting the same miRNA gene. Across 45 human cancer cell lines, only 217 (12%) of all targeted human miRNAs scored as a fitness gene in at least one model, and fitness effects for most miRNAs were confined to small subsets of cell lines. In contrast, we identified 49 common essential miRNAs with a homogenous fitness profile across the vast majority of all cell lines. Transcriptional profiling verified highly consistent gene expression changes in response to knockout of individual common essential miRNAs across a diverse set of cancer cell lines. Conclusions Our study presents a miRNA-targeting CRISPR-Cas9 knockout library with high gene coverage and optimized on- and off-target activities. Taking advantage of the lentiG-miR library, we define a catalogue of miRNA fitness genes in human cancer cell lines, providing the foundation for further investigation of miRNAs in human cancer.

Key Clinical Message The lack of pediatric subspecialists locally prior to 5 years ago, meant that some of our patients with rare, relapsing conditions were left behind. Familial Mediterranean fever can be diagnosed clinically and supported via genetic panel studies. Although neurological symptoms can be non‐specific, this system symptomatology may lead patients and carers to seek medical attention. When neurological symptoms progress, seemingly refractory to first‐line treatment, or suggestive of colchicine resistance, CNS demyelination should be considered by the neurologist. Abstract Familial Mediterranean fever (FMF) is an inherited disorder with episodic fevers accompanied by pain in the abdomen, joints, or chest. It is a clinical entity that can be confirmed with a specific genetic mutation. Neurological symptoms have not been a focal point in clinical case descriptions. We aim to present the long road to diagnosing our patient, where the diagnostic clues centered around her neurological symptoms.

Background & Aims: Although primary biliary cholangitis (PBC) is considered a rare disorder, accurate determination of its incidence and prevalence remains challenging due to limited comprehensive population-based registries. We aimed to assess the incidence and prevalence of PBC in the Netherlands over time through the nationwide Dutch PBC Cohort Study (DPCS). Methods: DPCS retrospectively included every identifiable patient with PBC in the Netherlands from 1990 onwards in all 71 Dutch hospitals. Incidence and prevalence were assessed between 2008-2018 by Poisson regression between sex and age groups over time. Results: On the 1st of January 2008, there were 1,458 patients with PBC in the Netherlands. Between 2008-2018, 2,187 individuals were newly diagnosed, 46 were transplanted and 468 died. The yearly incidence of PBC in 2008 was 1.38, increasing to 1.74 per 100,000 persons in 2018. When compared to those aged

Abstract Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the 6 domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and “behavioural issues”, or about the type/nature of feeding problems. Follow-up reports (n = 95) rarely contributed this additional phenotype data. In summary, phenotype information relevant to clinical management, genetic counselling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. The PHELIX (PHEnotype LIsting fiX) reporting guideline checklists were developed to improve phenotype reporting in the genomic era.

Abstract The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.

Researchers seeking to engage in projects related to Tribal communities and their citizens, lands, and non-human relatives are responsible for understanding and abiding by each Tribal nation’s research laws and review processes. Few studies, however, have described the many diverse forms of Tribal research review systems across the United States (US). This study provides one of the most comprehensive examinations of research review processes administered by Tribal Research Review Boards (TRRBs) in the US. Through a systematic analysis, we consider TRRBs’ online presence, online documentation, and themes across documents, for five entity types: Tribal nations and Tribal consortiums, Tribal colleges and universities, Tribal health organizations, Indian Health Services, and other Tribal organizations. Results include an assessment of online presence for 98 potential TRRBs, identification of 118 publicly available online documents, and analysis of 41 themes across four document types: Tribal research codes and TRRBs’ guidelines, applications, and post-approval documents. Altogether, this research provides a macro-level analysis of the most common types of TRRBs in the US in an effort to increase researchers’ understanding of these important processes as they prepare to ethically engage Tribal communities in research. These results aim to empower Tribal decision makers as they align their TRRBs’ online visibility and documentation with community priorities and strengthen their protections for the rights and wellbeing of their citizens and community. Ultimately, by expanding our knowledge of TRRBs across the US, this contribution seeks to uphold Tribal sovereignty in research and promote ethical approaches to research with Indigenous communities.

Responding to labor shortages and rising healthcare expenses, hospitals increasingly turn to self-check-in kiosks to streamline service delivery and improve patients’ experiences. The purpose of this study was to reflect on the implementation of these self-check-in kiosks in a Dutch university hospital, particularly in relation to access to care for more vulnerable patients and intended efficiency goals. We followed a technology-in-practice approach to better understand how new technologies shape care practices in relation to in/exclusion and carried out an ethnographic action study involving desk research, participatory observations, semi-structured interviews, and reflection sessions with developers and hospital staff. Data were analyzed through ethnographic content analysis. Our results show that although self-check-in kiosks work well for some patients, many people experience practical and psychosocial difficulties, especially those who go through a complex care pathway, are low-literate, experience a distance the online world, or have sensory, motor, or cognitive impairments. Kiosks are not yet attuned to these patients and typically leave little flexibility and room for negotiation and personal support in what is, for many, a foreign environment. Therefore, patients frequently seek confirmation and assistance from already downsized or busy staff. In conclusion, we find that digitalization under the banner of efficiency within a healthcare system already under pressure carries risks, as it can unintentionally generate extra (invisible) work for patients and care professionals and threaten access to and quality of care for patients most in need. A more concentrated effort on refining the digitalization of healthcare processes using an inclusive-technology-in-practice approach has the potential to contribute to fairer and more efficient care for all patients.

Purpose: To define the surgical anatomy of the meniscotibial ligament complex of the pediatric medial and lateral menisci and their relation to the proximal tibial physis and posterior joint capsule. Methods: Fourteen pediatric cadaveric knee specimens (aged 3 months to 11 years) were dissected to clarify the relation of the posterior knee capsule, the meniscus, and the meniscotibial ligament complex. Metallic markers were placed marking the meniscotibial ligament capsular attachment on the proximal tibia. Specimens underwent computed tomography scanning to evaluate pin placement and relation to the physis. A digital measurement tool was used to measure the distances between the proximal tibial physis and the pins (placed at 5 points on both the lateral and medial menisci). Results: In each specimen, clear separation was noted between the posterior joint capsule from the meniscus and meniscotibial ligament complex in the medial and lateral compartments. There was an increase in the distance between the proximal tibial physis and the insertion points of the meniscotibial ligament complex with increasing specimen age. For both the medical and lateral menisci in group 1, the median meniscotibial ligament insertion points were often less than 7 mm (interquartile range, 0.00-7.8 mm) away from the physis. The median meniscotibial ligament insertion points in group 2 tended to be farther from the physis but always less than 20 mm (interquartile range, 2.5-17.5 mm)—and as close as less than 5 mm (lateral posterior root). Conclusions: In this anatomic study of pediatric knees, we observed a distinct recess/cul-de-sac space between the posterior knee capsule and meniscal attachments in all specimens. This defines a distinct plane between the posterior knee capsule and the meniscotibial ligament complex, with a distance between the physis and meniscotibial ligament capsular attachments that increases with age. Clinical Relevance: The anatomic parameters evaluated in our study should be considered as future meniscal repair and transplantation techniques aim to restore the meniscal anatomy, stability, and mobility provided by the meniscotibial ligament complex and capsule structures.

Summary: The efficacy of T cell therapies in treating solid tumors is limited by poor in vivo persistence, proliferation, and cytotoxicity, which can be attributed to limited and variable ex vivo activation. Herein, we present a 10-day kinetic profile of T cells subjected to fluid shear stress (FSS) ex vivo, with and without stimulation utilizing bead-conjugated anti-CD3/CD28 antibodies. We demonstrate that mechanical stimulation via FSS combined with bead-bound anti-CD3/CD28 antibodies yields a synergistic effect, resulting in amplified and sustained downstream signaling (NF-κB, c-Fos, and NFAT), expression of activation markers (CD69 and CD25), proliferation and production of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2). This study represents the first characterization of the dynamic response of primary T cells to FSS. Collectively, our findings underscore the critical role of mechanosensitive ion channel-mediated mechanobiological signaling in T cell activation and fitness, enabling the development of strategies to address the current challenges associated with poor immunotherapy outcomes.

Abstract Background and Aims Water scarcity and poor water quality could lead to suboptimum menstrual hygiene practices, and subsequently urinary tract infection (UTI) and bacterial vaginosis (BV). In this study, we estimate the prevalence of self‐reported UTI and BV among indigenous adolescent girls during the water scarcity period in the Bandarban Hill Districts in south‐eastern Bangladesh. Methods Using a cross‐sectional design, a total of 242 indigenous adolescent girls were selected and interviewed during the seasonal water scarcity period (from February to May 2022) in Bandarban. The difference in prevalence of any self‐reported UTI or BV symptoms by respondents' characteristics was assessed by χ2 test. Multivariable logistic regression model was used to observe the associated factors. Results The prevalence of self‐reported UTI, BV, and any symptoms of UTI or BV among the respondents were 35.54%, 28.93%, and 43.80%, respectively. Ethnicity, studentship status, source of water used for menstrual hygiene, and perceived water quality were significantly associated with the prevalence of any self‐reported UTI or BV symptoms. Conclusion Findings recommend further research to cross‐check the validity of self‐reported prevalence and investigate if the episodes of UTI or BV could be attributable to water scarcity and poor water quality in study areas during dry period.

Abstract Antarctic coastal waters are home to several established or proposed Marine Protected Areas (MPAs) supporting exceptional biodiversity. Despite being threatened by anthropogenic climate change, uncertainties remain surrounding the future ocean acidification (OA) of these waters. Here we present 21st-century projections of OA in Antarctic MPAs under four emission scenarios using a high-resolution ocean–sea ice–biogeochemistry model with realistic ice-shelf geometry. By 2100, we project pH declines of up to 0.36 (total scale) for the top 200 m. Vigorous vertical mixing of anthropogenic carbon produces severe OA throughout the water column in coastal waters of proposed and existing MPAs. Consequently, end-of-century aragonite undersaturation is ubiquitous under the three highest emission scenarios. Given the cumulative threat to marine ecosystems by environmental change and activities such as fishing, our findings call for strong emission-mitigation efforts and further management strategies to reduce pressures on ecosystems, such as the continuation and expansion of Antarctic MPAs.

Abstract Background Currently all participants of the Dutch colorectal cancer (CRC) screening program with a positive faecal immunochemical test (FIT) are seen at the outpatient clinic to assess their health status, receive information on colonoscopy and CRC risk, and provide informed consent. However, for many patients this information could probably also safely be exchanged in an online setting, in order to reduce the burden for patients, healthcare system, and environment. In this study we will evaluate if a face-to-face pre-colonoscopy consultation can be replaced by a Digital Intake Tool (DIT) in a CRC screening population. Methods This is a prospective multicentre single-arm, non-randomized study with a non-inferiority design. The DIT will triage a total of 1000 participants and inform them about CRC risk, colonoscopy, sedation, and provide bowel preparation instructions. Participants identified as high-risk (i.e., red-triaged) will be contacted by phone or scheduled for an appointment at the outpatient clinic. The primary outcome measure will be adequate bowel preparation rate, defined as the proportion of participants with a Boston Bowel Preparation (BBPS) score ≥ 6. To compare our primary outcome, we will use colonoscopy data from 1000 FIT positive participants who visited the outpatient clinic for pre-colonoscopy consultation. Secondary outcomes will include participation rate, colonoscopy adherence rate, patient experience in terms of satisfaction and anxiety, knowledge transfer, number of outpatient visits that can be averted by the DIT, and cost-effectiveness of the tool. Ethical approval was obtained from the Medical Ethical Committee of the Erasmus Medical Center (MEC-2021-0098). Discussion This study aims to assess if a face-to-face pre-colonoscopy consultation can be replaced by an eHealth assessment and education tool in a FIT-based CRC screening program. In case favourable results are established, the intervention evaluated in this study could significantly impact CRC screening programs, benefiting both patients and healthcare systems on a (inter)national scale. Additionally, it would enable more personalized care as the DIT can be easily customized and made feasible in other languages, thereby enhancing healthcare accessibility. Trial registration Dutch Trial Register: NL9315 , date of registration: March 8th, 2021.

Abstract Marine bacterioplankton underpin the health and function of coral reefs and respond in a rapid and sensitive manner to environmental changes that affect reef ecosystem stability. Numerous meta-omics surveys over recent years have documented persistent associations of opportunistic seawater microbial taxa, and their associated functions, with metrics of environmental stress and poor reef health (e.g. elevated temperature, nutrient loads and macroalgae cover). Through positive feedback mechanisms, disturbance-triggered heterotrophic activity of seawater microbes is hypothesised to drive keystone benthic organisms towards the limit of their resilience and translate into shifts in biogeochemical cycles which influence marine food webs, ultimately affecting entire reef ecosystems. However, despite nearly two decades of work in this space, a major limitation to using seawater microbes in reef monitoring is a lack of a unified and focused approach that would move beyond the indicator discovery phase and towards the development of rapid microbial indicator assays for (near) real-time reef management and decision-making. By reviewing the current state of knowledge, we provide a comprehensive framework (defined as five phases of research and innovation) to catalyse a shift from fundamental to applied research, allowing us to move from descriptive to predictive reef monitoring, and from reactive to proactive reef management.

Abstract Managed honey bees have experienced high rates of colony loss recently, with pesticide exposure as a major cause. While pesticides can be lethal at high doses, lower doses can produce sublethal effects, which may substantially weaken colonies. Impaired learning performance is a behavioral sublethal effect, and is often present in bees exposed to insecticides. However, the effects of other pesticides (such as fungicides) on honey bee learning are understudied, as are the effects of pesticide formulations versus active ingredients. Here, we investigated the effects of acute exposure to the fungicide formulation Pristine (active ingredients: 25.2% boscalid, 12.8% pyraclostrobin) on honey bee olfactory learning performance in the proboscis extension reflex (PER) assay. We also exposed a subset of bees to only the active ingredients to test which formulation component(s) were driving the learning effects. We found that the formulation produced negative effects on memory, but this effect was not present in bees fed only boscalid and pyraclostrobin. This suggests that the trade secret “other ingredients” in the formulation mediated the learning effects, either through exerting their own toxic effects or by increasing the toxicities of the active ingredients. These results show that pesticide co-formulants should not be assumed inert and should instead be included when assessing pesticide risks.

Abstract Background Injuries are a leading cause of death and disability for Alaska Native (AN) people. Alaska Native Tribal Health Consortium (ANTHC) is supporting the development of a burn care system that includes a partnership between Alaska Native Medical Center (ANMC) in Anchorage, AK and UW Medicine Regional Burn Center at Harborview Medical Center (HMC) in Seattle, WA. We aimed to better understand the experiences of AN people with burn injuries across the care continuum to aid development of culturally appropriate care regionalization. Methods We performed focus groups with twelve AN people with burn injury and their caregivers. A multidisciplinary team of burn care providers, qualitative research experts, AN care coordinator, and AN cultural liaison led focus groups to elicit experiences across the burn care continuum. Transcripts were analyzed using a phenomenological approach and inductive coding to understand how AN people and families navigated the medical and community systems for burn care and areas for improvement. Results Three themes were identified: 1-Challenges with local burn care in remote communities including limited first aid, triage, pain management, and wound care, as well as long-distance transport to definitive care; 2-Divergence between cultural values and medical practices that generated mistrust in the medical system, isolation from their support systems, and recovery goals that were not aligned with their needs; 3-Difficulty accessing emotional health support and a survivor community that could empower their resilience. Conclusion Participants reported modifiable barriers to culturally competent treatment for burn injuries among AN people. The findings can inform initiatives that leverage existing resources, including expansion of the Extension for Community Healthcare Outcomes (ECHO) telementoring program, promulgation of the Phoenix Society Survivors Offering Assistance in Recovery (SOAR) to AK, coordination of regionalized care to reduce time away from AK and provide more comfortable community reintegration, and define rehabilitation goals in terms that align with personal goals and subsistence lifestyle skills. Long-distance transport times are non-modifiable, but better pre-hospital care could be achieved by harnessing existing telehealth services and adapting principles of prolonged field care to allow for triage, initial care, and resuscitation in remote environments.

Teachers are critically involved in the delivery of school-based mental health promotion (SMHP) interventions in school, though pre-service teacher education often leaves teachers feeling underprepared in this area. Thus, understanding how best to build teachers’ capacity for delivery through effective professional development (PD) is essential for teachers to fulfill their role as delivery agents to achieve SMHP outcomes. This systematized review focuses on identifying components of high-quality teacher PD for SMHP and examining the empirical support for these components. In a two-phase analysis, we examined the descriptive literature regarding teacher PD for SMHP to identify common elements. This resulted in the identification of components relevant to training (interactive, guided by staff input) and technical assistance (TA), including the goals (skill development, motivation, generalization/adaptation), approach (collaborative, individualized, data-driven, strengths-based), and activities (modeling, performance feedback, reflection, problem solving) involved. A second phase focused on the examination of empirical evidence for these PD components. While the empirical evidence for these components was limited, the identified components represent a current standard of practice in teacher PD for SMHP, based on the existing research. These components may provide a framework for practical use in planning teacher PD related to SMHP and for designing future research into effective capacity building in this area.

School mental health (SMH) teams have been widely recommended to support multi-tiered mental health program implementation in schools. Available research suggests emerging best practices that promote effective SMH teaming and indicates the importance of having team members who are highly engaged (e.g., actively involved, retained on the team). Despite evidence that these factors improve team functioning, there is limited knowledge of SMH team prevalence, best practice use, and factors impacting member engagement among a diverse sample of elementary schools. This study surveyed a cross-sectional sample of elementary principals (n = 314) across the United States whose schools implement multi-tiered SMH programs. Most principals (89%, n = 280) reported using teams to organize these programs. Schools in urban/suburban communities, with 300 or more students, or with specific school funding for SMH activities were more likely to have SMH teams. Only one-third of principals reported that their team members participated in related training. Other SMH team best practices were commonly reported (by two-thirds or more teams). Results of a linear regression model indicate that larger teams (six or more members) and teams with access to resources had significantly higher member engagement scores. The study’s findings provide recommendations for practice and future research directions.

Abstract Information on factors leading to pulmonary arterial hypertension (PAH) treatment discontinuation is limited. This study analyzed 12,902 new PAH medication users to identify predictors of treatment discontinuation. Treatment by accredited pulmonary hypertension centers and combination therapy with PAH agents from different classes were less likely to result in discontinuation.

Abstract The impacts of global change—from shifts in climate to overfishing to land use change—can depend heavily on local abiotic context. Building an understanding of how to downscale global change scenarios to local impacts is often difficult, however, and requires historical data across large gradients of variability. Such data are often not available—particularly in peer reviewed or gray literature. However, these data can sometimes be gleaned from casual records of natural history—field notebooks, data sheet marginalia, course notes, and more. Here, we provide an example of one such approach for the Gulf of Maine, as we seek to understand how environmental context can influence local outcomes of region‐wide shifts in subtidal community structure. We explore a decade of hand‐drawn algal cover maps around Appledore Island made by Dr. Art Borror while teaching at the Shoals Marine Lab. Appledore's steep wave exposure gradient—from exposed to the open ocean to fully protected—provides a living laboratory to test interactions between global change and local conditions. We then recreate Borror's methods two and a half decades later. We show that overfishing‐driven urchin outbreaks in the 1980s were slowed or stopped by wave exposure and benthic topography. Similarly, local variation appears to have curtailed current invasions by filamentous red algae. Last, some formerly dominant kelps have disappeared over the past 40 years—an observation verified by subtidal surveys. Global change is altering life in the seas around us. While underutilized, solid natural history observations stand as a key resource for us to begin to understand how global change will translate to the heterogeneous mosaic of life in a future Gulf of Maine and other ecosystems around the world.

ABSTRACTMycobacterium tuberculosis (Mtb), the pathogenic bacterium that causes tuberculosis, has evolved sophisticated defense mechanisms to counteract the cytotoxicity of reactive oxygen species (ROS) generated within host macrophages during infection. The melH gene in Mtb and Mycobacterium marinum (Mm) plays a crucial role in defense mechanisms against ROS generated during infection. We demonstrate that melH encodes an epoxide hydrolase and contributes to ROS detoxification. Deletion of melH in Mm resulted in a mutant with increased sensitivity to oxidative stress, increased accumulation of aldehyde species, and decreased production of mycothiol and ergothioneine. This heightened vulnerability is attributed to the increased expression of whiB3, a universal stress sensor. The absence of melH also resulted in reduced intracellular levels of NAD+, NADH, and ATP. Bacterial growth was impaired, even in the absence of external stressors, and the impairment was carbon source dependent. Initial MelH substrate specificity studies demonstrate a preference for epoxides with a single aromatic substituent. Taken together, these results highlight the role of melH in mycobacterial bioenergetic metabolism and provide new insights into the complex interplay between redox homeostasis and generation of reactive aldehyde species in mycobacteria.IMPORTANCEThis study unveils the pivotal role played by the melH gene in Mycobacterium tuberculosis and in Mycobacterium marinum in combatting the detrimental impact of oxidative conditions during infection. This investigation revealed notable alterations in the level of cytokinin-associated aldehyde, para-hydroxybenzaldehyde, as well as the redox buffer ergothioneine, upon deletion of melH. Moreover, changes in crucial cofactors responsible for electron transfer highlighted melH’s crucial function in maintaining a delicate equilibrium of redox and bioenergetic processes. MelH prefers epoxide small substrates with a phenyl substituted substrate. These findings collectively emphasize the potential of melH as an attractive target for the development of novel antitubercular therapies that sensitize mycobacteria to host stress, offering new avenues for combating tuberculosis.

Epithelial tissues are the most abundant tissue type in animals, lining body cavities and generating compartment barriers. The function of a monolayered epithelial tissue-whether protective, secretory, absorptive, or filtrative-relies on the side-by-side arrangement of its component cells. The mechanical parameters that determine the shape of epithelial cells in the apical-basal plane are not well-understood. Epithelial tissue architecture in culture is intimately connected to cell density, and cultured layers transition between architectures as they proliferate. This prompted us to ask to what extent epithelial architecture emerges from two mechanical considerations: A) the constraints of densification and B) cell-cell adhesion, a hallmark feature of epithelial cells. To address these questions, we developed a novel polyline cell-based computational model and used it to make theoretical predictions about epithelial architecture upon changes to density and cell-cell adhesion. We tested these predictions using cultured cell experiments. Our results show that the appearance of extended lateral cell-cell borders in culture arises as a consequence of crowding-independent of cell-cell adhesion. However, cadherin-mediated cell-cell adhesion is associated with a novel architectural transition. Our results suggest that this transition represents the initial appearance of a distinctive epithelial architecture. Together our work reveals the distinct mechanical roles of densification and adhesion to epithelial layer formation and provides a novel theoretical framework to understand the less well-studied apical-basal plane of epithelial tissues.

Background. The aim of this open-label, multicenter, randomized controlled study was to investigate whether the life cycle pharma (LCP)-tacrolimus compared with the extended-release (ER)-tacrolimus formulation results in a difference in the prevalence of posttransplant diabetes, hypertension and chronic kidney disease (CKD) at 12 mo after liver transplantation. Methods. Patients were 1:1 randomized to either of the 2 tacrolimus formulations. The primary endpoint was defined as a composite endpoint of any of 3 events: sustained (>3 mo postrandomization) posttransplant diabetes, new-onset hypertension, and/or CKD, defined as estimated glomerular filtration rate 3 m during the follow-up. Results. In total, 105 patients were included. In the intention-to-treat analysis, a statistically significant lower proportion of liver transplant recipients in the LCP-tacrolimus group reached the composite primary endpoint at 12 mo compared with the ER-tacrolimus group (50.9% [27/53], 95% confidence interval [CI], 37.9%-63.9% versus 71.2% [37/52], 95% CI, 57.7%-81.7%; risk difference: 0.202; 95% CI, 0.002-0.382; P = 0.046). No significant difference was found in the per protocol analysis. In the intention-to-treat and per protocol population, fewer liver transplant recipients in the LCP-tacrolimus group developed CKD and new-onset hypertension compared with the ER-tacrolimus group. No differences in rejection rate, graft and patient survival were found. Conclusions. A statistically significant and clinically relevant reduction in the prevalence of the composite primary endpoint was found in the LCP-tacrolimus group compared with the ER-tacrolimus group in the first year after liver transplantation with comparable efficacy.

Abstract Background Active surveillance (AS), where treatment is deferred until cancer progression is detected by a biopsy, is acknowledged as a way to reduce overtreatment in prostate cancer. However, a consensus on the frequency of taking biopsies while in AS is lacking. In former studies to optimize biopsy schedules, the delay in progression detection was taken as an evaluation indicator and believed to be associated with the long‐term outcome, prostate cancer mortality. Nevertheless, this relation was never investigated in empirical data. Here, we use simulated data from a microsimulation model to fill this knowledge gap. Methods In this study, the established MIcrosimulation SCreening Analysis model was extended with functionality to simulate the AS procedures. The biopsy sensitivity in the model was calibrated on the Canary Prostate Cancer Active Surveillance Study (PASS) data, and four (tri‐yearly, bi‐yearly, PASS, and yearly) AS programs were simulated. The relation between detection delay and prostate cancer mortality was investigated by Cox models. Results The biopsy sensitivity of progression detection was found to be 50%. The Cox models show a positive relation between a longer detection delay and a higher risk of prostate cancer death. A 2‐year delay resulted in a prostate cancer death risk of 2.46%–2.69% 5 years after progression detection and a 10‐year risk of 5.75%–5.91%. A 4‐year delay led to an approximately 8% greater 5‐year risk and an approximately 25% greater 10‐year risk. Conclusion The detection delay is confirmed as a surrogate for prostate cancer mortality. A cut‐off for a “safe” detection delay could not be identified.

BackgroundArtificial intelligence chatbots such as ChatGPT (OpenAI) have garnered excitement about their potential for delegating writing tasks ordinarily performed by humans. Many of these tasks (eg, writing recommendation letters) have social and professional ramifications, making the potential social biases in ChatGPT’s underlying language model a serious concern. ObjectiveThree preregistered studies used the text analysis program Linguistic Inquiry and Word Count to investigate gender bias in recommendation letters written by ChatGPT in human-use sessions (N=1400 total letters). MethodsWe conducted analyses using 22 existing Linguistic Inquiry and Word Count dictionaries, as well as 6 newly created dictionaries based on systematic reviews of gender bias in recommendation letters, to compare recommendation letters generated for the 200 most historically popular “male” and “female” names in the United States. Study 1 used 3 different letter-writing prompts intended to accentuate professional accomplishments associated with male stereotypes, female stereotypes, or neither. Study 2 examined whether lengthening each of the 3 prompts while holding the between-prompt word count constant modified the extent of bias. Study 3 examined the variability within letters generated for the same name and prompts. We hypothesized that when prompted with gender-stereotyped professional accomplishments, ChatGPT would evidence gender-based language differences replicating those found in systematic reviews of human-written recommendation letters (eg, more affiliative, social, and communal language for female names; more agentic and skill-based language for male names). ResultsSignificant differences in language between letters generated for female versus male names were observed across all prompts, including the prompt hypothesized to be neutral, and across nearly all language categories tested. Historically female names received significantly more social referents (5/6, 83% of prompts), communal or doubt-raising language (4/6, 67% of prompts), personal pronouns (4/6, 67% of prompts), and clout language (5/6, 83% of prompts). Contradicting the study hypotheses, some gender differences (eg, achievement language and agentic language) were significant in both the hypothesized and nonhypothesized directions, depending on the prompt. Heteroscedasticity between male and female names was observed in multiple linguistic categories, with greater variance for historically female names than for historically male names. ConclusionsChatGPT reproduces many gender-based language biases that have been reliably identified in investigations of human-written reference letters, although these differences vary across prompts and language categories. Caution should be taken when using ChatGPT for tasks that have social consequences, such as reference letter writing. The methods developed in this study may be useful for ongoing bias testing among progressive generations of chatbots across a range of real-world scenarios. Trial RegistrationOSF Registries osf.io/ztv96; https://osf.io/ztv96

Background. Parenthood after lung transplantation (LuTx) is uncommon. Although data exist regarding practice patterns surrounding pregnancy after heart transplantation, there are no data specific to LuTx recipients and parenthood more broadly. Methods. We conducted a voluntary, anonymous online survey between October and December 2021. It was distributed electronically to select LuTx units and advertised to LuTx providers internationally. Results. A total of 103 responses were included in our analysis. Respondents were primarily women (n = 63; 62%) and included LuTx pulmonologists (n = 59; 58%) or nurses and transplant coordinators (n = 28; 27%). The majority were from centers performing >40 LuTx annually (n = 53; 52%) and had >10 y of transplant experience (n = 56; 55%). Most respondents discuss fertility issues with recipients (n = 63; 62%), but centers lacked clear policies relating to female (n = 51; 70%) and male (n = 62; 83%) fertility and parenthood. Few were aware of policies regarding assisted reproduction and fertility preservation (n = 13; 13%) or pregnancy (n = 23; 22%). Many cited ethical concerns regarding parenthood post-LuTx (n = 38; 37%), but most were supportive of the use of surrogacy by female recipients (n = 74; 92%) and felt there were no contraindications to parenthood in male recipients (n = 59; 59%). Although geography influenced some logistical issues around care provision, general attitudes toward parenthood in LuTx recipients were unaffected by respondent age, sex, location, or experience. Conclusions. Although providers were overall supportive of post-LuTx parenthood, the absence of peer-reviewed evidence, expert consensus, and policy-driven guidance may be a significant barrier to safe and successful parenthood in LuTx recipients.

Abstract We developed a functional ex vivo anthracycline-based sensitivity test. Surgical resection material of primary breast cancer (BC) was used to determine criteria for the ex vivo sensitivity assay based on morphology, proliferation and apoptosis. Subsequently, a proof-of-concept study was performed correlating results of this assay on primary BC biopsies with in vivo response after treatment with anthracycline-containing neoadjuvant chemotherapy (NAC). Cut off values for the ex vivo anthracycline-based sensitivity test were established based on analysis of 21 primary breast tumor samples obtained after surgery. In the proof-of-concept study based on a new set of tumor biopsies, 41 patients were included. Eight biopsies did not contain tumor cells and three patients could not be biopsied for various reasons. In the remaining 30 biopsies, the success rate of the ex vivo test was 77% (23/30); six out of seven failed tests were due to excessive apoptosis, our pre-specified test criteria. Of the 23 patients with a successful ex vivo test result, three patients did not undergo NAC after the biopsy. Here we report the ex vivo anthracycline-based sensitivity assay is feasible on biopsy material and shows 75% concordance between ex vivo outcomes and in vivo MRI response. Unfortunately, the percentage of unsuccessful tests is rather high. This study provides the foundation for further development of ex vivo sensitivity assays.

Radiotherapy in the head-and-neck area is one of the main curative treatment options. However, this comes at the cost of varying levels of normal tissue toxicity, affecting up to 80% of patients. Mucositis can cause pain, weight loss and treatment delays, leading to worse outcomes and a decreased quality of life. Therefore, there is an urgent need for an approach to predicting normal mucosal responses in patients prior to treatment. We here describe an assay to detect irradiation responses in healthy oral mucosa tissue. Mucosa specimens from the oral cavity were obtained after surgical resection, cut into thin slices, irradiated and cultured for three days. Seven samples were irradiated with X-ray, and three additional samples were irradiated with both X-ray and protons. Healthy oral mucosa tissue slices maintained normal morphology and viability for three days. We measured a dose-dependent response to X-ray irradiation and compared X-ray and proton irradiation in the same mucosa sample using standardized automated image analysis. Furthermore, increased levels of inflammation-inducing factors—major drivers of mucositis development—could be detected after irradiation. This model can be utilized for investigating mechanistic aspects of mucositis development and can be developed into an assay to predict radiation-induced toxicity in normal mucosa.

Abstract Background Decisions to participate in cancer trials are associated with uncertainty, distress, wanting to help find a cure, the hope for benefit, and altruism. There is a gap in the literature regarding research examining participation in prospective cohort studies. The aim of this study was to examine the experiences of newly diagnosed women with breast cancer participating in the AMBER Study to identify potential strategies to support patients’ recruitment, retention, and motivation. Methods Newly diagnosed breast cancer patients were recruited from the Alberta Moving Beyond Breast Cancer (AMBER) cohort study. Data were collected using semi-structured conversational interviews with 21 participants from February to May 2020. Transcripts were imported into NVivo software for management, organization, and coding. Inductive content analysis was undertaken. Results Five main concepts associated with recruitment, retention, and motivation to participate were identified. These main concepts included: (1) personal interest in exercise and nutrition; (2) investment in individual results; (3) personal and professional interest in research; (4) burden of assessments; (5) importance of research staff. Conclusions Breast cancer survivors participating in this prospective cohort study had numerous reasons for participating and these reasons could be considered in future studies to enhance participant recruitment and retention. Improving recruitment and retention in prospective cancer cohort studies could result in more valid and generalizable study findings that could improve the care of cancer survivors.

Abstract This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2− breast cancer (BC). Eligible patients were women with ECOG 0–2, ER+/HER2− measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46–87); PS 1 (0–1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2–52). Adverse events were as expected for hormonal therapy. Significant (p

Abstract Background Racial disparities exist in maternal morbidity and mortality, with most of these events occurring in healthy pregnant people. A known driver of these outcomes is unplanned cesarean birth. Less understood is to what extent maternal presenting race/ethnicity is associated with unplanned cesarean birth in healthy laboring people, and if there are differences by race/ethnicity in intrapartum decision-making prior to cesarean birth. Methods This secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) dataset involved nulliparas with no significant health complications at pregnancy onset who had a trial of labor at ≥ 37 weeks with a singleton, non-anomalous fetus in cephalic presentation (N = 5,095). Logistic regression models were used to examine associations between participant-identified presenting race/ethnicity and unplanned cesarean birth. Participant-identified presenting race/ethnicity was used to capture the influence of racism on participant’s healthcare experiences. Results Unplanned cesarean birth occurred in 19.6% of labors. Rates were significantly higher among Black- (24.1%) and Hispanic- (24.7%) compared to white-presenting participants (17.4%). In adjusted models, white participants had 0.57 (97.5% CI [0.45–0.73], p

Abstract Pinatubo erupted during the first decadal survey of ocean biogeochemistry, embedding its climate fingerprint into foundational ocean biogeochemical observations and complicating the interpretation of long‐term biogeochemical change. Here, we quantify the influence of the Pinatubo climate perturbation on externally forced decadal and multi‐decadal changes in key ocean biogeochemical quantities using a large ensemble simulation of the Community Earth System Model designed to isolate the effects of Pinatubo, which cleanly captures the ocean biogeochemical response to the eruption. We find increased uptake of apparent oxygen utilization and preindustrial carbon over 1993–2003. Nearly 100% of the forced response in these quantities are attributable to Pinatubo. The eruption caused enhanced ventilation of the North Atlantic, as evidenced by deep ocean chlorofluorocarbon changes that appear 10–15 years after the eruption. Our results help contextualize observed change and contribute to improved constraints on uncertainty in the global carbon budget and ocean deoxygenation.

BackgroundCongenital cytomegalovirus (CMV) infection is the leading cause of hearing loss and neurocognitive delay among children. Affected infants may be asymptomatic at birth and even pass their universal hearing screen. Early identification of CMV-infected infants will allow earlier detection, evaluation and management. The prevalence of congenital CMV infection in the developed world varies geographically from 0.6% to 0.7% of all deliveries and certain regions are at higher risk. The prevalence of congenital CMV is unknown for our region.AimThe purpose of this study was to determine the prevalence of CMV infection among the neonatal population at an urban, tertiary hospital in northeast Florida which serves a large population of patients with low socioeconomic status to assess if universal screening program for congenital asymptomatic CMV infection can be determined.MethodsThe study was submitted and approved by our Institutional Review Board. We tested the urine for CMV infection in 100 asymptomatic newborns (>32 weeks gestational age and >1,750 g weight at the time of delivery) delivered between June 2016 and July 2017.ResultsUrine CMV was tested on 100 infants. One infant had a positive urine NAAT for CMV, making the prevalence of congenital CMV infection among asymptomatic newborns in our hospitals' population 1%.ConclusionCMV prevalence in our setting of an urban, tertiary hospital is relatively consistent with the national average of all congenital CMV infections. A policy of universal screening for congenital CMV may be necessary.

The use of biomarkers for the early detection of Alzheimer’s disease (AD) is crucial for developing potential therapeutic treatments. Positron Emission Tomography (PET) is a well-established tool used to detect β-amyloid (Aβ) plaques in the brain. Previous studies have shown that cross-sectional biomarkers can predict cognitive decline (Schindler et al.,2021). However, it is still unclear whether longitudinal Aβ-PET may have additional value for predicting time to cognitive impairment in AD. The current study aims to evaluate the ability of baseline- versus longitudinal rate of change in-11C-Pittsburgh compound B (PiB) Aβ-PET to predict cognitive decline. A cohort of 153 participants who previously underwent PiB-PET scans and comprehensive clinical assessments were used in this study. Our analyses revealed that baseline Aβ is significantly associated with the rate of change in cognitive composite scores, with cognition declining more rapidly when baseline PiB Aβ levels were higher. In contrast, no signification association was identified between the rate of change in PiB-PET Aβ and cognitive decline. Additionally, the ability of the rate of change in the PiB-PET measures to predict cognitive decline was significantly influenced by APOE ε4 carrier status. These results suggest that a single PiB-PET scan is sufficient to predict cognitive decline and that longitudinal measures of Aβ accumulation do not improve the prediction of cognitive decline once someone is amyloid positive.

Abstract Legume crops are widely grown worldwide and a primary source of proteins across many least developed countries. These food crops are inherently produced in environmentally sustainable manner and are also an economical source of plant‐based proteins versus animal‐based proteins. The nutrient composition of legumes is very rich, that is, high content of protein, fiber, and bioactive compounds and relatively lower carbohydrates than cereal crops. Although food legumes are a staple in more than 70 countries mostly in Asian, African, and South American regions, the per capita consumption in the Western countries continues to be low in spite of legumes' demonstrated health benefits. However, emerging consumer trends and preferences toward heathy foods, animal protein alternatives, and environmental concerns can enhance the consumption of legume‐based foods. The functional attributes of legume ingredients (e.g., thickening, water‐holding index, gelation, emulsification, and foaming capacity) make legumes suitable for replacing proteins from other sources. The development and marketing of legume‐based ingredients for use in various value‐added food applications have been increasing. The value‐added use of pulse protein isolates and concentrates is expanding fast with substantial use as meat extenders/replacers and meat analogs, milk substitutes, and gluten‐free applications. To increase the utilization of legumes, including legume‐based foods, it is important to focus on research and development efforts that promote “easy‐to‐cook”/prepare foods for consumers, who often avoid legumes due to long cooking times. Addressing this aspect of convenience is particularly critical in developed countries due to the busy lifestyles of consumers and potentially increase legume consumption.

ObjectivesWhile the association between insomnia and traumatic brain injury (TBI) is well established, TBI rehabilitation programs that focus on sleep as a primary target are limited. Cognitive behavioral therapy for insomnia (CBTi) is an effective treatment for insomnia, however; its use within TBI clinics is relatively unknown. Therefore, our aim was to evaluate the implementation of CBTi, used in conjunction with a smartphone app for insomnia, within a US military TBI program to improve care within this setting.SettingA TBI clinic at a US military installation.MethodsMHS beneficiaries underwent 6 sessions of CBTi and a 1-month post-treatment follow up session. Data was collected at each treatment session as part of routine clinical care.ResultsA total of 69 US MHS beneficiaries seen at a TBI clinic with a diagnosis of insomnia began CBTi. Attrition rate at the end of the CBTi program and 1-month posttreatment session was 35% and 48%, respectively. Results demonstrated that sleep onset latency (SOL) and wake after sleep onset (WASO) decreased during treatment (p's < 0.001). Further, symptoms reported on the Insomnia Severity Index (ISI) improved during CBTi (p < 0.001).ConclusionFindings demonstrate how CBTi used in conjunction with a CBTi smartphone application can be used to effectively treat insomnia for MHS beneficiaries seeking care for TBIs. This evaluation provides the basis for further research on how CBTi may improve care within TBI programs.

Background and aims Historical paired liver biopsy studies are likely to underestimate current progression of disease in patients with chronic hepatitis C virus (HCV) infection. We aimed to assess liver disease progression according to the non-invasive Fibrosis-4 (FIB-4) index in patients with chronic HCV and early disease.Methods and results Patients diagnosed with chronic HCV and FIB-4 3.25 during follow-up. Survival analyses were used to assess time to FIB-4 >3.25.In total, 4286 patients were followed for a median of 5.0 (IQR 1.7–9.4) years, during which 41 071 FIB-4 measurements were collected. At baseline, median age was 47 (IQR 39–55) years, 2529 (59.0%) were male, and 2787 (65.0%) patients had a FIB-4

For young women, im/migration can impact education, employment, and family dynamics in ways that shape the courses of their lives and health. The purpose of this study is to deepen understandings of how im/migration shapes young women's experiences of pregnancy, motherhood, and marriage. Guided by intersectionality theory and the structural and social determinants of health, we analyzed qualitative interviews conducted with young im/migrants ages 15-30, who identify as women, and who had experiences of pregnancy, motherhood, and/or marriage (N ​= ​34). Participants were interviewed as part of the IRIS study in British Columbia, Canada between May 2019 to February 2021. Young im/migrant women described how im/migration shaped experiences of pregnancy, motherhood, and marriage by way of health, social, legal, and economic drivers. These included being ineligible for health insurance and unable to prevent pregnancy and experiencing workplace discrimination in form of reduced hours and no maternity benefits. Demanding caregiving roles and unsafe home environments were also described as being exacerbated by unaffordable childcare in destination settings and unequal gender roles and power dynamics after im/migration. Our findings suggest structural changes necessary to improve young im/migrant women's health. We recommend that health systems decouple im/migration status from health insurance; that governments provide all people with accessible childcare and maternity benefits; and that governments fund community-based efforts towards dismantling structures of patriarchy.

The extent to which dengue virus has been circulating globally and especially in Africa is largely unknown. Testing available blood samples from previous cross-sectional serological surveys offers a convenient strategy to investigate past dengue infections, as such serosurveys provide the ideal data to reconstruct the age-dependent immunity profile of the population and to estimate the average per-capita annual risk of infection: the force of infection (FOI), which is a fundamental measure of transmission intensity. In this study, we present a novel methodological approach to inform the size and age distribution of blood samples to test when samples are acquired from previous surveys. The method was used to inform SERODEN, a dengue seroprevalence survey which is currently being conducted in Ghana among other countries utilizing samples previously collected for a SARS-CoV-2 serosurvey. The method described in this paper can be employed to determine sample sizes and testing strategies for different diseases and transmission settings.

Abstract Orbital precession has been linked to glacial cycles and the atmospheric carbon dioxide (CO2) concentration, yet the direct impact of precession on the carbon cycle is not well understood. We analyze output from an Earth system model configured under different orbital parameters to isolate the impact of precession on air‐sea CO2 flux in the Southern Ocean—a component of the global carbon cycle that is thought to play a key role on past atmospheric CO2 variations. Here, we demonstrate that periods of high precession are coincident with anomalous CO2 outgassing from the Southern Ocean. Under high precession, we find a poleward shift in the southern westerly winds, enhanced Southern Ocean meridional overturning, and an increase in the surface ocean partial pressure of CO2 along the core of the Antarctic Circumpolar Current. These results suggest that orbital precession may have played an important role in driving changes in atmospheric CO2.

Abstract Anthropogenic carbon emissions and associated climate change are driving rapid warming, acidification, and deoxygenation in the ocean, which increasingly stress marine ecosystems. On top of long‐term trends, short term variability of marine stressors can have major implications for marine ecosystems and their management. As such, there is a growing need for predictions of marine ecosystem stressors on monthly, seasonal, and multi‐month timescales. Previous studies have demonstrated the ability to make reliable predictions of the surface ocean physical and biogeochemical state months to years in advance, but few studies have investigated forecast skill of multiple stressors simultaneously or assessed the forecast skill below the surface. Here, we use the Community Earth System Model (CESM) Seasonal to Multiyear Large Ensemble (SMYLE) along with novel observation‐based biogeochemical and physical products to quantify the predictive skill of dissolved inorganic carbon (DIC), dissolved oxygen, and temperature in the surface and subsurface ocean. CESM SMYLE demonstrates high physical and biogeochemical predictive skill multiple months in advance in key oceanic regions and frequently outperforms persistence forecasts. We find up to 10 months of skillful forecasts, with particularly high skill in the Northeast Pacific (Gulf of Alaska and California Current Large Marine Ecosystems) for temperature, surface DIC, and subsurface oxygen. Our findings suggest that dynamical marine ecosystem prediction could support actionable advice for decision making.

Subject. An unstable environment has a significant effect on the functioning of society and its sustainable development. One of the factors determining the potential for sustainable development is trust. To study the potential of trust as a factor of stability in society it is necessary to measure the level of trust. This is, however, hindered by the lack of a unified approach and the limitations of the existing approaches. Purpose. The purpose of our study was to analyse the main approaches to measuring the level of trust in a community and to identify the limitations of each approach. We analysed the survey-based and the experiment-based approaches, as well as cases of the indirect assessment of the level of trust based on social dysfunctions and using econometric tools. Methodology. To achieve our purpose, we studied the relevant literature by both Russian and international scholars and methodological guidelines of international organisations concerning the subject. We also used the dialectical method and performed an analysis. Conclusions. In this article, we systematised the existing methods and approaches to measuring the level of trust in society and analysed the main advantages and disadvantages of the survey- and experiment-based approaches that are most commonly used to measure trust. We also studied the cases of measuring the level of trust based on social dysfunctions and social capital. Taking into account the limitations of the existing methods and approaches, we considered the possibility of using mathematical modelling in order to search for connections between various socio-economic parameters and the level of trust (the article presents a model with latent variables and describes its advantages). As a result, we determined the strengths and the limitations of the existing approaches to measuring trust and identified the need for further research in the area and elaboration of these approaches.

Tumors with a pathogenic BRCA1/2 mutation are homologous recombination (HR)-deficient (HRD) and consequently sensitive to platinum-based chemotherapy and Poly-[ADP-Ribose]-Polymerase inhibitors (PARPi). We hypothesized that functional HR status better reflects real-time HR status than BRCA1/2 mutation status. Therefore, we determined the functional HR status of 53 breast cancer (BC) and 38 ovarian cancer (OC) cell lines by measuring the formation of RAD51 foci after irradiation. Discrepancies between functional HR and BRCA1/2 mutation status were investigated using exome sequencing, methylation and gene expression data from 50 HR-related genes. A pathogenic BRCA1/2 mutation was found in 10/53 (18.9%) of BC and 7/38 (18.4%) of OC cell lines. Among BRCA1/2-mutant cell lines, 14/17 (82.4%) were HR-proficient (HRP), while 1/74 (1.4%) wild-type cell lines was HRD. For most (80%) cell lines, we explained the discrepancy between functional HR and BRCA1/2 mutation status. Importantly, 12/14 (85.7%) BRCA1/2-mutant HRP cell lines were explained by mechanisms directly acting on BRCA1/2. Finally, functional HR status was strongly associated with COSMIC single base substitution signature 3, but not BRCA1/2 mutation status. Thus, the majority of BRCA1/2-mutant cell lines do not represent a suitable model for HRD. Moreover, exclusively determining BRCA1/2 mutation status may not suffice for platinum-based chemotherapy or PARPi patient selection.

Abstract Multidecadal satellite observations indicate that the Antarctic Ice Sheet (AIS) is losing mass at an accelerating rate, which has the potential to impact many aspects of the climate system. While previous studies demonstrated the importance of AIS freshwater (FW) discharge for regional and global climate processes using climate model experiments, many have applied unrealistic FW forcings. Here, we explore potential Southern Ocean (SO) impacts of realistic AIS mass loss over the 21st century in the Community Earth System Model version 2 by applying observation‐based historical and ice sheet model‐based future AIS FW forcing. The added FW reduces wintertime deep convective area by 72% while retaining 83% more sea ice. Congruent with other studies, we find the increased FW discharge extensively impacts local and remote SO surface and subsurface temperature and stratification. These results demonstrate the necessity of accounting for AIS mass loss in global climate models for projecting future climate.