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Abstract Background Given that South Africa has one of the highest rates of pregnancy amongst adolescent girls and young women (AGYW) globally, the provision of contraceptives to this group has been a key focus in recent years. Pregnancy prevention involves an on-going continuum of decision-making around contraceptive method choice, uptake, use, experience, continuation, and discontinuation. Methods This paper presents analysis of data from a cross-sectional survey with 2376 AGYW, as well as qualitative in-depth interviews (IDIs) with 54 AGYW, inclusive of contraceptive journey narratives. We examine the preferences, valued characteristics, choices, beliefs, understandings and experiences of choosing and using contraceptives amongst AGYW in two South African communities characterised by high rates of pregnancy. Results These findings shed light on the preferences towards, beliefs about, and experiences of choosing, using and discontinuing contraceptive methods amongst this population, with survey data suggesting that the most popular methods were the injection, followed by the implant, and then the oral pill. Findings illustrate the complexity and dynamic nature of contraceptive decision-making and the varied embodied and lived experiences of contraceptive use, and how these are impacted by contraception service provision. Conclusions Our findings show that contraception experiences of each individual are cumulative, and comprise a continuum of method initiation, use, discontinuation, method switching and on-going circular decision-making influenced by multiple social, structural, contextual and interpersonal factors, combined with shifting preferences, values and needs. To maximise the use of contraceptives amongst South African AGYW, it is necessary to provide responsive contraception service provision to reflect the changing contexts and preferences of users, in order to ensure that pregnancy prevention needs are catered for throughout their reproductive life course.

Abstract Background Access and use of contraception services by adolescent girls and young women (AGYW) remains suboptimal, exposing AGYW to early and often unexpected pregnancy. Unexpected pregnancies are a public health concern, associated with poor neonatal and maternal health outcomes, as well as school dropout, which may result in economic hardships. This study aimed to explore (a) AGYW perceptions and experiences of receiving contraception services from health care providers and (b) health care providers’ perceptions and experiences of providing contraception services to AGYW. Methods Data were collected through semi-structured individual interviews with AGYW aged 15–24 years old and health care providers working in eight health care facilities around the Cape Town metropolitan area, in South Africa’s Western Cape Province. Thematic analysis was used to analyse the data. Results AGYW and health care providers voiced varying, and often contrasting, perceptions of some of the barriers that hinder AGYW’s access to contraception services. AGYW indicated that provider-imposed rules about when to access contraceptive services hindered access, while health care providers felt that these rules were necessary for coordinating their work. In addition, AGYW highlighted health care providers’ hostile attitudes towards them as an important factor discouraging access. On the contrary, health care providers did not think that their attitudes hampered AGYW’s access to and use of contraception services, instead they emphasised that challenges at the health system level were a major issue, which they feel they have little control over. Such challenges made health care providers’ work unpleasant and frustrating, impacting on their work approach and how they receive and offer services to AGYW. Conclusion The expectation of negative attitudes from health care providers continues to be at the centre of AGYW discouragement towards accessing contraception services. System challenges are among some of the key drivers of health care provider’s hostile attitudes, posing challenges to the efficient provision of services. In order to improve AGYW’s access to and use of contraception services, and subsequently achieve the country’s SDGs, conscious efforts need to be directed towards improving the workload and working conditions of health care providers.

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

Abstract Parkinson’s disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of α-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of α-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the α-Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical α-Syn pathology, indicated by reduced numbers of pS129 α-Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic α-Syn species. We further validated these findings on pS129 α-Syn levels in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable in vitro and in vivo. We found that CDK14 inhibition decreases total and pathologically aggregated α-Syn in human neurons, in PFF-challenged rat neurons and in the brains of α-Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy.

Knowledge graphs have become a common approach for knowledge representation. Yet, the application of graph methodology is elusive due to the sheer number and complexity of knowledge sources. In addition, semantic incompatibilities hinder efforts to harmonize and integrate across these diverse sources. As part of The Biomedical Translator Consortium, we have developed a knowledge graph-based question-answering system designed to augment human reasoning and accelerate translational scientific discovery: the Translator system. We have applied the Translator system to answer biomedical questions in the context of a broad array of diseases and syndromes, including Fanconi anemia, primary ciliary dyskinesia, multiple sclerosis, and others. A variety of collaborative approaches have been used to research and develop the Translator system. One recent approach involved the establishment of a monthly "Question-of-the-Month (QotM) Challenge" series. Herein, we describe the structure of the QotM Challenge; the six challenges that have been conducted to date on drug-induced liver injury, cannabidiol toxicity, coronavirus infection, diabetes, psoriatic arthritis, and ATP1A3-related phenotypes; the scientific insights that have been gleaned during the challenges; and the technical issues that were identified over the course of the challenges and that can now be addressed to foster further development of the prototype Translator system. We close with a discussion on Large Language Models such as ChatGPT and highlight differences between those models and the Translator system.

ObjectiveExamine the impact of vaccination status on hospital cost and course for patients admitted with COVID-19 infection.DesignRetrospective cohort study characterizing vaccinated and unvaccinated individuals hospitalized for COVID-19 between April 2021 to January 2022.SettingLarge academic medical center.MethodsPatients were included if they were greater than 18 years old, fully vaccinated or unvaccinated against COVID-19, and admitted for COVID-19 infection.Patients437 consecutively admitted patients for COVID-19 infection met inclusion criteria. Of these, 79 were excluded for unknown or partial vaccination status, transfer from an outside hospital, or multiple COVID-19 related admissions.ResultsOverall, 279 (77.9%) unvaccinated patients compared to 79 (22.1%) vaccinated patients were hospitalized with a diagnosis of COVID-19. Average length of stay was significantly lower in the vaccinated group (6.47 days versus 8.92 days, P = 0.03). Vaccinated patients experienced a 70.6% lower risk of ICU admission (OR = 0.29, 95% CI 0.12-0.71, P = 0.006). The unadjusted cost of hospitalization was not found to be statistically significant ($119,630 versus $191,146, P = 0.06). After adjusting for age and comorbidities, vaccinated patients experienced a 26% lower cost of hospitalization compared to unvaccinated patients (P = 0.004). Unvaccinated patients incurred a significantly higher cost of hospitalization per day ($29,425 vs $13,845 P < 0.0001). Unvaccinated patients (n = 118, 42.9%) were more likely than vaccinated patients (n = 16, 20.3%) to require high-flow oxygen or mechanical ventilation (OR = 2.95, 95% CI 1.62-5.38, P = 0.0004).ConclusionVaccinated patients experienced a lower cost of hospitalization after adjusting for age and comorbidities and shorter length of stay compared to unvaccinated patients admitted for COVID-19.

Summary: Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.

Clinical, biomedical, and translational science has reached an inflection point in the breadth and diversity of available data and the potential impact of such data to improve human health and well-being. However, the data are often siloed, disorganized, and not broadly accessible due to discipline-specific differences in terminology and representation. To address these challenges, the Biomedical Data Translator Consortium has developed and tested a pilot knowledge graph-based "Translator" system capable of integrating existing biomedical data sets and "translating" those data into insights intended to augment human reasoning and accelerate translational science. Having demonstrated feasibility of the Translator system, the Translator program has since moved into development, and the Translator Consortium has made significant progress in the research, design, and implementation of an operational system. Herein, we describe the current system's architecture, performance, and quality of results. We apply Translator to several real-world use cases developed in collaboration with subject-matter experts. Finally, we discuss the scientific and technical features of Translator and compare those features to other state-of-the-art, biomedical graph-based question-answering systems.

Within clinical, biomedical, and translational science, an increasing number of projects are adopting graphs for knowledge representation. Graph-based data models elucidate the interconnectedness among core biomedical concepts, enable data structures to be easily updated, and support intuitive queries, visualizations, and inference algorithms. However, knowledge discovery across these "knowledge graphs" (KGs) has remained difficult. Data set heterogeneity and complexity; the proliferation of ad hoc data formats; poor compliance with guidelines on findability, accessibility, interoperability, and reusability; and, in particular, the lack of a universally accepted, open-access model for standardization across biomedical KGs has left the task of reconciling data sources to downstream consumers. Biolink Model is an open-source data model that can be used to formalize the relationships between data structures in translational science. It incorporates object-oriented classification and graph-oriented features. The core of the model is a set of hierarchical, interconnected classes (or categories) and relationships between them (or predicates) representing biomedical entities such as gene, disease, chemical, anatomic structure, and phenotype. The model provides class and edge attributes and associations that guide how entities should relate to one another. Here, we highlight the need for a standardized data model for KGs, describe Biolink Model, and compare it with other models. We demonstrate the utility of Biolink Model in various initiatives, including the Biomedical Data Translator Consortium and the Monarch Initiative, and show how it has supported easier integration and interoperability of biomedical KGs, bringing together knowledge from multiple sources and helping to realize the goals of translational science.

BackgroundTrauma patients are at high risk for venous thromboembolism (VTE) and bleeding. The purpose of this study was to characterize percentage of VTE chemoprophylaxis given to trauma patients with and without a VTE.Study designThis retrospective case-control study evaluated trauma patients admitted to a Level I trauma center. Adult patients were included when hospitalized at least 2 days and had a head abbreviated injury score of 1 or less. Non-VTE patients were matched by decade of life and injury severity score (ISS). The primary outcome was percentage of VTE chemoprophylaxis received over the first 14 days of admission. Descriptive statistics, chi-squared test, Student's t-test, and Cox proportional hazard were used for analysis.ResultsA total of 44 VTE patients were included with 125 matched non-VTE patients. Baseline demographics included age in years (50.7 ± 19.6 vs 49.6 ± 19.4), ISS (18.9 ± 11.3 vs 19 ± 11.6), and lower extremity fracture (54.5% vs 40%), for VTE and non-VTE groups, respectively. The primary outcome of VTE chemoprophylaxis doses given was significantly lower for VTE patients than non-VTE patients (49.3% vs 59.3%, p = 0.0069). Significant predictors of VTE were percentage of VTE chemoprophylaxis doses given (p < 0.0001) and weight (p = 0.0042) based on regression analysis. Notably, there was a 7% decrease in the hazard for VTE for every 1% increase in VTE chemoprophylaxis given.ConclusionsPatients who developed VTE were more likely to have delays and disruptions in VTE chemoprophylaxis, even after controlling for age, sex, ISS, lower extremity fractures, and number of operations.

Introduction Pediatric behavioral and mental health (BMH) disorders are increasingly common, but most pediatricians feel inadequately trained to manage them. We implemented a case-based, longitudinal curriculum in BMH within a pediatric residency program to prepare trainees to diagnose and manage these conditions. Methods The pediatric residency program at Wright State University/Wright-Patterson Medical Center implemented a new BMH curriculum in 2020–2021. The curriculum consisted of five simulated cases involving depression, anxiety, attention deficit disorder with hyperactivity (ADHD), developmental delays, behavioral concerns, and autism. To reflect follow-up within a continuity clinic, cases included initial encounters and multiple follow-up visits. Faculty facilitators led residents in monthly small-group meetings over the academic year, with each session consisting of two to three simulated patient encounters. Residents completed pre-post surveys regarding their confidence in diagnosing and managing BMH conditions and pre- and posttests to evaluate the impact of the curriculum on knowledge gains. Results All 47 pediatric residents participated in the curriculum; 38 (81%) completed pre-post surveys. Upon completion of the curriculum, residents reported significantly increased confidence in managing ADHD, treating depression, creating safety plans for suicidality, recognizing autism, and counseling patients and families on special education services. Knowledge-based pre- and posttests completed by 25 residents (53%) also demonstrated significant improvement (M = 92.4, SD = 10.9, pre vs. M = 99.3, SD = 6.6, post, p = .009). Discussion This case-based, longitudinal curriculum in pediatric BMH simulating patient continuity improved residents’ confidence and knowledge in diagnosing and managing common BMH conditions.

Objective:. We sought to determine if and how providers use elements of shared decision-making (SDM) in the care of surgical patients in the intensive care unit (ICU). Background:. SDM is the gold standard for decision-making in the ICU. However, it is unknown if this communication style is used in caring for critically ill surgical patients. Methods:. Qualitative interviews were conducted with providers who provide ICU-level care to surgical patients in Veterans Affairs hospitals. Interviews were designed to examine end-of-life care among veterans who have undergone surgery and require ICU-level care. Results:. Forty-eight providers across 14 Veterans Affairs hospitals were interviewed. These participants were diverse with respect to age, race, and sex. Participant dialogue was deductively mapped into 8 established SDM components: describing treatment options; determining roles in the decision-making process; fostering partnerships; health care professional preferences; learning about the patient; patient preferences; supporting the decision-making process; and tailoring the information. Within these components, participants shared preferred tools and tactics used to satisfy a given SDM component. Participants also noted numerous barriers to achieving SDM among surgical patients. Conclusions:. Providers use elements of SDM when caring for critically ill surgical patients. Additionally, this work identifies facilitators that can be leveraged and barriers that can be addressed to facilitate better communication and decision-making through SDM. These findings are of value for future interventions that seek to enhance SDM among surgical patients both in the ICU and in other settings.

Abstract Skeletal muscle fibers express distinct gene programs during development and maturation, but the underlying gene regulatory networks that confer stage-specific myofiber properties remain unknown. To decipher these distinctive gene programs and how they respond to neural activity, we generated a combined multi-omic single-nucleus RNA-seq and ATAC-seq atlas of mouse skeletal muscle development at multiple stages of embryonic, fetal, and postnatal life. We found that Myogenin, Klf5, and Tead4 form a transcriptional complex that synergistically activates the expression of muscle genes in developing myofibers. During myofiber maturation, the transcription factor Maf acts as a transcriptional switch to activate the mature fast muscle gene program. In skeletal muscles of mutant mice lacking voltage-gated L-type Ca2+ channels (Cav1.1), Maf expression and myofiber maturation are impaired. These findings provide a transcriptional atlas of muscle development and reveal genetic links between myofiber formation, maturation, and contraction.

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease of progressive muscle weakness and wasting caused by the absence of dystrophin protein. Current gene therapy approaches using antisense oligonucleotides require lifelong dosing and have limited efficacy in restoring dystrophin production. A gene editing approach could permanently correct the genome and restore dystrophin protein expression. Here, we describe single-swap editing, in which an adenine base editor edits a single base pair at a splice donor site or splice acceptor site to enable exon skipping or reframing. In human induced pluripotent stem cell-derived cardiomyocytes, we demonstrate that single-swap editing can enable beneficial exon skipping or reframing for the three most therapeutically relevant exons—DMD exons 45, 51, and 53—which could be beneficial for 30% of all DMD patients. Furthermore, an adeno-associated virus delivery method for base editing components can efficiently restore dystrophin production locally and systemically in skeletal and cardiac muscles of a DMD mouse model containing a deletion of Dmd exon 44. Our studies demonstrate single-swap editing as a potential gene editing therapy for common DMD mutations.

Cardiovascular diseases are the most common cause of worldwide morbidity and mortality, highlighting the necessity for advanced therapeutic strategies. [Ca.sup.2+]/calmodulin-dependent protein kinase IIS (CaMKII[beta]) is a prominent inducer of various cardiac disorders, which is mediated by 2 oxidation-sensitive methionine residues within the regulatory domain. We have previously shown that ablation of CaMKII[beta] oxidation by CRISPR-Cas9 base editing enables the heart to recover function from otherwise severe damage following ischemia/reperfusion (IR) injury. Here, we extended this therapeutic concept toward potential clinical translation. We generated a humanized CAMK2D knockin mouse model in which the genomic sequence encoding the entire regulatory domain was replaced with the human sequence. This enabled comparison and optimization of two different editing strategies for the human genome in mice. To edit CAMK2D in vivo, we packaged the optimized editing components into an engineered myotropic adeno-associated virus (MyoAAV 2A), which enabled efficient delivery at a very low AAV dose into the humanized mice at the time of IR injury. CAMK2D-edited mice recovered cardiac function, showed improved exercise performance, and were protected from myocardial fibrosis, which was otherwise observed in injured control mice after IR. Our findings identify a potentially effective strategy for cardioprotection in response to oxidative damage., Introduction Cardiovascular diseases, in particular coronary artery heart disease with subsequent myocardial infarction, are the most common cause of death worldwide, highlighting the necessity for advanced therapeutic strategies (1). Chronic [...]

To determine whether the use of flumazenil reverses hypoactive delirium and increases delirium-free days in critically ill patients who were exposed to benzodiazepine therapy during the ICU admission. Design:This was a single-center, double-blinded, randomized placebo-controlled pilot study. Setting:Adult ICUs at a large academic medical center in the United States. Patients:Adult, critically ill patients with benzodiazepine exposure and hypoactive delirium based on the Confusion Assessment Method-ICU and Richmond Agitation Sedation Scale assessments were considered for enrollment. Interventions:Patients received a test dose of flumazenil starting at 0.1 mg intravenously and titrated up every 5 minutes by 0.1 mg increments up to a maximum total dose of 2 mg. Patients who demonstrated a Richmond Agitation Sedation Scale score increase of greater than 1 point were considered responders and randomized to flumazenil (0.05-0.3 mg/hr) or placebo infusion for up to 72 hours. Confusion Assessment Method-ICU scores were assessed twice daily for resolution of delirium. Measurements and Main Results:The trial was stopped early based on the observed size effect and power analysis. Twenty-two of the 25 patients responded to the flumazenil test dose (88%). The median number of delirium-free days alive without coma within 14 days of enrollment was similar between the two infusion groups (12.7 vs 9.2; p = 0.19). There was no difference in the probability of delirium resolution within the first 14 days with 90% versus 70% in the flumazenil and placebo groups, respectively (p = 0.2). There was no statistical difference (odds ratio, 0.17; 95% CI, 0.022-1.23; p = 0.079) in delirium- and coma-free days at the end of the study drug infusion. There was no difference between groups in ICU length of stay (7.8 ± 4.8 vs 7 ± 8; p = 0.74). No serious adverse events occurred. Conclusions:This study found that flumazenil test dose and infusion present a potential option for hypoactive delirium associated with benzodiazepine exposure; however, the possible benefit is unknown. Larger studies are warranted to further evaluate these findings.

Abstract Background Human pluripotent stem cell‐derived muscle models show great potential for translational research. Here, we describe developmentally inspired methods for the derivation of skeletal muscle cells and their utility in skeletal muscle tissue engineering with the aim to model skeletal muscle regeneration and dystrophy in vitro. Methods Key steps include the directed differentiation of human pluripotent stem cells to embryonic muscle progenitors followed by primary and secondary foetal myogenesis into three‐dimensional muscle. To simulate Duchenne muscular dystrophy (DMD), a patient‐specific induced pluripotent stem cell line was compared to a CRISPR/Cas9‐edited isogenic control line. Results The established skeletal muscle differentiation protocol robustly and faithfully recapitulates critical steps of embryonic myogenesis in two‐dimensional and three‐dimensional cultures, resulting in functional human skeletal muscle organoids (SMOs) and engineered skeletal muscles (ESMs) with a regeneration‐competent satellite‐like cell pool. Tissue‐engineered muscle exhibits organotypic maturation and function (up to 5.7 ± 0.5 mN tetanic twitch tension at 100 Hz in ESM). Contractile performance could be further enhanced by timed thyroid hormone treatment, increasing the speed of contraction (time to peak contraction) as well as relaxation (time to 50% relaxation) of single twitches from 107 ± 2 to 75 ± 4 ms (P