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Importance: Positive airway pressure (PAP) is the first-line treatment for obstructive sleep apnea (OSA), but evidence on its beneficial effect on major adverse cardiovascular events (MACE) and mortality prevention is limited. Objective: To determine whether PAP initiation and utilization are associated with lower mortality and incidence of MACE among older adults with OSA living in the central US. Design, Setting, and Participants: This retrospective clinical cohort study included Medicare beneficiaries with 2 or more distinct OSA claims identified from multistate, statewide, multiyear (2011-2020) Medicare fee-for-service claims data. Individuals were followed up until death or censoring on December 31, 2020. Analyses were performed between December 2021 and December 2023. Exposures: Evidence of PAP initiation and utilization based on PAP claims after OSA diagnosis. Main Outcomes and Measures: All-cause mortality and MACE, defined as a composite of myocardial infarction, heart failure, stroke, or coronary revascularization. Doubly robust Cox proportional hazards models with inverse probability of treatment weights were used to estimate treatment effect sizes controlling for sociodemographic and clinical factors. Results: Among 888â¯835 beneficiaries with OSA included in the analyses (median [IQR] age, 73 [69-78] years; 390â¯598 women [43.9%]; 8115 Asian [0.9%], 47â¯122 Black [5.3%], and 760â¯324 White [85.5%] participants; median [IQR] follow-up, 3.1 [1.5-5.1] years), those with evidence of PAP initiation (290â¯015 [32.6%]) had significantly lower all-cause mortality (hazard ratio [HR], 0.53; 95% CI, 0.52-0.54) and MACE incidence risk (HR, 0.90; 95% CI, 0.89-0.91). Higher quartiles (Q) of annual PAP claims were progressively associated with lower mortality (Q2 HR, 0.84; 95% CI, 0.81-0.87; Q3 HR, 0.76; 95% CI, 0.74-0.79; Q4 HR, 0.74; 95% CI, 0.72-0.77) and MACE incidence risk (Q2 HR, 0.92; 95% CI, 0.89-0.95; Q3 HR, 0.89; 95% CI, 0.86-0.91; Q4 HR, 0.87; 95% CI, 0.85-0.90). Conclusions and Relevance: In this cohort study of Medicare beneficiaries with OSA, PAP utilization was associated with lower all-cause mortality and MACE incidence. Results might inform trials assessing the importance of OSA therapy toward minimizing cardiovascular risk and mortality in older adults.
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Doenças Cardiovasculares , Pressão Positiva Contínua nas Vias Aéreas , Medicare , Apneia Obstrutiva do Sono , Humanos , Feminino , Masculino , Idoso , Estudos Retrospectivos , Estados Unidos/epidemiologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/epidemiologia , Apneia Obstrutiva do Sono/mortalidade , Apneia Obstrutiva do Sono/terapia , Apneia Obstrutiva do Sono/complicações , Medicare/estatística & dados numéricos , Idoso de 80 Anos ou mais , Incidência , Fatores de Risco de Doenças CardíacasRESUMO
After egg fertilization, an initially silent embryonic genome is transcriptionally activated during the maternal-to-zygotic transition. In zebrafish, maternal vertebrate pluripotency factors Nanog, Pou5f3 (OCT4 homolog), and Sox19b (SOX2 homolog) (NPS) play essential roles in orchestrating embryonic genome activation, acting as "pioneers" that open condensed chromatin and mediate acquisition of activating histone modifications. However, some embryonic gene transcription still occurs in the absence of these factors, suggesting the existence of other mechanisms regulating genome activation. To identify chromatin signatures of these unknown pathways, we profiled the histone modification landscape of zebrafish embryos using CUT&RUN. Our regulatory map revealed two subclasses of enhancers distinguished by presence or absence of H3K4me2. Enhancers lacking H3K4me2 tend to require NPS factors for de novo activation, while enhancers bearing H3K4me2 are epigenetically bookmarked by DNA hypomethylation to recapitulate gamete activity in the embryo, independent of NPS pioneering. Thus, parallel enhancer activation pathways combine to induce transcriptional reprogramming to pluripotency in the early embryo.
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Borrelia burgdorferi, the bacterium responsible for Lyme disease, has been shown to form antimicrobial-tolerant biofilms, which protect it from unfavorable conditions. Bacterial biofilms are known to significantly contribute to severe inflammation, such as carditis, a common manifestation of Lyme disease. However, the role of B. burgdorferi biofilms in the development of Lyme carditis has not been thoroughly investigated due to the absence of an appropriate model system. In this study, we examined heart tissues from mice infected with B. burgdorferi for the presence of biofilms and inflammatory markers using immunohistochemistry (IHC), combined fluorescence in situ hybridization FISH/IHC, 3D microscopy, and atomic force microscopy techniques. Our results reveal that B. burgdorferi spirochetes form aggregates with a known biofilm marker (alginate) in mouse heart tissues. Furthermore, these biofilms induce inflammation, as indicated by elevated levels of murine C-reactive protein near the biofilms. This research provides evidence that B. burgdorferi can form biofilms in mouse heart tissue and trigger inflammatory processes, suggesting that the mouse model is a valuable tool for future studies on B. burgdorferi biofilms.
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BACKGROUND: Penicillin (PCN) allergy labels are the most common drug allergy label and limit use of first-line antibiotics for many pediatric bacterial infections. Improving access to PCN allergy evaluations is a priority for allergy and immunology (A&I) and infectious diseases (ID) programs. OBJECTIVE: To increase the number of completed PCN allergy evaluations from 6 to 24 per month from January 2022 to December 2023. METHODS: A collaborative PCN allergy stewardship team was established in the A&I and ID divisions at Texas Children's Hospital. Telemedicine evaluations and, when clinically indicated, in-person PCN allergy evaluations were conducted from January 2022 to December 2023. Plan-do-study-act cycles were conducted to increase awareness about the clinics. The primary outcome measure was the average number of monthly completed PCN allergy evaluations. RESULTS: The average number of completed PCN allergy evaluations increased from 6 to 19 per month. Children were seen rapidly in the ID telemedicine clinic (20 vs 62 days, P < .001), and 428 of 627 (68%) children who required in-person challenge were scheduled for their in-person evaluation. Among the 211 children delabeled, 71 (33.6%) were subsequently diagnosed with a bacterial infection requiring PCN during the study period. CONCLUSION: A collaborative PCN allergy stewardship team consisting of ID and A&I specialists increased the number of completed PCN allergy evaluations 3-fold. ID telemedicine services allowed prompt access to care, and most children were delabeled and subsequently able to receive PCN antibiotics for bacterial respiratory tract infections. Future work should explore ways to minimize barriers to PCN allergy evaluations and further expand testing services in other settings.
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BACKGROUND: Artificial intelligence (AI) is increasingly used for prevention, diagnosis, monitoring, and treatment of cardiovascular diseases. Despite the potential for AI to improve care, ethical concerns and mistrust in AI-enabled healthcare exist among the public and medical community. Given the rapid and transformative recent growth of AI in cardiovascular care, to inform practice guidelines and regulatory policies that facilitate ethical and trustworthy use of AI in medicine, we conducted a literature review to identify key ethical and trust barriers and facilitators from patients' and healthcare providers' perspectives when using AI in cardiovascular care. METHODS: In this rapid literature review, we searched six bibliographic databases to identify publications discussing transparency, trust, or ethical concerns (outcomes of interest) associated with AI-based medical devices (interventions of interest) in the context of cardiovascular care from patients', caregivers', or healthcare providers' perspectives. The search was completed on May 24, 2022 and was not limited by date or study design. RESULTS: After reviewing 7,925 papers from six databases and 3,603 papers identified through citation chasing, 145 articles were included. Key ethical concerns included privacy, security, or confidentiality issues (n = 59, 40.7%); risk of healthcare inequity or disparity (n = 36, 24.8%); risk of patient harm (n = 24, 16.6%); accountability and responsibility concerns (n = 19, 13.1%); problematic informed consent and potential loss of patient autonomy (n = 17, 11.7%); and issues related to data ownership (n = 11, 7.6%). Major trust barriers included data privacy and security concerns, potential risk of patient harm, perceived lack of transparency about AI-enabled medical devices, concerns about AI replacing human aspects of care, concerns about prioritizing profits over patients' interests, and lack of robust evidence related to the accuracy and limitations of AI-based medical devices. Ethical and trust facilitators included ensuring data privacy and data validation, conducting clinical trials in diverse cohorts, providing appropriate training and resources to patients and healthcare providers and improving their engagement in different phases of AI implementation, and establishing further regulatory oversights. CONCLUSION: This review revealed key ethical concerns and barriers and facilitators of trust in AI-enabled medical devices from patients' and healthcare providers' perspectives. Successful integration of AI into cardiovascular care necessitates implementation of mitigation strategies. These strategies should focus on enhanced regulatory oversight on the use of patient data and promoting transparency around the use of AI in patient care.
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Inteligência Artificial , Doenças Cardiovasculares , Confiança , Humanos , Inteligência Artificial/ética , Doenças Cardiovasculares/terapiaRESUMO
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic AIRE variants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic AIRE variant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of AIRE-expressing primary patient monocyte-derived dendritic cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109-base pair frame-shifting pseudoexon. We also found low-level AIRE expression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic AIRE-expressing cell lines. Through protein modeling and transcriptomic analyses of AIRE-transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal AIRE transcript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing AIRE variant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED.
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Proteína AIRE , Éxons , Íntrons , Oligonucleotídeos Antissenso , Poliendocrinopatias Autoimunes , Fatores de Transcrição , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Sequência de Bases , Linhagem Celular , Éxons/genética , Íntrons/genética , Mutação/genética , Linhagem , Poliendocrinopatias Autoimunes/genética , Splicing de RNA/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Despite its high cost, the success rate for in vitro fertilization (IVF) remains < 33% in humans, driving the need for new techniques to improve embryo culture outcomes. The well-of-the-well (WOW) culture system is a platform for in-vitro mammalian embryo culture that has been shown to enhance the developmental competence of embryos and clinical pregnancy rates in humans. However, discovery and testing of the best design for optimal embryo culture quality is hindered by the lack of a method to flexibly produce WOW dishes of various designs. Here, we present a low-cost and simple method to fabricate WOW dishes with microwells of arbitrary shapes and dimensions. We use a low-cost 3D printing service to fabricate a poly(dimethylsiloxane) (PDMS)-based WOW insert that can be paired with a standard in vitro fertilization (IVF) dish to create WOW dishes with new microwell shapes, including pyramidal and hemispherical designs. We validate the fabrication quality of the WOW inserts and demonstrate the utility of the assembled WOW dishes for observation and grading of mouse embryo quality. Moreover, our results indicate that WOW dishes with hemispherical microwells result in better culture outcomes than traditional flat-bottomed IVF dishes and those with other microwell shapes, including the semi-elliptical microwells used in commercial WOW dishes. The proposed fabrication strategy thus provides a way to rapidly fabricate and test new WOW dishes that may bolster IVF success rates.
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Técnicas de Cultura Embrionária , Fertilização in vitro , Impressão Tridimensional , Técnicas de Cultura Embrionária/métodos , Técnicas de Cultura Embrionária/instrumentação , Animais , Camundongos , Fertilização in vitro/métodos , Feminino , Embrião de Mamíferos , Desenvolvimento Embrionário , Humanos , Dimetilpolisiloxanos/químicaRESUMO
Successful multichannel intraluminal impedance and pH monitoring (MII-pHM) studies rely on constant attendants (CAs) or family members (and sometimes the patients themselves) to assist in the execution and facilitation of the MII-pHM study. While "pushing buttons" [corresponding to specific symptoms, body position (upright versus recumbent), and meal start and stop times] on the MII-pHM system recording box is indeed a big part of MII-pHM study execution and facilitation, there are other concerns and duties that are equally as important. This paper outlines some of the important duties of the study facilitator (or patient) during a MII-pHM study. When provided with the proper training, study facilitators invigilating the MII-pHM study will be better able to contribute to the data collection process and ultimately to produce data that when analyzed will lead to better interpretations, clinical recommendations, and good clinical outcomes. When executed properly, MII-pHM studies have the potential to assess diurnal exposure of the esophageal mucosa to gastric/duodenal contents, provide insight regarding the proximal extent of gastroesophageal reflux (GER), provide a measurement of the mean esophageal pH, and assess mucosal integrity and temporal relationship between GER and the symptoms of interest. While several groups have offered recommendations for proper execution of the MII-pHM study, to our knowledge, there have not been publications wherein recommendations were compiled to form a single source document.
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Objective: To develop a reference standard based on US Food and Drug Administration and stakeholder guidance for pharmaceutical companies' policies on diversity in clinical trials and to assess these policies. Design: Development of a reference standard and structured audit for clinical trial diversity policies. Setting: 50 pharmaceutical companies selected from the top 500 by their market capitalizations in 2021 (the 25 largest companies and 25 non-large companies, randomly selected from the remaining 475 companies). Population: Data from pharmaceutical company websites and annual reports. Policy guidance from the Pharmaceutical Research and Manufacturers of America, International Federation of Pharmaceutical Manufacturers and Associations, Biotechnology Industry Organization, International Committee of Medical Journal Editors, the US Food and Drug Administration, European Medicines Agency, and World Health Organization, up to 15 May 2023. Main outcome measures: Multicomponent measure based on distinct themes derived from FDA and stakeholder guidance. Results: Reviewing FDA and stakeholder guidance identified 14 distinct themes recommended for improving diversity in clinical trials, which were built into a reference standard: (1) enrollment targets that reflect the prevalence of targeted conditions in populations, (2) broad eligibility criteria for trials, (3) diversity in the workforce, (4) identification and remedy of barriers to trial recruitment and retention, (5) incorporation of patient input into trial design, (6) health literacy, (7) multidimensional approaches to diversity, (8) sites with diverse providers and patient populations, (9) data collection after product approval, (10) diverse enrollment in every country where trials are conducted, (11) diverse enrollment should be a focus for all phases of clinical trials, not just later stage or pivotal trials, (12) varied trial design, (13) expanded access, and (14) public reporting of the personal characteristics of participants in trials. Applying this reference standard, 48% (24/50) of companies had no public policy on diversity in clinical trials; among those with policies, content varied widely. Large companies were more likely to have a public policy than non-large companies (21/25, 84% v 5/25, 20%, P<0.001). Large companies most frequently committed to using epidemiological based trial enrollment targets representing the prevalence of indicated conditions in various populations (n=15, 71%), dealing with barriers to trial recruitment (n=15, 71%), and improving patient awareness of trial opportunities (n=14, 67%). The location of the company was not associated with having a public diversity policy (P=0.17). The average company policy had five of the 14 commitments (36%, range 0-8) recommended in FDA and stakeholder guidance. Conclusions: The findings of the study showed that many pharmaceutical companies did not have public policies on diversity in clinical trials, although policies were more common in large than non-large companies. Policies that were publicly available varied widely and lacked important commitments recommended by stakeholder guidance. The results of the study suggest that corporate policies can be better leveraged to promote representation and fair inclusion in research, and implementation of FDA and stakeholder guidance.
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18S nonfunctional rRNA decay (NRD) detects and eliminates translationally nonfunctional 18S rRNA. While this process is critical for ribosome quality control, the mechanisms underlying nonfunctional 18S rRNA turnover remain elusive. NRD was originally identified and has exclusively been studied in Saccharomyces cerevisiae. Here, we show that 18S NRD is conserved in mammals. Using genome-wide CRISPR genetic interaction screens, we find that mammalian NRD acts through the integrated stress response (ISR) via GCN2 and ribosomal protein ubiquitination by RNF10. Selective ribosome profiling reveals nonfunctional 18S rRNA induces translational arrest at start sites. Indeed, biochemical analyses demonstrate that ISR activation limits translation initiation and attenuates collisions between scanning 43S preinitiation complexes and nonfunctional 80S ribosomes arrested at start sites. Overall, the ISR promotes nonfunctional 18S rRNA and 40S ribosomal protein turnover by RNF10-mediated ubiquitination. These findings establish a dynamic feedback mechanism by which the GCN2-RNF10 axis surveils ribosome functionality at translation initiation.
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Uterine leiomyoma or fibroids are prevalent noncancerous tumors of the uterine muscle layer, yet their origin and development remain poorly understood. We analyzed RNA expression profiles of 15 epigenetic mediators in uterine fibroids compared to myometrium using publicly available RNA sequencing (RNA-seq) data. To validate our findings, we performed RT-qPCR on a separate cohort of uterine fibroids targeting these modifiers confirming our RNA-seq data. We then examined protein profiles of key N6-methyladenosine (m6A) modifiers in fibroids and their matched myometrium, showing no significant differences in concordance with our RNA expression profiles. To determine RNA modification abundance, mRNA and small RNA from fibroids and matched myometrium were analyzed by ultra-high performance liquid chromatography-mass spectrometry identifying prevalent m6A and 11 other known modifiers. However, no aberrant expression in fibroids was detected. We then mined a previously published dataset and identified differential expression of m6A modifiers that were specific to fibroid genetic subtype. Our analysis also identified m6A consensus motifs on genes previously identified to be dysregulated in uterine fibroids. Overall, using state-of-the-art mass spectrometry, RNA expression, and protein profiles, we characterized and identified differentially expressed m6A modifiers in relation to driver mutations. Despite the use of several different approaches, we identified limited differential expression of RNA modifiers and associated modifications in uterine fibroids. However, considering the highly heterogenous genomic and cellular nature of fibroids, and the possible contribution of single molecule m6A modifications to fibroid pathology, there is a need for greater in-depth characterization of m6A marks and modifiers in a larger and diverse patient cohort.
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Adenosina , Leiomioma , Neoplasias Uterinas , Leiomioma/genética , Leiomioma/metabolismo , Humanos , Feminino , Adenosina/análogos & derivados , Adenosina/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Miométrio/metabolismo , Miométrio/patologia , Pessoa de Meia-Idade , Adulto , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , RNA/genética , RNA/metabolismo , Processamento Pós-Transcricional do RNA , Epigênese GenéticaRESUMO
OBJECTIVE: To evaluate experiential pharmacy preceptor perceptions of student pharmacists' ability to administer pediatric immunizations. METHODS: Semi-structured, qualitative key informant interviews using the Outcomes Evaluation Framework were conducted with 10 pharmacist preceptors in outpatient community pharmacies where pediatric immunizations were provided. Interviews were audio-recorded, transcribed, and deidentified prior to analysis by the research team. Qualitative analysis and thematic coding procedures were used to identify relevant themes. RESULTS: Saturation was met after 10 pharmacists participated. All stated that it was beneficial for student pharmacists to administer pediatric vaccines if trained in proper technique. Participants acknowledged that the training students currently receive in immunization administration within the PharmD curriculum is valuable but did identify general confidence and child-comforting techniques during and after vaccination as areas of improvement for students. Just-in-time training, preceptor coaching, and hands-on practice outside of the didactic curriculum were utilized to help build confidence. Barriers to the implementation or expansion of pediatric immunization delivered by students in community pharmacies were identified as competing priorities, time, and reimbursement. CONCLUSION: Student pharmacists can be helpful in easing the challenges of incorporating pediatric immunization services into the community pharmacy setting. Results demonstrate that the integration of student pharmacists into these services is beneficial. Pediatric immunizations are still relatively new to many pharmacists and specific training for pediatric immunization administration may not be integrated into all Doctor of Pharmacy curricula but the experiential education of pediatric immunization training can be beneficial to help prepare student pharmacists for hands-on practice.
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Imunização , Preceptoria , Estudantes de Farmácia , Humanos , Serviços Comunitários de Farmácia , Farmacêuticos , Currículo , Retroalimentação , Educação em Farmácia/métodos , Competência Clínica , Feminino , Masculino , CriançaRESUMO
INTRODUCTION: Diet can affect ammoniagenesis in cirrhosis and hepatic encephalopathy (HE), but the impact of dietary preferences on metabolomics in cirrhosis is unclear. As most Western populations follow meat-based diets, we aimed to determine the impact of substituting a single meat-based meal with an equal protein-containing vegan/vegetarian alternative on ammonia and metabolomics in outpatients with cirrhosis on a meat-based diet. METHODS: Outpatients with cirrhosis with and without prior HE on a stable Western meat-based diet were randomized 1:1:1 into 3 groups. Patients were given a burger with 20 g protein of meat, vegan, or vegetarian. Blood for metabolomics via liquid chromatography-mass spectrometry and ammonia was drawn at baseline and hourly for 3 hours after meal while patients under observation. Stool microbiome characteristics, changes in ammonia, and metabolomics were compared between/within groups. RESULTS: Stool microbiome composition was similar at baseline. Serum ammonia increased from baseline in the meat group but not the vegetarian or vegan group. Metabolites of branched chain and acylcarnitines decreased in the meat group compared with the non-meat groups. Alterations in lipid profile (higher sphingomyelins and lower lysophospholipids) were noted in the meat group when compared with the vegan and vegetarian groups. DISCUSSION: Substitution of a single meat-based meal with a non-meat alternatives results in lower ammoniagenesis and altered serum metabolomics centered on branched-chain amino acids, acylcarnitines, lysophospholipids, and sphingomyelins in patients with cirrhosis regardless of HE or stool microbiome. Intermittent meat substitution with vegan or vegetarian alternatives could be helpful in reducing ammonia generation in cirrhosis.
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Amônia , Dieta Vegana , Dieta Vegetariana , Fezes , Microbioma Gastrointestinal , Encefalopatia Hepática , Cirrose Hepática , Metabolômica , Humanos , Amônia/sangue , Amônia/metabolismo , Cirrose Hepática/dietoterapia , Cirrose Hepática/metabolismo , Cirrose Hepática/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Encefalopatia Hepática/dietoterapia , Encefalopatia Hepática/sangue , Encefalopatia Hepática/etiologia , Fezes/química , Fezes/microbiologia , Idoso , Carnitina/análogos & derivados , Carnitina/sangue , Carnitina/metabolismo , Carne , Aminoácidos de Cadeia Ramificada/sangue , Aminoácidos de Cadeia Ramificada/metabolismo , AdultoRESUMO
Background: Representation of diverse study populations in pivotal clinical trials for medical devices and subgroup analyses for demographic groups to explore differences in safety and effectiveness are essential to understanding the benefits and risks in diverse populations. The US Food and Drug Administration (FDA) has taken many steps to improve transparency and subgroup analyses over the past decade, but there has not been a recent evaluation of demographic reporting and subgroup analyses. Methods: We reviewed all FDA Premarket Approvals for high-risk cardiovascular devices from 2014 to 2022, focusing on pivotal studies supporting device approval. We abstracted detailed demographic data about the age, sex, race, ethnicity, and socioeconomic position of study participants. We also assessed the presence and results of subgroup analyses to understand the safety and effectiveness of devices across trial populations. Results: Analysis of 92 pivotal studies revealed that age and sex were reported in 96.7% of the studies, while race and ethnicity were reported in 71.7% and 58.7%, respectively. However, only 7.9% of studies explicitly detailed the participation of older adults (≥65 years) and no studies reported patients' socioeconomic position. Subgroup analyses by sex were conducted in 70.7% of studies, with 12.3% reporting significant differences. In contrast, analyses by race and ethnicity were performed in only 12.0% of the studies, with 9.1% reporting significant differences. Conclusion: Approximately one-third of pivotal studies for high-risk cardiovascular devices approved by the FDA from 2014 to 2022 did not report the race of study participants, nearly 40% did not report ethnicity, and more than 90% did not report the participation of older adults (≥65 years). Subgroup analyses were infrequently conducted by age or race and ethnicity. There is a need for better trial demographic reporting and conduct of subgroup analyses in premarketing studies to ensure the safety and effectiveness of medical devices for all patients.
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Introduction: As the shortage of primary care providers widens nationwide, access to care utilizing non-physician providers is one strategy to ensure equitable access to care. This study aimed to compare community pharmacist-provided care for minor ailments to care provided at three traditional sites of care: primary care, urgent care, and emergency department, to determine if care provided by pharmacists improved access with comparable quality and reduced financial strain on the healthcare system. Methods: Pharmacy data was provided from 46 pharmacies and 175 pharmacists who participated across five pharmacy corporations over a 3-year period (2016-2019). Data for non-pharmacy sites of care was provided by a large health plan, matching episodes of care for conditions seen in the community pharmacy. Cost-of-care analysis was conducted using superiority study design and revisit data analysis was conducted using noninferiority study design. Results: Median cost-of-care across traditional sites of care was $277.78 higher than care provided at the pharmacies, showing superiority. Noninferiority was demonstrated for revisit care when the initial visit was conducted by a pharmacist compared to traditional sites. Discussion: The authors conclude community pharmacist-provided care for minor ailments improved cost-effective access for patients with comparable quality and reduced financial strains on the healthcare system.
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Introduction: Group living skills (GLS), that is, being tidy and considerate of others, are an important skillset for teams who live and work together. However, this construct does not have a validated measure to enable an understanding of how group living skills influence team dynamics over time. We developed and validated a short measure of group living skills for teams living in extreme work environments. Methods: We collected data from 83 individuals in 24 teams living and working in space and spaceflight analog environments on missions of 45-240 days. Results: We provide evidence of reliability and validity for the GLS Survey over time and identify a two-factor structure. We also demonstrate its use as a measure of team-level dynamics and its utility as a sociometric measure to identify a person's degree of group living skills. Discussion: We outline recommendations for using this new measure in future research and applied settings to understand this unique aspect of teams living and working together.
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BACKGROUND: Hypothalamic obesity resulting from hypothalamic damage might affect melanocortin signalling. We investigated the melanocortin-4 receptor agonist setmelanotide for treatment of hypothalamic obesity. METHODS: This phase 2, open-label, multicentre trial was done in five centres in the USA. Eligible patients were aged between 6 and 40 years with obesity and history of hypothalamic injury or diagnosis of a non-malignant tumour affecting the hypothalamus that was treated with surgery, chemotherapy, or radiation. Setmelanotide was titrated up to a dose of 3·0 mg and administered subcutaneously once a day for a total duration of 16 weeks. The primary endpoint was the proportion of patients with a reduction in BMI of at least 5% from baseline after 16 weeks, compared with a historic control rate of less than 5% in this population. The primary endpoint was analysed using the full analysis set, which includes all patients with baseline data who received at least one dose of setmelanotide. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04725240) and is complete. FINDINGS: Between June 6, 2021, and Jan 13, 2022, 19 patients were screened for inclusion. One patient was excluded, and 18 were enrolled and received at least one dose of setmelanotide. Patients were primarily White (n=14 [78%]) and male (n=11 [61%]). Enrolled patients had a mean age of 15·0 years (SD 5·3) and a mean BMI of 38·0 kg/m2 (SD 6·5). Of 18 patients enrolled, 16 (89%) of 18 patients completed the study and met the primary endpoint of reduction in BMI of at least 5% from baseline after 16 weeks (p<0·0001). The mean reduction in BMI across all patients was 15% (SD 10). A composite proportion of patients had a clinically meaningful change (89%, 90% CI 69-98%; p<0·0001), comprising a reduction in BMI Z score of at least 0·2 points for patients younger than 18 years (92%, 68-100%; p<0·0001) and reduction in bodyweight of at least 5% for patients aged 18 years or older (80%, 34-99%; p<0·0001). Patients aged 12 years or older had a mean reduction in hunger score of 45%. Frequent adverse events included nausea (61%), vomiting (33%), skin hyperpigmentation (33%), and diarrhoea (22%). Of 14 patients who continued treatment in a long-term extension study (NCT03651765), 12 completed at least 12 months of treatment at the time of publication and had a mean change in BMI of -26% (SD 12) from index trial baseline. INTERPRETATION: These findings support setmelanotide as a novel effective treatment of hypothalamic obesity. FUNDING: Rhythm Pharmaceuticals.
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Doenças Hipotalâmicas , Obesidade , alfa-MSH , Humanos , Masculino , Feminino , Adulto , Adolescente , Obesidade/tratamento farmacológico , Adulto Jovem , Doenças Hipotalâmicas/tratamento farmacológico , Criança , alfa-MSH/análogos & derivados , alfa-MSH/uso terapêutico , alfa-MSH/administração & dosagem , Receptor Tipo 4 de Melanocortina/agonistas , Resultado do Tratamento , Índice de Massa CorporalRESUMO
OBJECTIVE: Due to systemic inequities, Black adolescents with type 1 diabetes are more likely to have suboptimal glycemic control and high rates of diabetes distress, but tailored interventions for this population are lacking. In primary outcomes of a randomized clinical trial, a family-based eHealth intervention improved glycemic control in Black adolescents with type 1 diabetes and elevated depressive symptoms. The present study is a secondary analysis of these clinical trial data examining the moderating effect of diabetes distress on the efficacy of the intervention. METHODS: Using secondary data from a multicenter randomized clinical trial (Clinicaltrials.gov [NCT03168867]), caregiver-adolescent dyads were randomly assigned to either up to three sessions of an eHealth parenting intervention (n = 75) or a standard medical care control group (n = 74). Black adolescents (10 years, 0 months to 14 years, 11 months old) with type 1 diabetes and a caregiver willing to participate were eligible. Adolescents reported their diabetes distress at baseline, and hemoglobin A1c (HbA1c) data were collected at baseline, 6-, 13-, and 18-month follow-up. RESULTS: No between-group contrasts emerged in a linear mixed-effects regression (p's > .09). Within-group contrasts emerged such that adolescents assigned to the intervention who reported high diabetes distress had lower HbA1c at the 18-month follow-up relative to baseline (p = .004); the 18-month decrease in HbA1c was -1.03%. CONCLUSIONS: Black adolescents with type 1 diabetes and high levels of diabetes distress showed significant decreases in HbA1c following a family-based eHealth intervention, suggesting diabetes distress may be a key moderator of intervention efficacy within this population.