Identifying 'avoidable harm' in family practice: A RAND/UCLA Appropriateness Method consensus study

BackgroundHealth care-related harm is an internationally recognized threat to public health. The United Kingdom’s national health services demonstrate that upwards of 90% of health care encounters can be delivered in ambulatory settings. Other countries are transitioning to more family practice-based health care systems, and efforts to understand avoidable harm in these settings is needed.MethodsWe developed 100 scenarios reflecting a range of diseases and informed by the World Health Organization definition of ‘significant harm’. Scenarios included different types of patient safety incidents occurring by commission and omission, demonstrated variation in timeliness of intervention, and conditions where evidence-based guidelines are available or absent. We conducted a two-round RAND / UCLA Appropriateness Method consensus study with a panel of family practitioners in England to define “avoidable harm” within family practice. Panelists rated their perceptions of avoidability for each scenario. We ran a k-means cluster analysis of avoidability ratings.ResultsPanelists reached consensus for 95 out of 100 scenarios. The panel agreed avoidable harm occurs when a patient safety incident could have been probably, or totally, avoided by the timely intervention of a health care professional in family practice (e.g. investigations, treatment) and / or an administrative process (e.g. referrals, alerts in electronic health records, procedures for following up results) in accordance with accepted evidence-based practice and clinical governance. Fifty-four scenarios were deemed avoidable, whilst 31 scenarios were rated unavoidable and reflected outcomes deemed inevitable regardless of family practice intervention. Scenarios with low avoidability ratings (1 s or 2 s) were not represented by the categories that were used to generate scenarios, whereas scenarios with high avoidability ratings (7 s 8 s or 9 s) were represented by these a priori categories.DiscussionThe findings from this RAND/UCLA Appropriateness Method study define the characteristics and conditions that can be used to standardize measurement of outcomes for primary care patient safety.ConclusionWe have developed a definition of avoidable harm that has potential for researchers and practitioners to apply across primary care settings, and bolster international efforts to design interventions to target avoidable patient safety incidents that cause the most significant harm to patients

Retinoic acid enhances skeletal muscle progenitor formation and bypasses inhibition by bone morphogenetic protein 4 but not dominant negative β-catenin

<p>Abstract</p> <p>Background</p> <p>Understanding stem cell differentiation is essential for the future design of cell therapies. While retinoic acid (RA) is the most potent small molecule enhancer of skeletal myogenesis in stem cells, the stage and mechanism of its function has not yet been elucidated. Further, the intersection of RA with other signalling pathways that stimulate or inhibit myogenesis (such as Wnt and BMP4, respectively) is unknown. Thus, the purpose of this study is to examine the molecular mechanisms by which RA enhances skeletal myogenesis and interacts with Wnt and BMP4 signalling during P19 or mouse embryonic stem (ES) cell differentiation.</p> <p>Results</p> <p>Treatment of P19 or mouse ES cells with low levels of RA led to an enhancement of skeletal myogenesis by upregulating the expression of the mesodermal marker, Wnt3a, the skeletal muscle progenitor factors Pax3 and Meox1, and the myogenic regulatory factors (MRFs) MyoD and myogenin. By chromatin immunoprecipitation, RA receptors (RARs) bound directly to regulatory regions in the Wnt3a, Pax3, and Meox1 genes and RA activated a β-catenin-responsive promoter in aggregated P19 cells. In the presence of a dominant negative β-catenin/engrailed repressor fusion protein, RA could not bypass the inhibition of skeletal myogenesis nor upregulate Meox1 or MyoD. Thus, RA functions both upstream and downstream of Wnt signalling. In contrast, it functions downstream of BMP4, as it abrogates BMP4 inhibition of myogenesis and Meox1, Pax3, and MyoD expression. Furthermore, RA downregulated BMP4 expression and upregulated the BMP4 inhibitor, Tob1. Finally, RA inhibited cardiomyogenesis but not in the presence of BMP4.</p> <p>Conclusion</p> <p>RA can enhance skeletal myogenesis in stem cells at the muscle specification/progenitor stage by activating RARs bound directly to mesoderm and skeletal muscle progenitor genes, activating β-catenin function and inhibiting bone morphogenetic protein (BMP) signalling. Thus, a signalling pathway can function at multiple levels to positively regulate a developmental program and can function by abrogating inhibitory pathways. Finally, since RA enhances skeletal muscle progenitor formation, it will be a valuable tool for designing future stem cell therapies.</p

Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women

Little is known about fertility choices and pregnancy outcome rates among HIV-infected women in the current combination ART era

Twenty years of the Fabry Outcome Survey (FOS) : insights, achievements, and lessons learned from a global patient registry

Background: Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the efects of treatment on large patient populations with rare diseases. The year 2021 marks the 20th anniversary of the Fabry Outcome Survey (FOS), an international, multicenter, observational registry (NCT03289065). The primary aims of FOS are to broaden the understanding of Fabry disease (FD), an X-linked lysosomal storage disorder, and to improve the clinical management of afected patients. Here, we review the history of FOS and the analyses and publications disseminated from the registry, and we discuss the contributions FOS stud‑ ies have made in understanding FD. Results: FOS was initiated in April 2001 and, as of January 2021, 4484 patients with a confrmed diagnosis and patient informed consent have been enrolled from 144 centers across 26 countries. Data from FOS have been pub‑ lished in nearly 60 manuscripts on a wide variety of topics relevant to FD. Analyses of FOS data have investigated the long-term efectiveness and safety of enzyme replacement therapy (ERT) with agalsidase alfa and its efects on morbidity and mortality, as well as the benefts of prompt and early treatment with agalsidase alfa on the progression of cardiomyopathy and the decline in renal function associated with FD. Based on analyses of FOS data, ERT with agal‑ sidase alfa has also been shown to improve additional signs and symptoms of FD experienced by patients. FOS data analyses have provided a better understanding of the natural history of FD and the specifc populations of women, children, and the elderly, and have provided practical tools for the study of FD. FOS has also provided methodology and criteria for assessing disease severity which contributed to the continuous development of medical practice in FD and has largely improved our understanding of the challenges and needs of long-term data collection in rare diseases, aiding in future rare disease real-world evidence studies. Conclusion: FOS over the last 20 years has substantially increased the scientifc knowledge around improved patient management of FD and continues to expand our understanding of this rare disease

10-Year Resource Utilization and Costs for Cardiovascular Care

Background: Cardiovascular disease (CVD) imparts a heavy economic burden on the U.S. health care system. Evidence regarding the long-term costs after comprehensive CVD screening is limited. Objectives: This study calculated 10-year health care costs for 6,814 asymptomatic participants enrolled in MESA (Multi-Ethnic Study of Atherosclerosis), a registry sponsored by the National Heart, Lung, and Blood Institute, National Institutes of Health. Methods: Cumulative 10-year costs for CVD medications, office visits, diagnostic procedures, coronary revascularization, and hospitalizations were calculated from detailed follow-up data. Costs were derived by using Medicare nationwide and zip code–specific costs, inflation corrected, discounted at 3% per year, and presented in 2014 U.S. dollars. Results: Risk factor prevalence increased dramatically and, by 10 years, diabetes, hypertension, and dyslipidemia was reported in 19%, 57%, and 53%, respectively. Self-reported symptoms (i.e., chest pain or shortness of breath) were common (approximately 40% of enrollees). At 10 years, approximately one-third of enrollees reported having an echocardiogram or exercise test, whereas 7% underwent invasive coronary angiography. These utilization patterns resulted in 10-year health care costs of $23,142. The largest proportion of costs was associated with CVD medication use (78$2 of every $10 were spent for outpatient visits and diagnostic testing among the elderly, obese, those with a high-sensitivity C-reactive protein level \u3e3 mg/l, or coronary artery calcium score (CACS) ≥400. Costs varied widely from \u3c$7,700 for low-risk (Framingham risk score \u3c6%, 0 CACS, and normal glucose measurements at baseline) to \u3e$35,800 for high-risk (persons with diabetes, Framingham risk score ≥20$74 million of the $155 million consumed by MESA participants. Conclusions: Longitudinal patterns of health care resource use after screening revealed new evidence on the economic burden of treatment and testing patterns not previously reported. Maintenance of a healthy population has the potential to markedly reduce the economic burden of CVD among asymptomatic individuals

Understanding the epidemiology of avoidable significant harm in primary care:Protocol for a retrospective cross-sectional study

Introduction: Most patient safety research has focused on specialist-care settings where there is an appreciation of the frequency and causes of medical errors, and the resulting burden of adverse events. There have, however, been few large-scale robust studies that have investigated the extent and severity of avoidable harm in primary care. To address this, we will conduct a 12-month retrospective cross-sectional study involving case note review of primary care patients. Methods and Analysis: We will conduct electronic searches of general practice (GP) clinical computer systems to identify patients with avoidable significant harm. Up to sixteen general practices from three areas of England (East Midlands, London and the North West) will be recruited based on practice size, to obtain a sample of around 100,000 patients. Our investigations will include an ‘enhanced sample’ of patients with the highest risk of avoidable significant harm. We will estimate the incidence of avoidable significant harm and express this as ‘per 100,000 patients per year’. Univariate and multivariate analysis will be conducted to identify the factors associated with avoidable significant harm. Ethics/Dissemination: The decision regarding participation by general practices in the study is entirely voluntary; the consent to participate may be withdrawn at any time. We will not seek individual patient consent for the retrospective case note review, but if patients respond to publicity about the project and say they do not wish their records to be included we will follow these instructions. We will produce a report for the Department of Health’s Policy Research Programme and several high-quality peer-reviewed publications in scientific journals. The study has been granted a favourable opinion by the East Midlands Nottingham 2 Research Ethics Committee (reference 15/EM/0411) and Confidentiality Advisory Group approval for access to medical records without consent under section 251 of the NHS Act 2006 (reference 15/CAG/0182)

Novel Materials for Biofilm Inhibition

Microbial contamination onboard the International Space Station (ISS) continues to pose significant mission risks, both terms of crew health and functionality of mechanical systems