Applying a research ethics review processes in rural practice-based research

Introduction: Partnering with rural primary care in practice-based research allows researchers access to a vital segment of the health care sector and a window into some of the most vulnerable, high-risk, high-need patient populations. The readiness for rural primary care to fully embrace research partnerships, however, is often tempered by ethical questions in conducting research in close-knit settings. This research provides practices with a refined decision support tool for evaluating the fit of research opportunities for their unique practices. Materials and Methods: A two-phase effort was conducted to glean insight from currently available literature on ethical considerations in practice-based research and augment this information by consulting with state-based subject matter experts. Qualitative data were gathered through semi-structured interviews with key stakeholders at each of the West Virginia medical schools. Results: The literature clearly acknowledges the need to ensure ethical standards in practice-based research – from the standpoints of the clinician and the researcher. The need to ensure comprehensive, culturally appropriate institutional review board approval is essential in developing and safeguarding participants. From discussions with subject matter experts, we find complementary guidance. However, tempering this sentiment is an overall caution of the unique role of rural primary care in representing and protecting the needs of the community. Five fundamental cautions regarding the conduct of practice-based research in rural settings are here identified, spanning the protection of individual patients, their communities, and clinicians. Discussion: Findings from this study can support and empower primary care clinicians and practices, especially those in rural and close-knit communities, to address essential considerations in practice-based research. Results allow for framing of a refined decision support tool for primary care practices and clinicians to use in evaluating the fit of research opportunities for their unique practices, instilling a sense of shared power in the research process by better equipping primary care to proactively engage in substantive dialogue with research partners

Applying a research ethics review processes in rural practice-based research

Introduction: Partnering with rural primary care in practice-based research allows researchers access to a vital segment of the health care sector and a window into some of the most vulnerable, high-risk, high-need patient populations. The readiness for rural primary care to fully embrace research partnerships, however, is often tempered by ethical questions in conducting research in close-knit settings. This research provides practices with a refined decision support tool for evaluating the fit of research opportunities for their unique practices. Materials and Methods: A two-phase effort was conducted to glean insight from currently available literature on ethical considerations in practice-based research and augment this information by consulting with state-based subject matter experts. Qualitative data were gathered through semi-structured interviews with key stakeholders at each of the West Virginia medical schools. Results: The literature clearly acknowledges the need to ensure ethical standards in practice-based research – from the standpoints of the clinician and the researcher. The need to ensure comprehensive, culturally appropriate institutional review board approval is essential in developing and safeguarding participants. From discussions with subject matter experts, we find complementary guidance. However, tempering this sentiment is an overall caution of the unique role of rural primary care in representing and protecting the needs of the community. Five fundamental cautions regarding the conduct of practice-based research in rural settings are here identified, spanning the protection of individual patients, their communities, and clinicians. Discussion: Findings from this study can support and empower primary care clinicians and practices, especially those in rural and close-knit communities, to address essential considerations in practice-based research. Results allow for framing of a refined decision support tool for primary care practices and clinicians to use in evaluating the fit of research opportunities for their unique practices, instilling a sense of shared power in the research process by better equipping primary care to proactively engage in substantive dialogue with research partners

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Schistosoma mansoni Hemozoin Modulates Alternative Activation of Macrophages via Specific Suppression of Retnla Expression and Secretion

The trematode Schistosoma mansoni is one of the etiological agents of schistosomiasis, a key neglected tropical disease responsible for an estimated annual loss of 70 million disability-adjusted life years. Hematophagy represents the primary nutrient acquisition pathway of this parasite, but digestion of hemoglobin also liberates toxic heme. Schistosomes detoxify heme via crystallization into hemozoin, which is subsequently regurgitated into the host's circulation. Here we demonstrate that during experimental schistosomiasis, hemozoin accumulating in the mouse liver is taken up by phagocytes at a time coincident with the development of the egg-induced T-helper 2 (Th2) granulomatous immune response. Furthermore, the uptake of hemozoin also coincides with the hepatic expression of markers of alternative macrophage activation. Alternatively activated macrophages are a key effector cell population associated with protection against schistosomiasis, making hemozoin well placed to play an important immunomodulatory role in this disease. To systematically explore this hypothesis, S. mansoni hemozoin was purified and added to in vitro bone marrow-derived macrophage cultures concurrently exposed to cytokines chosen to reflect the shifting state of macrophage activation in vivo. Macrophages undergoing interleukin-4 (IL-4)-induced alternative activation in the presence of hemozoin developed a phenotype specifically lacking in Retnla, a characteristic alternatively activated macrophage product associated with regulation of Th2 inflammatory responses. As such, in addition to its important detoxification role during hematophagy, we propose that schistosome hemozoin also provides a potent immunomodulatory function in the coevolved network of host-parasite relationships during schistosomiasis