Episodic population fragmentation and gene flow reveal a trade-off between heterozygosity and allelic richness

In episodic environments like deserts, populations of some animal species exhibit irregular fluctuations such that populations are alternately large and connected or small and isolated. Such dynamics are typically driven by periodic resource pulses due, for example, to large but infrequent rainfall events. The repeated population bottlenecks resulting from fragmentation should lower genetic diversity over time, yet species undergoing these fluctuations appear to maintain high levels of genetic diversity. To resolve this apparent paradox, we simulated a metapopulation of constant size undergoing repeat episodes of fragmentation and change in gene flow to mimic outcomes experienced by mammals in an Australian desert. We show that episodic fragmentation and gene flow have contrasting effects on two measures of genetic diversity: heterozygosity and allelic richness. Specifically, fragmentation into many, small subpopulations, coupled with periods of infrequent gene flow, preserves allelic richness at the expense of heterozygosity. In contrast, fragmentation into a few, large subpopulations maintains heterozygosity at the expense of allelic richness. The strength of the trade-off between heterozygosity and allelic richness depends on the amount of gene flow and the frequency of gene flow events. Our results imply that the type of genetic diversity maintained among species living in strongly fluctuating environments will depend on the way populations fragment, with our results highlighting different mechanisms for maintaining allelic richness and heterozygosity in small, fragmented populations

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension

Aims Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk

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

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Research as Interacting Dialogic Processes: Implications for Reflexivity

Das Verständnis von Forschung innerhalb eines postmodernen Rahmens eröffnet eine Arena, in der Subjektivität vorausgesetzt und geschätzt wird. Es wird möglich, sich damit zu beschäftigen, wie Subjektivität (von Forschenden und Forschungsteilnehmenden) und Intersubjektivität (zwischen/unter Forschenden und zwischen Forschenden und Teilnehmenden) den Forschungsprozess anreichern kann. In diesem Beitrag untersuchen wir ein solches Modell: das Verständnis von qualitativer Forschung als einer verbundenen und sich gegenseitig beeinflussenden Folge von dialogischen Prozessen. Ein dialogisches Modell ermöglicht es, jeden wesentlichen Aspekt eines Forschungsprogramms daraufhin zu betrachten, dass ihm – was wir für wünschenswert erachten – das Entstehen synergistischer Kommunikation zwischen den Teilnehmenden innewohnt. Da dieser Ansatz sich auf die Ideen dialogischer Kommunikation stützt, geht er per se von der Reflexivität einer jeden kommunizierenden Person, also jeder/jedes einzelnen Forschenden und jeder/jedes einzelnen Teilnehmenden, aus. Ebenfalls verdeutlicht wird der reflexive Wert, der erwächst, wenn Forschung in einem Forschungsteam durchgeführt wird, und die Rolle von Reflexivität wird für jeden Schritt der Forschungsbemühungen untersucht: angefangen von der Formulierung der Fragestellung, über die Informationssammlung und das Analysieren von Informationen bis hin zur Zusammenarbeit mit anderen Forschenden und der "Rückgabe" der Forschungserträge an die Teilnehmenden. Wir diskutieren die Zentralität von Reflexivität für jeden dieser Schritte, verdeutlicht an eigenen Forschungsbeispielen und an den Erfahrungen anderer Forschender.Research within a postmodern frame moves us into arenas where subjectivity is both assumed and appreciated. This framework provides an opportunity to attend to how subjectivity (of researcher[s] and of research participants) and inter-subjectivity (between/among researcher[s] and between researcher[s] and participants) can enhance the research process. In this paper, we explore a framework that involves one such model: an understanding of qualitative research as an interconnected and mutually influential series of dialogic processes. A dialogic framework allows us to view each major aspect of a research program as having, as an important hope, the creation of synergistic communication between or among participants. Because this approach relies on ideas about dialogic communication, it carries an intrinsic investment in the reflexivity of every conversant—i.e., every researcher and every participant. It emphasizes the reflexive value of conducting research in the context of a team of researchers, and it examines the role of reflexivity at each step of the research endeavor: formulating the question, gathering information, analyzing this information, collaborating with other researchers, and "returning" the fruits of the research to participants. The paper discusses the centrality of reflexivity at each of these steps, both in descriptive terms and through illustrations drawn from our own research as well as from the experiences of other researchers.La investigación dentro del marco posmoderno nos lleva a terrenos donde la subjetividad es tanto asumida como apreciada. Este marco provee una oportunidad para prestar atención y observar cómo la subjetividad (de los investigadores y de los participantes en la investigación) y la inter-subjetividad (entre los investigadores así como entre los investigadores y los participantes) puede enriquecer el proceso de investigación. En el presente artículo exploramos un marco que utiliza uno de tales modelos: la comprensión de la investigación cualitativa como una serie de procesos dialógicos interconectados y mutuamente influenciados. Tal marco dialógico nos permite analizar cada aspecto importante de un programa de investigación como la posibilidad de creación de una comunicación sinergética entre los participantes. Dado que esta perspectiva está basada en ideas acerca de la comunicación dialógica, ella le otorga una importancia intrínseca a la reflexividad de cada uno de los interlocutores, i.e., a cada investigador y a cada participante. Enfatiza el valor reflexivo de realizar los estudios en equipos de investigadores, y examina el papel de la reflexividad en cada paso del esfuerzo de investigación: al formular las preguntas, al reunir la información, al analizar dicha información, al colaborar con otros investigadores y al "devolver" los frutos de la investigación a los participantes. Este artículo discute la importancia de la reflexividad en cada uno de estos pasos, tanto en términos descriptivos y a través de ilustraciones obtenidas de nuestras propias investigaciones, como de experiencias de otros investigadores

La investigación como procesos dialógicos interactivos: Implicaciones para la reflexividad

Das Verständnis von Forschung innerhalb eines postmodernen Rahmens eröffnet eine Arena, in der Subjektivität vorausgesetzt und geschätzt wird. Es wird möglich, sich damit zu beschäftigen, wie Subjektivität (von Forschenden und Forschungsteilnehmenden) und Intersubjektivität (zwischen/unter Forschenden und zwischen Forschenden und Teilnehmenden) den Forschungsprozess anreichern kann. In diesem Beitrag untersuchen wir ein solches Modell: das Verständnis von qualitativer Forschung als einer verbundenen und sich gegenseitig beeinflussenden Folge von dialogischen Prozessen. Ein dialogisches Modell ermöglicht es, jeden wesentlichen Aspekt eines Forschungsprogramms daraufhin zu betrachten, dass ihm – was wir für wünschenswert erachten – das Entstehen synergistischer Kommunikation zwischen den Teilnehmenden innewohnt. Da dieser Ansatz sich auf die Ideen dialogischer Kommunikation stützt, geht er per se von der Reflexivität einer jeden kommunizierenden Person, also jeder/jedes einzelnen Forschenden und jeder/jedes einzelnen Teilnehmenden, aus. Ebenfalls verdeutlicht wird der reflexive Wert, der erwächst, wenn Forschung in einem Forschungsteam durchgeführt wird, und die Rolle von Reflexivität wird für jeden Schritt der Forschungsbemühungen untersucht: angefangen von der Formulierung der Fragestellung, über die Informationssammlung und das Analysieren von Informationen bis hin zur Zusammenarbeit mit anderen Forschenden und der "Rückgabe" der Forschungserträge an die Teilnehmenden. Wir diskutieren die Zentralität von Reflexivität für jeden dieser Schritte, verdeutlicht an eigenen Forschungsbeispielen und an den Erfahrungen anderer Forschender. URN: urn:nbn:de:0114-fqs0203181Research within a postmodern frame moves us into arenas where subjectivity is both assumed and appreciated. This framework provides an opportunity to attend to how subjectivity (of researcher[s] and of research participants) and inter-subjectivity (between/among researcher[s] and between researcher[s] and participants) can enhance the research process. In this paper, we explore a framework that involves one such model: an understanding of qualitative research as an interconnected and mutually influential series of dialogic processes. A dialogic framework allows us to view each major aspect of a research program as having, as an important hope, the creation of synergistic communication between or among participants. Because this approach relies on ideas about dialogic communication, it carries an intrinsic investment in the reflexivity of every conversant—i.e., every researcher and every participant. It emphasizes the reflexive value of conducting research in the context of a team of researchers, and it examines the role of reflexivity at each step of the research endeavor: formulating the question, gathering information, analyzing this information, collaborating with other researchers, and "returning" the fruits of the research to participants. The paper discusses the centrality of reflexivity at each of these steps, both in descriptive terms and through illustrations drawn from our own research as well as from the experiences of other researchers. URN: urn:nbn:de:0114-fqs0203181La investigación dentro del marco posmoderno nos lleva a terrenos donde la subjetividad es tanto asumida como apreciada. Este marco provee una oportunidad para prestar atención y observar cómo la subjetividad (de los investigadores y de los participantes en la investigación) y la inter-subjetividad (entre los investigadores así como entre los investigadores y los participantes) puede enriquecer el proceso de investigación. En el presente artículo exploramos un marco que utiliza uno de tales modelos: la comprensión de la investigación cualitativa como una serie de procesos dialógicos interconectados y mutuamente influenciados. Tal marco dialógico nos permite analizar cada aspecto importante de un programa de investigación como la posibilidad de creación de una comunicación sinergética entre los participantes. Dado que esta perspectiva está basada en ideas acerca de la comunicación dialógica, ella le otorga una importancia intrínseca a la reflexividad de cada uno de los interlocutores, i.e., a cada investigador y a cada participante. Enfatiza el valor reflexivo de realizar los estudios en equipos de investigadores, y examina el papel de la reflexividad en cada paso del esfuerzo de investigación: al formular las preguntas, al reunir la información, al analizar dicha información, al colaborar con otros investigadores y al "devolver" los frutos de la investigación a los participantes. Este artículo discute la importancia de la reflexividad en cada uno de estos pasos, tanto en términos descriptivos y a través de ilustraciones obtenidas de nuestras propias investigaciones, como de experiencias de otros investigadores. URN: urn:nbn:de:0114-fqs020318

Gay youth and gay adults: Bridging the generation gap

Recent discussion of lesbian, gay, bisexual, and trans (LGBT) youth has included two emphases: the burgeoning trend toward youth-supportive organizations and focus on risk factors experienced by these Youth. In practice, the two are intertwined: the need for youth-supportive endeavors is typically demonstrated by appeals to the risks LGBT youth face. Relatively little attention has been given to relationships between youth and adults in LGBT communities. This article employs data from a long-term qualitative study with LGBT youth, supported by information from numerous other settings to suggest that a failure on the part of both groups fully to comprehend the experience of the other hampers the optimal functioning of everyone involved. In particular, we suggest that the discourse about the dangers faced by LGBT youth, despite its being thoroughly well-intentioned, may actually place these teens at greater risk. © 2002 by The Haworth Press. Inc. All rights re reserved

Lipidomics Analysis of Behavioral Variant Frontotemporal Dementia: A Scope for Biomarker Development

Behavioral variant frontotemporal dementia (bvFTD) is the most prevalent form of FTD syndromes. bvFTD is characterized clinically by changes in behavior and cognition and pathologically by focal brain atrophy and concomitant loss of lipids. bvFTD is further characterized by eating abnormalities that result in dyslipidemia. Although dyslipidemia is apparent in bvFTD, very little is known about global lipid changes in bvFTD and lipid dysregulation underlying bvFTD. Here, we undertook a comprehensive lipidomics analysis of blood plasma from patients with bvFTD, patients with Alzheimer’s disease (AD) and controls, using liquid chromatography-tandem mass spectrometry, with the aim of understanding lipid dysregulation in bvFTD. In our analysis, we detected all four major classes of lipids (glycerolipids, phospholipids, sphingolipids, sterols), 17 subclasses of lipids, and 3,225 putative individual lipid species in total, as well as a group of dietary lipids. We found that the levels of numerous lipid species were significantly altered in bvFTD compared to AD and control. We found that the total abundance of triglyceride (TG) increased significantly in bvFTD, whereas phosphatidylserine and phosphatidylglycerol decreased significantly in bvFTD. These results suggest manifestation of hypertriglyceridemia and hypoalphalipoproteinemia in bvFTD. We also identified five lipid molecules—TG (16:0/16:0/16:0), diglyceride (18:1/22:0), phosphatidylcholine (32:0), phosphatidylserine (41:5), and sphingomyelin (36:4)—that could potentially be used for developing biomarkers for bvFTD. Furthermore, an analysis of plant lipids revealed significant decreases in monogalactosyldiacylglycerol and sitosteryl ester in bvFTD, indicating altered eating behavior in bvFTD. This study represents the first lipidomics analysis of bvFTD and has provided new insights into an unrecognized perturbed pathology in bvFTD, providing evidence in support of considerable lipid dysregulation in bvFTD