Genetically altering organismal metabolism by leptin-deficiency benefits a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease that causes death of motor neurons. ALS patients and mouse models of familial ALS display organismal level metabolic dysfunction, which includes increased energy expenditure despite decreased lean mass. The pathophysiological relevance of abnormal energy homeostasis to motor neuron disease remains unclear. Leptin is an adipocyte-derived hormone that regulates whole-animal energy expenditure. Here, we report that placing mutant superoxide dismutase 1 (SOD1) mice in a leptin-deficient background improves energy homeostasis and slows disease progression. Leptin-deficient mutant SOD1 mice possess increased bodyweight and fat mass, as well as decreased energy expenditure. These observations coincide with enhanced survival, improved strength and decreased motor neuron loss. These results suggest that altering whole-body energy metabolism in mutant SOD1 mice can mitigate disease progression. We propose that manipulations that increase fat mass and reduce energy expenditure will be beneficial in the setting of motor neuron diseas

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Striving Against Sonlessness: The Moral Uses of Medical Pluralism in Western Indian Quests for a Boy

Amid patriarchal conditions that render one son necessary and multiple daughters burdensome, selective abortion of female fetuses has become pervasive in India. Public responses often cast sex selection as self-evidently ignorant, cruel, and misogynistic - an obvious evil meriting denunciation and eradication. Drawing on ethnographic fieldwork in Gujarat state, this article zooms out from ultrasound and abortion to survey the landscape of biomedical, herbal, and religious son production techniques surrounding them. Doing so clarifies the lived moral experience in which sex selection is embedded. Resort to multiple son production techniques is both an abstract moral indicator reflecting prevailing concerns and a pragmatic moral intervention aimed at harnessing every available means in response to those concerns. Fundamentally, people live out the multimodal quest that sometimes leads to selective abortion as aspiration - social, bodily, spiritual - toward an indispensable good, not as heartless rejection of daughters. Pluralistic son production illuminates the moral uses of medical pluralism for care-seekers, social scientists, and policymakers and practitioners. The case underscores that "complementary" therapies, rather than being just desperate behaviors, barriers to biomedical therapy, or curiosities to be integrated into care, may in fact be the clearest markers of the moral conditions in which public health problems unfold

The narrative governance of life: Morality, melodrama, and the limits of biopower in western Indian efforts against sex selection

Selective abortion of female fetuses is a widespread, illegal, and profoundly consequential form of family planning in contemporary India. In Gujarat state, public health campaigns against the practice rely on narratives exhibiting the hallmarks of melodrama: good-evil binaries, stock characters, emotional provocations, simplistic diagnoses, and inevitable triumphs. As biopolitical truths, such narratives resonate ethically and emotionally for people. By individualizing blame, obscuring structure, circumscribing discourse, and legitimizing authority, such narratives also exert many classic biopolitical effects. But they do not necessarily transform subjectivity or behavior, as biopower is often assumed to. Anti-sex selection messaging illustrates how moralistic, sentimentalized interventions against potentially harmful practices can provoke strong responses without changing actions. In highlighting resonance as a relevant biopolitical limit, the not-quite-paradoxes of Gujarati public health narratives-encapsulation without accuracy, regulation without discipline, authority without efficacy, participation without transformation-suggest one approach for analyzing the governance of life without falling into determinism

Polarized ZZ pairs in gluon fusion and vector boson fusion at the LHC

Pair production of helicity-polarized weak bosons $(V_\lambda=W^\pm_\lambda, Z_\lambda)$ from gluon fusion $(gg\to V_\lambda V'_{\lambda'})$ and weak boson fusion $(V_1V_2\to V_\lambda V'_{\lambda'})$ are powerful probes of the Standard Model, new physics, and properties of quantum systems. Measuring cross sections of polarized processes is a chief objective of the Large Hadron Collider's (LHC) Run 3 and high luminosity programs, but progress is limited by the simulation tools that are presently available. We propose a method for computing polarized cross sections that works by directly modifying Feynman rules instead of (squared) amplitudes. The method is applicable to loop-induced processes, and can capture the interference between arbitrary polarization configurations, interference with non-resonant diagrams, as well as off-shell/finite-width effects. By construction, previous results that work at the (squared) amplitude level are recoverable. As a demonstration, we report the prospect of observing and studying polarized $Z_\lambda Z_{\lambda'}$ pairs when produced via gluon fusion and electroweak processes in final-states with four charged leptons at the LHC, using the new method to simulate the gluon fusion process. Our Feynman rules are publicly available as a set of \textit{Universal FeynRules Object} libraries called \texttt{SM\_Loop\_VPolar}.Comment: Published version: additional discussion, results, and references. 16 pages, 6 figures, FeynRules UFO available from https://feynrules.irmp.ucl.ac.be/wiki/VPolarization, mg5amc configuration files available from https://gitlab.cern.ch/riruiz/public-projects/-/tree/master/VPolar_ggZ

A Necessary Sin : An Ethnographic Study Of Sex Selection In Western India

This dissertation analyzes sex-selective abortion in western India as a lived process with profound cultural, ethical, and demographic implications. Over the past three decades, selective elimination of female fetuses has emerged as a disturbing form of family planning across parts of Europe and Asia. In India, the practice remains widespread despite extensive efforts to combat it, with drastically skewed girl-to-boy ratios resulting in many locales. Drawing on eighteen months of ethnographic fieldwork with families and clinicians practicing sex selection, as well as with government officials and activists attempting to regulate it, this dissertation examines how prenatal sex determination marks fetuses with gender and incorporates them into local systems of kinship, biomedicine, and governance. Elucidating a kinship logic that renders daughters threatening and sons indispensable, I follow prospective parents and clinicians as they imagine divergent futures for children-to-be, navigate a clandestine black market, and employ specific biomedical techniques to produce and act on gendered fetuses. In the process of sex selection, fetuses become subject to complex ethical deliberations, familial struggles over reproductive decision-making, herbal and religious modalities of son production, and a host of public interventions aimed at saving daughters-to-be. I argue that the diverse actions around prenatal sex determination presuppose, shape, and intervene on a “gendered fetal subject”—an imagined or potential person whose liminal status (between human and non-human, between alive and un-alive) makes it a point of connection among households, clinics, and governance institutions. Tracing the production, transformation, and elimination of gendered fetal subjects reveals how kinship extends prenatally, as well as how fetuses become incorporated into social life. Furthermore, as suggested by prospective parents’ fraught reflections on the notion of a “necessary sin” (profoundly unethical but nonetheless unavoidable), understanding gendered fetal subjects provides an entry point for untangling the moral complexities of sex selection as a liminal form of violence—a gendered violation at the very threshold of human social existence

Subsequent Event Risk in Individuals with Established Coronary Heart Disease:Design and Rationale of the GENIUS-CHD Consortium

BACKGROUND: The "GENetIcs of sUbSequent Coronary Heart Disease" (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators

The Intersection of Diabetes and Cardiovascular Disease—A Focus on New Therapies

Diabetes is a leading cause of cardiovascular disease and its associated morbidity. While the medical community has had access to numerous glucose lowering therapies over the last decades, it was not until recently that newer agents demonstrated improvement in cardiovascular outcomes. In particular, diabetes care and management of its attendant cardiovascular risk is now being revolutionized with the development and provision of the SGLT-2 inhibitors and GLP1-receptor agonists. Given the exciting data with these new classes of diabetes therapeutics, there is a clear need to improve education and utilization of these evidence-based medications across a wide spectrum of clinicians, including cardiologists. The aim of this review is to familiarize the cardiovascular specialist with the benefits and harms of the most commonly used oral anti- hyperglycemic medications, with an emphasis on SGLT-2 inhibitors and GLP-1 receptor agonists

Everything in Moderation: Investigating the U-Shaped Link Between HDL Cholesterol and Adverse Outcomes

Despite historical evidence suggesting an inverse association between HDL cholesterol (HDL-C) and adverse cardiovascular events, pharmacological efforts to increase HDL-C and improve outcomes have not been successful. Recently, a U-shaped association between HDL-C and adverse events has been demonstrated in several population cohorts, further complicating our understanding of the clinical significance of HDL. Potential explanations for this finding include genetic mutations linked to very high HDL-C, impaired HDL function at high HDL-C levels, and residual confounding. However, our understanding of this association remains premature and needs further investigation

Community and Healthcare Perspectives on Implementing Hypertension Interventions for a Multiethnic Safety-Net Population.

ObjectiveTo synthesize community and healthcare informants' perspectives on contextual considerations and tailoring recommendations for high-quality, sustainable implementation of evidence-based practices (EBPs) for managing hypertension (HTN) in a multiethnic safety-net population.DesignStructured focus-group discussions and semistructured qualitative interviews.BackgroundHigh-quality, sustainable implementation of HTN-related EBPs can promote equitable care. Implementation challenges extend beyond individual patients to span multiple levels of context. Few studies have systematically engaged community and healthcare perspectives to inform the design of HTN intervention trials.SettingA large safety-net healthcare system.Participants/methodsWe conducted four structured discussions with each of five race- or ethnicity-specific community action boards (CABs) to understand community members' HTN-related norms, assets, needs, and experiences across local healthcare systems. We interviewed 41 personnel with diverse roles in our partnered healthcare system to understand the system's HTN-related strengths and needs. We solicited EBP tailoring recommendations from both groups. We summarized the findings using rapid content analysis.ResultsParticipants identified contextual considerations spanning seven themes: social determinants, healthcare engagement, clinical interaction, system operations, standardization, patient education, and partnerships and funding. They offered tailoring recommendations spanning nine themes: addressing complex contexts, addressing social needs, system operations, healthcare system training and resources, linguistic and cultural tailoring, behavioral engagement, relational engagement, illness-course engagement, and community partnerships.ConclusionsEngaging community and healthcare informants can ground implementation in the policy, community, healthcare system, clinical, and interpersonal contexts surrounding diverse patients at risk for disparities. Such grounding can reframe inequitable implementation as a multilevel social problem facing communities and healthcare systems, rather than individuals