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Abstract Aims To estimate the incidence of major adverse cardiovascular events (MACE), expanded MACE, and MACE or Death across Fibrosis- 4 score (FIB-4) categories in people with type 2 diabetes and to determine whether efpeglenatide’s effect varies with increasing FIB-4 severity. Materials and methods AMPLITUDE-O trial data were used to estimate the relationship of FIB-4 score categories to the hazard of MACE, expanded MACE, and MACE or death. Interactions on these outcomes between baseline FIB-4 score, and between FIB-4 score and efpeglenatide were also assessed. Results Baseline FIB-4 score was available for 4059 participants (99.6%) allowing subdivision of the population in tertiles. During a median follow-up of 1.8 years, numerical increases in the incidence of all 3 outcomes did not change significantly across tertiles of FIB-4 score (P for trend ≥ 0.25) with negligible relationship of the score to incident outcomes (MACE HR, per 1 SD higher score, 95% CI: 1.00, 0.89–1.13). Efpeglenatide’s effect on all MACE outcomes did not vary across FIB-4 tertiles (all interaction p values ≥ 0.64). Conclusions In high-risk people with type 2 diabetes, the degree of liver fibrosis, as estimated by FIB-4 score, was not related to incident cardiovascular outcomes. The beneficial effect of efpeglenatide on these outcomes is independent of FIB-4 category.

Abstract Information on the effects of changing agricultural management on crop and livestock performance is critical for developing evidence-based policies, investments, and programs. Evidence for Resilient Agriculture (ERA) v1.0.1 presents a dataset that harmonizes and aggregates 112,859 observations from 2,011 agricultural studies taken place in Africa between 1934 and 2018. The dataset includes information on the effect of 364 combinations of management practices and technologies on 87 environmental, social, and economic indicators of outcomes. Observations are geolocated and temporally tagged and thus can be linked to other datasets such as historical weather, soil properties, and road networks. ERA offers a new resource for understanding the impacts of changing farming practices under diverse environmental contexts, providing data to support strategic interventions aimed to enhance productivity, resilience, and sustainability of African agriculture.

Abstract Introduction Persons with diabetes are at risk for developing a cardiomyopathy through several pathophysiological mechanisms independent of traditional risk factors for heart failure. Among those with diabetic cardiomyopathy (DbCM), the relationship between natriuretic peptides, cardiac structural abnormalities and functional capacity is largely unknown. Methods In this prespecified subgroup analysis of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) trial, 685 participants with asymptomatic DbCM underwent baseline echocardiography data, laboratory investigations, and functional assessments. Participants were stratified by N-terminal pro-B type natriuretic peptide (NT-proBNP) quartiles, and correlation with echocardiographic and functional parameters were assessed using Spearman correlation test. Results The median NT-proBNP was 71 (Q1, Q3: 33, 135) ng/L. No association was observed between NT-proBNP concentrations and echocardiographic parameters of either diastolic or systolic dysfunction including global longitudinal strain, left ventricular ejection fraction, left ventricular mass index, left atrial volume index, E/E’, or right ventricular systolic pressure. In contrast, NT-proBNP was significantly correlated with overall Kansas City Cardiomyopathy Questionnaire score (rho = − 0.10; p = 0.007), the Physical Activity Scale in the Elderly (rho = − 0.12; p = 0.004), duration of cardiopulmonary exercise testing (rho = − 0.28; p 95 for females or > 115 for males or E/e’ >13 or left atrial volume index > 34. †Normal ECHO is defined as the absence of these abnormalities. Low NT-proBNP is defined as

Abstract An under-recognised aspect of the current humanitarian catastrophe in Gaza is the impact of the war on the environment and the associated risks for human health. This commentary contextualises these impacts against the background of human suffering produced by the overwhelming violence associated with the use of military force against the general population of Gaza. In calling for an immediate cessation to the violence, the authors draw attention to the urgent need to rebuild the health care system and restore the physical and human infrastructure that makes a liveable environment possible and promotes human health and well-being, especially for the most vulnerable in the population. Environmental remediation should therefore form one of the most important parts of international efforts to assist reconstruction, through which we hope Palestinians and Israelis will achieve lasting peace, health, and sustainable development, all as part of accepted international human rights obligations.

Astrocytes are the predominant glial cells that provide essential support to neurons and promote microenvironment changes in neuropathological states. Astrocyte and astrocytic-like cell culture have substantially contributed to elucidating the molecular pathways involved in key glial roles, including those relevant to neurodevelopment, brain physiology and metabolism, which are not readily accessible with traditional approaches. The in vitro methodology has also been applied to neuroinflammatory and neurodegeneration contexts, revealing cellular changes involved in brain dysfunction. Astrocytes studies in culture started with primary cell approaches using embryonic and postmortem tissue. Further developments included newborn rodent primary cells, cell lines and immortalized astrocytes, which resulted in homogeneous cell-type preparations grown on flat surfaces. To overcome some in vitro shortcomings, tridimensional bioprinted models and organoid culture enabled the mimicking of tissue cellular arrangements and, above these achievements, complex astrocyte cell culture can be generated from induced pluripotent stem cells (iPSCs) to model diseases. These unprecedented breakthroughs allowed the development of platforms to test new therapies in brain cells derived from human material noninvasively obtained from live patients. In this work, we reviewed the most studied astrocytic cell models for discussing limitations, advantages and reliable experimental readouts for neuroinflammation in neurodegeneration research.

Abstract Background Diabetic cardiomyopathy (DbCM) is a form of Stage B heart failure (HF) at high risk for progression to overt disease. Using baseline characteristics of study participants from the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) Trial we sought to characterize clinical characteristics of individuals with findings consistent with DbCM. Methods Among study participants meeting inclusion criteria, clinical characteristics, laboratory testing, imaging, Kansas City Cardiomyopathy Questionnaire (KCCQ), Physical Activity Scale of the Elderly (PASE) and cardiopulmonary exercise testing (CPET) results were tabulated. Cluster phenogroups were identified. Results Among 691 study participants (mean age 67.4 years; 50% were female), mean duration of type 2 diabetes mellitus (T2DM) was 14.5 years. The median (Q1, Q3) N-terminal pro-B type natriuretic peptide and high sensitivity cardiac troponin T were 71 (35, 135) ng/L and 9 [6, 12] ng/L. The most common echocardiographic abnormalities were reduced global longitudinal strain in 25.3% and impaired diastolic relaxation in 17.7%. Despite rather well-preserved KCCQ scores the average PASE score was markedly impaired at 155 accompanied by an average maximal oxygen consumption of 15.7 mL/Kg/minute on CPET. In K-means clustering, 4 phenogroups were identified including a higher-risk group with more advanced age, greater elevation of cardiac biomarkers, and more prevalent evidence for diastolic dysfunction and left ventricular hypertrophy. Conclusions Baseline data from the ARISE-HF Trial provide clinical characterization of individuals with T2DM and features of stage B HF, and may help clarify the diagnosis of DbCM. Trial Registration ARISE-HF, NCT04083339.

Introduction Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hypercortisolism in Patients with Difficult to Control Type 2 Diabetes Despite Receiving Standard-of-Care Therapies: Prevalence and Treatment with Korlym® (Mifepristone) (CATALYST) trial.Methods and analysis In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%–11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym®). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life.Ethics and dissemination The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals.Trial registration number NCT05772169.

The objective of this review was to comprehensively present and summarize trends in reported rates of hypoglycemia with one or two times per day basal insulin analogs in individuals with type 2 diabetes to help address and contextualize the emerging theoretical concern of increased hypoglycemic risk with once-weekly basal insulins.Hypoglycemia data were extracted from treat-to-target randomized clinical trials conducted during 2000–2022. Published articles were identified on PubMed or within the US Food and Drug Administration submission documents. Overall, 57 articles were identified: 44 assessed hypoglycemic outcomes in participants receiving basal-only therapy (33 in insulin-naive participants; 11 in insulin-experienced participants), 4 in a mixed population (insulin-naive and insulin-experienced participants) and 9 in participants receiving basal-bolus therapy. For the analysis, emphasis was placed on level 2 (blood glucose

Hyperglucagonemia contributes to hyperglycemia in patients with type 1 diabetes (T1D); however, novel therapeutics that block glucagon action could improve glycemic control. This phase 2 study evaluated the safety and efficacy of volagidemab, an antagonistic monoclonal glucagon receptor (GCGR) antibody, as an adjunct to insulin therapy in adults with T1D. The primary endpoint was change in daily insulin use at week 12. Secondary endpoints included changes in hemoglobin A1c (HbA1c) at week 13, in average daily blood glucose concentration and time within target range as assessed by continuous blood glucose monitoring (CGM) and seven-point glucose profile at week 12, incidence of hypoglycemic events, the proportion of subjects who achieve HbA1c reduction of ≥0.4%, volagidemab drug concentrations and incidence of anti-drug antibodies. Eligible participants (n = 79) were randomized to receive weekly subcutaneous injections of placebo, 35 mg volagidemab or 70 mg volagidemab. Volagidemab produced a reduction in total daily insulin use at week 12 (35 mg volagidemab: -7.59 units (U) (95% confidence interval (CI) -11.79, -3.39; P = 0.040 versus placebo); 70 mg volagidemab: -6.64 U (95% CI -10.99, -2.29; P = 0.084 versus placebo); placebo: -1.27 U (95% CI -5.4, 2.9)) without meeting the prespecified significance level (P

Wood–polymer composites (WPCs) with polypropylene (PP) matrix suffer from low toughness, and fossil-based impact modifiers are used to improve their performance. Material substitution of virgin fossil-based materials and material recycling are key aspects of sustainable development and therefore recycled denim fabric, and elastomer were evaluated to replace the virgin elastomer modifier commonly used in commercial WPCs. Microtomography images showed that the extrusion process fibrillated the denim fabric into long, thin fibers that were well dispersed within the WPC, while the recycled elastomer was found close to the wood fibers, acting as a soft interphase between the wood fibers and PP. The fracture toughness (KIC) of the WPC with recycled denim fabric matched the commercial WPC which was 1.4 MPa m1/2 and improved the composite tensile strength by 18% and E-modulus by 54%. Recycled elastomer resulted in slightly lower KIC, 1.1 MPa m1/2, as well as strength and modulus while increasing elongation and contributing to toughness. The results of this study showed that recycled materials can potentially be used to replace virgin fossil-based elastomeric modifiers in commercial WPCs, thereby reducing the CO2 footprint by 23% and contributing to more efficient use of resources.

Extreme events, such as those caused by climate change, economic or geopolitical shocks, and pest or disease epidemics, threaten global food security. The complexity of causation, as well as the myriad ways that an event, or a sequence of events, creates cascading and systemic impacts, poses significant challenges to food systems research and policy alike. To identify priority food security risks and research opportunities, we asked experts from a range of fields and geographies to describe key threats to global food security over the next two decades and to suggest key research questions and gaps on this topic. Here, we present a prioritization of threats to global food security from extreme events, as well as emerging research questions that highlight the conceptual and practical challenges that exist in designing, adopting, and governing resilient food systems. We hope that these findings help in directing research funding and resources toward food system transformations needed to help society tackle major food system risks and food insecurity under extreme events.

As the rate of homelessness increases across urban centers in America, vast amounts of unhoused people are being criminalized and being subjected to forced displacement by state authorities. Most of the existing literature written on homelessness services focus on formalservices that take place in an office setting rather than on-the-ground outreach. These present insightful learnings, but they do not provide a clear understanding of the process of outreach nor unhoused individuals’ experiences. To address this gap, we conducted a qualitative analysis,collecting narratives about unhoused individuals’ lived experiences with formal and informal systems of outreach in Koreatown, Los Angeles. We sought to understand what forms of outreach made unhoused individuals feel supported. We conducted semi-structured conversational interviews with volunteers and engaged in participatory ethnography duringweekly outreach. We inquired about unhoused peoples’ experiences with formal and informaloutreach to understand how these systems differ, what potential improvements can be made, and which initiatives have been successful. We found that unhoused individuals were able to formmore trusting relationships with volunteers than with case-workers due to consistency,expectation management skills, and respect towards unhoused people. Given our findings, future recommendations include partnerships between the formal and informal sectors, further fundingfor formal outreach, and adhering to existing recommendations regarding formal outreach reform.

Objective: In a random sample of undergraduate students, we aimed to: (1) establish the prevalence of choking and being choked; (2) examine demographic and situational predictors of being choked, and (3) examine demographic and situational predictors of choking someone. Participants: 4168 randomly sampled undergraduates at a large public U.S. university. Methods: A cross-sectional, confidential online survey. Results: We found that 26.5% of women, 6.6% of men, and 22.3% of transgender and gender non-binary participants reported having been choked during their most recent sexual event. Additionally, 5.7% of women, 24.8% of men, and 25.9% of transgender and non-binary participants reported that they choked their partner at their most recent event. Choking was more prevalent among sexual minority students. Conclusions: Choking is prevalent among undergraduate students; implications for college sexual health education are discussed.

Respecting the Circle of Life (RCL) is a teen pregnancy prevention program that was evaluated for effectiveness on sexual health risk behaviors through a two-arm randomized control trial (RCT) with American Indian (AI) youth ages 11-19. The objective of this study is to investigate the effects of RCL compared to a control group on items of condom and contraception self-efficacy. Linear regression analysis was used to compare differences in each item that included condom and contraception self-efficacy scales among the intervention and control participants at baseline, 3 and 9 months post intervention. Youth enrolled in the intervention reported higher levels of condom and contraception self-efficacy across almost all individual items. Exceptions include items related to partner negotiation of condom self-efficacy at 3 months (p = 0.227) and 9 months (p = 0.074) post intervention. Findings indicate RCL is effective at improving overall condom and contraception self-efficacy but did not impact the specific component of partner negotiation for either condom or contraception self-efficacy. This inquiry provides rationale to further explore components of RCL related to partner negotiation.

In 2019, Native youth had the highest rate of teen pregnancy of all racial/ethnic groups. "Respecting the Circle of Life" (RCL) is one of the first evidence-based teen pregnancy prevention programs for Native teens and there is interest in replicating the program across tribal communities. To inform replication, it is important to consider process data including quality, fidelity, and dosage as these may all moderate impact of the program. Participants were Native youth aged 11-19 and a trusted adult. This study includes participants randomized to the RCL program only (N = 266). Data sources include independent observations, facilitator self-assessments, attendance logs, and self-report assessments completed by enrolled youth at baseline and 3 months post assessment. Data was compiled and summed by cohort. Dosage was number of minutes participating in activities separated by theoretical constructs. Linear regression models were utilized to assess moderation of the effects of the intervention dosage on outcomes of interest. Eighteen facilitators delivered RCL. One hundred eighteen independent observations and 320 facilitator self-assessments were collected and entered. Findings indicate RCL was implemented with high fidelity and quality (4.40 to 4.82 out of a 5-point Likert scale; 96.6% of planned activities completed). Dosage was high with an average completion of 7 out of 9 lessons. There was no association between theoretical construct dosage and outcomes of interest. Overall, this study indicates RCL was delivered with high fidelity, quality, and dosage in this trial. This paper informs future replication of RCL and provides support for hiring paraprofessionals from the local community as facilitators, delivering the RCL to peer groups of the same age and sex, delivering the RCL with short duration and high frequency, and encouraging youth to attend all RCL lessons, but continue to serve youth who have missed one or more lessons.

ObjectiveSurgical resection of motor eloquent tumors poses the risk of causing postoperative motor deficits which leads to reduced quality of life in these patients. Currently, rehabilitative procedures are limited with physical therapy being the main treatment option. This study investigated the efficacy of repetitive navigated transcranial magnetic stimulation (rTMS) for treatment of motor deficits after supratentorial tumor resection.MethodsThis randomized, double-blind, sham-controlled trial (DRKS00010043) recruited patients with a postoperatively worsened upper extremity motor function immediately postoperatively. They were randomly assigned to receive rTMS (1Hz, 110% RMT, 15 minutes, 7 days) or sham stimulation to the motor cortex contralateral to the injury followed by physical therapy. Motor and neurological function as well as quality of life were assessed directly after the intervention, one month and three months postoperatively.ResultsThirty patients were recruited for this study. There was no significant difference between both groups in the primary outcome, the Fugl Meyer score three months postoperatively [Group difference (95%-CI): 5.05 (-16.0; 26.1); p=0.631]. Patients in the rTMS group presented with better hand motor function one month postoperatively. Additionally, a subgroup of patients with motor eloquent ischemia showed lower NIHSS scores at all timepoints.ConclusionsLow-frequency rTMS facilitated the recovery process in stimulated hand muscles, but with limited generalization to other functional deficits. Long-term motor deficits were not impacted by rTMS. Given the reduced life expectancy in these patients a shortened recovery duration of deficits can still be of high significance.Clinical Trial Registrationhttps://drks.de/DRKS00010043.

Abstract Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas‐entrapping material containing CO in a pre‐clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.

The GINI project investigates the dynamics of inequality among populations over the long term by synthesising global archaeological housing data. This project brings archaeologists together from around the world to assess hypotheses concerning the causes and consequences of inequality that are of relevance to contemporary societies globally. Keywords: socioeconomic inequality, income, Gini coefficient, households, distributions of housing, Introduction Growing economic disparity around the world has prompted a renewed interest in the long-term dynamics of inequality (Borgerhoff Mulder et al. 2009; Flannery & Marcus 2012; Piketty 2014). Archaeology [...]