Alterations of urine microRNA-7977/G6PD level in patients with diabetic kidney disease and its association with dysfunction of albumin-induced autophagy in proximal epithelial tubular cells.

Diabetic kidney disease (DKD) remains as one of the leading long-term complications of type 2 diabetic mellitus (T2DM). Studies have shown that decreased expression of glucose-6-phosphate dehydrogenase (G6PD) plays an important role in DKD. However, the upstream and downstream pathways of G6PD downregulation leading to DKD have not been elucidated. We conducted a series of studies including clinical study, animal studies, and in vitro studies to explore this. First, a total of 90 subjects were evaluated including 30 healthy subjects, 30 patients with T2DM, and 30 patients with DKD. The urinary G6PD activity and its association with the clinical markers were analyzed. Multivariate linear regression analysis was used to analyze the risk factors of urinary G6PD in these patients. Then, microRNAs that were differentially expressed in urine and could bind and degrade G6PD were screened and verified in patients with DKD. After that, high glucose (HG)-cultured human kidney cells (HK-2) and Zucker diabetic fatty (ZDF) rats were used to test the roles of miR-7977/G6PD/albumin-induced autophagy in DKD. Beclin and P62 were used as markers of kidney autophagy indicators. A dual-luciferase reporter assay system was used to test the binding of G6PD by mir-7977. The plasma and urinary G6PD activity were decreased significantly in patients with DKD, accompanied by increased urinary mir-7977 level. The fasting plasma glucose (FPG), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and urinary albumin excretion were independent predictors of urinary G6PD activity, according to multiple linear regression analysis. The increased expression of miR-7977 and decreased expression of G6PD were also found in the kidney of ZDF rats with early renal tubular damage. The correlation analysis showed that beclin protein expression levels were positively correlated with kidney G6PD activity, whereas P62 protein expression was negatively correlated with kidney G6PD activity in rats. In HK-2 cells cultured with normal situation, a low level of albumin could induce autophagy along with the stimulation of G6PD, although this was impaired under high glucose. Overexpression of G6PD reversed albumin-induced autophagy in HK-2 cells under high glucose. Further study revealed that G6PD was a downstream target of miR-7977. Inhibition of miR-7977 expression led to significantly increased expression of G6PD and reversed the effects of high glucose on albumin-induced autophagy. In conclusion, our study supports a new mechanism of G6PD downregulation in DKD. Therapeutic measures targeting the miR-7977/G6PD/autophagy signaling pathway may help in the prevention and treatment of DKD.NEW & NOTEWORTHY This study provides new evidence that reduced glucose-6-phosphate dehydrogenase (G6PD) may damage the endocytosis of renal tubular epithelial cells by reducing albumin-induced autophagy. More importantly, for the first time, our study has provided evidence from humans that the decrease in urinary G6PD activity is positively associated with renal injury, and abnormal glucose and lipid metabolism may be important reasons for reduced G6PD levels. Increased miR-7977 may at least in part explain the downregulation of G6PD.

Healthcare Professional Perspectives on the Impact of the Physical Health Nurse Consultant.

Early mortality experienced by people living with mental health issues (hereon termed consumers) is largely preventable. Healthcare professionals perceive healthcare system inadequacies such as diagnostic overshadowing, stigma and fragmentation of physical and mental healthcare services can be resolved through effective integration approaches. Service- and individual-level integration approaches involve multidisciplinary teams collaborating and coordinating care to holistically meet consumers' physical and mental health needs. Evidence suggests appropriately trained healthcare professionals can deliver effective integrated treatment without financial or organisational restructuring. Specialist nursing positions such as Physical Health Nurse Consultants can support and integrate physical and mental health care. Consumers report the Physical Health Nurse Consultant as providing dedicated, integrated, coordinated and holistic mental and physical health care. This study aimed to explore the Physical Health Nurse Consultant role from the perspectives of healthcare professionals. A qualitative exploratory study design was used. Fourteen healthcare professionals participated in individual interviews or focus groups. Interview recordings were transcribed, and thematically analysed. Three themes were identified: (i) role functions, including integration of physical and mental health care, (ii) impact on consumer physical health outcomes and (iii) impact on service delivery. Healthcare professionals perceive the Physical Health Nurse Consultant effectively integrates physical and mental health care and subsequently support the continuation and embedding of the role in routine practice. Future research is required to explore healthcare professionals' experiences and perceptions of how these roles be translated to routine clinical practice. Examining the professional development requirements, service provider constraints and economic implication to achieve these outcomes also warrants attention.

Nurse-led physical health interventions for people with mental illness: an integrative review of international literature.

BACKGROUND: People experiencing mental illness receive physical healthcare from nurses in a variety of settings including acute inpatient, secure extended care, forensic, and community services. While nurse-led clinical practice addressing sub-optimal consumer physical health is salient, a detailed understanding and description of the contribution by nurses to physical health interventions in people experiencing mental illness is not clearly articulated in the literature. AIMS: The aim of this integrative review is to describe the state of knowledge on nurse-led physical health intervention for consumers, focusing on nursing roles, nursing assessment, and intervention settings. METHODS: A systematic search of six databases using Medical Subject Headings from 2001 and 2022 inclusive was conducted. The Mixed Methods Appraisal Tool (MMAT) was utilised for quality appraisal. RESULTS: Seventy-four studies were identified as "nurse-led". Interventions were most common among community settings (n = 34, 46%). Nurses performed varied roles, often concurrently, including the collection of 341 physical health outcomes, and multiple roles with 225 distinct nursing actions identified across the included studies. A nurse as lead author was common among the included studies (n = 46, 62%). However, nurses were not always recognised for their efforts or contributions in authorship. CONCLUSIONS: There is potential gap in role recognition that should be considered when designing and reporting nurse-led physical health interventions.

The implementation of exercise therapy within hospital-based mental healthcare: Delphi study.

BACKGROUND: The physical health comorbidities and premature mortality experienced by people with mental illness has led to an increase in exercise services embedded as part of standard care in hospital-based mental health services. Despite the increase in access to exercise services for people experiencing mental illness, there is currently a lack of guidelines on the assessment and triage of patients into exercise therapy. AIMS: To develop guidelines for the pre-exercise screening and health assessment of patients engaged with exercise services in hospital-based mental healthcare and to establish an exercise therapy triage framework for use in hospital-based mental healthcare. METHOD: A Delphi technique consisting of two online surveys and two rounds of focus group discussions was used to gain consensus from a multidisciplinary panel of experts. RESULTS: Consensus was reached on aspects of pre-exercise health screening, health domain assessment, assessment tools representing high-value clinical assessment, and the creation and proposed utilisation of an exercise therapy triage framework within exercise therapy. CONCLUSIONS: This study is the first of its kind to provide guidance on the implementation of exercise therapy within Australian hospital-based mental healthcare. The results provide recommendations for appropriate health assessment and screening of patients in exercise therapy, and provide guidance on the implementation and triage of patients into exercise therapy via a stepped framework to determine (a) the timeliness of exercise therapy required and (b) the level of support required in the delivery of their exercise therapy.

The Physical Health Nurse Consultant: Perceptions and Experiences of Those Who Care for People with Mental Illness.

Mental health carers are crucial in improving the physical health outcomes of people diagnosed with a mental illness (hereafter referred to as consumers). The long-term and multifaceted mental and physical health support carers provide to consumers can contribute to caregiver burden. Consequently, carers advocate for coordinated and integrated physical healthcare to improve the physical health outcomes of consumers and alleviate caregiver burden. The aim of this qualitative exploratory study is to explore carers' perceptions and experiences with the Physical Health Nurse Consultant role. Semi-structured interviews with nine carers nominated by consumers were conducted. Interviews were transcribed and reflexively thematically analysed. Three main themes were identified: (i) Therapeutic relationship s were a catalyst for health behaviour change; (ii) Overt and covert positive changes were observed by carer and (iii) Cares' involvement in integrated mental health and physical health care. Nine carers who were nominated by consumers to be involved in their physical healthcare planning, preferred to adopt a supporting role as this prevented or reduced caregiver burden. The findings support the adoption and continuation of the Physical Health Nurse Consultant role to facilitate positive physical health outcomes for consumers and a reduction in caregiving burden. The benefits of the Physical Health Nurse Consultant provide a compelling argument to embed the role in routine practice. Mental healthcare services should advocate for continued funding and career development for such positions to provide long term benefits for consumers and carers. Future research is required to explore carer and consumer involvement in co-producing future and localised iterations of the Physical Health Nurse Consultant role. This research should also measure the outputs and outcomes of co-production to clarify how the process worked in practice.

Temporal Trends and Racial Disparities in Long-Term Survival After Stroke.

BACKGROUND AND OBJECTIVES: Few studies have examined trends and disparities in long-term outcome after stroke in a representative US population. We used a population-based stroke study in the Greater Cincinnati Northern Kentucky region to examine trends and racial disparities in poststroke 5-year mortality. METHODS: All patients with acute ischemic strokes (AISs) and intracerebral hemorrhages (ICHs) among residents ≥20 years old were ascertained using ICD codes and physician-adjudicated using a consistent case definition during 5 periods: July 1993-June 1994 and calendar years 1999, 2005, 2010, and 2015. Race was obtained from the medical record; only those identified as White or Black were included. Premorbid functional status was assessed using the modified Rankin Scale, with a score of 0-1 being considered "good." Mortality was assessed with the National Death Index. Trends and racial disparities for each subtype were analyzed with logistic regression. RESULTS: We identified 8,428 AIS cases (19.3% Black, 56.3% female, median age 72) and 1,501 ICH cases (23.5% Black, 54.8% female, median age 72). Among patients with AIS, 5-year mortality improved after adjustment for age, race, and sex (53% in 1993/94 to 48.3% in 2015, overall effect of study year p = 0.009). The absolute decline in 5-year mortality in patients with AIS was larger than what would be expected in the general population (5.1% vs 2.8%). Black individuals were at a higher risk of death after AIS (odds ratio [OR] 1.23, 95% CI 1.08-1.39) even after adjustment for age and sex, and this effect was consistent across study years. When premorbid functional status and comorbidities were included in the model, the primary effect of Black race was attenuated but race interacted with sex and premorbid functional status. Among male patients with a good baseline functional status, Black race remained associated with 5-year mortality (OR 1.4, 95% CI 1.1-1.7, p = 0.002). There were no changes in 5-year mortality after ICH over time (64.4% in 1993/94 to 69.2% in 2015, overall effect of study year p = 0.32). DISCUSSION: Long-term survival improved after AIS but not after ICH. Black individuals, particularly Black male patients with good premorbid function, have a higher mortality after AIS, and this disparity did not change over time.

Impact of Poverty on Stroke Recurrence: A Population-Based Study.

BACKGROUND AND OBJECTIVES: Poverty is associated with greater stroke incidence. The relationship between poverty and stroke recurrence is less clear. METHODS: In this population-based study, incident strokes within the Greater Cincinnati/Northern Kentucky region were ascertained during the 2015 study period and followed up for recurrence until December 31, 2018. The primary exposure was neighborhood socioeconomic status (nSES), defined by the percentage of households below the federal poverty line in each census tract in 4 categories (≤5%, >5%-10%, >10%-25%, >25%). Poisson regression models provided recurrence rate estimates per 100,000 residents using population data from the 2015 5-year American Community Survey, adjusting for age, sex, and race. In a secondary analysis, Cox models allowed for the inclusion of vascular risk factors in the assessment of recurrence risk by nSES among those with incident stroke. RESULTS: Of 2,125 patients with incident stroke, 245 had a recurrent stroke during the study period. Poorer nSES was associated with increased stroke recurrence, with rates of 12.5, 17.5, 25.4, and 29.9 per 100,000 in census tracts with ≤5%, >5%-10%, >10%-25%, and >25% below the poverty line, respectively (p < 0.01). The relative risk (95% CI) for recurrent stroke among Black vs White individuals was 2.54 (1.91-3.37) before adjusting for nSES, and 2.00 (1.47-2.74) after adjusting for nSES, a 35.1% decrease. In the secondary analysis, poorer nSES (HR 1.74, 95% CI 1.10-2.76 for lowest vs highest category) and Black race (HR 1.31, 95% CI 1.01-1.70) were both independently associated with recurrence risk, though neither retained significance after full adjustment. Age, diabetes, and left ventricular hypertrophy were associated with increased recurrence risk in fully adjusted models. DISCUSSION: Residents of poorer neighborhoods had a dose-dependent increase in stroke recurrence risk, and neighborhood poverty accounted for approximately one-third of the excess risk among Black individuals. These results highlight the importance of poverty, race, and the intersection of the 2 as potent drivers of stroke recurrence.

Racial Disparities in Blood Pressure at Time of Acute Ischemic Stroke Presentation: A Population Study.

BACKGROUND: Hypertension is a stroke risk factor with known disparities in prevalence and management between Black and White patients. We sought to identify if racial differences in presenting blood pressure (BP) during acute ischemic stroke exist. METHODS AND RESULTS: Adults with acute ischemic stroke presenting to an emergency department within 24 hours of last known normal during study epochs 2005, 2010, and 2015 within the Greater Cincinnati/Northern Kentucky Stroke Study were included. Demographics, histories, arrival BP, National Institutes of Health Stroke Scale score, and time from last known normal were collected. Multivariable linear regression was used to determine differences in mean BP between Black and White patients, adjusting for age, sex, National Institutes of Health Stroke Scale score, history of hypertension, hyperlipidemia, smoking, stroke, body mass index, and study epoch. Of 4048 patients, 853 Black and 3195 White patients were included. In adjusted analysis, Black patients had higher presenting systolic BP (161 mm Hg [95% CI, 159-164] versus 158 mm Hg [95% CI, 157-159], P<0.01), diastolic BP (86 mm Hg [95% CI, 85-88] versus 83 mm Hg [95% CI, 82-84], P<0.01), and mean arterial pressure (111 mm Hg [95% CI, 110-113] versus 108 mm Hg [95% CI, 107-109], P<0.01) compared with White patients. In adjusted subanalysis of patients <4.5 hours from last known normal, diastolic BP (88 mm Hg [95% CI, 86-90] versus 83 mm Hg [95% CI, 82-84], P<0.01) and mean arterial pressure (112 mm Hg [95% CI, 110-114] versus 108 mm Hg [95% CI, 107-109], P<0.01) were also higher in Black patients. CONCLUSIONS: This population-based study suggests differences in presenting BP between Black and White patients during acute ischemic stroke. Further study is needed to determine whether these differences influence clinical decision-making, outcome, or clinical trial eligibility.

Omega-3 Fatty Acids and Risk of Ischemic Stroke in REGARDS.

We examined associations between lipidomic profiles and incident ischemic stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Plasma lipids (n = 195) were measured from baseline blood samples, and lipids were consolidated into underlying factors using exploratory factor analysis. Cox proportional hazards models were used to test associations between lipid factors and incident stroke, linear regressions to determine associations between dietary intake and lipid factors, and the inverse odds ratio weighting (IORW) approach to test mediation. The study followed participants over a median (IQR) of 7 (3.4-11) years, and the case-cohort substudy included 1075 incident ischemic stroke and 968 non-stroke participants. One lipid factor, enriched for docosahexaenoic acid (DHA, an omega-3 fatty acid), was inversely associated with stroke risk in a base model (HR = 0.84; 95%CI 0.79-0.90; P = 8.33 × 10-8) and fully adjusted model (HR = 0.88; 95%CI 0.83-0.94; P = 2.79 × 10-4). This factor was associated with a healthy diet pattern (ß = 0.21; 95%CI 0.12-0.30; P = 2.06 × 10-6), specifically with fish intake (ß = 1.96; 95%CI 0.95-2.96; P = 1.36 × 10-4). DHA was a mediator between fish intake and incident ischemic stroke (30% P = 5.78 × 10-3). Taken together, DHA-containing plasma lipids were inversely associated with incident ischemic stroke and mediated the relationship between fish intake and stroke risk.

Large-scale chemoproteomics expedites ligand discovery and predicts ligand behavior in cells.

Chemical modulation of proteins enables a mechanistic understanding of biology and represents the foundation of most therapeutics. However, despite decades of research, 80% of the human proteome lacks functional ligands. Chemical proteomics has advanced fragment-based ligand discovery toward cellular systems, but throughput limitations have stymied the scalable identification of fragment-protein interactions. We report proteome-wide maps of protein-binding propensity for 407 structurally diverse small-molecule fragments. We verified that identified interactions can be advanced to active chemical probes of E3 ubiquitin ligases, transporters, and kinases. Integrating machine learning binary classifiers further enabled interpretable predictions of fragment behavior in cells. The resulting resource of fragment-protein interactions and predictive models will help to elucidate principles of molecular recognition and expedite ligand discovery efforts for hitherto undrugged proteins.

Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial.

Importance: Atrial cardiopathy is associated with stroke in the absence of clinically apparent atrial fibrillation. It is unknown whether anticoagulation, which has proven benefit in atrial fibrillation, prevents stroke in patients with atrial cardiopathy and no atrial fibrillation. Objective: To compare anticoagulation vs antiplatelet therapy for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy. Design, Setting, and Participants: Multicenter, double-blind, phase 3 randomized clinical trial of 1015 participants with cryptogenic stroke and evidence of atrial cardiopathy, defined as P-wave terminal force greater than 5000 µV × ms in electrocardiogram lead V1, serum N-terminal pro-B-type natriuretic peptide level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m2 or greater on echocardiogram. Participants had no evidence of atrial fibrillation at the time of randomization. Enrollment and follow-up occurred from February 1, 2018, through February 28, 2023, at 185 sites in the National Institutes of Health StrokeNet and the Canadian Stroke Consortium. Interventions: Apixaban, 5 mg or 2.5 mg, twice daily (n = 507) vs aspirin, 81 mg, once daily (n = 508). Main Outcomes and Measures: The primary efficacy outcome in a time-to-event analysis was recurrent stroke. All participants, including those diagnosed with atrial fibrillation after randomization, were analyzed according to the groups to which they were randomized. The primary safety outcomes were symptomatic intracranial hemorrhage and other major hemorrhage. Results: With 1015 of the target 1100 participants enrolled and mean follow-up of 1.8 years, the trial was stopped for futility after a planned interim analysis. The mean (SD) age of participants was 68.0 (11.0) years, 54.3% were female, and 87.5% completed the full duration of follow-up. Recurrent stroke occurred in 40 patients in the apixaban group (annualized rate, 4.4%) and 40 patients in the aspirin group (annualized rate, 4.4%) (hazard ratio, 1.00 [95% CI, 0.64-1.55]). Symptomatic intracranial hemorrhage occurred in 0 patients taking apixaban and 7 patients taking aspirin (annualized rate, 1.1%). Other major hemorrhages occurred in 5 patients taking apixaban (annualized rate, 0.7%) and 5 patients taking aspirin (annualized rate, 0.8%) (hazard ratio, 1.02 [95% CI, 0.29-3.52]). Conclusions and Relevance: In patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation, apixaban did not significantly reduce recurrent stroke risk compared with aspirin. Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.

Ethical challenges for nurses delivering coercive interventions in community mental health settings: A scoping review.

The number of Australians subject to coercive interventions in community mental health services continues to increase. This is in the context of a growing awareness of the harms from coercion, increasing concerns about potential breaches of human rights and an ongoing uncertainty regarding the clinical benefits of community treatment orders, the primary instrument of legislated coercion in community mental health services. Nurses in community mental health services are on the frontline with regard to coercion. They police the requirements of the community treatment order, administer medication to people in community settings without their consent and facilitate re-hospitalisation if indicated. Coercive practice contradicts the person-centred, recovery-oriented and trauma-informed care principles that inform contemporary mental health nursing. This contradiction may generate ethical challenges for nurses and result in ethical distress. The aim of this scoping review was to map the research literature on how nurses in community mental health settings recognise and manage the harm associated with the administration of coercive interventions and consider the ethical challenges that may arise within this practice. The search strategy yielded 562 studies with author consensus determining a total of three articles as meeting the inclusion criteria. The resulting literature identified three themes: (1) maintaining the therapeutic relationship, (2) promoting autonomy and (3) using subtle forms of control. This review demonstrated that there is minimal research that has considered the ethical challenges related to the use of coercion by nurses in community mental health settings.

Charge Carrier Dynamics at the Interface of 2D Metal-Organic Frameworks and Hybrid Perovskites for Solar Energy Harvesting.

Interfacing perovskites with two-dimensional materials such as metal-organic frameworks (MOFs) for improved stability and electron or hole extraction has emerged as a promising path forward for the generation of highly efficient and stable solar cells. In this work, we examine the structural properties and excitation dynamics of two MOF-perovskite systems: UMCM309-a@MAPbI3 and ZrL3@MAPbI3. We find that precise band alignment and electronegativity of the MOF-linkers are necessary to facilitate the capture of excited charge carriers. Furthermore, we demonstrate that intraband relaxation of hot electrons to the MOF subsystem results in optically disallowed transitions across the band gap, suppressing radiative recombination. Furthermore, we elucidate the key mechanisms associated with improved structural stability afforded to the perovskites by the two-dimensional MOFs, highlighting the necessity of broad surface coverage and strong MOF-perovskite interaction.

Temporal Trends in Public Stroke Knowledge, 1995-2021.

BACKGROUND: Outreach campaigns have sought to reduce the burden of stroke by improving knowledge of stroke risk factors (RF) and warning signs (WS). We describe trends in stroke knowledge from 1995 to 2021. METHODS: From 1995 to 2021, 6 separate surveys were conducted in the Greater Cincinnati Northern Kentucky Region. Temporal trends in RF/WS knowledge were analyzed using logistic regression adjusting for Race, sex, age, and education. RESULTS: In 1995, 28.6% of participants (537/1880) could name ≥2 WS, compared with 50.6% (983/1944) in 2021 (trend P<0.0001 after adjustment). In 1995, 44.5% of participants (836/1880) knew ≥2 RF, compared with 56.7% (1103/1944) in 2021 (trend P<0.0001 after adjustment). Although still improved compared with 1995, fewer participants could identify ≥2 RF in 2021 (1103/1944, 56.7%) when compared with 2011 (1287/2036, 63.2%, pairwise P<0.05). This decline in RF knowledge was disproportionately larger in women (odds ratio of 0.67 for knowledge in 2021 compared with 2011 in females, P=0.047 for the interaction between sex and study year). CONCLUSIONS: Although stroke knowledge has overall improved since 1995, there is evidence for lost gains since 2011, particularly in women. Stroke outreach campaigns need ongoing evaluation.

Pyrovskite: A software package for the high-throughput construction, analysis, and featurization of two- and three-dimensional perovskite systems.

The increased computational and experimental interest in perovskite systems comprising novel phases and reduced dimensionality has greatly expanded the search space for this class of materials. In similar fields, unified frameworks exist for the procedural generation and subsequent analysis of these complex condensed matter systems. Given the relatively recent rise in popularity of these novel perovskite phases, such a framework is yet to be created. In this work, we introduce Pyrovskite, an open source software package, to aid in both the high-throughput and fine-grained generation, simulation, and subsequent analysis of this expanded family of perovskite systems. Additionally, we introduce a new descriptor for octahedral distortions in systems, including, but not limited to, perovskites. This descriptor quantifies diagonal displacements of the B-site cation in a BX6 octahedral coordination environment, which has been shown to contribute to increased Rashba-Dresselhaus splitting in perovskite systems.