Identification of Meibomian gland stem cell populations and mechanisms of aging.

Meibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and niche of Meibomian gland stem cells and the signals controlling their activity are poorly defined. Using snRNA-seq, in vivo lineage tracing, ex vivo live imaging, and genetic studies in mice, we identified markers for stem cell populations that maintain distinct regions of the gland and uncovered Hh signaling as a key regulator of stem cell proliferation. Consistent with this, human Meibomian gland carcinoma exhibited increased Hh signaling. Aged glands displayed decreased Hh and EGF signaling, deficient innervation, and loss of collagen I in niche fibroblasts, indicating that alterations in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These findings suggest new approaches to treat aging-associated Meibomian gland loss.

The efficacy of interventions to prevent type 2 diabetes among women with recent gestational diabetes mellitus-A living systematic review and meta-analysis.

BACKGROUND: While previously considered a transient condition, with no lasting adverse impact, gestational diabetes mellitus (GDM) is now a well-established risk factor for developing type 2 diabetes mellitus (T2DM). The risk of developing T2DM appears to be particularly high in the first few years after childbirth, providing a compelling case for early intervention. This review provides an up-to-date systematic review and meta-analysis to assess the effectiveness of interventions to reduce incidence of T2DM in women with a recent history of GDM. METHODS: The search was conducted on October 20, 2023 with an annual surveillance planned for the next 5 years to maintain a living systematic review. The inclusion criteria were randomized controlled trials of any type in women within 5 years of GDM-complicated pregnancy that reported outcomes of T2DM diagnosis or measures of dysglycemia with a follow-up of at least 12 months. RESULTS: Seventeen studies met our inclusion criteria and have been included in this review. There were 3 pharmacological and 14 lifestyle interventions. Intervention was not associated with significant reduction in the primary outcome of T2DM (risk ratio, 0.78; 95% confidence interval [CI]: 0.43-1.41; p = 0.41; I2 = 79%) compared with the control group (placebo or usual care). However, meta-analysis of the four studies reporting hazard ratios suggested a reduction in diabetes incidence (hazard ratio, 0.68; 95% CI: 0.48-0.97; p = 0.03; I2 = 31%). CONCLUSION: This review provides equivocal evidence about the efficacy of interventions to reduce the risk of T2DM in women within 5 years of GDM-complicated pregnancy and highlights the need for further studies, including pharmacotherapy.

3D Brain Vascular Niche Model Captures Invasive Behavior and Gene Signatures of Glioblastoma.

Glioblastoma (GBM) is a lethal brain cancer with no effective treatment; understanding how GBM cells respond to tumor microenvironment remains challenging as conventional cell cultures lack proper cytoarchitecture while in vivo animal models present complexity all at once. Developing a culture system to bridge the gap is thus crucial. Here, we employed a multicellular approach using human glia and vascular cells to optimize a 3-dimensional (3D) brain vascular niche model that enabled not only long-term culture of patient derived GBM cells but also recapitulation of key features of GBM heterogeneity, in particular invasion behavior and vascular association. Comparative transcriptomics of identical patient derived GBM cells in 3D and in vivo xenotransplants models revealed that glia-vascular contact induced genes concerning neural/glia development, synaptic regulation, as well as immune suppression. This gene signature displayed region specific enrichment in the leading edge and microvascular proliferation zones in human GBM and predicted poor prognosis. Gene variance analysis also uncovered histone demethylation and xylosyltransferase activity as main themes for gene adaption of GBM cells in vivo . Furthermore, our 3D model also demonstrated the capacity to provide a quiescence and a protective niche against chemotherapy. In summary, an advanced 3D brain vascular model can bridge the gap between 2D cultures and in vivo models in capturing key features of GBM heterogeneity and unveil previously unrecognized influence of glia-vascular contact for transcriptional adaption in GBM cells featuring neural/synaptic interaction and immunosuppression.

Utility of a virtual small group cognitive behaviour program for autistic children during the pandemic: evidence from a community-based implementation study.

BACKGROUND: Autistic children often experience socioemotional difficulties relating to emotion regulation and mental health problems. Supports for autistic children involve the use of adapted interventions that target emotion regulation and social skills, alongside mental health symptoms. The Secret Agent Society Small Group (SAS: SG), an adapted cognitive behavioural program, has demonstrated efficacy through lab-delivered randomized control trials. However, research is still needed on its effectiveness when delivered by publicly funded, community-based autism providers under real-world ecologically valid conditions, especially within the context of a pandemic. The COVID-19 pandemic has disrupted access to community-based supports and services for autistic children, and programs have adapted their services to online platforms. However, questions remain about the feasibility and clinical utility of evidence-based interventions and services delivered virtually in community-based settings. METHODS: The 9-week SAS: SG program was delivered virtually by seven community-based autism service providers during 2020-2021. The program included the use of computer-based games, role-playing tasks, and home missions. Caregivers completed surveys at three timepoints: pre-, post-intervention, and after a 3-month follow-up session. Surveys assessed caregivers' perception of the program's acceptability and level of satisfaction, as well as their child's social and emotional regulation skills and related mental health challenges. RESULTS: A total of 77 caregivers (94% gender identity females; Mean = 42.1 years, SD = 6.5 years) and their children (79% gender identity males; Mean = 9.9 years, SD = 1.3 years) completed the SAS: SG program. Caregivers agreed that the program was acceptable (95%) and were highly satisfied (90%). Caregivers reported significant reduction in their child's emotion reactivity from pre- to post-intervention (-1.78 (95% CI, -3.20 to -0.29), p = 0.01, d = 0.36), that continued to decrease after the 3-month booster session (-1.75 (95% CI, -3.34 to -0.16), p = 0.02, d = 0.33). Similarly, improvements in anxiety symptoms were observed (3.05 (95% CI, 0.72 to 5.36), p = 0.006, d = 0.39). CONCLUSIONS: As online delivery of interventions for autistic children remains popular past the pandemic, our findings shed light on future considerations for community-based services, including therapists and agency leaders, on how best to tailor and optimally deliver virtually based programming. TRIAL REGISTRATION: This study has been registered with ISRCTN Registry (ISRCTN98068608) on 15/09/2023. The study was retroactively registered.

Management of Dry Eye Toxicity After Treatment With 177Lu-PSMA-617 Radioligand Therapy.

Treatment options for patients with metastatic castration-resistant prostate cancer include use of radioligand therapy with 177Lu-PSMA-617. 177Lu-PSMA-617 is used to target prostate cancer cells selectively by targeting prostate specific membrane antigen (PSMA); however, PSMA is also expressed on lacrimal glands among other tissues. Herein, we report on a case of a Common Terminology Criteria for Adverse Events version 5 grade 3 dry eye event with concomitant blepharitis after administration of 177Lu-PSMA-617. The patient was managed with neomycin-polymyxin-dexamethasone 3.5-10000-0.1 ophthalmic suspension, artificial tears, lubricating ointments, lid scrubs, and oral antihistamines.

Frozen Section Histoanatomy of the Peritarsal Eyelid.

BACKGROUND: Mohs surgery of eyelid skin cancers requires detailed knowledge of anatomy for precise surgery and accurate evaluation of histology. OBJECTIVE: To review the histology of the peritarsal eyelid using frozen sections as encountered intraoperatively by Mohs surgeons. METHODS: The authors review the literature describing the anatomy and histology of the peritarsal eyelid from the lens of a Mohs surgeon. Histology from select Mohs cases is used to frame the discussion of the microanatomy of this region. RESULTS: The peritarsal eyelids contain a unique mixture of skin, muscle, tarsus, glandular tissue, and conjunctiva. The histologic appearance of many of these structures differs from skin found outside of this anatomic region. Tumors of the eyelid and periocular region may mimic normal histologic structures found within the peritarsal eyelid. CONCLUSION: The peritarsal eyelids have unique anatomy and associated histologic structures. Knowledge of the detailed histoanatomy is required for confident execution of Mohs surgery in this anatomic region.

COVID-19 Vaccination and Incidence of Pediatric SARS-CoV-2 Infection and Hospitalization.

Importance: A SARS-CoV-2 vaccine was approved for adolescents aged 12 to 15 years on May 10, 2021, with approval for younger age groups following thereafter. The population level impact of the pediatric COVID-19 vaccination program has not yet been established. Objective: To identify whether California's pediatric COVID-19 immunization program was associated with changes in pediatric COVID-19 incidence and hospitalizations. Design, Setting, and Participants: A case series on COVID-19 vaccination including children aged 6 months to 15 years was conducted in California. Data were obtained on COVID-19 cases in California between April 1, 2020, and February 27, 2023. Exposure: Postvaccination evaluation periods spanned 141 days (June 10 to October 29, 2021) for adolescents aged 12 to 15 years, 199 days (November 29, 2021, to June 17, 2022) for children aged 5 to 11 years, and 225 days (July 17, 2022, to February 27, 2023) for those aged 6 to 59 months. During these periods, statewide vaccine coverage reached 53.5% among adolescents aged 12 to 15 years, 34.8% among children aged 5 to 11 years, and 7.9% among those aged 6 to 59 months. Main Outcomes and Measures: Age-stepped implementation of COVID-19 vaccination was used to compare observed county-level incidence and hospitalization rates during periods when each age group became vaccine eligible to counterfactual rates predicted from observations among other age groups. COVID-19 case and hospitalization data were obtained from the California reportable disease surveillance system. Results: Between April 1, 2020, and February 27, 2023, a total of 3 913 063 pediatric COVID-19 cases and 12 740 hospitalizations were reported in California. Reductions of 146 210 cases (95% prediction interval [PI], 136 056-158 948) were estimated among adolescents aged 12 to 15 years, corresponding to a 37.1% (35.5%-39.1%) reduction from counterfactual predictions. Reductions of 230 134 (200 170-265 149) cases were estimated among children aged 5 to 11 years, corresponding to a 23.7% (20.6%-27.3%) reduction from counterfactual predictions. No evidence of reductions in COVID-19 cases statewide were found among children aged 6 to 59 months (estimated averted cases, -259; 95% PI, -1938 to 1019), although low transmission during the evaluation period may have limited the ability to do so. An estimated 168 hospitalizations (95% PI, 42-324) were averted among children aged 6 to 59 months, corresponding to a 24.4% (95% PI, 6.1%-47.1%) reduction. In meta-analyses, county-level vaccination coverage was associated with averted cases for all age groups. Despite low vaccination coverage, pediatric COVID-19 immunization in California averted 376 085 (95% PI, 348 355-417 328) reported cases and 273 (95% PI, 77-605) hospitalizations among children aged 6 months to 15 years over approximately 4 to 7 months following vaccination availability. Conclusions and Relevance: The findings of this case series analysis of 3 913 063 cases suggest reduced pediatric SARS-CoV-2 transmission following immunization. These results support the use of COVID-19 vaccines to reduce COVID-19 incidence and hospitalization in pediatric populations.

Knowledge, attitudes, and behaviors related to dietary salt intake and the acceptability of salt substitute among the Australian culturally and linguistically diverse community: An online survey.

The Australian culturally and linguistically diverse (CALD) communities may be at higher risk of salt intake than recommended given the use of a combination of discretionary sources and exposure to processed foods within a western country. This survey aimed to understand the knowledge, attitudes, and behaviors toward dietary salt and the acceptability of salt substitutes in the CALD communities. An online cross-sectional survey was conducted among adults who self-reported being a part of a CALD community, which was defined as non-Indigenous cultural groups in Australia having cultural or linguistic connections with their overseas place of birth, ancestry or ethnic origin, religion, preferred language or language spoken at home. A total of 218 respondents opened the survey link. A total of 196 completed the entire survey. The majority of respondents (162, 83%) were aware that high salt intake causes serious health problems. Altogether 134 (69%) respondents were aware that there is a recommended amount for daily salt consumption although only 59 (44%) knew precise recommendations as <5 g salt per day. Around one quarter of the respondents rarely or never looked for ?low in salt'' or ?reduced salt'' messages on food labels when shopping. Over half specified they always or often added salt during cooking or preparing foods in the household. Almost 4 in 5 CALD respondents were willing to reduce their salt intake for health and 3 in 4 were open to trying a salt substitute. Further research into the utility of a salt substitute intervention in the Australian CALD community is warranted.

Sox9 marks limbal stem cells and is required for asymmetric cell fate switch in the corneal epithelium.

Adult tissues with high cellular turnover require a balance between stem cell renewal and differentiation, yet the mechanisms underlying this equilibrium are unclear. The cornea exhibits a polarized lateral flow of progenitors from the peripheral stem cell niche to the center; attributed to differences in cellular fate. To identify genes that are critical for regulating the asymmetric fates of limbal stem cells and their transient amplified progeny in the central cornea, we utilized an in vivo cell cycle reporter to isolate proliferating basal cells across the anterior ocular surface epithelium and performed single-cell transcriptional analysis. This strategy greatly increased the resolution and revealed distinct basal cell identities with unique expression profiles of structural genes and transcription factors. We focused on Sox9; a transcription factor implicated in stem cell regulation across various organs. Sox9 was found to be differentially expressed between limbal stem cells and their progeny in the central corneal. Lineage tracing analysis confirmed that Sox9 marks long-lived limbal stem cells and conditional deletion led to abnormal differentiation and squamous metaplasia in the central cornea. These data suggest a requirement for Sox9 for the switch to asymmetric fate and commitment toward differentiation, as transient cells exit the limbal niche. By inhibiting terminal differentiation of corneal progenitors and forcing them into perpetual symmetric divisions, we replicated the Sox9 loss-of-function phenotype. Our findings reveal an essential role for Sox9 for the spatial regulation of asymmetric fate in the corneal epithelium that is required to sustain tissue homeostasis.

The Effect of Weight Loss Through Lifestyle Interventions in Patients With Heart Failure With Preserved Ejection Fraction-A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for >50% of heart failure cases and is associated with significant morbidity and health system burden. To date, there have been limited treatment options proven to improve outcomes in these patients, with sodium glucose co-transporter 2 (SGLT2) inhibitors the first class of drug to demonstrate significant clinical benefits, including reductions in heart failure hospitalisation. Obesity is associated with all forms of heart failure and has been linked with worse clinical outcomes. Numerous reviews support the benefits of weight loss in heart failure, more specifically in patients with heart failure with reduced ejection fraction. However, the evidence in HFpEF patients is less clear. With limited pharmacotherapy options and growing support for weight loss in patients with HFpEF, this systematic review and meta-analysis aims to examine the effects of lifestyle interventions on weight loss and other health outcomes in patients with HFpEF. METHODS: Web of Science, Embase, Scopus, and PubMed databases were searched to identify relevant studies up to February 2023. Included studies were randomised controlled trials (with a duration of four weeks or more) of lifestyle interventions conducted in adults with HFpEF that reported weight loss. Outcomes of interest were body weight, body mass index (BMI), blood pressure (systolic and diastolic), aerobic capacity (6-minute walk distance), New York Heart Association (NYHA) Functional Classification, self-reported health quality of life (Minnesota Living with Heart Failure Questionnaire; MLHFQ), and N-terminal pro B-Type Natriuretic Peptide (NT-proBNP) levels. Review Manager software was used to conduct random effect meta-analyses, forest plots were generated for each outcome, and between-study heterogeneity was estimated using the I2 test statistic. Risk-of-bias assessment used the Cochrane risk-of-bias tool, and the certainty of the evidence was assessed using GRADE. RESULTS: From 2,282 records identified, six studies with a total of 375 participants, between three to six months in duration, were included in this systematic review and meta-analysis. Lifestyle interventions consisted of diet only, exercise only, combination of diet and exercise, and education and exercise. Over a mean follow-up of 4.5 months, pooled effects of the interventions were associated with a reduction in body weight of >5kg (weight mean difference (WMD): -5.30 kg; 95% CI: -8.72 to -1.87; p=0.002), and a reduction in resting systolic (WMD: -2.98 mmHg; 95% CI: -4.20 to -1.76; p<0.001) and diastolic blood pressure (WMD: -4.51 mmHg; 95% CI: -8.39 to -0.64; p=0.02) compared with those who received usual care. Interventions also improved 6-minute walk distance (WMD: 43.63 m; 95% CI: 22.28 to 64.97; p<0.001), NYHA class (WMD: -0.54; 95% CI: -0.75 to -0.33; p<0.001), and MLHFQ score (WMD: -17.77; 95% CL: -19.00 to -16.53; p<0.001). CONCLUSION: In patients with HFpEF, lifestyle intervention was associated with a significant reduction in body weight and had favourable effects on blood pressure, aerobic capacity, NYHA class, and health-related quality of life. Further research is needed in this population to examine the feasibility and durability of weight loss interventions and to examine the potential impact on hard clinical endpoints.

An architecturally rational hemostat for rapid stopping of massive bleeding on anticoagulation therapy.

Hemostatic devices are critical for managing emergent severe bleeding. With the increased use of anticoagulant therapy, there is a need for next-generation hemostats. We rationalized that a hemostat with an architecture designed to increase contact with blood, and engineered from a material that activates a distinct and undrugged coagulation pathway can address the emerging need. Inspired by lung alveolar architecture, here, we describe the engineering of a next-generation single-phase chitosan hemostat with a tortuous spherical microporous design that enables rapid blood absorption and concentrated platelets and fibrin microthrombi in localized regions, a phenomenon less observed with other classical hemostats without structural optimization. The interaction between blood components and the porous hemostat was further amplified based on the charged surface of chitosan. Contrary to the dogma that chitosan does not directly affect physiological clotting mechanism, the hemostat induced coagulation via a direct activation of platelet Toll-like receptor 2. Our engineered porous hemostat effectively stopped the bleeding from murine liver wounds, swine liver and carotid artery injuries, and the human radial artery puncture site within a few minutes with significantly reduced blood loss, even under the anticoagulant treatment. The integration of engineering design principles with an understanding of the molecular mechanisms can lead to hemostats with improved functions to address emerging medical needs.

Disruption of H3K36 methylation provokes cellular plasticity to drive aberrant glandular formation and squamous carcinogenesis.

Chromatin organization is essential for maintaining cell-fate trajectories and developmental programs. Here, we find that disruption of H3K36 methylation dramatically impairs normal epithelial differentiation and development, which promotes increased cellular plasticity and enrichment of alternative cell fates. Specifically, we observe a striking increase in the aberrant generation of excessive epithelial glandular tissues, including hypertrophic salivary, sebaceous, and meibomian glands, as well as enhanced squamous tumorigenesis. These phenotypic and gene expression manifestations are associated with loss of H3K36me2 and rewiring of repressive H3K27me3, changes we also observe in human patients with glandular hyperplasia. Collectively, these results have identified a critical role for H3K36 methylation in both in vivo epithelial cell-fate decisions and the prevention of squamous carcinogenesis and suggest that H3K36 methylation modulation may offer new avenues for the treatment of numerous common disorders driven by altered glandular function, which collectively affect large segments of the human population.

The role of thriving in mental health among people with intellectual and developmental disabilities during the COVID-19 pandemic in Canada.

BACKGROUND: The COVID-19 pandemic has had a negative impact on the mental health of people with intellectual and developmental disabilities. Numerous pandemic-related stressors experienced by people with intellectual and developmental disabilities may have impacted their ability to thrive, which has been linked to mental health outcomes. The current study examined the associations among COVID-19 stressors, thriving, and mental health problems among youth and adults with intellectual and developmental disabilities. METHOD: Caregivers of 159 people with intellectual and developmental disabilities between 12 and 35 years of age from Canada completed an online questionnaire. RESULTS: A mediation analysis revealed that COVID-19 stressors were positively associated with mental health problems, and that thriving partially mediated this association. CONCLUSION: Our findings suggest that experiences of thriving may be an important target for mental health support for people with intellectual and developmental disabilities.

Decreasing Blood Culture Collection in Hospitalized Patients with CAP, SSTI, and UTI.

Background: Blood culture collection in pediatric patients with community-acquired pneumonia (CAP), skin and soft tissue infections (SSTI), and urinary tract infections (UTI) remains high despite evidence of its limited utility. We aimed to decrease the number of cultures collected in children hospitalized for CAP, SSTI, and UTI by 25% over 11 months. Methods: Quality improvement initiative at a children's hospital among well-appearing patients aged 2 months or more to 18 years diagnosed with CAP, SSTI, or UTI. Our primary and secondary outcomes were blood culture collection rate and positivity rate, respectively. Interventions focused on three key drivers: academic detailing, physician awareness of personal performance, and data transparency. Results: Over the 2-year study period, there were 105 blood cultures collected in 223 hospitalized patients. Blood culture collection rates demonstrated special cause variation, decreasing from 63.5% to 24.5%. For patients with UTI, 86% (18/21) of blood cultures were negative, whereas 100% were negative for CAP and SSTI. All three patients with bacteremic UTI had a concurrent urine culture growing the same pathogen. Balancing measures remained unchanged, including escalation to a higher level of care and return to the emergency department or hospital within 14 days for the same infection. Conclusions: A multifaceted quality improvement approach can reduce blood culture collection for hospitalized patients with CAP, SSTI, and UTI without significant changes to balancing measures. Despite the reduction achieved, the near-universal negative culture results suggest continued overutilization and highlight the need for more targeted approaches to blood culture collection.

Cingulate cortex facilitates auditory perception under challenging listening conditions.

We often exert greater cognitive resources (i.e., listening effort) to understand speech under challenging acoustic conditions. This mechanism can be overwhelmed in those with hearing loss, resulting in cognitive fatigue in adults, and potentially impeding language acquisition in children. However, the neural mechanisms that support listening effort are uncertain. Evidence from human studies suggest that the cingulate cortex is engaged under difficult listening conditions, and may exert top-down modulation of the auditory cortex (AC). Here, we asked whether the gerbil cingulate cortex (Cg) sends anatomical projections to the AC that facilitate perceptual performance. To model challenging listening conditions, we used a sound discrimination task in which stimulus parameters were presented in either 'Easy' or 'Hard' blocks (i.e., long or short stimulus duration, respectively). Gerbils achieved statistically identical psychometric performance in Easy and Hard blocks. Anatomical tracing experiments revealed a strong, descending projection from layer 2/3 of the Cg1 subregion of the cingulate cortex to superficial and deep layers of primary and dorsal AC. To determine whether Cg improves task performance under challenging conditions, we bilaterally infused muscimol to inactivate Cg1, and found that psychometric thresholds were degraded for only Hard blocks. To test whether the Cg-to-AC projection facilitates task performance, we chemogenetically inactivated these inputs and found that performance was only degraded during Hard blocks. Taken together, the results reveal a descending cortical pathway that facilitates perceptual performance during challenging listening conditions. Significance Statement: Sensory perception often occurs under challenging conditions, such a noisy background or dim environment, yet stimulus sensitivity can remain unaffected. One hypothesis is that cognitive resources are recruited to the task, thereby facilitating perceptual performance. Here, we identify a top-down cortical circuit, from cingulate to auditory cortex in the gerbils, that supports auditory perceptual performance under challenging listening conditions. This pathway is a plausible circuit that supports effortful listening, and may be degraded by hearing loss.

The effects of canagliflozin in type 2 diabetes in subgroups defined by population-specific body mass index: Insights from the CANVAS Program and CREDENCE trial.

AIM: To assess the effects of canagliflozin on clinical outcomes and intermediate markers across population-specific body mass index (BMI) categories in the CANVAS Program and CREDENCE trial. METHODS: Individual participant data were pooled and analysed in subgroups according to population-specific BMI. The main outcomes of interest were: major adverse cardiovascular events (MACE, a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death); composite renal outcome; and changes in systolic blood pressure (SBP), body weight, albuminuria and estimated glomerular filtration rate (eGFR) slope. Cox proportional hazards models and mixed-effect models were used. RESULTS: A total of 14 520 participants were included, of whom 9378 (65%) had obesity. Overall, canagliflozin reduced the risk of MACE (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75 to 0.93) with no heterogeneity of treatment effect across BMI subgroups (Pheterogeneity = 0.76). Similarly, canagliflozin reduced composite renal outcomes (HR 0.75, 95% CI 0.66 to 0.84) with no heterogeneity across subgroups observed (Pheterogeneity = 0.72). The effects of canagliflozin on body weight and SBP differed across BMI subgroups (Pheterogeneity <0.01 and 0.04, respectively) but were consistent for albuminuria (Pheterogeneity = 0.60). Chronic eGFR slope with canagliflozin treatment was consistent across subgroups (Pheterogeneity >0.95). CONCLUSIONS: The cardiovascular and renal benefits of canagliflozin and its safety profile were consistent across population-specific BMI subgroups for adults in the CANVAS Program and CREDENCE trial.

Sacubitril/valsartan versus valsartan in regressing myocardial fibrosis in hypertension: a prospective, randomized, open-label, blinded endpoint clinical trial protocol.

Background: Diffuse interstitial myocardial fibrosis is a key common pathological manifestation in hypertensive heart disease (HHD) progressing to heart failure (HF). Angiotensin receptor-neprilysin inhibitors (ARNi), now a front-line treatment for HF, confer benefits independent of blood pressure, signifying a multifactorial mode of action beyond hemodynamic regulation. We aim to test the hypothesis that compared with angiotensin II receptor blockade (ARB) alone, ARNi is more effective in regressing diffuse interstitial myocardial fibrosis in HHD. Methods: Role of ARNi in Ventricular Remodeling in Hypertensive LVH (REVERSE-LVH) is a prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial. Adults with hypertension and left ventricular hypertrophy (LVH) according to Asian sex- and age-specific thresholds on cardiovascular magnetic resonance (CMR) imaging are randomized to treatment with either sacubitril/valsartan (an ARNi) or valsartan (an ARB) in 1:1 ratio for a duration of 52 weeks, at the end of which a repeat CMR is performed to assess differential changes from baseline between the two groups. The primary endpoint is the change in CMR-derived diffuse interstitial fibrosis volume. Secondary endpoints include changes in CMR-derived left ventricular mass, volumes, and functional parameters. Serum samples are collected and stored to assess the effects of ARNi, compared with ARB, on circulating biomarkers of cardiac remodeling. The endpoints will be analyzed with reference to the corresponding baseline parameters to evaluate the therapeutic effect of sacubitril/valsartan vs. valsartan. Discussion: REVERSE-LVH will examine the anti-fibrotic potential of sacubitril/valsartan and will offer mechanistic insights into the clinical benefits of sacubitril/valsartan in hypertension in relation to cardiac remodeling. Advancing the knowledge of the pathophysiology of HHD will consolidate effective risk stratification and personalized treatment through a multimodal manner integrating complementary CMR and biomarkers into the conventional care approach.Clinical Trial Registration: ClinicalTrials.gov, identifier, NCT03553810.

Advancements in Marburg (MARV) Virus Vaccine Research With Its Recent Reemergence in Equatorial Guinea and Tanzania: A Scoping Review.

Given the recent outbreaks of the Marburg (MARV) virus within the first quarter of the year 2023, interest in the MARV virus has been re-ignited given its shared phylogeny with the dreadful Ebola virus. This relation gives some insight into its virulence, associated morbidities, and mortality rates. The first outbreak of MARV recorded was in Germany, in 1967, of which seven died out of 31 reported cases. Ever since, subsequent cases have been reported all over Africa, a continent replete with failing healthcare systems.  This reality impresses a need for a contemporary and concise revision of the MARV virus existing publications especially in the areas of vaccine research. A functional MARV vaccine will serve as a panacea to ailing communities within the African healthcare landscape.  The objective of this scoping review is to provide pertinent information relating to MARV vaccine research beginning with an outline of MARV's pathology and pathogenesis in addition to the related morbidities, existing therapies, established outbreak protocols as well as areas of opportunities.