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Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis ( Mtb ), infects approximately one-fourth of the world's population. While most infected individuals are asymptomatic, latent TB infection (LTBI) can progress to cause pulmonary TB (PTB). We recently reported an increased accumulation of mast cells (MCs) in lungs of macaques with PTB, compared with LTBI in macaques. MCs respond in vitro to Mtb exposure via degranulation and by inducing proinflammatory cytokines. In the current study, we show the dominant production of chymase by MCs in granulomas of humans and macaques with PTB. Using scRNA seq analysis, we show that MCs found in LTBI and healthy lungs in macaques are enriched in genes involved in tumor necrosis factor alpha, cholesterol and transforming growth factor beta signaling. In contrast, MCs clusters found in PTB express transcriptional signatures associated with interferon gamma, oxidative phosphorylation, and MYC signaling. Additionally, MC deficiency in the mouse model showed improved control of Mtb infection that coincided with reduced accumulation of lung myeloid cells and diminished inflammation at chronic stages. Thus, these collective results provide novel evidence for the pathological contribution of MCs during Mtb infection and may represent a novel target for host directive therapy for TB., Competing Interests: Competing interests. The authors declare no competing interests.

Introduction: Initiation of breastfeeding right after birth and exclusive breastfeeding for the first 6 months of life is highly recommended. In this survey, we assessed the knowledge and practice of ever-married women towards early initiation of breastfeeding and exclusive breastfeeding in the Nuristan province of Afghanistan., Methods: In a cross-sectional household survey, we enrolled 640 ever-married 15-49 years women having a child aged 0-23 months in the Parun district of Nuristan province from September to October 2021. Using a standardized data collection form and face-to-face interview, we measured self-reported demographic characteristics and the study outcomes (awareness and practice towards the initiation of breastfeeding within an hour of birth and exclusive breastfeeding for the first 6 months of life). We analyzed the data using survey methods and used bivariate and multiple Poisson regression to assess the covariates of the study outcomes., Results: About 46.9% of ever-married women were 25-34 years old, 67.5% never attended school, 30.4% were unemployed, and 86.4% had < $60 monthly income. Overall, 56.8% (95% CI 52.9-60.6) of the women had correct knowledge of the early initiation of breastfeeding, and 51.4% (95% CI 47.5-55.3) initiated breastfeeding early for their last baby. Also, 85.9% (95% CI 82.9-88.4) of the women had correct knowledge of exclusive breastfeeding, but only 32.6% (95% CI 29.1-36.4) exclusively breastfed their last baby for 6 months after birth. After adjustment for covariates, women who were 45-49 years old (Adjusted Prevalence Ratio [APR] = 1.26), Divorced/Separated (APR 1.68), ever attended school (APR 1.39), monthly income > $115 (APR 1.50) were more likely to start early breastfeeding. Moreover, women who were Divorced/Separated (APR 3.53) were more likely to exclusively breastfeed their babies for 6 months after birth., Discussion: Only over half of the women were aware of and initiated early breastfeeding. Although most women knew about exclusive breastfeeding, less than one-third exclusively breast their babies for 6 months after birth. We found several contributing factors, such as age, marital status, education, and income that should be considered for targeted interventions., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To determine if treatment of co-occurring adult ADHD and Cannabis Use Disorder (CUD) with extended-release mixed amphetamine salts (MAS-ER) would be effective at improving ADHD symptoms and promoting abstinence., Method: A 12-week randomized, double-blind, two-arm pilot feasibility trial of adults with comorbid ADHD and CUD ( n  = 28) comparing MAS-ER (80 mg) to placebo. Main outcomes: ADHD: ≥30% symptom reduction, measured by the Adult ADHD Investigator Symptom Rating Scale (AISRS). CUD: Abstinence during last 2 observed weeks of maintenance phase., Results: Overall, medication was well-tolerated. There was no significant difference in ADHD symptom reduction (MAS-ER: 83.3%; placebo: 71.4%; p  = .65) or cannabis abstinence (MAS-ER: 15.4%; placebo: 0%; p  = .27). MAS-ER group showed a significant decrease in weekly cannabis use days over time compared to placebo ( p  < .0001)., Conclusions: MAS-ER was generally well-tolerated. The small sample size precluded a determination of MAS-ER's superiority reducing ADHD symptoms or promoting abstinence. Notably, MAS-ER significantly reduced weekly days of use over time., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Frances R. Levin receives research support from NCATS, SAMHSA, US World Meds, and Aelis Pharmaceuticals. She also receives medication from Indivior for research and royalties from APA publishing. In addition, Dr. Levin served as a nonpaid member of a Scientific Advisory Board for Alkermes, Indivior, Novartis, Teva, and US WorldMeds and is a consultant to Major League Baseball. John J Mariani has served as a consultant to Indivior, Inc. Martina Pavlicova has no conflicts to report. C. Jean Choi has no conflicts to report. Cale Basaraba has no conflicts to report. Amy L. Mahony has no conflicts to report. Daniel J. Brooks has no conflicts to report. Christina A. Brezing has no conflicts to report. Nasir Naqvi has no conflicts to report.

Lay Abstract: The Autism Stigma and Knowledge Questionnaire (ASK-Q) was developed to assess autism knowledge across cultural contexts. The current study aimed to examine cultural equivalence of the measure using a large, international database. These analyses identified 18 items in need of examination for removal or revision. A team of autism experts recommended several additional changes to reduce stigma and increase cross-cultural sensitivity and accuracy of the items on the measure. These changes resulted in a briefer measure with maintained statistical support., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objective: Cannabis Use Disorder (CUD) has no FDA approved treatment. Serotonin-2c (5HT2c) agonists have preclinical and human laboratory evidence for potential efficacy for CUD. We assessed the tolerability and effects of lorcaserin (5HT2c agonist) on CUD., Methods: In a 10-week, open label, uncontrolled trial, the tolerability of lorcaserin was tested in outpatients with CUD. Adverse events (AE) were assessed weekly. Cannabis use was assessed twice weekly by the Timeline follow-back and quantitative urine metabolites., Results: 17 participants enrolled, and 14 received medication. Participants' average age was 35 years; majority were male (N=12). The medication was well tolerated in males. There were no serious adverse events (SAE). The most common AE's were headache/migraine (N=4, all females), anorexia (N=3), and irritability (N=2). Participants decreased their frequency of cannabis use significantly (p < 0.001), adjusted for baseline use. By the end of the trial, participants decreased by 1.76 (SE=0.47) cannabis using days/week. Average daily amount of cannabis and urine THC metabolite levels did not change significantly., Conclusions: Lorcaserin was well tolerated in males but not females suggesting possible sex differences. Future trials of other 5HT2c agonists (lorcaserin was withdrawn at the request of the FDA) should consider longer dose titration phases., Trial Registration: NCT02932215.

Background: The COVID-19 pandemic led to an unprecedented need for virtual healthcare that was safe, acceptable and feasible to deliver. In May 2020, we launched the Long-term In-Home Ventilator Engagement (LIVE) program for ventilator assisted individuals using ventilators hosted on an e-platform in Ontario, Canada., Objectives: To assess the acceptability, appropriateness, feasibility and usability of the LIVE program reported by patients, family caregivers, and healthcare providers (HCP)., Design and Methods: We conducted a cross-sectional study. We provided HCPs participating in the LIVE program anonymized questionnaires (Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), Feasibility of Intervention Measure (FIM), and mHealth App Usability (MAUQ). Patients and family caregivers completed the AIM and MAUQ. Questionnaires were administered via an e-platform., Results: We recruited 105/251 (42%) patients and family caregivers and 42/48 (87.5%) HCPs. Patients and caregivers rated a mean (SD) overall AIM score of 4.3 (0.7) (maximum score 5; higher scores indicate greater acceptability) and a mean (SD) overall MAUQ score of 5.8 (1.5) (maximum score 7; higher scores indicate greater useability). HCPs rated a mean (SD) overall AIM score of 4.3 (0.7), IAM score of 4.3 (0.8), FIM score of 4.2 (0.7) and overall MAUQ score of 5.6 ± 1.5. There were no differences in AIM ((4.3 (0.7) vs 4.3 (0.8), p  = 1) or MAUQ (5.8 (1.5) vs 5.6 (1.5), p  = 0.5) scores between patients/ family caregivers and HCPs., Interpretation: This study suggests that the LIVE program was acceptable, appropriate, feasible, and usable from the perspective of patients, family caregivers and HCPs., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Introduction: Obstetric anal sphincter injuries (OASIS) predispose to development of anorectal symptoms that affect women's quality of life., Methods: A retrospective cohort study was conducted for all women with singleton vaginal deliveries who had a primary OASIS repair and attended the Postpartum Perineal Clinic between July 1st 2017 and December 31st 2020. This study was approved by the Research Ethics Board. The purpose of this study was (1) to determine correlation between endoanal ultrasound (EAUS) findings and anorectal symptoms quantified by the St. Mark's Incontinence Score (SMIS), (2) to determine the incidence of residual anal sphincter defects, and (3) to determine the rate of clinical overdiagnosis of OASIS. Pearson correlation coefficient was used to assess correlation between anorectal symptoms and EAUS findings., Results: A total of 247 participants with clinical diagnosis of OASIS met the inclusion criteria. A 3rd-degree tear was identified in 126 (51.0%) and 4th-degree tear was identified in 30 (12.1%) participants. In participants with sonographic evidence of OASIS, there was a statistically significant weak positive correlation between the size of residual defect and SMIS for both external anal sphincter (EAS) (r = .3723, p < .0001) and internal anal sphincter (IAS) (r = .3122, p = .0180). Residual defect in the anorectal sphincter of greater than 1 hour (> 30°) in width was present in 64.3% participants with 3rd-degree tear and 86.7% participants with 4th-degree tear. The rate of overdiagnosis was 36.8%., Conclusion: The size of residual defect of EAS and IAS has a weak positive correlation with anorectal symptoms, emphasizing the importance of EAUS for counselling regarding mode of subsequent delivery., (© 2023. Crown.)

Acinetobacter spp. have been a primary cause of nosocomial infections worldwide, causing significant morbidity and mortality, especially in Pakistan. The purpose of this study was to investigate the trend of antimicrobial resistance over a 5-year period in a tertiary care hospital in Pakistan., Methods: A retrospective cross-sectional study regarding the occurrence and antimicrobial resistance of Acinetobacter spp. recovered from clinical specimens that were referred to the Pathology Laboratory of Northwest General Hospital, Peshawar. The data from 2014 to 2019 was recorded and analyzed by the laboratory. Sociodemographic characteristics and laboratory record data was analyzed using SPSS, version 25. A chi-square test was applied to see the significance., Results: Of 59 483 clinical samples, Acinetobacter baumannii strains were detected in 114 of them. The majority of the clinical samples were from blood (89.5%) followed by sputum (7.9%), wound swab (1.8%), and bone marrow (0.9%). A. baumannii has been found in 52 men (67.53%) and 28 women (75.67%), with an overall risk of 0.669 times. In 76 men (98.70%), sensitivity for ertapenem (99.1), colistin (96.49), and tigecycline (78.9%) were also observed which indicated the potential viability of these drugs to treat multidrug-resistant (MDR) Acinetobacter infections. The male-to-female risk ratio was 0.98 for colistin and 0.71 for amikacin., Conclusion: Increased frequency of MDR supports the need for continuous surveillance to determine the prevalence and evolution of MDR Acinetobacter spp. in Pakistan. Colistin, tigecyclines, and ertapenem remain the possible line of drugs to treat MDR Acinetobacter ., Competing Interests: The authors declare that they have no financial conflict of interest with regard to the content of this report., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Adolescent girls and young women (AGYW) aged 15-24 years and adolescent boys and young men (ABYM) aged 15-34 years represent one of the populations at highest risk for HIV-infection in South Africa. The National Department of Health adopted the universal test and treat (UTT) strategy in 2016, resulting in increases in same-day antiretroviral therapy initiations and linkage to care. Monitoring progress towards attainment of South Africa's 95-95-95 targets amongst AGYW and ABYM relies on high quality data to identify and address gaps in linkage to care. The aim of this study is to describe the current approaches for engaging AGYW and ABYM in the treatment continuum to generate knowledge that can guide efforts to improve linkage to, and retention in, HIV care among these populations in KwaZulu-Natal, South Africa., Methods and Analysis: This is a mixed methods study, which will be conducted in uMgungundlovu district of KwaZulu-Natal, over a 24-month period, in 22 purposively selected HIV testing and treatment service delivery points (SDPs). For the quantitative component, a sample of 1100 AGYW aged 15-24 years and ABYM aged 15-35 years old will be recruited into the study, in addition to 231 healthcare providers (HCPs) involved in the implementation of the UTT program. The qualitative component will include 30 participating patients who were successfully linked to care, 30 who were not, and 30 who have never tested for HIV. Key informant interviews will also be conducted with 24 HCPs. Logistic regression will be used to model the primary outcomes on SDP types, while a time to event analysis will be conducted using a Cox regression model and adjusting the standard errors of the hazard ratio for the clustering of participants within SDPs. For qualitative data, a general inductive approach of analysis will be used., Dissemination: Findings from the study will be communicated to the study population and results will be presented to stakeholders and at appropriate local and international conferences. Outputs will also include a policy brief, peer reviewed journal articles and research capacity building through research degrees., Competing Interests: The authors declare no competing interest., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

In the combination antiretroviral era, there are limited data regarding the pathogenesis of histoplasmosis immune reconstitution inflammatory syndrome (IRIS) in people with human immunodeficiency virus (HIV). We immunologically characterized 10 cases of histoplasmosis, 4 of whom developed histoplasmosis IRIS. CD4+ T cells in histoplasmosis IRIS demonstrated a significant polyfunctional cytokine response to histoplasma antigen., Competing Interests: Potential conflicts of interest. G. S. D. reports NIH funded grants NIH R01 AI 106269, NIH R01 AI 133797, and NIH R21 AI 160722. All other authors report no potential conflicts. erest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To compare the effect of intra-cuff lidocaine versus alkalinized lidocaine in the prevention of post-operative sore throat., Methods: The cross-sectional study was conducted from June 15 to July 15, 2019, at the Department of Anaesthesiology, Liaquat National Hospital and Medical College, Karachi, and comprised patients of either gender aged 15-50 years classified as American Society of Anaesthesiologist class 1-2 and undergoing general anaesthesia with endotracheal intubation expected to last more than one hour. The patients were randomised into Group L and Group LA. General anaesthesia was given using induction dose of propofol 2-3mg/kg, nalbuphine 0.1mg/kg and atracurium 0.5mg/kg and female patients were intubated with 7.0mm size endotracheal tube and males patients with 8.0mm. All intubations were performed by an anaesthesiologist with minimum of two-year experience. The endotracheal tube cuff was inflated by using plain lidocaine 2% in group L and 2% lidocaine with 8.4% sodium bicarbonate in LA group till the air leak diminished. Post-surgery, the patients were assessed on extubation for any emergence phenomenon and were re-assessed at 1st, 6th, 12th and 24th hour. The assessment was done by the on-call anaesthesiology resident who was blinded to the study group. Data was collected using a proforma. The analysis was done using software IBM SPSS Statistics 23.0. Chi-Square Test was applied to analyse the data., Results: Of the 58 patients, 33(56.9%) were male and 25(43.1%) were female. There were 26(44.8%) patients aged 25-36 years, while 12(20.7%) each were aged 36-45 years and 46-55 years. There were 29(50%) patients in each of the 2 groups. After 24 hours, 44(75.9%) patients in Group L did not complain of any pain, while in group LA the corresponding number was 56(96.6%). Both in terms of cough and hoarseness at 24 hours, 56(96.6%) patients in Group L did not have complaints, while in Group LA there were no such complaints. In Group L, heart rate 60-80 was noted in 20(69%) patients and 81-100 in 9(31%). In Group LA, the corresponding values were 17(58.6%) and 12(41.4%)., Conclusion: Alkalinized lidocaine was found to be highly effective in preventing post-operative throat complications compared to lidocaine.

Primary cardiomyocytes are invaluable for understanding postnatal heart development. However, a universal method to obtain freshly purified cardiomyocytes without using different age-dependent isolation procedures and cell culture, is lacking. Here, we report the development of a standardised method that allows rapid isolation and purification of high-quality cardiomyocytes from individual neonatal through to adult C57BL/6J murine hearts. Langendorff retrograde perfusion, which is currently limited to adult hearts, was adapted for use in neonatal and infant hearts by developing an easier in situ aortic cannulation technique. Tissue digestion conditions were optimised to achieve efficient digestion of hearts of all ages in a comparable timeframe (<14 min). This resulted in a high yield (1.56-2.2 × 10 6 cells/heart) and viability (~70-100%) of cardiomyocytes post-isolation. An immunomagnetic cell separation step was then applied to yield highly purified cardiomyocytes (~95%) as confirmed by immunocytochemistry, flow cytometry, and qRT-PCR. For cell type-specific studies, cardiomyocyte DNA, RNA, and protein could be extracted in sufficient yields to conduct molecular experiments. We generated transcriptomic datasets for neonatal cardiomyocytes from individual hearts, for the first time, which revealed nine sex-specific genes (FDR < 0.05) encoded on the sex chromosomes. Finally, we also developed an in situ fixation protocol that preserved the native cytoarchitecture of cardiomyocytes (~94% rod-shaped post-isolation), and used it to evaluate cell morphology during cardiomyocyte maturation, as well as capture spindle-shaped neonatal cells undergoing cytokinesis. Together, these procedures allow molecular and morphological profiling of high-quality cardiomyocytes from individual hearts of any postnatal age., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: The purpose of this study is to provide expert consensus recommendations to establish a global ultrasound curriculum for undergraduate medical students., Methods: 64 multi-disciplinary ultrasound experts from 16 countries, 50 multi-disciplinary ultrasound consultants, and 21 medical students and residents contributed to these recommendations. A modified Delphi consensus method was used that included a systematic literature search, evaluation of the quality of literature by the GRADE system, and the RAND appropriateness method for panel judgment and consensus decisions. The process included four in-person international discussion sessions and two rounds of online voting., Results: A total of 332 consensus conference statements in four curricular domains were considered: (1) curricular scope (4 statements), (2) curricular rationale (10 statements), (3) curricular characteristics (14 statements), and (4) curricular content (304 statements). Of these 332 statements, 145 were recommended, 126 were strongly recommended, and 61 were not recommended. Important aspects of an undergraduate ultrasound curriculum identified include curricular integration across the basic and clinical sciences and a competency and entrustable professional activity-based model. The curriculum should form the foundation of a life-long continuum of ultrasound education that prepares students for advanced training and patient care. In addition, the curriculum should complement and support the medical school curriculum as a whole with enhanced understanding of anatomy, physiology, pathophysiological processes and clinical practice without displacing other important undergraduate learning. The content of the curriculum should be appropriate for the medical student level of training, evidence and expert opinion based, and include ongoing collaborative research and development to ensure optimum educational value and patient care., Conclusions: The international consensus conference has provided the first comprehensive document of recommendations for a basic ultrasound curriculum. The document reflects the opinion of a diverse and representative group of international expert ultrasound practitioners, educators, and learners. These recommendations can standardize undergraduate medical student ultrasound education while serving as a basis for additional research in medical education and the application of ultrasound in clinical practice., (© 2022. The Author(s).)

Background: It is widely acknowledged that the invasion by colonial powers of the Australian continent had profound and detrimental impacts on Aboriginal Communities, including food security. Policies of successive governments since European arrival have since further exacerbated the situation, with food insecurity now affecting 20-25% of Aboriginal and Torres Strait Islander people. Food insecurity contributes to long-term impacts on health, in particular diet-sensitive chronic diseases. This study aimed to describe Aboriginal community and stakeholder perspectives on food insecurity to get a better understanding of the key contributing factors and recommendations for potential strategies to address this issue in Aboriginal communities in urban and regional Australia., Methods: Semi-structured interviews were conducted with 44 participants who were purposively selected. This included Aboriginal people in two communities and both Aboriginal and non-Aboriginal stakeholders from local food relief agencies, food suppliers, schools, and government in an urban and regional location in NSW. A conceptual framework was developed from literature on food security, and sensitizing concepts of availability, affordability, accessibility and acceptability or the lack thereof of healthy food were used to elicit responses from the participants. Interview transcripts were analysed thematically., Results: All participants felt strongly that food insecurity was a major problem experienced in their local Aboriginal communities. Five core areas impacting on food security were identified: trapped in financial disadvantage; gaps in the local food system; limitations of non-Aboriginal food relief services; on-going impacts of colonization; and maintaining family, cultural and community commitments and responsibilities. Participants suggested a number of actions that could help ease food insecurity and emphasized that Aboriginal values and culture must be strongly embedded in potential programs., Conclusions: This study found Aboriginal families in urban and regional Australia are experiencing food insecurity on a regular basis, which is impacted by a range of socio-economic, environmental, systemic and cultural factors, as reported by the participants. Study findings highlight the need to address system level changes in the food environment and acknowledge Aboriginal history, culture and food preferences when considering the development of programs to alleviate food insecurity among Aboriginal people., (© 2022. The Author(s).)

Renewal of the myocardium by preexisting cardiomyocytes is a powerful strategy for restoring the architecture and function of hearts injured by myocardial infarction. To advance this strategy, we show that combining two clinically approved drugs, but neither alone, muscularizes the heart through cardiomyocyte proliferation. Specifically, in adult murine cardiomyocytes, metoprolol, a cardioselective β 1 -adrenergic receptor blocker, when given with triiodothyronine (T3, a thyroid hormone) accentuates the ability of T3 to stimulate ERK1/2 phosphorylation and proliferative signaling by inhibiting expression of the nuclear phospho-ERK1/2-specific phosphatase, dual-specificity phosphatase-5. While short-duration metoprolol plus T3 therapy generates new heart muscle in healthy mice, in mice with myocardial infarction-induced left ventricular dysfunction and pathological remodeling, it remuscularizes the heart, restores contractile function and reverses chamber dilatation; outcomes that are enduring. If the beneficial effects of metoprolol plus T3 are replicated in humans, this therapeutic strategy has the potential to definitively address ischemic heart failure., (© 2022. The Author(s).)

In this study, we conducted a systematic literature review of the various micronutrient deficiencies (MNDs) that affect children in India and an examination of whether there is a geographic basis for MNDs. MNDs are a common problem in the developing world, in particular, among children in South Asia. According to the United Nations Children's Fund, millions of children suffer from stunted growth, cognitive delays, weakened immunity, and diseases because of MNDs. These physical ailments have several economic, social, and public health implications, and they can severely hamper a country's growth. This study aims to clarify existing data on this topic and highlight the disparities between children living in urban and rural areas in India. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to conduct this systematic literature review of a total of five studies. Study quality was assessed using appropriate checklists, and the studies strengthened the hypothesis that MNDs are common among children in India. Because the selected studies were heterogeneous, no statistical conclusions are drawn here. However, a central premise is that MNDs in children are prevalent in India and are related to poverty. No link between geographic location and MNDs is established; rather, recommendations are made for further research on the topic., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Vaidya et al.)

Heart failure in adults is a leading cause of morbidity and mortality worldwide. It can arise from a variety of diseases, with most resulting in a loss of cardiomyocytes that cannot be replaced due to their inability to replicate, as well as to a lack of resident cardiomyocyte progenitor cells in the adult heart. Identifying and exploiting mechanisms underlying loss of developmental cardiomyocyte replicative capacity has proved to be useful in developing therapeutics to effect adult cardiac regeneration. Of course, effective regeneration of myocardium after injury requires not just expansion of cardiomyocytes, but also neovascularization to allow appropriate perfusion and resolution of injury-induced inflammation and interstitial fibrosis, but also reversal of adverse left ventricular remodeling. In addition to overcoming these challenges, a regenerative therapy needs to be safe and easily translatable. Failure to address these critical issues will delay the translation of regenerative approaches. This review critically analyzes current regenerative approaches while also providing a framework for future experimental studies aimed at enhancing success in regenerating the injured heart., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Naqvi, Iismaa, Graham and Husain.)

Diabetes mellitus (DM) is a chronic metabolic disorder with a multi-systemic involvement, the gastrointestinal (GI) system being one of them. In this study, we have compiled and analyzed findings from various studies to conclude that peripheral insulin resistance and hyperglycemia are the two key factors that play a role in the pathogenesis of the web of disorders associated with diabetes. These two key factors, when clubbed with autoimmunity, autonomic neuropathy, and genetic and environmental factors, play a substantial role in the development of GI disorders in DM. This article examines GI disorders such as gastric autonomic neuropathy, non-alcoholic fatty liver disease (NAFLD), celiac disease (CD), etc. It also highlights the importance of regular screening and assessment of DM in preventing the GI tangent of the disease. A prompt blood glucose control through lifestyle modifications, dietary management, and weight reduction, coupled with pharmacotherapy for existing DM, can lead to a better outcome and an optimistic perspective on the disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Modi et al.)

Systemic sclerosis (SSc) is an autoimmune disease that leads the patient to have a diverse clinical presentation encompassing several systems and a worse prognosis, mainly when complications arise. Most SSc-related deaths are caused by pulmonary hypertension (PH) and interstitial lung disease (ILD). This article focuses on pulmonary artery hypertension (PAH) and ILD as pulmonary consequences of SSc. We examined the grave effects regarding SSc's respiratory complications, which are concealed by the disease's clinical heterogeneity. In this article, we briefly reviewed the discussion of clinical features and management and the mortality associated with the sequelae. We further addressed the benefits and significance of screening for the disease and associated respiratory complications in SSc patients in this study., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Syed Gaggatur et al.)

Inflammatory bowel disease (IBD) is associated with extra-intestinal manifestations (EIMs) that tend to parallel intestinal activity and have a debilitating effect on the quality of life. EIMs primarily affect the joints, skin, and eyes with less frequent involvement of the liver, kidney, and pancreas. This article reviews the prevalence of musculoskeletal, dermatological, ocular, and other manifestations in IBD and their coalition with underlying intestinal inflammation. EIMs occurring independently of intestinal activity are managed by targeted therapies, categorical regimens, and specific treatments. On the other hand, EIMs paralleling the bowel activity are carefully monitored while the IBD is brought under control. Since the etiology of the disease is responsible for the development of the EIMs, the research scrutinizes the identified pathogenic mechanisms that tend to involve genetic susceptibility, aberrant self-recognition, and autoantibodies directed against organ-specific antigens shared by intestinal and extra-intestinal organs. This article also provides an overview of the epidemiology, clinical features, diagnostic modalities, and management of the EIMs associated with IBD., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Sange et al.)

Diabetes mellitus is a leading cause of morbidity and mortality and a significant risk factor for the early onset of chronic kidney disease and heart disease. Hyperglycemia and insulin resistance are key factors that play a role in the pathogenesis of type 2 diabetes. Renal glucose reabsorption is a critical component of glycemic regulation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, commonly known as gliflozins, lower blood sugar levels by inhibiting glucose absorption in the proximal tubule of the kidney. SGLT2 inhibitors are currently used primarily as antidiabetic medications; however, their advantages go well beyond just glycemic control. This article has reviewed the mechanisms behind cardiac and renal involvement in type 2 diabetes and their inseparable interconnections. This article has also discussed the pharmacokinetic and pharmacodynamic profile of different SGLT2 inhibitors available in the market. Finally, this review has provided a perspective on the outcome trials, which provide evidence supporting a potential benefit of SGLT2 inhibitors in reducing cardiovascular and renal risks and possible mechanisms that mediate the renal and cardiovascular protection conferred., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Srinivas et al.)

Proton pump inhibitors (PPIs) are among the most extensively prescribed medications internationally for gastroesophageal reflux disease treatment and the prevention of gastrointestinal bleeding. Their efficiency, ease of availability, and low side effect profile offer several advantages over other treatment modalities. Long-term use and inappropriate prescribing habits have increased the presence of this class of drugs, prompting several studies to reassess their adverse effects. This article explored the possibility of a relationship between PPIs and cardiovascular adverse effects while highlighting the current prescription guidelines for PPIs. We further examined the need for more research into the etiology of PPI-related cardiovascular adverse effects and strategies to alleviate these risks., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Sarnaik et al.)

Background : There is a need for alcohol use disorder (AUD) pharmacotherapy that can be administered to actively drinking outpatients. Pregabalin, a gabapentoid anticonvulsant, has preliminary evidence supporting effects on alcohol withdrawal and AUD. Objectives : To evaluate the safety, tolerability, and optimal dosing of pregabalin for treating AUD. Methods : In an open-label, 8-week, outpatient trial of eighteen adults (nine women) with AUD, participants were titrated to 600 mg/day (or the maximum tolerated dose) over 3 weeks and then maintained for 5 weeks. Results : The majority (11/14, 78.6%) of participants with at least one-week of medication exposure achieved a maximum dose of 600 mg/day. Mean retention was 6.8 weeks (SD = 2.6). Eighty percent (12/15) of participants with post-enrollment data reported any adverse effects during the trial; and for those reporting adverse effects the most common were drowsiness (33.3%, 4/12), and fogginess (25%, 3/12), dizziness (25%, 3/12), and insomnia (25%, 3/12). Two participants discontinued study medication due to adverse effects and one had a dose reduction. Mean Heavy Drinking Days (HDD)/week decreased significantly by 3.43 days (SD = 2.47; median (IQR) = 4.00 (1.00 to 5.50)); Wilcoxon signed rank test statistic ((S) = 49.5, p = .0006). Mean proportion of HDD significantly decreased on average by 48.7% (SD = 35.1%; median (IQR) = 57.1% (14.3% to 78.6%)). The proportion of abstinent days increased significantly on average by 36.1% (SD = 35.0%; median (IQR) = 17.9% (14.3% to 75.0%); S = 49.5, p = .0005). Conclusions : Pregabalin treatment of AUD appears to be safe and well tolerated in doses up to 600 mg per day. Trial Registration : clinicaltrials.gov identifier: NCT03256253.

The early interactions between the vaccine Mycobacterium bovis Bacillus Calmette Guerin (BCG) and host peripheral innate immune cells like Mast cells (MCs) may pave the way for generating appropriate protective innate and adaptive immune responses. Mice on administration of BCG by intratracheal instillation showed a massive increase in MC numbers in the infected lung. In vitro co-culture of BCG and rodent Rat Basophilic Leukaemia (RBL-2H3) MCs led to significant killing of BCG. RBL-2H3 MCs were able to phagocytose BCG, take up BCG-derived antigens by macropinocytosis, generate Reactive Oxygen Species (ROS) and degranulate. Further, a few MCs died and released MC extracellular traps (MCETs) having DNA, histones and tryptase to trap BCG. This study highlights the multi-pronged effector responses of MCs on encountering BCG. These responses or their evasion may lead to success or failure of BCG vaccine to provide long term immunity to infections., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rationale: Doxorubicin is a widely used anticancer drug. However, its major side effect, cardiotoxicity, results from cardiomyocyte loss that causes left ventricle (LV) wall thinning, chronic LV dysfunction and heart failure. Cardiomyocyte number expansion by thyroid hormone (T3) during preadolescence is suppressed by the developmental induction of an ERK1/2-specific dual specificity phosphatase 5 (DUSP5). Here, we sought to determine if a brief course of combined DUSP5 suppression plus T3 therapy replaces cardiomyocytes lost due to preexisting doxorubicin injury and reverses heart failure. Methods: We used in vivo -jetPEI to deliver DUSP5 or scrambled siRNA to ~5-week-old C57BL6 mice followed by 5 daily injections of T3 (2 ng/µg body weight). Genetic lineage tracing using Myh6 -Mer Cre Mer::Rosa26fs-Confetti mice and direct cardiomyocyte number counting, along with cell cycle inhibition (danusertib), was used to test if this treatment leads to de novo cardiomyocyte generation and improves LV contractile function. Three doses of doxorubicin (20 µg/g) given at 2-weekly intervals, starting at 5-weeks of age in C57BL6 mice, caused severe heart failure, as evident by a decrease in LV ejection fraction. Mice with an ~40 percentage point decrease in LVEF post-doxorubicin injury were randomized to receive either DUSP5 siRNA plus T3, or scrambled siRNA plus vehicle for T3. Age-matched mice without doxorubicin injury served as controls. Results: In uninjured adult mice, transient therapy with DUSP5 siRNA and T3 increases cardiomyocyte numbers, which is required for the associated increase in LV contractile function, since both are blocked by danusertib. In mice with chronic doxorubicin injury, DUSP5 siRNA plus T3 therapy rebuilds LV muscle by increasing cardiomyocyte numbers, which reverses LV dysfunction and prevents progressive chamber dilatation. Conclusion: RNA therapies are showing great potential. Importantly, a GMP compliant in vivo -jetPEI system for delivery of siRNA is already in use in humans, as is T3. Given these considerations, our findings provide a potentially highly translatable strategy for addressing doxorubicin cardiomyopathy, a currently untreatable condition., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Opioid Use Disorder (OUD) is a significant public health problem associated with severe morbidity and mortality. While effective pharmacotherapies are available, limitations exist with each. Induction onto extended-release naltrexone (XR-NTX) is more difficult than initiation of buprenorphine or methadone, even in inpatient settings, as it is recommended that patients remain abstinent for at least 7 days prior to initiating XR-NTX. The purpose of this trial was to determine if lorcaserin, a 5HT2c agonist, improves outpatient XR-NTX induction rates., Methods: An 8-week trial beginning with a brief detoxification period and induction onto XR-NTX. Sixty participants with OUD were enrolled in the trial, with 49 participants at the initiation of detoxification randomized to lorcaserin or placebo for 39 days. Additionally, ancillary medications were provided. The primary outcome was the proportion of participants inducted onto the first XR-NTX injection. Secondary outcomes were withdrawal severity (measured by COWS and SOWS) prior to the first injection and the proportion of participants receiving the second XR-NTX injection., Results: The proportion of participants inducted onto the first (lorcaserin: 36 %; placebo: 44 %; p = .67) and the second XR-NTX injection (lorcaserin: 27 %; placebo: 31 %; p = .77) was not significantly different between treatment arms. Prior to the first injection, withdrawal scores did not significantly differ between treatment arms over time (treatment*time interaction COWS: p = .11; SOWS: p = .39)., Conclusions: Lorcaserin failed to improve outpatient XR-NTX induction rates. Although this study is small, the findings do not support the use of lorcaserin in promoting induction onto XR-NTX or in mitigating withdrawal symptoms., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Mucus is an integral part of the respiratory physiology. It protects the respiratory tract by acting as a physical barrier against inhaled particles and microbes. Excessive inflammation in conditions such as COVID-19 can result in over-production of mucus which obstructs the airway. Build-up of mucus can also contribute to recurrent airway infection, causing further obstruction. This article summarizes the current understanding and knowledge of respiratory mucus production and proposes the role of cytokine storm in inducing sudden mucus hypersecretion in COVID-19. Based on these cascades, the active constituents that inhibit or activate several potential targets are outlined for further research. These may be explored for the discovery and design of drugs to combat cytokine storm and its ensuing complications., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Khan et al.)

Backround: Pharmacotherapy for cannabis use disorder (CUD) is an important unmet public health need., Methods: In a 12-week randomized double-blind placebo-controlled trial, the efficacy of quetiapine (300 mg nightly) for the treatment of CUD was tested in 130 outpatients. Weekly cannabis use was categorized into three groups: heavy use (5-7 days), moderate use (2-4 days) and light use (0-1 days)., Results: At baseline both groups were considered heavy users (using days per week: median = 7.0; interquartile range (IQR): 6.5-7.0; daily dollar value: median = $121.4; IQR: 73.8-206.3). The week-by-treatment interaction was marginally significant (χ 2 (2) = 5.56, P = .06). With each week, the odds of moderate compared to heavy use significantly increased in the quetiapine group (OR=1.17, P < .0001), but not significantly in the placebo group (OR=1.05, P = .16). The odds of light versus heavy use did not significantly differ over time (P = .12). Treatment was also associated with reduced cannabis withdrawal symptoms by 10.4% each week (95% CI: 8.9-11.8). No serious adverse events occurred during the study and no evidence of development of a movement disorder was detected. Adverse effects were not significantly different between the quetiapine and placebo treatment arms., Conclusions: The use of quetiapine to treat CUD was associated with an increased likelihood of heavy frequency use transitioning to moderate use, but not light use. The clinical significance of reductions in cannabis use, short of abstinence warrants further study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Soil amendments like ethylene-diamine-tetraacetic-acid (EDTA) have extensively been used for enhancing lead (Pb) phytoextraction. But due to its toxic effects, environment friendly substitute is required. Therefore, the present study was conducted to investigate the effect of EDTA and Di-iso-propanol-amine (DIPA) to enhance Pb phytoavailability and uptake by Pelargonium hortorum along with comparative toxicities of both organic amendments. For this purpose, soil was spiked with Pb concentrations (0, 500, 750, 1000 and 1500 mg kg 1 ) and amended with EDTA and DIPA at dosage levels (0, 1.5, 3, 5, 7.5, 10 mmol kg -1 ) for plantation of Pelargonium hortorum. Soil samples were extracted with MgCl 2 , plant samples were acid digested and analyzed for metal content. Biomass and root/shoot length of Pelargonium hortorum was decreased with increase in concentration of Pb and chelating agents. Phytoavailability of Pb at 1500 mg kg -1 with EDTA 10 mmol kg -1 was 0.3-folds in comparison to DIPA at the same dosage. Pelargonium hortorum plants amended with EDTA and DIPA at 10 mmol kg -1 with Pb 1000 mg kg -1 were found to uptake Pb 5.3-fold and 2.5-folds, respectively in comparison to Pb 1000 mg kg -1 alone. Pb uptake decreased at 1500 mg kg -1 with both chelating agents. The EDTA alone and in combination with 1500 mg Pb kg -1 showed maximum genotoxicity by reducing the mitotic index and increasing the micronuclei formation. EDTA+Pb showed maximum toxicity followed by Pb and DIPA. Overall, 10 mmol kg -1 of EDTA and DIPA performed better among all dosages in enhancing phytoavailability and uptake of Pb. DIPA showed less toxicity than that caused by EDTA, with comparable ability to promote Pb phytoextraction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cardiomyocytes of newborn mice proliferate after injury or exposure to growth factors. However, these responses are diminished after postnatal day-6 (P6), representing a barrier to building new cardiac muscle in adults. We have previously shown that exogenous thyroid hormone (T3) stimulates cardiomyocyte proliferation in P2 cardiomyocytes, by activating insulin-like growth factor-1 receptor (IGF-1R)-mediated ERK1/2 signaling. But whether exogenous T3 functions as a mitogen in post-P6 murine hearts is not known. Here, we show that exogenous T3 increases the cardiomyocyte endowment of P8 hearts, but the proliferative response is confined to cardiomyocytes of the left ventricular (LV) apex. Exogenous T3 stimulates proliferative ERK1/2 signaling in apical cardiomyocytes, but not in those of the LV base, which is inhibited by expression of the nuclear phospho-ERK1/2-specific dual-specificity phosphatase, DUSP5. Developmentally, between P7 and P14, DUSP5 expression increases in the myocardium from the LV base to its apex; after this period, it is uniformly expressed throughout the LV. In young adult hearts, exogenous T3 increases cardiomyocyte numbers after DUSP5 depletion, which might be useful for eliciting cardiac regeneration.

Mast cells (MCs) are skin-resident immune cells whose role in leishmaniasis has been recently explored. Researchers report varying inferences, that is, mast cells promote, eliminate, or have no role in leishmaniasis. This article discusses this heterogeneity in mast cell roles to facilitate potential therapeutic and vaccine interventions for these diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Mycobacterium tuberculosis ( M. tb ), the intracellular pathogen causing tuberculosis, has developed mechanisms that endow infectivity and allow it to modulate host immune response for its survival. Genomic and proteomic analyses of non-pathogenic and pathogenic mycobacteria showed presence of genes and proteins that are specific to M. tb . In silico studies predicted that M.tb Rv1954A is a hypothetical secretory protein that exhibits intrinsically disordered regions and possess B cell/T cell epitopes. Treatment of macrophages with Rv1954A led to TLR4-mediated activation with concomitant increase in secretion of pro-inflammatory cytokines, IL-12 and TNF-α. In vitro studies showed that rRv1954A protein or Rv1954A knock-in M. smegmatis (Ms&#95;Rv1954A) activates macrophages by enhancing the expression of CD80 and CD86. An upregulation in the expression of CD40 and MHC I/II was noted in the presence of Rv1954A, pointing to its role in enhancing the association of APCs with T cells and in the modulation of antigen presentation, respectively. Ms&#95;Rv1954A showed increased infectivity, induction of ROS and RNS, and apoptosis in RAW264.7 macrophage cells. Rv1954A imparted protection against oxidative and nitrosative stress, thereby enhancing the survival of Ms&#95;Rv1954A inside macrophages. Mice immunized with Ms&#95;Rv1954A showed that splenomegaly and primed splenocytes restimulated with Rv1954A elicited a Th1 response. Infection of Ms&#95;Rv1954A in mice through intratracheal instillation leads to enhanced infiltration of lymphocytes in the lungs without formation of granuloma. While Rv1954A is immunogenic, it did not cause adverse pathology. Purified Rv1954A or Rv1954A knock-in M. smegmatis (Ms&#95;Rv1954A) elicited a nearly two-fold higher titer of IgG response in mice, and PTB patients possess a higher IgG titer against Rv1954A, also pointing to its utility as a diagnostic marker for TB. The observed modulation of innate and adaptive immunity renders Rv1954A a vital protein in the pathophysiology of this pathogen., (Copyright © 2020 Arora, Naqvi, Alam, Ahmad, Alsati, Sheikh, Kumar, Mitra, Rahman, Hasnain and Ehtesham.)

Animal models of pressure overload are valuable for understanding hypertensive heart disease. We characterised a surgical model of pressure overload-induced hypertrophy in C57BL/6J mice produced by suprarenal aortic constriction (SAC). Compared to sham controls, at one week post-SAC systolic blood pressure was significantly elevated and left ventricular (LV) hypertrophy was evident by a 50% increase in the LV weight-to-tibia length ratio due to cardiomyocyte hypertrophy. As a result, LV end-diastolic wall thickness-to-chamber radius (h/R) ratio increased, consistent with the development of concentric hypertrophy. LV wall thickening was not sufficient to normalise LV wall stress, which also increased, resulting in LV systolic dysfunction with reductions in ejection fraction and fractional shortening, but no evidence of heart failure. Pathological LV remodelling was evident by the re-expression of fetal genes and coronary artery perivascular fibrosis, with ischaemia indicated by enhanced cardiomyocyte Hif1a expression. The expression of stem cell factor receptor, c-Kit, was low basally in cardiomyocytes and did not change following the development of robust hypertrophy, suggesting there is no role for cardiomyocyte c-Kit signalling in pathological LV remodelling following pressure overload.

Mycobacterium tuberculosis ( M. tb ) persists as latent infection in nearly a quarter of the global population and remains the leading cause of death among infectious diseases. While BCG is the only vaccine for TB, its inability to provide complete protection makes it imperative to engineer BCG such that it expresses immunodominant antigens that can enhance its protective potential. In-silico comparative genomic analysis of Mycobacterium species identified M. tb Rv1507A as a "signature protein" found exclusively in M. tb . In-vitro (cell lines) and in-vivo experiments carried out in mice, using purified recombinant Rv1507A revealed it to be a pro-inflammatory molecule, eliciting significantly high levels of IL-6, TNF-α, and IL-12. There was increased expression of activation markers CD69, CD80, CD86, antigen presentation molecules (MHC I/MHCII), and associated Th1 type of immune response. Rv1507A knocked-in M. smegmatis also induced significantly higher pro-inflammatory Th1 response and higher survivability under stress conditions, both in-vitro (macrophage RAW264.7 cells) and in-vivo (mice). Sera derived from human TB patients showed significantly enhanced B-cell response against M. tb Rv1507A. The ability of M. tb Rv1507A to induce immuno-modulatory effect, B cell response, and significant memory response, renders it a putative vaccine candidate that demands further exploration., (Copyright © 2020 Arora, Alam, Naqvi, Ahmad, Sheikh, Rahman, Hasnain and Ehtesham.)

Uremic cardiomyopathy, characterized by hypertension, cardiac hypertrophy, and fibrosis, is a complication of chronic kidney disease (CKD). Urea transporter (UT) inhibition increases the excretion of water and urea, but the effect on uremic cardiomyopathy has not been studied. We tested UT inhibition by dimethylthiourea (DMTU) in 5/6 nephrectomy mice. This treatment suppressed CKD-induced hypertension and cardiac hypertrophy. In CKD mice, cardiac fibrosis was associated with upregulation of UT and vimentin abundance. Inhibition of UT suppressed vimentin amount. Left ventricular mass index in DMTU-treated CKD was less compared with non-treated CKD mice as measured by echocardiography. Nephrectomy was performed in UT-A1/A3 knockout (UT-KO) to further confirm our finding. UT-A1/A3 deletion attenuates the CKD-induced increase in cardiac fibrosis and hypertension. The amount of α-smooth muscle actin and tgf-β were significantly less in UT-KO with CKD than WT/CKD mice. To study the possibility that UT inhibition could benefit heart, we measured the mRNA of renin and angiotensin-converting enzyme (ACE), and found both were sharply increased in CKD heart; DMTU treatment and UT-KO significantly abolished these increases. Conclusion: Inhibition of UT reduced hypertension, cardiac fibrosis, and improved heart function. These changes are accompanied by inhibition of renin and ACE., (© 2020 Federation of American Societies for Experimental Biology.)

Objective: We aimed to assess the change in global and regional myocardial function before and after surgical revascularization and their added value when compared with conventional measures in children with anomalous left coronary artery from the pulmonary artery (ALCAPA)., Methods: Advanced echocardiographic assessment was performed pre- and postoperatively in 22 children with ALCAPA (eight male; median surgery age, 0.4 years; interquartile range, 0.21-1.05) and 22 healthy controls. Measurements included global and segmental longitudinal, radial, and circumferential two-dimensional speckle-tracking strain and postsystolic index., Results: Global strains were lower in preoperative patients than in controls (longitudinal: -9% vs -21%; P < .001; circumferential: -11% vs -21%; P < .001; radial: 18% vs 60%; P < .001) and improved postoperatively when compared with preoperative findings (longitudinal: -9% pre vs -16% post; P = .002, circumferential:-11% pre vs -17% post; P = .012, radial: 18% pre vs 53% post; P = .001). Preoperatively, patients with normal global systolic function on conventional echocardiography had significantly impaired global longitudinal and radial strain compared with healthy controls. Global mechanical dyssynchrony improved significantly postoperatively (longitudinal postsystolic index 43 pre vs 6 post, P < .001; circumferential 15 pre vs 2 post, P = .001; radial 48 pre vs 5 post, P = .003). Despite overall improvement in most segments, global longitudinal and circumferential and segmental peak strain in some of the segments supplied by the ALCAPA remained postoperatively abnormal., Conclusions: This study shows that myocardial deformation indices were a more sensitive measure of LV dysfunction in patients before and after ALCAPA repair than conventional echocardiographic measures. We believe, therefore, they should be added to routine preoperative and serial postoperative follow-up assessment., (Copyright © 2020 American Society of Echocardiography. All rights reserved.)

Previous studies evaluating fracture liaison service (FLS) programs have found them to be cost-effective, efficient, and reduce the risk of fracture. However, few studies have evaluated the clinical effectiveness of these programs. We compared the patient populations of those referred for osteoporosis management by FLS to those referred by primary care physicians (PCP), within the Canadian healthcare system in the province of Ontario. Specifically, we investigated if a referral from FLS is similarly effective as PCP at identifying patients at risk for future osteoporotic fractures and if osteoporosis therapies have been previously initiated. A retrospective chart review of patients assessed by a single Ontario rheumatology practice affiliated with FLS between January 1, 2014, and December 31, 2017, was performed identifying two groups: those referred by FLS within Hamilton and those referred by their PCP for osteoporosis management. Fracture risk of each patient was determined using FRAX. A total of 573 patients ( n  = 225 (FLS group) and n  = 227 (PCP group)) were evaluated. Between the FLS and PCP groups, there were no significant differences in the absolute 10-year risk of a major osteoporotic fracture (15.6% (SD = 10.2) vs 15.3% (SD = 10.3)) and 10-year risk of hip fracture (4.7% (SD = 8.3) vs 4.7% (SD = 6.8)), respectively. 10.7% of patients referred by FLS and 40.5% of patients referred by their PCP were on osteoporosis medication prior to fracture. Our study suggests that referral from FLS is similarly effective as PCP at identifying patients at risk for future osteoporotic fractures, and clinically effective at identifying the care gap with the previous use of targeted osteoporosis therapies from referral from PCP being low and much lower in those referred by FLS. Interventional programs such as FLS can help close the treatment gap by providing appropriate care to patients that were not previously identified to be at risk for fracture by their primary care physician and initiate proper medical management., Competing Interests: A.N. Lau has received consulting fee (less than $10,000 each), speaking fee, and/or honoraria from Amgen Inc., Abbvie, Bristol Meyers Squibb, Roche, and UCB Pharma. J.D. Adachi has received consulting fee (less than $10,000 each), speaking fee, and/or honoraria from AgNovos, Amgen Inc., Eli Lilly, and Merck. M. Wong-Pack, N. Naqvi, and G. Ioannidis have no conflicts of interest to declare., (Copyright © 2020 Matthew Wong-Pack et al.)

Background DJ-1 is a ubiquitously expressed protein typically associated with the development of early onset Parkinson disease. Recent data suggest that it also plays a role in the cellular response to stress. Here, we sought to determine the role DJ-1 plays in the development of heart failure. Methods and Results Initial studies found that DJ-1 deficient mice (DJ-1 knockout; male; 8-10 weeks of age) exhibited more severe left ventricular cavity dilatation, cardiac dysfunction, hypertrophy, and fibrosis in the setting of ischemia-reperfusion-induced heart failure when compared with wild-type littermates. In contrast, the overexpression of the active form of DJ-1 using a viral vector approach resulted in significant improvements in the severity of heart failure when compared with mice treated with a control virus. Subsequent studies aimed at evaluating the underlying protective mechanisms found that cardiac DJ-1 reduces the accumulation of advanced glycation end products and activation of the receptor for advanced glycation end products-thus, reducing glycative stress. Conclusions These results indicate that DJ-1 is an endogenous cytoprotective protein that protects against the development of ischemia-reperfusion-induced heart failure by reducing glycative stress. Our findings also demonstrate the feasibility of using a gene therapy approach to deliver the active form of DJ-1 to the heart as a therapeutic strategy to protect against the consequences of ischemic injury, which is a major cause of death in western populations.

Background: Cocaine use disorder (CUD) remains a substantial public health problem with no clearly effective pharmacotherapy available. In a prior trial, combined amphetamine and topiramate treatment significantly reduced cocaine use among individuals demonstrating the most frequent use at baseline. This trial targeted such frequent users., Methods: A double-blind, randomized placebo-controlled trial, testing the combination of mixed amphetamine salts extended-release (MAS-ER) and topiramate or placebo over a 12-week medication phase was conducted. The two-site outpatient trial included 127 adults (96 males) with CUD using at least 9 days in the prior month. MAS-ER was titrated to a maximum dose of 60 mg/day and topiramate to a maximum dose of 100 mg twice/day. The primary outcome was the proportion of individuals who achieved three consecutive abstinent weeks at the end of the study (EOS) as measured by urine toxicology and self-report., Results: The proportion of participants achieving three abstinent weeks at the EOS was significantly (P = .03) larger in the treatment (14.1%) compared to the placebo group (0.0%), while controlling for baseline cocaine use, sex, current alcohol use disorder, and site. Of note, due to conservative cardiac safety-parameters a considerable number of individuals in the treatment group were discontinued from study medication (20.3%)., Conclusions: While these findings provide further evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in CUD adults with frequent use it remains possible that the combination treatment is no more effective than either treatment alone. Despite this, the study provides a valuable "proof of concept.", (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To help clinicians recognize that hypertension, hypertensive urgency, and hypertensive emergency can arise in patients detoxifying from alcohol. Diagnostic and treatment implications are reviewed to help clinicians manage blood pressure in these situations., Data Sources: PubMed was searched with no restrictions on publication date or study type in June 2019 using the terms (alcohol withdrawal) AND hypertension., Study Selection: Of 531 studies retrieved, all were reviewed, and articles older than 20 years were excluded. Of the remaining 158 articles, all were reviewed by full-text reading, and 17 were selected based on relevance. Seven UpToDate articles and 2 older papers were also included for relevance., Data Extraction: Various other searches were also performed; however, no relevant hits resulted when the following terms were entered: (hypertensive urgency/emergency) AND alcohol withdrawal OR detoxification; (hypertensive urgency/emergency) AND (alcohol withdrawal OR detoxification) AND treatment-resistant hypertension., Results: Hypertension is typically self-limited in alcohol withdrawal syndrome; however, treatment is important to prevent hypertensive urgency or emergency. There is a paucity of data on how best to manage hypertension in patients withdrawing from alcohol, with treatment often individualized. Patients with underlying treatment-resistant hypertension may have more difficult-to-control blood pressure, especially in the first 24 hours of withdrawal., Conclusions: Multiple medications may be used to treat hypertension in the setting of alcohol withdrawal, with selection based on side effect profile and the patient's other comorbidities. In patients for whom there is concern for hypertensive urgency versus emergency, full medical evaluation is indicated to identify any potential end-organ damage., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

Mitochondria-generated reactive oxygen species (mROS) are frequently associated with DNA damage and cell cycle arrest, but physiological increases in mROS serve to regulate specific cell functions. T3 is a major regulator of mROS, including hydrogen peroxide (H 2 O 2 ). Here we show that exogenous thyroid hormone (T3) administration increases cardiomyocyte numbers in neonatal murine hearts. The mechanism involves signaling by mitochondria-generated H 2 O 2 (mH 2 O 2 ) acting via the redox sensor, peroxiredoxin-1, a thiol peroxidase with high reactivity towards H 2 O 2 that activates c-Jun N-terminal kinase-2α2 (JNK2α2). JNK2α2, a relatively rare member of the JNK family of mitogen-activated protein kinases (MAPK), phosphorylates c-Jun, a component of the activator protein 1 (AP-1) early response transcription factor, resulting in enhanced insulin-like growth factor 1 (IGF-1) expression and activation of proliferative ERK1/2 signaling. This non-canonical mechanism of MAPK activation couples T3 actions on mitochondria to cell cycle activation. Although T3 is regarded as a maturation factor for cardiomyocytes, these studies identify a novel redox pathway that is permissive for T3-mediated cardiomyocyte proliferation-this because of the expression of a pro-proliferative JNK isoform that results in growth factor elaboration and ERK1/2 cell cycle activation.

Competing Interests: Competing interests: None declared.

Glycosylphosphatidylinositol (GPI)-anchored proteins are important for virulence of many pathogenic organisms including the human fungal pathogen, Candida albicans. GPI biosynthesis is initiated by a multi-subunit enzyme, GPI-N-acetylglucosaminyltransferase (GPI-GnT). We showed previously that two GPI-GnT subunits, encoded by CaGPI2 and CaGPI19, are mutually repressive. CaGPI19 also co-regulates CaERG11, the target of azoles while CaGPI2 controls Ras signaling and hyphal morphogenesis. Here, we investigated the role of a third subunit. We show that CaGpi15 is functionally homologous to Saccharomyces cerevisiae Gpi15. CaGPI15 is a master activator of CaGPI2 and CaGPI19. Hence, CaGPI15 mutants are azole-sensitive and hypofilamentous. Altering CaGPI19 or CaGPI2 expression in CaGPI15 mutant can elicit alterations in azole sensitivity via CaERG11 expression or hyphal morphogenesis, respectively. Thus, CaGPI2 and CaGPI19 function downstream of CaGPI15. One mode of regulation is via H3 acetylation of the respective GPI-GnT gene promoters by Rtt109. Azole sensitivity of GPI-GnT mutants is also due to decreased H3 acetylation at the CaERG11 promoter by Rtt109. Using double heterozygous mutants, we also show that CaGPI2 and CaGPI19 can independently activate CaGPI15. CaGPI15 mutant is more susceptible to killing by macrophages and epithelial cells and has reduced ability to damage either of these cell lines relative to the wild type strain, suggesting that it is attenuated in virulence.

Uremic cardiomyopathy and muscle atrophy are associated with insulin resistance and contribute to chronic kidney disease (CKD)-induced morbidity and mortality. We hypothesized that restoration of miR-26a levels would enhance exosome-mediated microRNA transfer to improve muscle wasting and cardiomyopathy that occur in CKD. Methods: Using next generation sequencing and qPCR, we found that CKD mice had a decreased level of miR-26a in heart and skeletal muscle. We engineered an exosome vector that contained Lamp2b, an exosomal membrane protein gene fused with a muscle-specific surface peptide that targets muscle delivery. We transfected this vector into muscle satellite cells and then transduced these cells with adenovirus that expresses miR-26a to produce exosomes encapsulated miR-26a (Exo/ miR-26a ). Exo/ miR-26a was injected once per week for 8 weeks into the tibialis anterior (TA) muscle of 5/6 nephrectomized CKD mice. Results: Treatment with Exo/ miR-26a resulted in increased expression of miR-26a in skeletal muscle and heart. Overexpression of miR-26a increased the skeletal muscle cross-sectional area, decreased the upregulation of FBXO32/atrogin-1 and TRIM63/MuRF1 and depressed cardiac fibrosis lesions. In the hearts of CKD mice, FoxO1 was activated, and connective tissue growth factor, fibronectin and collagen type I alpha 1 were increased. These responses were blunted by injection of Exo/ miR-26a . Echocardiograms showed that cardiac function was improved in CKD mice treated with Exo/ miR-26a . Conclusion: Overexpression of miR-26a in muscle prevented CKD-induced muscle wasting and attenuated cardiomyopathy via exosome-mediated miR-26a transfer. These results suggest possible therapeutic strategies for using exosome delivery of miR-26a to treat complications of CKD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background Lymphatic vessels interconnect with blood vessels to form an elaborate system that aids in the control of tissue pressure and edema formation. Although the lymphatic system has been known to exist in a heart, little is known about the role the cardiac lymphatic system plays in the development of heart failure. Methods and Results Mice (C57 BL /6J, male, 8 to 12 weeks of age) were subjected to either myocardial ischemia or myocardial ischemia and reperfusion for up to 28 days. Analysis revealed that both models increased the protein expression of vascular endothelial growth factor C and VEGF receptor 3 starting at 1 day after the onset of injury, whereas a significant increase in lymphatic vessel density was observed starting at 3 days. Further studies aimed to determine the consequences of inhibiting the endogenous lymphangiogenesis response on the development of heart failure. Using 2 different pharmacological approaches, we found that inhibiting VEGF receptor 3 with MAZ -51 and blocking endogenous vascular endothelial growth factor C with a neutralizing antibody blunted the increase in lymphatic vessel density, blunted lymphatic transport, increased inflammation, increased edema, and increased cardiac dysfunction. Subsequent studies revealed that augmentation of the endogenous lymphangiogenesis response with vascular endothelial growth factor C treatment reduced inflammation, reduced edema, and improved cardiac dysfunction. Conclusions These results suggest that the endogenous lymphangiogenesis response plays an adaptive role in the development of ischemic-induced heart failure and supports the emerging concept that therapeutic lymphangiogenesis is a promising new approach for the treatment of cardiovascular disease.

Deficiencies in the septum separating the two atrial chambers are among the most common of congenital heart malformations. This article reviews the developmental aspects of the partitioning of the primitive atrium into right and left atrial chambers, the anatomical components of the atrial septum, and deficiencies that produce the various types of interatrial communications. Knowledge of the components of the true atrial septum in the developed heart clarifies the morphology of various types of interatrial communications. The oval fossa defect (also termed secundum ASD) is located within the true septum. The patent foramen ovale (PFO) is a tunnel-like passageway between the free edge of the overlapping ovale fossa valve and its muscular rim. Other defects such as superior and inferior sinus venosus defects, coronary sinus defects, and ostium primum defects lie outside the area of the true septum., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The ability of Candida albicans to switch between yeast to hyphal form is a property that is primarily associated with the invasion and virulence of this human pathogenic fungus. Several glycosylphosphatidylinositol (GPI)-anchored proteins are expressed only during hyphal morphogenesis. One of the major pathways that controls hyphal morphogenesis is the Ras-signaling pathway. We examine the cross-talk between GPI anchor biosynthesis and Ras signaling in C. albicans. We show that the first step of GPI biosynthesis is activated by Ras in C. albicans This is diametrically opposite to what is reported in Saccharomyces cerevisiae Of the two C. albicans Ras proteins, CaRas1 alone activates GPI-GnT activity; activity is further stimulated by constitutively activated CaRas1. CaRas1 localized to the cytoplasm or endoplasmic reticulum (ER) is sufficient for GPI-GnT activation. Of the six subunits of the GPI- N -acetylglucosaminyltransferase (GPI-GnT) that catalyze the first step of GPI biosynthesis, CaGpi2 is the key player involved in activating Ras signaling and hyphal morphogenesis. Activation of Ras signaling is independent of the catalytic competence of GPI-GnT. This too is unlike what is observed in S. cerevisiae where multiple subunits were identified as inhibiting Ras2. Fluorescence resonance energy transfer (FRET) studies indicate a specific physical interaction between CaRas1 and CaGpi2 in the ER, which would explain the ability of CaRas1 to activate GPI-GnT. CaGpi2, in turn, promotes activation of the Ras-signaling pathway and hyphal morphogenesis. The Cagpi2 mutant is also more susceptible to macrophage-mediated killing, and macrophage cells show better survival when co-cultured with Cagpi2 ., Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objective: Commercial airplanes fly with an equivalent cabin fraction of inspired oxygen of 0.15, leading to reduced oxygen saturation (SpO 2 ) in passengers. How this affects children with complex congenital heart disease (CHD) is unknown. We conducted Hypoxic Challenge Testing (HCT) to assess need for inflight supplemental oxygen., Methods: Children aged <16 years had a standard HCT. They were grouped as (A) normal versus abnormal baseline SpO 2 (≥95% vs <95%) and (B) absence versus presence of an actual/potential right-to-left (R-L) shunt. We measured SpO 2 , heart rate, QT interval corrected for heart rate and partial pressure of carbon dioxide measured transcutaneously (PtcCO 2 ). A test failed when children with (1) normal baseline SpO 2 desaturated to 85%, (2) baseline SpO 2 85%-94% desaturated by 15% of baseline; and (3) baseline SpO 2 75%-84% desaturated to 70%., Results: There were 68 children, mean age 3.3 years (range 10 weeks-14.5 years). Children with normal (n=36) baseline SpO 2 desaturated from median 99% to 91%, P<0.0001, and 3/36 (8%) failed the test. Those with abnormal baseline SpO 2 (n=32) desaturated from median 84% to 76%, P<0.0001, and 5/32 (16%) failed (no significant difference between groups). Children with no R-L shunt (n=25) desaturated from median 99% to 93%, P<0.0001, but 0/25 failed. Those with an actual/potential R-L shunt (n=43) desaturated from median 87% to 78%, P<0.0001, and 8/43 (19%) failed (difference between groups P<0.02). PtcCO 2 , heart rate and QT interval corrected for heart rate were unaffected by the hypoxic state., Conclusions: This is the first evidence to help guide which children with CHD need a preflight HCT. We suggest all children with an actual or potential R-L shunt should be tested., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)