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In response to osmotic shock, the components of high-osmolarity glycerol (HOG) pathway regulate the level of intracellular glycerol in yeast and ensure cell survival. Glycerol is a compatible solute and a stabiliser of proteins. Its role in maintaining proteostasis is less explored. We show that mild stress in the form of dietary restriction leads to increased glycerol level which increases cell viability. However, dietary restriction coupled with protein aggregation decreases intracellular glycerol level and attenuates cell viability. The transcript level of FPS1, the glycerol transporter channel, remains unchanged. However, its activity is altered under enhanced proteotoxic stress. Our results provide evidence for a probable role of the Fps1p channel in the cellular proteostasis network. KEY POINTS: • Dietary restriction led to increased accumulation of glycerol in Fps1-deleted yeast cells. • This led to lower protein aggregation in these cells. • Increased production of glycerol under dietary restriction was not linked to increased level of Fps1.

Most prior studies have compared myocardial infarction with non-obstructive coronary arteries (MINOCA), to obstructive acute coronary syndrome (ACS) often requiring revascularisation. However, these were subject to treatment bias given the significant differences in management. This study uniquely compares the management and outcomes of MINOCA patients with a medically managed obstructive ACS (M-ACS) population. We retrospectively analysed registry data for consecutive patients admitted to the Gold Coast University Hospital with ACS requiring coronary angiography and identified patients with MINOCA and M-ACS. Baseline characteristics, pharmacological therapy and in-hospital outcomes were compared. In hospital outcomes were composite NACE, heart failure, stroke and major bleeding. Multivariate regression analysis was also performed to identify independent predictors of MINOCA. Multivariate regression analysis was also performed to identify independent predictors of MINOCA. We identified 139 patients with MINOCA and 142 patients with medically managed obstructive ACS (M-ACS). Multivariate regression analysis also identified female sex and cancer as independent predictors of MINOCA with odds ratios of 5.57 and 3.01, respectively. MINOCA patients were significantly less likely to receive cardioprotective medications at admission and discharge, specifically aspirin, beta-blockers, ACE-I and statins, compared to those with M-ACS. While mortality was higher among M-ACS patients (0.0% vs. 3.6%; p = 0.03), no significant differences were noted for composite NACE, heart failure, stroke and major bleeding. MINOCA patients have similar outcomes to M-ACS. Despite this, we noted a discrepancy in the use of cardioprotective medications. We also identified female sex and cancer were independent predictors of MINOCA. This may represent a missed opportunity to prevent adverse events among patients with MINOCA. Large, randomised trials are required to provide more definitive evidence.

Extracellular vesicles (EVs) have emerged into a novel vaccine platform, a biomarker and a nano-carrier for approved drugs. Their accurate detection and visualization are central to their utility in varied biomedical fields. Owing to the limitations of fluorescent dyes and antibodies, here, we describe DNA aptamer as a promising tool for visualizing mycobacterial EVs in vitro. Employing SELEX from a large DNA aptamer library, we identified a best-performing aptamer that is highly specific and binds at nanomolar affinity to EVs derived from three diverse mycobacterial strains (pathogenic, attenuated and avirulent). Confocal microscopy revealed that this aptamer was not only bound to in vitro-enriched mycobacterial EVs but also detected EVs that were internalized by THP-1 macrophages and released by infecting mycobacteria. To the best of our knowledge, this is the first study that detects EVs released by mycobacteria during infection in host macrophages. Within 4 h, most released mycobacterial EVs spread to other parts of the host cell. We predict that this tool will soon hold huge potential in not only delineating mycobacterial EVs-driven pathogenic functions but also in harboring immense propensity to act as a non-invasive diagnostic tool against tuberculosis in general, and extra-pulmonary tuberculosis in particular.

Introduction Recurrent event rates after myocardial infarction (MI) remain unacceptably high, in part because of the continued growth and destabilization of residual coronary atherosclerotic plaques, which may occur despite lipid-lowering therapy. Inflammation is an important contributor to this ongoing risk. Recent studies have shown that the broad-acting anti-inflammatory agent, colchicine, may reduce adverse cardiovascular events in patients post-MI, although the mechanistic basis for this remains unclear. Advances in endovascular arterial wall imaging have allowed detailed characterization of the burden and compositional phenotype of coronary plaque, along with its natural history and responsiveness to treatment. One such example has been the use of optical coherence tomography (OCT) to demonstrate the plaque-stabilizing effects of statins on both fibrous cap thickness and the size of lipid pools within plaque. Methods The Phase 2, multi-centre, double-blind colchicine for coronary plaque modification in acute coronary syndrome (COCOMO-ACS) study will evaluate the effect of colchicine 0.5 mg daily on coronary plaque features using serial OCT imaging in patients following MI. Recruitment for the trial has been completed with 64 participants with non-ST elevation MI randomized 1:1 to colchicine or placebo in addition to guideline recommended therapies, including high-intensity statins. The primary endpoint is the effect of colchicine on the minimal fibrous cap thickness of non-culprit plaque over an 18-month period. Summary The COCOMO-ACS study will determine whether addition of colchicine 0.5 mg daily to standard post-MI treatment has incremental benefits on high-risk features of coronary artery plaques. If confirmed, this will provide new mechanistic insights into how colchicine may confer clinical benefits in patients with atherosclerotic cardiovascular disease. Trial Registration ANZCTR trial registration number: ACTRN12618000809235. Date of trial registration: 11th of May 2018.

A core aspect of epithelial cell function is barrier integrity. A loss of barrier integrity is a feature of a number of respiratory diseases, including asthma, allergic rhinitis, and chronic obstructive pulmonary disease. Restoration of barrier integrity is a target for respiratory disease drug discovery. Traditional methods for assessing barrier integrity have their limitations. Transepithelial electrical resistance (TEER) and dextran permeability methods can give poor in vitro assay robustness. Traditional junctional complex imaging approaches are labor-intensive and tend to be qualitative but not quantitative. To provide a robust and quantitative assessment of barrier integrity, high-content imaging of junctional complexes was combined with TEER. A scalable immunofluorescent high-content imaging technique, with automated quantification of junctional complex proteins zonula occludens-1 and occludin, was established in 3D pseudostratified primary human bronchial epithelial cells cultured at an air-liquid interface. Ionic permeability was measured using TEER on the same culture wells.The improvements to current technologies include the design of a novel 24-well holder to enable scalable in situ confocal cell imaging without Transwell membrane excision, the development of image analysis pipelines to quantify in-focus junctional complex structures in each plane of a Z stack, and the enhancement of the TEER data analysis process to enable statistical evaluation of treatment effects on barrier integrity. This novel approach was validated by demonstrating measurable changes in barrier integrity in cells grown under conditions known to perturb epithelial cell function.

Tocilizumab is an interleukin (IL)-6 receptor inhibitor that has been proposed as a therapeutic agent for treating coronavirus disease 2019 (COVID-19). The aim of this umbrella review was to determine the efficacy of tocilizumab in treating COVID-19, and to provide an overview of all systematic reviews on this topic. We systematically searched PubMed, Scopus, the Web of Science collection, the Cochrane library, Epistemonikos, and Google Scholar, as well as the medRxiv preprint server. These databases were searched up to 30 September 2021, using the following keywords: 'SARS-CoV-2', 'COVID-19', 'tocilizumab', 'RHPM-1', 'systematic review', and 'meta-analysis'. Studies were included if they were systematic reviews (with or without meta-analysis) investigating the efficacy or safety of tocilizumab in confirmed COVID-19 patients. The AMSTAR 2 checklist was used to assess quality of the included articles, while publication bias was examined using Egger's test. A total of 50 eligible systematic reviews were included. The pooled estimates showed significant reductions in clinical failure (risk ratio (RR) 0.75; 95% confidence interval (CI), 0.61-0.93), deaths (RR 0.78; 95%CI, 0.71-0.85) and the need for mechanical ventilation (RR 0.77; 95%CI, 0.64-0.92) for those receiving tocilizumab compared with the control group. Also, an emerging survival benefit was demonstrated for those who received tocilizumab, over those in the control group (adjusted hazard ratio (aHR) 0.52; 95%CI, 0.43-0.63). In addition, tocilizumab substantially increased the number of ventilator-free days, compared with the control treatments (weighted mean difference (WMD) 3.38; 95%CI, 0.51-6.25). Furthermore, lymphocyte count (WMD 0.26 × 10sup9/sup/L; 95%CI, 0.14-0.37), IL-6 (WMD 176.99 pg/mL; 95%CI, 76.34-277.64) and D-dimer (WMD 741.08 ng/mL; 95%CI, 109.42-1372.75) were all significantly elevated in those receiving tocilizumab. However, the level of lactate dehydrogenase (LDH) (WMD -30.88 U/L; 95%CI, -51.52, -10.24) and C-reactive protein (CRP) (WMD -104.83 mg/L; 95%CI, -133.21, -76.46) were both significantly lower after treatment with tocilizumab. Tocilizumab treatment reduced the risk of intubation, mortality and the length of hospital stay, without increasing the risk of superimposed infections in COVID-19 patients. Therefore, tocilizumab can be considered an effective therapeutic agent for treating patients with COVID-19.

IntroductionTransradial access (TRA) has rapidly emerged as the preferred vascular access site for coronary angiography and percutaneous coronary intervention. Radial artery occlusion (RAO) remains as an important complication of TRA as it precludes future ipsilateral transradial procedures. While intraprocedural anticoagulation has been studied extensively, the definitive role of postprocedural anticoagulation has not yet been established.Methods and analysisThe Rivaroxaban Post-Transradial Access for the Prevention of Radial Artery Occlusion trial is a multicentre, prospective, randomised, open-label, blinded-endpoint design study investigating the efficacy and safety of rivaroxaban to reduce the incidence of RAO. Eligible patients will undergo randomisation to receive either rivaroxaban 15 mg once daily for 7 days or to no additional postprocedural anticoagulation. Doppler ultrasound to assess radial artery patency will be performed at 30 days.Ethics and disseminationThe study protocol has been approved by the Ottawa Health Science Network Research Ethics Board (approval number 20180319-01H). The study results will be disseminated via conference presentations and peer-reviewed publications.Trial registration numberNCT03630055.

Baharudin Abdullah,1 Amir Hamzah Abdul Latiff,2 Anura Michelle Manuel,3 Faizah Mohamed Jamli,4 Harvinder Singh Dalip Singh,5 Intan Hakimah Ismail,6 Jeevanan Jahendran,2 Jeyasakthy Saniasiaya,7Kent Chee Keen Woo,8 Phaik Choo Khoo,9 Kuljit Singh,3 Nurashikin Mohammad,10 Sakinah Mohamad,1 Salina Husain,11 Ralph Mösges12,13 1Department of Otorhinolaryngology - Head and Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia; 2Pantai Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; 3Prince Court Medical Centre, Kuala Lumpur, Malaysia; 4Department of Paediatrics, Hospital Serdang, Selangor, Malaysia; 5Department of Otorhinolaryngology - Head and Neck Surgery, Hospital Raja Permaisuri Bainun, Ipoh, Perak; 6Department of Paediatrics, Universiti Putra Malaysia, Selangor, Malaysia; 7Department of Otorhinolaryngology, Universiti Malaya, Kuala Lumpur, Malaysia; 8Gleneagles Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; 9Subang Jaya Medical Centre (SJMC), Selangor, Malaysia; 10Department of Internal Medicine, Universiti Sains Malaysia, Kelantan, Malaysia; 11Department of Otorhinolaryngology-Head & Neck Surgery, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia; 12Institute of Medical Statistics and Computational Biology, University of Cologne, Cologne, Germany; 13ClinCompetence Cologne GmbH, Cologne, GermanyCorrespondence: Baharudin Abdullah, Department of Otorhinolaryngology - Head and Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia, Tel +60 97676416, Fax +60 97676424, Email baharudin@usm.my; profbaha@gmail.comAbstract: The goal of allergic rhinitis (AR) management is to achieve satisfactory symptom control to ensure good quality of life. Most patients with AR are currently treated with pharmacotherapy. However, knowledge gaps on the use of pharmacotherapy still exist among physicians, particularly in the primary care setting, despite the availability of guideline recommendations. Furthermore, it is common for physicians in the secondary care setting to express uncertainty regarding the use of new combination therapies like intranasal corticosteroid plus antihistamine combinations. Inadequate treatment leads to significant reduction of quality of life that affects daily activities at home, work, and school. With these concerns in mind, a practical consensus statement was developed to complement existing guidelines on the rational use of pharmacotherapy in both the primary and secondary care settings.Keywords: allergic rhinitis, pharmacotherapy, consensus, primary care, secondary care, Malaysia

Leishmaniasis is a neglected tropical disease and remains a global concern for healthcare. It is caused by an opportunistic protozoan parasite belonging to the genus Leishmania and affects millions worldwide. This disease is mainly prevalent in tropical and subtropical regions and is associated with a high risk of public morbidity and mortality if left untreated. Transmission of this deadly disease is aggravated by the bite of female sand-fly vectors (Phlebotomus and Lutzomyia). With time, significant advancement in leishmaniasis-related research has been carried out to cope with the disease burden. Still, the Leishmania parasite has also co-evolved with its host and adapted successfully within the host's lethal milieu/environment. Thus, understanding and knowledge of various leishmanial virulence factors responsible for the parasitic infection are essential for exploring drug targets and vaccine candidates. The present review elucidates the importance of virulence factors in pathogenesis and summarizes the major leishmanial virulence molecules contributing to the parasitic infection during host-pathogen interaction. Furthermore, we have also elaborated on the potential contribution of leishmanial virulence proteins in developing vaccine candidates and exploring novel therapeutics against this parasitic disease. We aim to represent a clearer picture of parasite pathogenesis within the human host that can further aid in unraveling new strategies to fight against the deadly infection of leishmaniasis.

Transcatheter aortic valve implantation (TAVI) is relatively contraindicated in the bicuspid aortic valve, and to our knowledge has not been tried where the true native annulus is of a size far in excess of current device capabilities. We present here a case of a successful emergency TAVI of a 73-year-old previously healthy man, who presented with cardiogenic shock, ventricular tachycardia storm and severe left ventricular dysfunction because of the underlying critical bicuspid aortic stenosis with aortic annulus area of 991.9 mm2 and associated moderate aortic incompetence (the Society of Thoracic Surgeons (STS) risk score; score mortality of 40.9%). Despite the critical condition of the patient and technically challenging anatomy, successful TAVI was performed and the patient remains well with near-normal left ventricle (LV) function at 6 months follow-up.

Objective: The aim of this systematic review and meta-analysis was to provide a comprehensive estimate for spontaneous coronary artery dissection (SCAD) related mortality, and explore factors associated with an increased risk of death. Background: SCAD is an infrequent but increasingly recognized cause of acute coronary syndrome. Despite a growing body of evidence, there have been few detailed examinations of SCAD associated mortality. Methods: We searched MEDLINE, EMBASE, Cochrane, Web of Science and Google Scholar databases through May 7, 2020. We included studies reporting mortality data, confirmed SCAD with coronary angiography and included ≥10 participants. We excluded non-English studies, conference abstracts, review articles and duplicate datasets. Random-effects meta-analysis and meta-regression were used to evaluate estimates and predictors of mortality. Results: From an initial 1,131 articles, 34 studies with 2,817 patients were eligible for inclusion. The weighted mean age was 50 years, and 84% of participants were female. The pooled estimate for SCAD mortality was 1% (Proportion 0.01; 95% CI, 0.00–0.02). The mean duration of follow-up was 33 months. Meta-regression showed male sex was associated with 3.5-fold increased odds of mortality (OR, 3.50; 95% CI, 1.22–10.03). In addition, smoking (current or previous) was associated with a 15-fold increased risk of mortality (OR 15.32; 95% CI, 2.88–81.41). Conclusions: This meta-analysis has shown that SCAD is associated with favorable survival outcomes with an estimated mortality of 1% over a mean follow-up period of 33 months. We also found male sex and smoking were associated with an increased risk of mortality.

The oral delivery of drugs undergoing extensive first-pass metabolism is a tedious task, as the bioavailability of such agents is severely hampered, resulting in poor pharmacological response and compromised dose economics. Cardiovascular diseases are a leading cause of mortality and morbidity all over the globe, wherein nifedipine is such a prescribed drug with extensive first-pass metabolism and compromised bioavailability. In an attempt to alleviate the concerns of nifedipine employing simple materials and methods, orodispersible tablets (ODTs) of nifedipine were explored using various methods and materials. Out of various methods viz. lyophilization technique, wet granulation, dry granulation and cotton-candy process, the last method fetched with ODTs with acceptable disintegration time, wetting time and drug release profile over 10 minutes in Sorenson's buffer simulating saliva. The novel material used Calcium Cross-Linked Cassia Fistula gum offered substantially improved ODT product over the conventional material, i.e., Croscarmellose Sodium (CCS). The optimized ODT not only improved the bioavailability of the drug by decreasing the drug extraction at the liver site, as evident from in-vivo pharmacokinetic studies, but also offered substantial reduction in the systolic blood pressure in L-NAME antihypertensive studies in Wistar rats. The in-vivo performance of the selected ODT was far more improved than that the available marketed product as well as the plain drug, advocating the superiority of the developed system over the marketed one. The pharmacokinetic, biodistribution and pharmacological evidences coupled with the results from the in-vitro parameters like wetting time, disintegration time and drug release profile provide a ray of hope for a commercially viable ODT product for nifedipine to manage the hypertension related problems.

Objective: The present investigation was aimed towards developing calcium crosslinked derivative of carboxymethylated cassia fistula gum and crosscarmellose sodium based orodispersible tablets (ODTs) of propranolol hydrochloride for enhancing the bioavailability and efficacy. Methods: Orodispersible tablets (ODTs) of propranolol hydrochloride was formulated using natural (a carboxymethylated derivative of cassia fistula gum) and synthetic polymer (crosscarmellose sodium) by wet and dry granulation, lyophilization and cotton candy methods and then finally compressed by direct compression. The prepared ODTs were evaluated for several parameters such as hardness, friability, in vitro disintegration time, in vitro drug release. In vivo and stability studies were carried out on optimized formulation coding PC1. Results: Drug polymer interaction were judged by FT-IR, DSC and XRD. The optimized formulation coding PC1 prepared by cotton candy process containing 2.5% w/w of crosslinked cassia fistula gum has the least disintegration time (18.9±0.4s), weeting time (12.5±0.8s) and relased the drug of 88.2% within 10 min in contrast to croscarmellose sodium. In vivo absorption studies revealed that same formulation has Cmax (µg/ml) 2.13±0.73, tmax (h) 0.21±0.17 and (µg ml-1 h-1) 14.33±1.59. Conclusion: This research manuscript clearly shows the successful development of the ODTs loaded with an antihypertensive drug, namely propranolol hydrochloride. The formulation developed by cotton candy process utilizing crosslinked cassia fistula gum as a natural superdisintegrant in contrast to other existing techniques can be a best option over synthetic superdisintegrant i.e. crosscarmellose sodium. The prepared ODTs was enhanced the absorption rate by lowering tmax, which inturn enhance the bioavailability and the efficacy of drug.

There have been several local and systemic adverse events associated with mRNA COVID-19 vaccines. Pericarditis, myocarditis and myocardial infarction are examples of cardiac complications related to these vaccines. In this article, we conducted a systematic review of case reports and case series to identify the clinical profile, investigations, and management of reported cardiac complications post-mRNA COVID-19 vaccines. We systematically searched PubMed, Scopus, Web of Science, and Google Scholar, as well as the medRxiv preprint server, with terms including: 'SARS-CoV-2', 'COVID-19', 'messenger RNA vaccine*', 'mRNA-1273 vaccine', 'BNT162 vaccine', 'myocarditis', 'pericarditis', 'stroke' and 'Myocardial Ischemia' up to 25 September 2021. Studies were excluded if they were not case reports or case series, or reported cases from non-mRNA vaccines. Case reports and case series were included that investigated the potential cardiac complications associated with mRNA COVID-19 vaccines. The JBI checklist was used to assess quality and data synthesis was conducted using a qualitative methodology called narrative synthesis. Sixty-nine studies, including 43 case reports and 26 case series, were included. Myocarditis/myopericarditis and pericarditis were the most common adverse events among the 243 reported cardiac complications, post mRNA COVID-19 vaccination. Males with a median age of 21 years had the highest frequency of myocarditis. Almost three quarters (74.4%) of cases with myocarditis had received the BNT162b2 vaccine and 87.7% had received the second dose of the vaccine. Chest pain (96.1%) and fever (38.2%) were the most common presentations. CK-MB, troponin, and NT-proBNP were elevated in 100%, 99.5% and 78.3% of subjects, respectively. ST-segment abnormality was the most common electrocardiogram feature. Cardiac magnetic resonance imaging, which is the gold-standard approach for diagnosing myocarditis, was abnormal in all patients diagnosed with myocarditis. Non-steroidal anti-inflammatory drugs were the most prescribed medication for the management of myocarditis. Apart from inflammatory conditions, some rare cases of Takotsubo cardiomyopathy, myocardial infarction, myocardial infarction with non-obstructive coronary arteries, and isolated tachycardia were also reported following immunisation with mRNA COVID-19 vaccines. We acknowledge that only reviewing case reports and case series studies is one potential limitation of our study. We found that myocarditis was the most commonly reported adverse cardiac event associated with mRNA COVID-19 vaccines, which presented as chest pain with a rise in cardiac biomarkers. Further large-scale observational studies are recommended.

IntroductionVarenicline tartrate is superior for smoking cessation to other tobacco cessation therapies by 52 weeks, in the outpatient setting. We aimed to evaluate the long-term (104 week) efficacy following a standard course of inpatient-initiated varenicline tartrate plus Quitline-counselling compared to Quitline-counselling alone.MethodsAdult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to one of three hospitals, were randomised to receive either 12-weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice-daily) plus Quitline-counselling, (n = 196) or Quitline-counselling alone, (n = 196), with continuous abstinence from smoking assessed at 104 weeks.ResultsA total of 1959 potential participants were screened for eligibility between August 2008 and December 2011. The proportion of participants who remained continuously abstinent (intention-to-treat) at 104 weeks were significantly greater in the varenicline tartrate plus counselling arm (29.2% n = 56) compared to counselling alone (18.8% n = 36; p = 0.02; odds ratio 1.78; 95%CI 1.10 to 2.86, p = 0.02). Twenty-two deaths occurred during the 104 week study (n = 10 for varenicline tartrate plus counselling and n = 12 for Quitline-counselling alone). All of these participants had known or developed underlying co-morbidities.ConclusionsThis is the first study to examine the efficacy and safety of varenicline tartrate over 104 weeks within any setting. Varenicline tartrate plus Quitline-counselling was found to be an effective opportunistic treatment when initiated for inpatient smokers who had been admitted with tobacco-related disease.

Aims To report the prevalence, deaths, and disability-adjusted life years (DALYs) associated with ischemic heart disease (IHD) and its attributable risk factors in 204 countries and territories from 1990 to 2019, by age, sex, and socio-demographic index (SDI). Methods and results Ischemic heart disease was defined as acute myocardial infarction (MI) and chronic IHD (angina; asymptomatic IHD following MI). Cause of death ensemble modelling was used to produce fatality estimates. The prevalence of the non-fatal sequalae of IHD was estimated using DisMod MR 2.1. All estimates were presented as counts and age-standardized rates per 100 000 population. In 2019, IHD accounted for 197.2 million (177.7–219.5) prevalent cases, 9.1 million (8.4–9.7) deaths, and 182.0 million (170.2–193.5) DALYs worldwide. There were decreases in the global age-standardized prevalence rates of IHD [−4.6% (−5.7, −3.6)], deaths [−30.8% (−34.8, −27.2)], and DALYs [−28.6% (−33.3, −24.2)] from 1990 to 2019. In 2019, the global prevalence and death rates of IHD were higher among males across all age groups, while the death rate peaked in the oldest group for both sexes. A negative association was found between the age-standardized DALY rates and SDI. Globally, high systolic blood pressure (54.6%), high low-density lipoprotein cholesterol (46.6%), and smoking (23.9%) were the three largest contributors to the DALYs attributable to IHD. Conclusion Although the global age-standardized prevalence, death, and DALY rates all decreased. Prevention and control programmes should be implemented to reduce population exposure to risk factors, reduce the risk of IHD in high-risk populations, and provide appropriate care for communities.

Leishmaniasis, a neglected tropical disease, still remains a global concern for the healthcare sector. The primary causative agents of the disease comprise diverse leishmanial species, leading to recurring failures in disease diagnosis and delaying the initiation of appropriate chemotherapy. Various species of the Leishmania parasite cause diverse clinical manifestations ranging from skin ulcers to systemic infections. Therefore, host immunity in response to different forms of infecting species of Leishmania becomes pivotal in disease progression or regression. Thus, understanding the paradox of immune arsenals during host and parasite interface becomes crucial to eliminate this deadly disease. In the present review, we have elaborated on the immunological perspectives of the disease and discussed primary host immune cells that form a defense line to counteract parasite infection. Furthermore, we also have shed light on the immune cells and effector molecules responsible for parasite survival in host lethal milieu/ environment. Next, we have highlighted recent molecules/compounds showing potent leishmanicidal activities pertaining to their pro-oxidant and immuno-modulatory mechanisms. This review addresses an immuno-biological overview of the factors influencing the parasitic disease, as this knowledge can aid in the unraveling/ identification of potential biomarkers, novel therapeutics, and vaccine candidates against leishmaniasis.

Background Globalisation has seen a shift towards international multicentre randomised controlled trials (RCTs). The amalgamation of heterogenous patient populations is thought to be responsible for the geographic variation in treatment effect noted in recent trials. Furthermore, there is significant underrepresentation of lower- income countries in cardiovascular disease (CVD) research. These issues raise important questions about the generalisability of these trial results. Given the central role of statin therapy in CVD risk reduction, we evaluated for geographic variation in treatment effect in the primary and secondary prevention statin RCTs. Methods We conducted a comprehensive literature search using the terms: “statin”, “coronary disease”, “reduce” and “cholesterol”. We included statin RCTs with >1000 participants, therapy >2 years and CVD outcomes. We analysed each study for regional recruitment data and geographic subgroup analysis. Results From an initial 2154 studies, we identified 20 eligible for inclusion. This amounted to 138,612 participants across multiple continents including Europe 69,086 (49.8%), Asia 14,672 (10.6%), South America 5128 (3.7%), North America 33,393 (24.1%), Oceania 9445 (6.8%) and Africa 2801 (2%). Data were unavailable for 4087 (2.9%) participants. Despite together comprising 35% of the world's population, China and India represented only 2.7% and 1.3% of the studied population respectively. None of the 6 multi-continent trials provided regional analysis. Conclusion We were unable to identify significant geographic variation in the outcomes of the statin RCTs, primarily due to a lack of data. We also observed regarding statin RCT data, there is limited involvement of countries with the greatest burden of CVD.

Most prior studies have compared myocardial infarction with non-obstructive coronary arteries (MINOCA), to obstructive acute coronary syndrome (ACS) often requiring revascularisation. However, these were subject to treatment bias given the significant differences in management. This study uniquely compares the management and outcomes of MINOCA patients with a medically managed obstructive ACS (M-ACS) population. We retrospectively analysed registry data for consecutive patients admitted to the Gold Coast University Hospital with ACS requiring coronary angiography and identified patients with MINOCA and M-ACS. Baseline characteristics, pharmacological therapy and in-hospital outcomes were compared. In hospital outcomes were composite NACE, heart failure, stroke and major bleeding. Multivariate regression analysis was also performed to identify independent predictors of MINOCA. Multivariate regression analysis was also performed to identify independent predictors of MINOCA. We identified 139 patients with MINOCA and 142 patients with medically managed obstructive ACS (M-ACS). Multivariate regression analysis also identified female sex and cancer as independent predictors of MINOCA with odds ratios of 5.57 and 3.01, respectively. MINOCA patients were significantly less likely to receive cardioprotective medications at admission and discharge, specifically aspirin, beta-blockers, ACE-I and statins, compared to those with M-ACS. While mortality was higher among M-ACS patients (0.0% vs. 3.6%; p = 0.03), no significant differences were noted for composite NACE, heart failure, stroke and major bleeding. MINOCA patients have similar outcomes to M-ACS. Despite this, we noted a discrepancy in the use of cardioprotective medications. We also identified female sex and cancer were independent predictors of MINOCA. This may represent a missed opportunity to prevent adverse events among patients with MINOCA. Large, randomised trials are required to provide more definitive evidence.

Patients with thoracolumbar kyphoscoliosis present unique challenges to anesthesia. We report an interesting and challenging case of kyphoscoliosis presenting with a displaced right intertrochanteric femur fracture who was planned for spinal anesthesia. However, spinal anesthesia was not successful even with the use of intraoperative fluoroscopy. The patient was again planned for spinal anesthesia the next day after reviewing his preoperative lumbar X-rays, which were suggestive of severe canal stenosis and sclerosis of the spine at L4-L5 and L5-S1 level thus causing the failure of contrast to spread up. Using appropriate space (L3-L4) after viewing X-ray, successful spinal anesthesia could be given. This report underscores the importance of reviewing the preoperative radiology of the diseased spine by the anesthesiologist to administer an effective and safe spinal anesthesia in such patients.

Background: Protein misfolding is a critical factor in the progression of a large number of neurodegenerative diseases. The incorrectly folded protein is prone to aggregation, leading to aberrant interaction with other cellular proteins, elevated oxidative stress, impaired cellular machinery, finally resulting in cell death. Due to its monogenic origin, Huntington’s disease (HD) is a poster child of protein misfolding neurodegenerative disorders. The presence of neuronal inclusions of mutant huntingtin N-terminal fragments, mainly in the cortex and striatum, is a neuropathological hallmark of HD. Inhibition of protein misfolding and aggregation has been attempted using a variety of conventional protein stabilizers. Methods: This review describes how, in recent times, nucleic acid therapeutics has emerged as a selective tool to downregulate the aberrant transcript and reduce expression of mutant huntingtin, thereby alleviating protein aggregation. Different strategies of use of nucleic acids, including antisense oligonucleotides, short inhibitory RNA sequences and aptamers have been discussed. The following patent databases were consulted: European Patent Office (EPO), the United States Patent and Trademark Office (USPTO), Patent scope Search International and National Patent Collections (WIPO) and Google Patents. Results: Tools such as RNA interference (RNAi) and antisense oligonucleotides (ASOs) are potential therapeutic agents which target the post-transcriptional step, accelerating mRNA degradation and inhibiting the production of the mutant protein. These nucleic acid sequences not only target the elongated CAG triplet repeat translating to an expanded polyglutamine tract in the mutant protein, but have also been used to target single nucleotide polymorphisms associated with the mutant allele. The therapeutic sequences have been investigated in a number of cells and animal models of HD. One antisense sequence, with desirable safety properties, has recently shown downregulation of huntingtin protein in a limited clinical trial. RNA aptamers have also shown promising results in inhibiting protein aggregation in a yeast model of HD. Novel drug delivery techniques have been employed to overcome the blood brain barrier for the use of these therapeutic sequences. Conclusion: The selectivity and specificity imparted by nucleic acids, along with novel delivery techniques, make them hopeful candidates for the development of a curative strategy for HD.

COVID-19 caused by SARS-CoV-2 is an ongoing global pandemic. SARS-CoV-2 affects the human respiratory tract's epithelial cells, leading to a proinflammatory cytokine storm and chronic lung inflammation. With numerous patients dying daily, a vaccine and specific antiviral drug regimens are being explored. Probiotics are live microorganisms with proven beneficial effects on human health. While probiotics as nutritional supplements are long practiced in different cuisines across various countries, the emerging scientific evidence supports the antiviral and general immune-strengthening health effects of the probiotics. Here, we present an overview of the experimental studies published in the last 10 years that provide a scientific basis for unexplored probiotics as a preventive approach to respiratory viral infections. Based on collated insights from these experimental data, we identify promising microbial strains that may serve as lead prophylactic and immune-boosting probiotics in COVID-19 management.

AIM: Recurrence is a well-established complication of spontaneous coronary artery dissection (SCAD). However, the exact incidence and correlates of recurrence are unknown. We, therefore, performed a systematic review and meta-analysis to determine and consolidate the evidence on the global incidence of SCAD recurrence. METHODS: A comprehensive search of the four major databases (EMBASE, OVID Medline, PubMed and Google Scholar) was performed from their inception to 17 January 2019. We included original research studies, recruiting ≥10 participants, with ≥12 months follow-up that reported data on recurrence in patients with SCAD. RESULTS: Out of 556 studies searched, 19 cohorts (1538 SCAD patients) were included in the analysis. There were 153 cases of de novo recurrence over a mean follow-up period of 31.2 months (95% confidence interval, 25-41 months). Type 1, 2 and 3 SCAD was noted in 33.2, 73.2 and 5.3%, respectively. The involved coronary artery was left anterior descending artery, left anterior descending artery, right coronary artery, left circumflex artery and multivessel coronary artery disease, respectively, in 3.5, 53.4, 19.8, 20.4 and 12.6% of cases. The overall SCAD de novo recurrence was 7% (ES 0.07, 95% confidence interval, 0.04-0.10, I2 = 65.3%). On meta-regression, we found discharge medications at index admission, including β-blockers, ACE inhibitors, statins, as well as baseline cardiac risk factors, did not correlate with recurrence. CONCLUSION: SCAD recurrence is common, occurring in 7% of patients over medium-term follow up. No specific medications at discharge were found to reduce recurrence. Further long-term and prospective data are required.

Introduction: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in ~10% of all patients with acute myocardial infarction (AMI), with an over-representation amongst women. Remarkably, it is estimated that as many as 1 in 4 patients with MINOCA experience ongoing angina at 12 months despite having no flow-restricting stenoses in their epicardial arteries. This manuscript presents the rationale behind Randomized Evaluation of Beta Blocker and Angiotensin-converting enzyme inhibitors/Angiotensin Receptor Blocker Treatment (ACEI/ARB) for Post Infarct Angina in MINOCA patients—The MINOCA BAT post infarct angina sub study.Methods: This trial is a registry-based, randomized, parallel, open-label, multicenter trial with 2 × 2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce post infarct angina in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 664 patients will be randomized into four groups; (i) ACEI/ARB with beta blocker, (ii) beta blocker only, (iii) ACEI/ARB only, or (iv) neither ACEI/ARB nor beta blocker and followed for 12 months.Results: The trial is currently recruiting in Australia and Sweden. Fifty six patients have been recruited thus far. Both sexes were equally distributed (52% women and 48% men) and the mean age was 56.3 ± 9.9 years.Conclusions: It remains unclear whether conventional secondary preventive therapies are beneficial to MINOCA patients in regard to post infarct angina. Existing registry-based literature suggest cardioprotective agents are less likely to be used in MINOCA patients. Thus, results from this trial will provide insights for future treatment strategies and guidelines specific to MINOCA patients.

The emergence of drug resistance continues to afflict TB control where drug resistant strains have become a global health concern. Contrary to drug-sensitive TB, the treatment of MDR/XDR-TB is more complicated requiring the administration of second-line drugs that are inefficient than the first line drugs and are associated with greater side effects. The emergence of drug resistant Mtb strains had coincided with an innovation void in the field of drug discovery of anti-mycobacterials. However, the approval of bedaquiline and delamanid recently for use in MDR/XDR-TB has given an impetus to the TB drug discovery. The review discusses the drug discovery efforts in the field of tuberculosis with a focus on the strategies adopted and challenges confronted by TB research community. Here, we discuss the diverse clinical candidates in the current TB drug discovery pipeline. There is an urgent need to combat the current TB menace through multidisciplinary approaches and strategies making use of the recent advances in understanding the molecular biology and pathogenesis of Mtb. The review highlights the recent advances in drug discovery, with the host directed therapeutics and nanoparticles-drug delivery coming up as important tools to fight tuberculosis in the future.

The differential impact of young age and female gender on transradial access (TRA) outcomes remains to be confirmed. The primary objective was to assess the impact of young age and female gender on in-hospital net adverse cardiovascular events (NACE). Among 12 346 patients from the Coronary Angiogram Database of South Australia (CADOSA) Registry, the impact of gender; men (transfemoral access [TFA] 1995, TRA 6168) and women (TFA 1249, TRA 2934), and a median split of age, ≤63 years (TFA 1617, TRA 4727) and >63 years (TFA 1627, TRA 4375) were analyzed on in-hospital outcomes by creating 5 separate propensity-matched cohorts (entire cohort, men, women, ≤63 and > 63 years). Net adverse cardiovascular event reduction with TRA was limited to the >63 years old cohort (odds ratio [OR] = 0.56, 95% CI: 0.34-0.93, P = .02) and women (OR = 0.37, 95% CI: 0.18-0.76, P = .007). In both the age groups and genders, TRA was associated with a lower risk of bleeding and all-cause mortality. On multivariate logistic regression, TRA was associated with a significant reduction in NACE, major bleeding, and mortality in the overall cohort. In conclusion, a reduction in bleeding and mortality was noted with TRA in all the subgroups in this observational study.

Current Development in drug delivery system has been employed with an endeavour to enhance the bioavailability of the drug, mask its taste, induce the rapid onset of action and improve patient compliance. An alternative approach to the conventional dosage form is being employed to triumph over all these issues named as Orodispersible system. Over the past three decades, this novel dosage form has gained considerable attention as compared to other conventional solid dosage forms such as tablets and capsules. ODTs dissolve or disintegrate within a few seconds or a minute when put on the tongue, without the need for water. ODT has an advantageous effect on paediatrics and geriatrics patients with dysphagia. Over the last decade, widespread advances in the formulation of ODTs have been executed in academia and industry that resulted in the emergence of a large number of patents. Products developed from ODT mechanics launched in the market in the 1980s have grown bit by bit in demand and their products are rapidly escalating. Expanding in the technology forum based on industrialization, these systems include the use of lyophilization, cotton candy, sublimation, melt extrusion and direct compression in addition to the conventional wet granulation processes and patent techniques. The present study focused on non-patent and patent citations concerning ODT along with active ingredients, techniques used and results of the innovations.

Severe acute respiratory distress syndrome (ARDS) can complicate novel pandemic coronavirus disease (COVID-19). Extracorporeal life support (ECLS) represents the final possible rescue strategy. Variations in practice, combined with a paucity of rigorous guidelines, may complicate blood product resource availability and allocation during a pandemic. We conducted a literature review around venovenous extracorporeal membrane oxygenation (VV-ECMO) transfusion practices for platelets, packed red blood cells, fresh frozen plasma, prothrombin complex concentrate, and antithrombin. Pertinent society guidelines were examined, and the practice of Canadian ECLS experts was sampled through an environmental scan. This paper represents a synthesis of these explorations, combined with input from the Canadian Cardiovascular Critical Care (CANCARE) Society, Canadian Society of Cardiac Surgeons, and the Canadian Critical Care Society. We offer a pragmatic guidance document for restrictive transfusion thresholds in non-bleeding VV-ECMO patients, which may attenuate transfusion-related complications, and simultaneously shield national blood product inventory from strain during pandemic-induced activation of the National Plan for the Management of Shortages of Labile Blood Components., Venovenous extracorporeal membrane oxygenation (VV-ECMO) rescue for COVID-19 patients may strain national blood product inventory and allocation during pandemic-induced activation of the National Plan for the Management of Shortages of Labile Blood Components. This expert consensus document offers pragmatic guidance for restrictive transfusion thresholds in non-bleeding VV-ECMO patients, which may attenuate transfusion-related complications and simultaneously shield blood product inventory.

Supplemental Material, Supplementary_files for Impact of Young Age and Gender on Outcomes of Transradial Versus Transfemoral Access Coronary Angiography by Kuljit Singh, Rosanna Tavella, Tracy Air, Matthew Worthley, Ajay Sinhal, Margaret Arstall, Christopher Zeitz and John Beltrame in Angiology

A pharmacoinvasive strategy for ST-segment elevation myocardial infarction (STEMI) management combines the use of fibrinolysis with the routine transfer to coronary angiography, with percutaneous coronary intervention (PCI) if needed. This method reduces the risk of major adverse cardiovascular event (MACE) compared with fibrinolysis alone; however, it is associated with higher bleeding risk. We sought to assess the bivalirudin compared with unfractionated heparin (UFH) used during PCI as part of a pharmacoinvasive strategy.We identified consecutive patients referred to the University of Ottawa Heart Institute between April 2009 and May 2011 as part of a pharmacoinvasive strategy for STEMI. The primary efficacy outcome was MACE, defined as a composite of death, reinfarction, or stroke during index hospitalization. The primary safety outcome was TIMI bleeding.We identified 200 patients meeting inclusion criteria: 123 patients (61.5%) in the bivalirudin group and 77 patients (37.5%) in the UFH group. Median fibrinolysis to balloon time was 324 minutes in the bivalirudin group and 226 minutes in the UFH group (P.001). Initial TIMI grade 3 flow was higher in the bivalirudin group vs the UFH group, but there was no difference in the rates post PCI. MACE rates were 4.9% vs 7.8% (P=.40) and TIMI bleeding rates were 7.3% vs 11.7% (P=.29) in patients treated with bivalirudin vs UFH, respectively.The periprocedural use of bivalirudin vs UFH was associated with similar rates of MACE and bleeding. Given the expense of bivalirudin and lack of demonstrable clinical superiority, UFH remains the first-line periprocedural anticoagulant in a pharmacoinvasive strategy.