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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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: Jeevanan Jahendran reports personal fees from Inova Pharmaceuticals (S’pore) Pte. Ltd. (M’sia Branch), Viatris, Menarini Singapore Pte Ltd, Reckitt Benckiser (Malaysia) Sdn. Bhd., and (M) Sdn Bhd, outside the submitted work. Ralph Mösges reports personal fees from Menarini Asian Pacific, during the conduct of the study, and received personal fees from ALK, grants from ASIT biotech, personal fees from Allergopharma, Allergy Therapeutics, grants and personal fees from Bencard, grants from Leti, grants, personal fees and non-financial support from Lofarma, non-financial support from Roxall, grants and personal fees from Stallergenes, grants from Optima, personal fees from Friulchem, personal fees from Hexal, Servier, Klosterfrau, non-financial support from Atmos, personal fees from Bayer, non-financial support from Bionorica, personal fees from FAES, GSK, MSD, Johnson & Johnson, Meda, personal fees and non-financial support from Novartis, non-financial support from Otonomy, personal fees from Stada, and UCB, non-financial support from Ferrero, grants from BitopAG, Hulka, personal fees from Nuvo, grants from Ursapharm, personal fees from Menarini, Mundipharma, Pohl-Boskamp, grants from Inmunotek. The authors report no other potential conflicts of interest in this work., (© 2022 Abdullah et al.)

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., (© 2021. Springer Japan KK, part of Springer Nature.)

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., 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 © 2021 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.

Leishmaniasis is regarded as a neglected tropical disease by World Health Organization (WHO) and is ranked next to malaria as the deadliest protozoan disease. The primary causative agents of the disease comprise of diverse leishmanial species sharing clinical features ranging from skin abrasions to lethal infection in the visceral organs. As several Leishmania species are involved in infection, the role of accurate diagnosis becomes pivotal in adding new dimensions to anti-leishmanial therapy. Diagnostic methods must be fast, reliable, easy to perform, highly sensitive, and specific to differentiate among similar parasitic diseases. Herein, we present the conventional and recent approaches impended for the disease diagnosis and their sensitivity, specificity, and clinical application in parasite detection. Furthermore, we have also elaborated various new methods to cure leishmaniasis, which include host-directed therapies, drug repurposing, nanotechnology, and combinational therapy. This review addresses novel techniques and innovations in leishmaniasis, which can aid in unraveling new strategies to fight against the deadly infection., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 LMCA, LAD, RCA, LCx and multi-vessel CAD 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., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., 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 Pasupathy, Lindahl, Tavella, Nordenskjöld, Zeitz, Arstall, Worthley, Neil, Singh, Turner, Rajwani, Mooney and Beltrame.)

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.

Introduction: Clinical characteristics and outcomes of patients diagnosed with myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) remain largely unknown. Furthermore, we do not yet understand if women with MINOCA have worse outcomes similar to what has historically been observed with MI. The aims of the current study were to evaluate the (1) incidence of MINOCA in patients presenting with MI, (2) compare in-hospital outcomes of MINOCA and obstructive atherosclerotic coronary artery disease MI (OACD-MI), and (3) comparison of in-hospital clinical outcomes of patients with MINOCA stratified by sex., Methods and Results: In this observational study, we combined data from two large university hospitals from Canada and Australia. Clinical characteristics and in-hospital outcomes of MINOCA and OACD-MI were analyzed by matching these patients in a 1:1 ratio after selecting patients with OACD-MI by systematic random sampling. Clinical characteristics associated with MINOCA were identified through multivariate logistic regression. Primary outcome of interest was net adverse cardiovascular events (NACE) defined as death, heart failure, stroke, and major bleeding. The incidence rate of MINOCA was 9.5%. Women, absence of traditional cardiac risk factors, and absence of ST-deviations on ECG were associated with diagnosis of MINOCA on angiography. NACE (P = 0.0001), death (P = 0.019), stroke (P = 0.002), and heart failure (P = 0.001) were significantly lower in patients with MINOCA. Subgroup analysis of women and men diagnosed with MINOCA revealed similar in-hospital outcomes., Conclusion: The incidence of MINOCA was 9.5%. Compared to OACD-MI, patients with MINOCA have less cardiac risk factors. In-hospital outcomes of patients diagnosed with MINOCA were better than OACD-MI.

Aims: Prolonged dual antiplatelet therapy (DAPT) requires consideration of both reduced thrombotic events and increased bleeding risk. The associated subtle balance between the benefits and harms depends upon patient's clinical factors and complexity of the coronary anatomy. Our aim was to assess the safety and efficacy of prolonged (>12 months) DAPT in patients undergoing complex percutaneous coronary intervention (PCI)., Methods and Results: A thorough computer-based search was performed using four major databases. Complex PCI was defined as a procedure with at least one of the following angiographic characteristics: 3 vessels treated, >3 stents implanted, >3 lesions treated, bifurcation lesions, total stent length >60 mm, left main or proximal left anterior descending, a vein graft stent, or chronic total occlusion as target lesion. Of the 3543 titles searched, 5 studies met the inclusion criteria comparing short and prolonged DAPT therapy. We applied a random-effects model to acknowledge the variation in study design, treatment duration, and length of follow-up among studies. There was a reduction in cardiac mortality [odds ratio (OR) 0.57, 95% confidence interval (CI): 0.35-0.92; P = 0.02, I = 0%] and major adverse cardiovascular events (OR 0.76, 95% CI: 0.59-0.96; P = 0.02, I = 22%) with prolonged DAPT. Major bleeding was increased with prolonged DAPT (OR 1.75, 95% CI: 1.20-2.20; P = 0.004, I = 0%). There was no difference in the all-cause mortality (OR 0.86, 95% CI: 0.61-1.22; P = 0.41, I = 0%)., Conclusion: Prolonged DAPT reduces cardiac mortality and major adverse cardiovascular events in complex PCI. The results would need confirmation in a larger randomized study.

Background: 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., Methods: 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., Results: 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., Conclusion: 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.

Leishmaniasis is second most neglected disease after malaria and seems to be a worldwide concern because of increased drug resistance and non-availability of approved vaccine. The underlying molecular mechanism of drug resistance (Amp B) in Leishmania parasites still remains elusive. Herein, the present study investigated differentially expressed secreted proteins of Amphotericin B sensitive (S) and resistant (R) isolate of Leishmania donovani by using label free quantitative LC-MS/MS approach. A total of 406 differentially expressed secreted proteins were found between sensitive (S) and resistant (R) isolate. Among 406 proteins, 32 were significantly up regulated (>2.0 fold) while 22 were down regulated (<0.5 fold) in resistant isolate of L. donovani. Further, differentially expressed proteins were classified into 11 various biological processes. Interestingly, identified up regulated proteins in resistant parasites were dominated in carbohydrate metabolism, stress response, transporters and proteolysis. Western blot and enzymatic activity of identified proteins validate our proteomic findings. Finally, our study demonstrated some new secreted proteins associated with Amp B resistance which provides a basis for further investigations to understand the role of proteins in L. donovani. BIOLOGICAL SIGNIFICANCE: Although great advances have been achieved in the diagnosis and treatment of leishmaniasis, still drug resistance is major hurdle in control of disease. Present study will enhance the deeper understanding of altered metabolic pathways involved in Amp B resistance mechanism and provide possible new proteins which can be potential candidate either for exploring as new drug target or vaccine. Protein-protein interactions highlighted the up-regulated metabolic pathways in resistant parasites which further unravel the adaptive mechanism of parasites., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Clinical outcomes in acute coronary syndrome patients treated with P2Y 12 inhibitors who require urgent coronary artery bypass grafting (CABG) have not been well studied., Methods: We examined clinical outcomes in acute coronary syndrome patients in relation to the timing of CABG following P2Y 12 inhibitor discontinuation (<72 h, 72 h to five days, >5 days). The primary ischemic outcome was a composite of death, reinfarction, need for revascularization, or stroke. The primary safety outcome was bleeding of at least moderate severity as defined by a Universal Definition of Perioperative Bleeding class ≥2., Results: Among 508 patients (95 ticagrelor, 413 clopidogrel), the timing of CABG following P2Y 12 inhibitor discontinuation was <72 h in 32.1%, 72 h to five days in 23.2% and >5 days in 44.7%. Compared with CABG within 72 h, CABG 72 h to five days (adjusted odds ratio (OR) 0.35; 95% confidence interval (CI) 0.14-0.85; p =0.02) but not >5 days (adjusted OR 0.62; 95% CI 0.33-1.16; p =0.14) after P2Y 12 inhibitor discontinuation was associated with lower odds of the primary ischemic outcome. Compared with CABG within 72 h, CABG 72 h to five days (adjusted OR 0.38; 95% CI 0.22-0.66; p =0.001) and >5 days (adjusted OR 0.33; 95% CI 0.20-0.53; p <0.001) after P2Y 12 inhibitor discontinuation were associated with lower rates of Universal Definition of Perioperative Bleeding class ≥2 bleeding., Conclusions: CABG within 72 h after P2Y 12 inhibitor discontinuation is associated with excess ischemia and bleeding. The rates of ischemic and bleeding events were comparable in patients undergoing CABG 72 h to five days compared with >5 days after P2Y 12 inhibitor discontinuation.

Background: During percutaneous cardiac procedures, the use of radial access is growing, but femoral access remains needed for large-bore, high-risk procedures. Methods are needed to make femoral access safer. In this systematic review and meta-analysis of randomized-controlled trials (RCTs), we assess whether ultrasound guidance is associated with a decreased risk of vascular complications during femoral artery catheterization., Methods: Medline, Embase, and Cochrane Central were searched from inception to April 2018. RCTs assessing the use of ultrasound among adult patients undergoing a femoral artery catheterization were included. The primary outcome was vascular-access related complications. Secondary outcomes included major and minor vascular access bleeding, success rate, venipuncture, number of attempts, and successful placement into the common femoral artery., Results: Five RCTs (n = 1553) met the inclusion criteria, with two trials using blinded outcome assessment. Ultrasound use was associated with a reduction in the rate of vascular-access related complications (1.9% vs 4.3%; odds ratio [OR], 0.44; 95% confidence interval [CI], 0.24-0.81; P<.01). This was primarily driven by a reduction in local hematomas; once hematomas were excluded, the association was no longer significant (0.6% vs 1.7%; OR, 0.39; 95% CI, 0.15-1.07; P=.07). There was no significant reduction in major bleeding (0.3% vs 1.3%; OR, 0.28; 95% CI, 0.07-0.1.16; P=.08) or minor bleeding (1.4% vs 2.8%; OR, 0.50; 95% CI, 0.24-1.05; P=.07)., Conclusions: Ultrasound guidance during femoral artery catheterization is associated with a decreased risk of vascular complications, primarily driven by a reduction in local hematomas. Larger trials are needed to determine the effect of ultrasound on major bleeding and vascular complications (excluding hematomas).

Aims: The durable polymer (DP) of a drug-eluting stent (DES) serves no function once drug elution is complete. To ascertain the benefits of bioabsorbable polymer (BP) over DP-DESs requires a longer follow-up period, to overcome the time taken for polymer absorption. The primary aim of this meta-analysis was to compare the safety and efficacy of BP-DES with the DP-DES over mid (2 years) to long-term (3-5 years) follow-up., Methods and Results: A thorough computer-based search was performed using Ovid MEDLINE, EMBASE, Google Scholar, and PubMed databases. We only included randomized controlled studies comparing clinical outcomes between BP-DESs and DP-DESs. Only studies where data were available for a minimum of 2 years were included. A separate analysis of 2-year outcomes and 3- to 5-year outcomes were conducted. Data from 6 and 8 studies were included in 3- to 5-year and 2-year follow-up, respectively. There were no differences between stent groups in cardiac mortality, stent thrombosis (ST), target lesion revascularization, target vessel failure, and reinfarction rates for either 2-year or 3- to 5-year follow-up. Subgroup analysis according to strut thickness (<100 µm, >100 µm) of BP-DES demonstrated similar results. The analyses of ST and very late ST favoured BP-DESs but did not reach statistically significant level., Conclusion: There were no differences in clinical outcomes between BP-DESs and DP-DESs over mid- and long-term follow-up., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Leishmaniasis, a parasitic protozoan disease, is still a worldwide concern due to persistent issues with chemotherapy, rapid emerging drug resistance; and non- availability of approved vaccine for the control of disease. Therefore, the search of parasite specific proteins to identify new anti-leishmanial drug targets and vaccine candidates is an urgent priority. In this context, proteins that are secreted, in vitro during parasite growth under defined conditions, can be explored as potential tool for studying their roles in parasite survival inside host and disease pathogenesis. From the last few years, various approaches have been exploited to identify the proteins secreted out by the parasites under defined conditions at particular stage or time. Due to availability of genomic information on various Leishmania species, proteomics have been emerged as most promising approach for analyzing the complexity of exoproteome of different Leishmania species. Herein, we have summarized various secretion mechanisms used by Leishmania parasites to export the proteins into the extracellular space; followed by the role of proteomics in exoproteome analysis along with special emphasis on various applications to study the exoproteome, which might provide potential targets for drug design or novel antigens for vaccine development., (Copyright © 2018. Published by Elsevier B.V.)

Previous studies have shown that patients with Takotsubo syndrome (TS) have supranormal nitric oxide signaling, and post-mortem studies of TS heart samples revealed nitrosative stress. Therefore, we first showed in a female rat model that isoproterenol induces TS-like echocardiographic changes, evidence of nitrosative stress, and consequent activation of the energy-depleting enzyme poly(ADP-ribose) polymerase-1. We subsequently showed that pre-treatment with an inhibitor of poly(ADP-ribose) polymerase-1 ameliorated contractile abnormalities. These findings thus add to previous reports of aberrant β-adrenoceptor signaling (coupled with nitric oxide synthase activation) to elucidate mechanisms of impaired cardiac function in TS and point to potential methods of treatment.

Background: Elderly (≥ 75 years) patients form a large sub-group of non-ST-segment elevation myocardial infarction (NSTEMI) population but are vastly under-represented in trials. Thus, the benefits of an early angiography in the elderly remain unclear. In this systematic review, we compared outcomes of "invasive" and "conservative" strategies of NSTEMI management in elderly patients., Methods: A comprehensive search of major databases was performed. We included comparative studies of any design that enrolled patients ≥ 75 years, and where outcomes of both strategies of NSTEMI management were available., Results: Among the included studies (3 randomized and 6 observational), there were 6340 patients in the "invasive" group and 13,358 patients in the "conservative" group. The 12-month mortality rate (odds ration [OR], 0.45; p < 0.00001), the 30-day mortality (OR, 0.50; p = 0.0009), and events of stroke (OR, 0.42; p < 0.00001) were significantly lower in the invasive group. Major bleeding was higher in the invasive cohort (OR, 1.63; p = 0.03). Analysis of randomised studies showed lower reinfarction with invasive approach at 12 months (p = 0.0001). Significant heterogeneity was noted among studies according to study design., Conclusion: The overall benefit with invasive strategy comes from the data of observational studies that are prone to selection bias. We believe that there is a need for a large randomized study in the elderly patients regarding management of NSTEMI., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Recent data from randomised and observational studies have reported non-inferior outcomes for transcatheter aortic valve implantation (TAVI) compared to surgical aortic valve replacement (SAVR) in intermediate-risk patients. We performed a systematic review to evaluate the mortality of TAVI compared to SAVR in intermediate-risk patients., Methods: A comprehensive search of four major databases (Embase, Ovid MEDLINE, PubMed, and Google Scholar) was performed from their inception to 29 April 2016. We included original research studies reporting data on TAVI and SAVR in intermediate-risk patients. We compared the outcomes of TAVI to SAVR., Results: A total of 2,375 and 2,377 intermediate-risk patients underwent TAVI and SAVR respectively. The 30-day all-cause (p=0.07), 30-day cardiac (p=0.53), and 12-month all-cause mortality (p=0.34) was similar between the two groups. However, TAVI through transfemoral access had a significantly lower mortality than SAVR (OR 0.58, p=0.006). The incidence of ≥moderate aortic incompetence (p<0.00001) and pacemaker implantation (p<0.0001) was higher in the TAVI group., Conclusions: In the intermediate-risk patients, the 30-day and 12-month mortality are similar between TAVI and SAVR. Increased operator experience and improved device technology have led to a significant reduction in mortality in intermediate-risk patients undergoing TAVI., (Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Aims: Recent studies have reported non-inferior outcomes for transcatheter aortic valve implantation (TAVI) compared with surgical aortic valve replacement (SAVR) in intermediate-risk patients. However, a comparison of outcomes among TAVI patients depending upon the surgical risk score has not been performed in a large study. Our aim was to compare the outcomes of TAVI in low-, intermediate-, and high-risk patients, to ascertain if the morbidity and mortality is related to the patient's risk profile or the procedure itself., Methods and Results: A thorough computer-based search was performed using Ovid MEDLINE, EMBASE, Google Scholar, and PubMed databases. We included original research studies reporting data on TAVI in the low-, intermediate-, and high-risk groups. Patients in intermediate-risk group were compared to the high-risk cohort for device success, mortality, and complications. A total of 2414 patients in the intermediate-risk group were compared with 1597 high-risk patients. On meta-analysis, intermediate-risk group demonstrated similar device success [odds ratio (OR) 1.29, 95% confidence interval (CI) 0.87-1.90, I2 = 0%, P = 0.2) but a lower 30-day mortality OR 0.54, 95% CI 0.34-0.86, I2 = 49%, P = 0.009). There was no difference in the incidence of stroke (OR 1.17, 95% CI 0.80-1.71, I2 = 36%, P = 0.42) or permanent pacemaker implantation between the two groups (OR 1.04, 95% CI 0.82-1.32, I2 = 41%, P = 0.74)., Conclusion: Transcatheter aortic valve implantation in intermediate-risk patients carries a low mortality and high success. Incidence of pacemaker and stroke remains high in the lower risk group., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Background: Transcatheter aortic valve implantation (TAVI) is an effective treatment for severe aortic stenosis in high-risk patients. Several complications related to the TAVI procedure, including aortic regurgitation (AR), cerebrovascular accident (CVA) and the requirement for permanent pacemaker (PPM), are thought to be secondary to balloon aortic valvuloplasty (BAV) before TAVI. The aim of the present review was to evaluate any beneficial role of the direct TAVI approach over BAVTAVI., Methods: A comprehensive search of major databases was performed. Only studies comparing TAVI with and without BAV were included. A total of nine full length articles was included in the analysis., Results: Among 2,650 patients, 1,043 underwent 'direct TAVI' without pre-BAV, while 1,607 underwent TAVI following BAV. Overall, there was no difference between the 30-day all-cause mortality (OR 0.96, 95% CI 0.63-1.47, p = 0.86), CVA (OR 0.81, 95% CI 0.34-1.92, p = 0.63) and PPM implantation (OR 0.84, 95% CI 0.66- 1.05, p = 0.12) between the two approaches. The rate of moderate to severe AR was significantly lower with direct TAVI implantation (OR 0.44, 95% CI 0.20-0.96, p = 0.04). In the case of self-expandable valves, direct TAVI was associated with a lower device success (OR 5.15, 95% CI 1.33-19.9, p = 0.02)., Conclusions: No difference was identified in mortality between direct TAVI and BAV-TAVI. However, direct TAVI is associated with a lower incidence of AR, a finding that would only be confirmed by conducting further randomized studies.

Background: Patients on dual antiplatelet therapy following percutaneous coronary intervention often have indications for concurrent oral anticoagulation or triple antithrombotic therapy (TT). Although TT may decrease ischemic complications, it may confer increased bleeding risk., Hypothesis: We hypothesize that the use of ticagrelor in TT is associated with higher risk of complications; accordingly, we sought to determine predictors of complications in patients on TT., Methods: Patients discharged on TT after percutaneous coronary intervention were followed prospectively for 12 months. The primary endpoint was a composite of ischemic (death, myocardial infarction, stroke) and major bleeding complications or net adverse clinical event (NACE). A major secondary endpoint was BARC (Bleeding Academic Research Consortium) types 2, 3, or 5 bleeding. Outcomes were compared between ticagrelor- and clopidogrel-treated patients. Multivariable analyses were performed to elucidate predictors of complications., Results: Twenty-seven of 152 patients discharged on TT were on ticagrelor. NACE occurred in 52% of patients and BARC 2, 3, or 5 bleeding occurred in 18%. There was no difference in the primary or secondary outcome between ticagrelor vs clopidogrel subgroup. On logistic regressions, use of TT in patients with acute coronary syndrome (P = 0.002) and bridging in with ticagrelor (P = 0.02) were associated with increased NACE. Low estimated glomerular filtration rate was an independent predictor of bleeding (P = 0.03)., Conclusions: The risk of bleeding and ischemic complications among patients on TT is similar between those on ticagrelor and clopidogrel. However, caution with use of bridging anticoagulation should be taken when using ticagrelor., (© 2016 Wiley Periodicals, Inc.)

Aims: Admission hyperglycaemia (AH) has been associated with worse outcomes in acute myocardial infarction (AMI). In the current review, we evaluated the impact of primary angioplasty (pPCI) on mortality in AMI patients with AH. Our second aim was to evaluate if AH is a marker of baseline risk or an independent predictor of mortality., Methods and Results: A comprehensive search of four major databases was performed. We included original research studies reporting data on mortality in AMI patients with AH (mean plasma glucose >156 mg/dL/8.7 mmol) and euglycaemia who were treated with pPCI. Of 481 citations, 12 studies were included in the analysis. Admission hyperglycaemia was associated with a higher 30-day [risk ratio (RR) 4.30, P < 0.0001] and 1- to 3-year mortality (RR 2.26, P < 0.0001). As well, AH was more prevalent in women and in patients with an increasing number of cardiac risk factors or angiographic predictors of mortality, such as previous AMI (RR 0.89, P = 0.01), multivessel coronary disease (RR 0.72, P = 0.0001), and involvement of left anterior descending artery (RR 0.92, P < 0.0001). Moreover, patients with AH had larger infarcts (higher creatine kinase-MB; P = 0.004) and more frequent ventricular arrhythmias (P = 0.002)., Conclusion: Despite rapid revascularization and treatment of hyperglycaemia, patients with AH continue to have a higher mortality. Admission hyperglycaemia occurs more commonly in patients who have traditional predictors of worse outcomes-specifically prior infarction, anterior wall infarctions, and multivessel disease. Likely, AH is a predictor of rather than a bona fide therapeutic target in AMI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

In the recently published MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX) trial, the use of transradial access (TRA) compared to transfemoral access (TFA) during percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) was associated with a reduction in net adverse cardiovascular events. However, the results of MATRIX must be interpreted with caution due to several limitations including the strong modulating effect of operator/center experience on the relative efficacy of TRA and the inclusion of 2 distinct patient populations (ST-segment elevation and non-ST-segment elevation ACS). Therefore, although important, the results of MATRIX have strong limitations and are not sufficient to definitively identify an approach of choice during PCI for ACS. Further research is needed before strong, evidence-based recommendations regarding the approach of choice during PCI for ACS can be made., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cardiac arrest (CA) is relatively rare but lethal complication of takotsubo cardiomyopathy (TTC). In most instances, patients are diagnosed with TTC after CA, making it difficult to distinguish if TTC is the precipitant or the consequence of the index event. In this systematic review, patient-level data were obtained to seek out the characteristics of patients in whom the underlying cause of CA is TTC. A comprehensive search of 4 major databases (Embase, Ovid MEDLINE, PubMed, and Google Scholar) was performed from their inception to the last week of September 2014. Of 186 citations, 62 case studies were included in the analysis, providing patient-level data on 77 patients. In 60 patients (78%), the diagnosis of TTC was made after CA. Patients presenting with CA were younger (mean age 49.5 ± 16 vs 64.9 ± 11 years, p <0.0001) and had relatively shorter corrected QT interval (mean 530 ± 101 vs 616 ± 140 ms) on electrocardiography. TTC-related hypotension was the major cause of CA in the acute phase, while a long corrected QT interval triggered CA in the subacute (24- to 72-hour) phase. In 11 patients, CA was not directly instigated by TTC despite a left ventricular appearance matching TTC. In conclusion, in TTC, CA typically develops within the first 3 days of presentation and is the result of long corrected QT interval-induced polymorphic ventricular tachycardia. Secondary TTC, in which patients present with typical left ventricular features after CA, likely represents a distinct cohort in which identifiable inheritable arrhythmias or structural heart disease should be sought., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Takotsubo cardiomyopathy (TTC) has generally been regarded as a relatively transient disorder, characterized by reversible regional left ventricular systolic dysfunction. However, most patients with TTC experience prolonged lassitude or dyspnea after acute attacks. Although this might reflect continued emotional stress, myocardial inflammation and accentuated brain-type natriuretic peptide (BNP) release persist for at least 3 months. We therefore tested the hypotheses that this continued inflammation is associated with (1) persistent contractile dysfunction and (2) consequent impairment of quality of life. Echocardiographic parameters (global longitudinal strain [GLS], longitudinal strain rate [LSR], and peak apical twist [AT]) were compared acutely and after 3 months in 36 female patients with TTC and 19 age-matched female controls. Furthermore, correlations were sought between putative functional anomalies, inflammatory markers (T2 score on cardiovascular magnetic resonance, plasma NT-proBNP, and high-sensitivity C-reactive protein levels), and the physical composite component of SF36 score (SF36-PCS). In TTC cases, left ventricular ejection fraction returned to normal within 3 months. GLS, LSR, and AT improved significantly over 3-month recovery, but GLS remained reduced compared to controls even at follow-up (-17.9 ± 3.1% vs -20.0 ± 1.8%, p = 0.003). Impaired GLS at 3 months was associated with both persistent NT-proBNP elevation (p = 0.03) and reduced SF36-PCS at ≥3 months (p = 0.04). In conclusion, despite normalization of left ventricular ejection fraction, GLS remains impaired for at least 3 months, possibly as a result of residual myocardial inflammation. Furthermore, perception of impaired physical exercise capacity ≥3 months after TTC may be explained by persistent myocardial dysfunction., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Takotsubo cardiomyopathy (TTC) is often associated with hypotension and shock. However, development of hypotension/shock in TTC is not closely related to extent of left ventricular (LV) hypokinesis. We sought to determine whether additional right ventricular (RV) involvement in TTC might contribute to hypotension and shock development and thus to prolonged hospital stay (PHS)., Methods: We evaluated 102 consecutive TTC patients with acute transthoracic echocardiography (TTE) to detect RV hypokinesis. Correlates of hypotension, shock and PHS were identified by univariate and multivariate analyses., Results: Of the 102 patients evaluated, 33% had RV hypokinesis but only 9% had extensive RV involvement. Within the first 24 hours of admission, severe hypotension (systolic blood pressure (SBP) ≤ 90 mmHg) occurred in 21% of the patients and shock (hypotension + peripheral organ hypo-perfusion) in 16.6% of cases. RV involvement was a univariate but not a multivariate correlate of either hypotension or shock and did not result in PHS. On the other hand, RV involvement predicted more extensive LV hypokinesis and LV systolic dysfunction., Conclusions: In TTC, RV hypokinesis occurs in approximately 33% of cases and correlates with more severe LV wall motion abnormality but not with development of hypotension or shock. These data therefore reinforce previous findings that hypotension/shock in TTC are not purely by impaired cardiac output., (Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Introduction: Inpatient medical settings offer an opportunistic environment for initiating smoking cessation interventions to patients reflecting on their health. Current evidence has shown the superior efficacy of varenicline tartrate (VT) for smoking cessation compared with other tobacco cessation therapies; however, recent evidence also has highlighted concerns about the safety and tolerability of VT. Given these apprehensions, we aimed to evaluate the safety and effectiveness of VT plus quitline-counseling compared to quitline-counseling alone in the inpatient medical setting., Methods: Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to 3 hospitals were randomized to receive either 12 weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice daily) plus quitline-counseling (VT+C), (n = 196) or quitline-counseling alone (n = 196)., Results: VT was well tolerated in the inpatient setting among subjects admitted with acute smoking-related illnesses (mean age 52.8±2.89 and 53.7±2.77 years in the VT+C and counseling alone groups, respectively). The most common self-reported adverse event during the 12-week treatment phase was nausea (16.3% in the VT+C group compared with 1.5% in the counseling alone group). Thirteen deaths occurred during the study period (n = 6 were in the VT+C arm compared with n = 7 in the counseling alone arm). All of these subjects had known comorbidities or developed underlying comorbidities., Conclusions: VT appears to be a safe and well-tolerated opportunistic treatment for inpatient smokers who have related chronic disease. Based on the proven efficacy of varenicline from outpatient studies and our recent inpatient evidence, we suggest it be considered as part of standard care in the hospital setting., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Takotsubo cardiomyopathy (TTC) is a disorder of myocardial inflammation induced by high catecholamine levels and is associated with acute complications. In the long-term TTC is associated with a risk of single or multiple recurrences, but risk of such occurrences is not clear. We performed a systematic review and meta-analysis to identify and consolidate the evidence on the incidence and clinical correlates of cases of TTC recurrence., Methods: A comprehensive search of four major databases (EMBASE, OVID Medline, PubMed and Google Scholar) was performed from their inception to first week of Jan 2014. We included original research studies, recruiting ≥ 5 participants, with ≥ 3 months follow-up, published in English language that reported data on recurrence in patients with TTC., Results: Out of 298 studies searched, 31 cohorts (1664 TTC patients) were included in the analyses. Out of 74 cases of recurrence, with a mean follow-up of 24.5 months (95% CI, 19.3 to 33 months), extensive recurrence data were available for 23 cases. Cumulative incidence of recurrence was approximately 5% at 6 years. Annual rate of recurrence was approximately 1.5%. Furthermore, 14% of cases had recurrent chest pain and 11% reported dyspnea without definite evidence of recurrent TTC. Discharge medications at index admission included β-adrenoceptor antagonists (BB) in 66.8% and ACE inhibitors (ACEi) and ARB in 67.4%. Recurrence rate was independent of clinic utilization of BB prescription, but inversely correlated (r=-0.45, p=0.016) with ACEi/ARB prescription. Patients with severe TTC at index admission were noted to have more recurrences., Conclusions: (1) TTC is associated with only 1-2% annual recurrence rate but substantially greater frequency of ongoing symptoms. (2) ACEi/ARB rather than BB may reduce risk of recurrence., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Despite the significant amount of experimental data available on trehalose, the molecular mechanism responsible for its intracellular stabilising properties has not emerged yet. The repair of cellular homeostasis in many protein-misfolding diseases by trehalose is credited to the disaccharide being an inducer of autophagy, a mechanism by which aggregates of misfolded proteins are cleared by the cell. In this work, we expressed the pathogenic N-terminal fragment of huntingtin in Δnth1 mutant (unable to degrade trehalose) of Saccharomyces cerevisiae BY4742 strain. We show that the presence of trehalose resulted in the partitioning of the mutant huntingtin in the soluble fraction of the cell. This led to reduced oxidative stress and improved cell survival. The beneficial effect was independent of the expression of the major cellular antioxidant enzyme, superoxide dismutase. Additionally, trehalose led to the overexpression of the heat shock protein, Hsp104p, in mutant huntingtin-expressing cells, and resulted in rescue of the endocytotic defect in the yeast cell. We propose that at least in the initial stages of aggregation, trehalose functions as a stabiliser, increasing the level of monomeric mutant huntingtin protein, with its concomitant beneficial effects, in addition to its role as an inducer of autophagy.

Importance: Statin use has been associated with depression; however studies of the association between statin use and depression have yielded mixed results., Objective: To determine whether statin use is associated with depression and to evaluate the evidence supporting this association., Data Sources: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, EMBASE, PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched through December 28, 2012., Study Selection: We included studies that evaluated exposure to statins, reported the development of depression, and relative risks or odds ratios (ORs) or provided data for their estimation. Two reviewers screened 981 abstracts independently using a standardized form, reviewed full text of 59 selected articles, and included 7 studies in this metaanalysis., Data Extraction and Synthesis: Study design, statin exposure, development of depression, and study quality were extracted by 2 independent reviewers. A pooled OR with 95% confidence interval (CI) was estimated using the random-effects model and heterogeneity was assessed using Cochran's Q test and the I(2) statistic., Results: Seven observational studies (4 cohort, 2 nested case-control, and 1 cross-sectional) from 5 countries enrolling 9187 patients were included. Statin users were 32% less likely to develop depression than nonusers (adjusted OR, 0.68; 95% CI, 0.52-0.89). Modest heterogeneity was observed between the studies (I(2)=55%, P=0.01), which could be accounted for by one study, exclusion of which removed the heterogeneity (P=0.40, I(2)=2%) and further strengthened the antidepressant effect of statin (adjusted OR, 0.63; 95% CI, 0.43-0.93). Heterogeneity could not be explained by study design or study population. The quality of supporting evidence was fair., Conclusions and Relevance: This systematic review and meta-analysis suggests that statin use is associated with lower risk for depression. However, higher-quality studies are needed to confirm the magnitude of this association., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The incidence and clinical correlates of acute in-hospital mortality of takotsubo cardiomyopathy (TTC) are not clear. We performed a systematic review and meta-analysis to consolidate the current evidence on acute mortality in TTC. We then assessed the impact of "secondary" TTC, male gender, advancing age, and catecholamine use on mortality. A comprehensive search of 4 major databases (EMBASE, Ovid MEDLINE, PubMed, and Google Scholar) was performed from their inception to the first week of July 2013. We included original research studies, recruiting ≥10 participants, published in English language, and those that reported data on mortality and cause of death in patients with TTC. Of 382 citations, 37 studies (2,120 patients with TTC) from 11 different countries were included in the analyses. The mean age of the cohort was 68 years (95% confidence interval [CI] 67 to 69) with female predominance (87%). The in-hospital mortality rate among patients with TTC was 4.5% (95% CI 3.1 to 6.2, I2=60.8%). Among all deaths, 38% were directly related to TTC complications and rest to underlying noncardiac conditions. Male gender was associated with higher TTC mortality rate (odds ratio 2.6, 95% CI 1.5 to 4.6, p=0.0008, I2=0%) so was "secondary" TTC (risk difference -0.11, 95% CI -0.18 to -0.04, p=0.003, I2=84%). The mean age of patients dying tended to be greater than that in the whole cohort (72±7 vs 65±7 years). In conclusion, TTC is not as benign as once thought. To reduce the mortality rate, greater efforts need to be directed to the diagnosis, treatment, and ultimately prevention of "secondary" TTC., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The use of β2 agonist as an intervention for acute lung injury (ALI) and ARDS patients is controversial, so we performed a systematic review and meta-analysis of the published randomized controlled trials of using β2 agonists to improve outcomes (mortality and ventilator free days) among patients with ALI/ARDS., Methods: A comprehensive search of 7 major databases (Ovid MEDLINE In-Process and other non-indexed citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials (CENTRAL), Ovid Cochrane Database of Systematic Reviews, Web of Science, and Scopus) for randomized controlled trials using β2 agonists for ALI from their origin to March 2013 was conducted. The effect size was measured by relative risk for dichotomous outcomes, and mean difference for continuous outcomes, with 95% CI. The statistical heterogeneity between the studies was assessed with the Cochran Q test and I(2) statistic. The heterogeneity of > 50% was considered significant for the analysis. The Cochrane risk of bias tool was used to ascertain the quality of the included studies., Results: Out of 219 studies screened, 3 randomized controlled trials reported mortality and ventilator-free days, in 646 ALI/ARDS subjects. Of the 646 subjects, 334 (51.7%) received β2 agonist and 312 (48.3%) received placebo. There was no significant decrease in 28-day mortality or hospital mortality in the β2-agonist group: relative risk 1.04, 95% CI 0.50-2.16, and relative risk 1.22, 95% CI 0.95-1.56, respectively. The ventilator-free days and organ-failure-free days were significantly lower for the ALI subjects who received β2 agonists: mean difference -2.19 days (95% CI -3.68 to -1.99 d) and mean difference -2.04 days (95% CI -3.74 to -0.35 d), respectively., Conclusions: In subjects with ALI/ARDS, β2 agonists were not only nonbeneficial in improving the survival, but were harmful and increased morbidity (reduced organ-failure-free days and ventilator-free days). The current evidence discourages the use of β2 agonist in ALI/ARDS patients. (International Prospective Register of Systematic Reviews, http://www.crd.york.ac.uk/prospero, 2012:CRD42012002616.).

Takotsubo cardiomyopathy (TTC) is a well-known condition, which leads to sudden transient regional systolic dysfunction. It mostly affects aging women and is usually precipitated by emotional or physical stress. Despite the tremendous amount of literature on TTC, cardiac sympathetic hyperactivity is the only thing known to be associated with pathogenesis. In our case, an elderly woman presented with an acute episode of TTC 24 hours after anti-influenza vaccination without any obvious stressor for sudden rise in the catecholamine level. Sudden postvaccination change in the cardiac sympathetic discharge is the most likely precipitant of TTC in this case.

Takotsubo cardiomyopathy (TTC) is uncommon emergency condition usually precipitated by emotional or physical stress and is characterized by near-normal coronary arteries and regional wall motion abnormalities that extend beyond a single coronary vascular territory. Variants of TTC include classic apical ballooning syndrome and less commonly, mid, basal, and biventricular variants. Cardiac arrest is an uncommon complication of TTC. In the convalescence phase of TTC, prolonged QTc interval may cause cardiac arrest, but the reason for cardiac arrest in the acute phase when QTc interval is normal is unclear. We report 3 cases of mid ventricular TTC, with out-of-hospital cardiac arrest as the presenting feature. All 3 patients had normal QTc interval and were found to have normal coronary arteries on cardiac catheterization at presentation. Mid ventricular TTC was confirmed on contrast left ventriculography and echocardiography. Cardiac arrest myocarditis was ruled out by myocardial biopsy in 2 deceased patients and by cardiac magnetic resonance imaging in the one who survived.