Preserved or slightly depressed ejection fraction and outcomes after myocardial infarction

BACKGROUND Left ventricular ejection fraction (EF) in post-myocardial infarction (MI) patients is a strong predictor of adverse cardiovascular events. Although resting EF as measured by transthoracic echocardiography (TTE), contrast ventriculography (CNV), and radionuclide angiography (RNA) exhibit high correlation, there is only modest agreement between these modalities. This study sought to explore whether modality of EF assessment influences prognostication of post-MI patients with normal or slightly reduced EF. METHODS AND RESULTS The National Heart, Lung, and Blood Institute (NHLBI) limited access dataset of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial (1996-2003, n=8290) comparing trandolapril versus placebo was used. The cohort was partitioned into TTE (n=2582), RNA (n=816), and CNV (n=1155) groups based on modality of EF assessment. EF was a significant predictor of cardiovascular mortality (HR 0.97, 95% CI 0.95 to 0.98; p<0.005) and all cause mortality (HR 0.98, 95% CI 0.97 to 0.99; p=0.0002) on multivariate analysis in this population with preserved or mildly depressed EF. Although CNV, TTE, and RNA groups differed significantly in terms of baseline variables, no appreciable differences were noted between RNA (HR 1.13, 95% CI 0.85 to 1.50; ns) and CNV (HR 1.13, 95% CI 0.99 to 1.27; ns) groups, compared with TTE for all cause mortality. Similarly, no significant differences were observed for cardiovascular mortality between RNA (HR 1.23, 95% CI 0.82 to 1.84; p=0.31) and CNV (HR 1.14, 95% CI 0.78 to 1.67, p=0.49) versus TTE. CONCLUSION EF is a significant predictor of all-cause mortality and cardiovascular mortality in patients with preserved or mildly depressed EF. Modalities of EF measurement are interchangeable and do not play a significant role in prognostication in a post-MI population.     

Comparison of Substance Use and Risky Sexual Behavior Among a Diverse Sample of Urban,HIV-Positive Men Who Have Sex with Men

ABSTRACT

The purpose of this study was to examine substance use among a racially and ethnically diverse group of HIV-positive men who have sex with men (MSM) living in six U.S. cities, model associations between drug use and serodiscordant unprotected anal intercourse (SDUAI), and characterize users of the substances strongly associated with risky sexual behavior. Baseline questionnaire data from 675 participants of the Positive Connections intervention trial were analyzed. Overall, substance use was common; however, the highest percentage of stimulant (30%), methamphetamine (27%), and popper (i.e., amyl nitrite) (46%) use was reported among white MSM and crack/cocaine (38%) use was highest among African American MSM. Popper use versus non-use (odds ratio = 2.46; 95% confidence interval = 1.55–3.94) and condom self-efficacy (1 standard deviation (sd) increase on scale; odds ratio = .58; 95% confidence interval = .46–.73) were significantly associated with SDUAI after adjusting for key demographic and psychosocial factors. These results highlight the importance of addressing drug use in the context of sex for possible HIV transmission risk.     

Synthesis, antimycobacterial activities and phototoxic evaluation of 5H-thiazolo[3,2-a]quinoline-4-carboxylic acid derivatives

Thirty four novel 7-fluoro/nitro-1,2-dihydro-5-oxo-8-(sub)-5H-thiazolo[3,2-a]quinoline-4-carboxylic acids were synthesized from 2,4-dichlorobenzoic acid and 2,4-dichloro-5-fluoroacetophenone by multi step reaction, evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesized compounds, 8-[6-[[(1,1-dimethylethoxy)carbonyl]amino]-3-azabicyclo[3.1.0]hex-3-yl]-1,2-dihydro-7-nitro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid (10q) was found to be the most active compound in vitro with MIC of 0.08 microM and <0.08 microM against MTB and MDR-TB respectively. Compound 10q was found to be 4.5 and >570 times more potent than isoniazid against MTB and MDR-TB respectively. In the in vivo animal model 10q decreased the bacterial load in lung and spleen tissues with 2.51 and 3.71-log10 protections respectively at the dose of 50 mg/kg body weight.     

The Clinical and Serological Profile of Pediatric Dengue

Objective

To classify suspected dengue into dengue, dengue with warning signs and severe dengue, based on clinical features as per the revised WHO guidelines with special emphasis on serology.

Methods

It was a prospective cross-sectional study for five years from 2011–2016 in a tertiary care medical college hospital in Bangalore. All cases of fever of three to five days duration with symptoms like dengue were enrolled for the study. They were categorized into three groups as per the Revised WHO 2012 criteria. Laboratory parameters, serology, ultrasound abdomen and X-ray were done in almost all patients. Data was analysed by SPSS software, version 16, and different groups were compared with Chi square test.

Results

Five hundred sixty eight children were diagnosed to have dengue fever; 4.2% of the sample belonged to infancy. Majority were in the age group of 5–10 y (42.6%). Fever and flushing were present in majority of the children. Gastrointestinal bleed was more commonly seen in the severe dengue group. Dengue nonstructural protein antigen (NS1Ag) was positive in 78%, immunoglobulin M (IgM) in 15.8% and immunoglobulin G (IgG) in 14.6%. Children with IgG had more complications, though not statistically significant. Mortality was reported in 1.2%. Dengue serology helped to confirm the diagnosis, however did not help in patient management.

Conclusions

There is a considerable overlap in the symptomatology of dengue with warning signs and severe dengue. More studies are required on the severity and type of response to treatment in infants and obese adoloscents with severe dengue.

     

Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours

Background:

Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation.

Methods:

A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival.

Results:

The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression.

Conclusions:

The quantitative pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.     

Prolonged combination anti-platelet therapy following per-cutaneous coronary intervention (PCI) is impractical in the elderly

A prolonged course of anti-platelet therapy is increasingly recommended following per-cutaneous coronary intervention based on the evidence from several clinical trials. However, the practicality and risk of such therapy in unselected patient population is as yet unclear. This study shows that such prolonged regimes of anti-platelet therapy are not practical in the elderly sub-group of patients.     

Discovery of antimycobacterial spiro-piperidin-4-ones: an atom economic, stereoselective synthesis, and biological intervention

An atom economic and stereoselective synthesis of several spiro-piperidin-4-ones through 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin and alpha-amino acids viz . proline, phenylglycine, and sarcosine to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones is described. These compounds were evaluated for their in vitro and in vivo activity against Mycobacterium tuberculosis H37Rv (MTB), multidrug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)). Compound 4-(4-fluorophenyl)-5-phenylpyrrolo(spiro[2.3']oxindole)spiro[3.3']-1'-methyl-5'-(4-fluorophenylmethylidene)piperidin-4'-one (4e) was found to be the most active in vitro with a MIC value of 0.07 microM against MTB and was 5.1 and 67.2 times more potent than isoniazid and ciprofloxacin, respectively. In vivo, compound 4e decreased the bacterial load in lung and spleen tissues with 1.30 and 3.73-log 10 protections respectively and was considered to be promising in reducing bacterial count in lung and spleen tissues.     

In vitro expression of vital virulent genes of clinical and environmental isolates of Cryptococcus neoformans/gattii in endothelial cells of human blood-brain barrier

BackgroundEvaluation of the pathogenesis of clinical and environmental cryptococcal isolates to the central nervous system is necessary for understanding the risk. This study was designed to determine the in vitro expression of six important virulent genes of Cryptococcus neoformans/gattii in Human Brain Microvascular Endothelial cells (hBMEC).MethodsThe hBMEC were infected with Cryptococcus to determine invasion and survival rate at 3, 12 and 24 hours by subsequent colony count of internalized yeasts. The whole RNA of the intracellular Cryptococcus was extracted to quantify the expression of CAP10, PLB1, ENA1, URE1, LAC1, and MATα genes by real-time quantitative PCR for 3 and 12 hours of infection.ResultsInvasion and survival rates were higher in clinical and standard strains of C. neoformans. A significant difference was observed among the clinical and environmental isolates for the expression of CAP10, ENA1, LAC1, MATα and URE1 at 3 hours, and ENA1, LAC1, MATα, PLB1 and URE1 at 12 hours. Clinical isolates showed significant upregulation of all the genes except PLB1, which was higher in environmental isolates. Relative expressions at the two time-points showed statistically significant (P = 0.043) changes for the clinical isolates and no significance (P = 0.063) for environmental isolates.ConclusionThe C. gattii (VGI) isolates showed significantly lower invasion and survival than C. neoformans (VNI, and VNII) irrespective of their sources. Clinical isolates exhibited higher expression for the majority of the virulent genes until 12 hours of infection, probably due to their better adaptation in the host system and enhanced pathogenicity than the environmental counterparts.