Effect of intensive versus standard blood pressure control on major adverse cardiac events and serious adverse events: A bivariate analysis of randomized controlled trials

Background: Intensive blood pressure (BP) lowering may offer protective effects against major adverse cardiac event (MACE) but is also associated with a greater risk of a serious adverse event (SAE). The risk-benefit profile of intensive versus standard BP control has not been comprehensively assessed. Methods: Four studies were identified from a systematic literature search for randomized controlled trials comparing intensive versus standard BP lowering that reported both MACE and SAE endpoints. A previously described statistical approach was applied to characterize the efficacy-safety tradeoff of BP control. The bivariate outcome was computed to quantitatively assess the net clinical benefit (NCB) of intensive BP lowering as compared to standard treatment, with positive values indicating increased risks and negative values indicating decreased risks. Results: Data from the SPRINT trial demonstrated that intensive strategy was superior in MACE but inferior in SAE, thereby eroding the NCB (bivariate outcome: 0.33% [?0.50% to 1.21%]). Intensive strategy from the SPS3 trial fulfilled non-inferiority in both MACE and SAE but did not reach a favorable NCB (?1.31% [?2.25% to 0.01%]). The ACCORD trial suggested that intensive strategy was non-inferior in MACE but inferior in SAE (?0.19% [?0.79% to 1.37%]). Results from the VALISH trial were inconclusive for SAE but suggested non-inferiority in MACE (?1.19% [?3.24% to 0.68%]). Conclusions: Compared to the standard blood pressure target, pooled data from randomized controlled trials suggest that intensive strategy did not achieve a net clinical benefit when weighing the benefit of MACE reduction against the risk of SAE under the bivariate framework.Abbreviations: Blood pressure (BP), diastolic blood pressure (DBP), major adverse cardiac event (MACE), net clinical benefit (NCB), serious adverse event (SAE), systolic blood pressure (SBP).     

Significance of 18F-FDG PET/CT in Characterization of Equivocal Lesions in High-Risk Testicular Carcinoma in Restaging Setting

Objectives: The present study aims to evaluate the role of Positron emission tomography (PET) -computed tomography (CT) with 18F-fluorodeoxyglucose (18F-FDG) in the restaging of high-risk testicular cancer. Methods: Forty-five patients (mean age of 38.1±11.3 years and range 23-81 years) with testicular carcinoma, underwent 18F-FDG PET-CT during their clinical course were prospectively selected. PET positivity was defined as a site of abnormal 18F-FDG uptake in tissue histologically proven or clinically or radiographically suspected to represent tissue involvement. The sites of disease were characterized as either nodal or extranodal. All patients were followed-up for at least 12 months with a diagnostic and/or functional imaging modality. Results: Of the 45 patients 38 (84%) patient presented with seminoma and 7 (16%) were Non-seminomatous germ cell tumors. Analysis of secondary disease spectrum showed nodal involvement in 65%, osseous involvement in 23% and mixed visceral/soft tissue lesions in 12% of patients. Nineteen (42%) were negative for any metastatic disease. All negative patients remain disease free in the follow-up of one year. Out of the positive 26/45 patients, PET-CT showed progressive disease in 3/26, stable disease 1/26 and partial response in 2/26 and complete metabolic resolution in 20/26 patients. 18F-FDG PET-CT was able to characterize all patients leading to significant change of primary decision of wait and watch to go for treatment and vice versa. Conclusion: 18F-FDG PET-CT scan is potentially an excellent tool for characterization of equivocal lesions on CT scan in the restaging settings and follow up of high-risk testicular cancer patients.     

Nutritional status and intestinal parasites among young children from pastoralist communities of the Ethiopian Somali region

Pastoralist children in the Ethiopian Somali Regional State (ESRS) are at high risk for undernutrition and intestinal parasitic infections (IPIs). We assessed the nutritional status and its association with IPIs in 500 children <5 years of age in a clustered cross‐sectional study in Adadle district, ESRS. Stool samples were microscopically examined for IPIs and biomarkers for iron and vitamin A status, anthropometry, and food variety score (FVS) were assessed. Median (interquartile range [IQR]) FVS was 2.0 (2.0, 4.0), and 35% of children were exclusively breastfed up to age 6 months. Prevalence of stunting, wasting, underweight and mid‐upper arm circumference (MUAC) <12.5 cm was 30, 34, 40, and 16%, respectively. Median (IQR) haemoglobin, ferritin, and retinol‐binding protein concentrations were 9.5 g dL^‐1 (8.2, 10.9), 6.2 μg L^‐1 (4.0, 10.2), and 0.8 μmol L^?1 (0.67, 0.91), respectively. Prevalence of anaemia, iron, and vitamin A deficiency was 75, 91, and 30%, respectively. IPIs' prevalence was 47%; the most prevalent IPIs were Giardia lamblia (22%) and Ascaris lumbricoides (15%). Giardial infections but not A. lumbricoides increased the risk for MUAC <12.5 cm (adjusted odds ratio [aOR]: 3.50, 95% confidence interval [CI] [2.21, 5.54]). The odds for anaemia were 97% (aOR: 0.03, 95% CI [0.03, 0.07]) and 89% (aOR: 0.11, 95% CI [0.11, 0.23]) less for children with FVS >2 or with exclusive breastfeeding up to 6 months, respectively. Undernutrition and IPIs are alarmingly high in <5 years of age children in ESRS. Giardial infections and low nutritional adequacy of the diet seem to be major contributing factors to the precarious nutritional status and should be addressed by appropriate interventions.     

Intranasal Delivery of Exendin-4 Confers Neuroprotective Effect Against Cerebral Ischemia in Mice

Exendin-4 is now considered as a promising drug for the treatment of cerebral ischemia. To determine the neuroprotective effects of intranasal exendin-4, C57BL/6J mice were intranasally administered with exendin-4 daily for 7 days before middle cerebral artery occlusion (MCAO) surgery. Intranasally administered exendin-4 produced higher brain concentrations and lower plasma concentrations when compared to identical doses administered interperitoneally. Neurological deficits and volume of infarcted lesions were analyzed 24 h after ischemia. Intranasal administration of exendin-4 exhibited significant neuroprotection in C57BL/6 mice subjected to MCAO by reducing neurological deficit scores and infarct volume. The neuroprotective effects of exendin-4 were blocked by the knockdown of GLP-1R with shRNA. However, exendin-4 has no impact on glucose and insulin levels which indicated that the neuroprotective effect was mediated by the activation of GLP-1R in the brain. Exendin-4 intranasal administration restored the balance between pro- and anti-apoptotic proteins and decreased the expression of Caspase-3. The anti-apoptotic effect was mediated by the cAMP/PKA and PI3K/Akt pathway. These findings provided evidence that exendin-4 intranasal administration exerted a neuroprotective effect mediated by an anti-apoptotic mechanism in MCAO mice and protected neurons against ischemic injury through the GLP-1R pathway in the brain. Intranasal delivery of exendin-4 might be a promising strategy for the treatment of ischemic stroke.     

Cinnamon Converts Poor Learning Mice to Good Learners: Implications for Memory Improvement

This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in converting poor learning mice to good learning ones. NaB, but not sodium formate, was found to upregulate plasticity-related molecules, stimulate NMDA- and AMPA-sensitive calcium influx and increase of spine density in cultured hippocampal neurons. NaB induced the activation of CREB in hippocampal neurons via protein kinase A (PKA), which was responsible for the upregulation of plasticity-related molecules. Finally, spatial memory consolidation-induced activation of CREB and expression of different plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones. However, oral treatment of cinnamon and NaB increased spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules in the hippocampus of poor-learning mice and converted poor learners into good learners. These results describe a novel property of cinnamon in switching poor learners to good learners via stimulating hippocampal plasticity.     

Efficacy and safety of topical difluprednate in persistent diabetic macular edema

To evaluate the efficacy and safety of treatment of diabetic macular edema (persistent type) with difluprednate ophthalmic emulsion 0.05 % (off label use). 20 patients with persistent diabetic macular edema were enrolled. In all subjects, more than 4 months had passed since prior treatment. All patients were treated with difluprednate ophthalmic emulsion 0.05 % three times daily for 3 months. At the end of 3 months the visual acuity had increased by two lines to a mean value of 0.61 ± 0.18 on logMAR from a baseline value of 0.885 ± 0.20 and the central retinal thickness had decreased from 423 ± 72.04 microns to 345 ± 68.7 microns. Hence, there was a total of 18.4 % decrease in retinal thickness on difluprednate. Major side effects included raised intraocular pressure in 20 %. Difluprednate is a potent and strong steroid which causes a rapid decrease in persistent diabetic macular edema. However, the potential side effect of raised intraocular pressure limits its use as an adjuvant therapy in non-steroid responders.