Meningoencephalitis associated with COVID-19: a systematic review

Journal of NeuroVirology - With the growing number of COVID-19 cases in recent times. significant set of patients with extra pulmonary symptoms has been reported worldwide. Here we venture out to...     

Development and validation of algorithms for heart failure patient care: a Delphi study

INTRODUCTION

Although heart failure (HF) management is available at primary and secondary care facilities in Malaysia, the optimisation of drug therapy is still suboptimal. Although pharmacists can help bridge the gap in optimising HF therapy, pharmacists in Malaysia currently do not manage and titrate HF pharmacotherapy. The aim of this study was to develop treatment algorithms and monitoring protocols for angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers and spironolactone based on extensive literature review for validation and utilisation by pharmacists involved in HF management.

METHODS

A Delphi survey involving 32 panellists from private and government hospitals that provide cardiac services in Malaysia was conducted to obtain a consensus of opinion on the treatment protocols. The panellists completed two rounds of self-administered questionnaires to determine their level of agreement with all the components in the protocols.

RESULTS

Consensus was achieved for most of the sections of the protocols for the four classes of drugs. The panellists’ opinions were taken into consideration when amending the components of the protocols that did not achieve consensus of opinion. Full consensus was achieved with the second survey conducted, enabling the finalisation of the drug titration protocols.

CONCLUSION

The resulting validated HF titration protocols can be used as a guide for pharmacists when recommending the initiation and titration of HF drug therapy in daily clinical practice. Recommendations should be made in collaboration with the patient’s treating physician, with concomitant monitoring of the patient’s response to the drugs.     

Baseline Polymorphisms and Emergence of Drug Resistance in the NS3/4A Protease of Hepatitis C Virus Genotype 1 following Treatment with Faldaprevir and Pegylated Interferon Alpha 2a/Ribavirin in Phase 2 and Phase 3 Studies

Analysis of data pooled from multiple phase 2 (SILEN-C1 to 3) and phase 3 studies (STARTVerso1 to 4) of the hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) protease inhibitor faldaprevir plus pegylated interferon alpha/ribavirin (PR) provides a comprehensive evaluation of baseline and treatment-emergent NS3/4A amino acid variants among HCV genotype-1 (GT-1)-infected patients. Pooled analyses of GT-1a and GT-1b NS3 population-based pretreatment sequences (n = 3,124) showed that faldaprevir resistance-associated variants (RAVs) at NS3 R155 and D168 were rare (<1%). No single, noncanonical NS3 protease or NS4A cofactor baseline polymorphism was associated with a reduced sustained virologic response (SVR) to faldaprevir plus PR, including Q80K. The GT-1b NS3 helicase polymorphism T344I was associated with reduced SVR to faldaprevir plus PR (P < 0.0001) but was not faldaprevir specific, as reduced SVR was also observed with placebo plus PR. Among patients who did not achieve SVR and had available NS3 population sequences (n = 507 GT-1a; n = 349 GT-1b), 94% of GT-1a and 83% of GT-1b encoded faldaprevir treatment-emergent RAVs. The predominant GT-1a RAV was R155K (88%), whereas GT-1b encoded D168 substitutions (78%) in which D168V was predominant (67%). The novel GT-1b NS3 S61L substitution emerged in 7% of virologic failures as a covariant with D168V, most often among the faldaprevir breakthroughs; S61L in combination with D168V had a minimal impact on faldaprevir susceptibility compared with that for D168V alone (1.5-fold difference in vitro). The median time to loss of D168 RAVs among GT-1b-infected patients who did not have a sustained virologic response at 12 weeks posttreatment (non-SVR12) after virologic failure was 5 months, which was shorter than the 14 months for R155 RAVs among GT-1a-infected non-SVR12 patients, suggesting that D168V is less fit than R155K in the absence of faldaprevir selective pressure.     

Synergistic actions of insulin-sensitive and Sirt1-mediated pathways in the differentiation of mouse embryonic stem cells to osteoblast

Murine embryonic stem cells (mESCs) have the potential to differentiate into almost any type of cell, and hence, represent a useful biological resource for tissue engineering. The differentiation of mESCs into osteoblasts in vitro is usually dampened by simultaneous differentiation of adipocytes. Insulin exerts a profound effect on bone development through increased differentiation of osteoblasts and concurrent formation of adipocytes. Comparatively, Sirt1, which plays a crucial role in osteoblast differentiation, has been reported to down regulate adipocyte formation during osteoblast differentiation. This study analyzed the combined effects of insulin and Sirt1 on the differentiation of osteoblasts. Osteoblast differentiation was quantified by estimating the accumulation of mineralized matrix and expression of osteogenic genes. The present data show that the simultaneous action of the insulin and Sirt1-mediated pathways increased the efficiency of osteoblast differentiation. When the cells were tested for ALP activity and Alizarin red staining, there was a respective increase of ~180% and ~166% (P<0.05) compared to the control. Furthermore, the mRNA expression patterns of osteoprotegerin, osterix, runx2, and osteopontin were increased by 3.6, 2.3, 1.8, and 1.7-fold, respectively, with a concomitant decrease in the mRNA expression levels of adipocyte marker genes. Interestingly, blocking the effects of both Sirt1 and insulin resulted in decreased osteoblastogenesis (60%) and subsequent increased adipocyte differentiation (195%) (P<0.05). Moreover, immunoblotting analysis demonstrated that this activation was via an Akt-dependent pathway. In conclusion, the present data suggests an enhanced process of osteoblast differentiation that can be exploited further to improve mESC differentiation.     

Comparison of the Proportion of Non‐Classic (CD14+CD16+) Monocytes/Macrophages in Peripheral Blood and Gingiva of Healthy Individuals and Patients With Chronic Periodontitis

Background: Monocyte subsets with low CD14 expression that coexpress CD16 (CD14+CD16+) are called non‐classic or hyperinflammatory monocytes. Previous studies have reported an increase in the percentage of CD14+CD16+ monocytes in the peripheral blood of patients with chronic periodontitis (CP). To our knowledge, there are no reports demonstrating the presence of CD14+CD16+ monocyte–derived macrophages (MDMs) in the gingival tissue. The objective of this study is to identify the proportion of non‐classic (CD14+CD16+) monocytes/macrophages in peripheral blood and gingiva of healthy individuals and patients with CP. Methods: A total of 60 individuals (n = 30 per group) were recruited for the study. Group 1 included 30 individuals with healthy gingiva, and group 2 included 30 patients with CP. Direct immunofluorescent staining was done in 200 μL whole‐blood and single‐cell suspensions obtained from gingival tissue, with fluorochrome‐conjugated monoclonal antibodies against CD14, CD16, and human leukocyte antigen‐DR (HLA‐DR), and subjected to flow cytometric analysis. Results: The mean percentage of CD14+CD16+ monocytes in the peripheral blood of healthy individuals was 9.10% ± 1.39%, and for patients with CP it was 14.18% ± 2.69% (P <0.05). The mean percentage of CD14+CD16+ MDMs in the gingival tissue of healthy individuals was found to be 0.93% ± 0.33%, whereas in patients with CP, it was 1.92% ± 0.78% (P <0.01). Non‐classic monocytes/macrophages showed a high median fluorescent intensity for HLA‐DR (DR++). Conclusion: This study demonstrates an increased proportion of CD14+CD16+HLA‐DR++ monocytes/macrophages in the peripheral blood and gingiva of patients with CP.     

Age and sex effects on brain morphology

1. 1. Brain morphology can be assessed readily in vivo using magnetic resonance imaging (MRI).

2. 2. In this study, the effects of age and sex on whole-brain morphology were examined using an operator-controlled computer-segmentation protocol.

3. 3. Results indicated that age was associated with gray-matter volume reduction.

4. 4. Brain-size differences between males and females were primarily attributable to whitematter volume.

5. 5. This study confirms the importance of controlling for age and sex in brain-morphology studies.

     

Long-term effects of rivastigmine in moderately severe Alzheimer's disease: does early initiation of therapy offer sustained benefits?

Goals of the study included evaluating the long-term efficacy of rivastigmine in Alzheimer's disease (AD) patient categories stratified by baseline dementia severity, and post hoc investigation of particular benefits of early initiation of rivastigmine treatment in moderately severe AD. Both rivastigmine-treated groups (originally randomized to 1-4 or 6-12 mg/day) experienced significantly smaller declines in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores from baseline than the projected placebo group after 52 weeks. Patients receiving rivastigmine from Day 1 experienced significantly less decline compared with patients originally receiving placebo and then initiating rivastigmine treatment after a 6-month delay. Furthermore, cognitive benefits were more robust in patients with moderately severe disease compared with previous reports in mild to moderately severe AD. Findings suggest that early treatment with rivastigmine 6-12 mg/day is associated with sustained long-term cognitive benefits in patients with moderately severe AD. The results support the value of early treatment of AD patients, particularly those with moderately severe AD.