ABSTRACT
Dilated cardiomyopathy (DCM) is a cardiac condition with structural and functional impairment, where either the left ventricle or both ventricular chambers are enlarged, coinciding with reduced systolic pump function (reduced ejection fraction, rEF). The prevalence of DCM is more than 1:250 individuals, and mortality largely due to heart failure in two-third of cases, and sudden cardiac death in one-third of patients. Damage to the myocardium, whether from a genetic or environmental cause such as viruses, triggers inflammation and recruits immune cells to the heart to repair the myocardium. Examination of myocardial biopsy tissue often reveals an inflammatory cell infiltrate, T lymphocyte (T cell) infiltration, or other activated immune cells. Despite medical therapy, adverse outcomes for DCM remain. The evidence base and existing literature suggest that upregulation of CX3CR1, migration of immune cells, together with cytomegalovirus (CMV) seropositivity is associated with worse outcomes in patients with dilated cardiomyopathy. We hypothesise that this potentially occurs through cardiac inflammation and fibrosis, resulting in adverse remodelling. Immune modulators to target this pathway may potentially improve outcomes above and beyond current guideline-recommended therapy.
Subject(s)
Cardiomyopathy, Dilated , Humans , Cardiomyopathy, Dilated/pathology , CX3C Chemokine Receptor 1 , Chemokine CX3CL1 , Inflammation , Immunomodulation , Receptors, Complement 3bABSTRACT
Objectives: To investigate the safety and pharmacokinetic profiles of long-acting injectable pre-exposure prophylaxis (LAI PrEP), notably cabotegravir (CAB-LA) and rilpivirine (RPV-LA), for the prevention of human immunodeficiency virus-1 (HIV-1) infection. Methods: Eligible randomized trials of LAI PrEP in HIV-uninfected and/or healthy patients were included and assessed with the Revised Cochrane risk-of-bias tool for randomized trials. Where feasible, a meta-analysis was performed for safety outcomes by using a random-effects model with risk ratios and their 95% confidence intervals as the common effect measure. The protocol was registered with PROSPERO CRD42020154772. Results: Eight studies cumulating a total of 666 participants were included in this systematic review, including five (362 intervention-arm volunteers) and four trials (194 intervention-arm volunteers) that investigated CAB-LA and RPV-LA, respectively. We found that both CAB-LA and RPV-LA were generally well-tolerated as their safety profiles were similar to placebo in terms of any adverse event (AE), serious AE, and AE-related withdrawals. Furthermore, pharmacokinetic analyses revealed favorable prospects in viral inhibitory activity of CAB-LA and RPV-LA. Intramuscular (IM) injection of CAB-LA 600 mg Q8W was superior to CAB-LA 800 mg Q12W in male participants, while the same was true for RPV-LA 1200 mg IM Q8W over other dosing regimens. Although these results are promising, further research is required to confirm the findings on RPV-LA as current evidence is limited. Conclusion: CAB-LA and RPV-LA have promising safety and pharmacokinetic profiles. The preventive efficacy of these agents is being evaluated in Phase 3 trials.
ABSTRACT
AIMS: To investigate the prognostic value of admission blood glucose (BG) in predicting COVID-19 outcomes, including poor composite outcomes (mortality/severity), mortality, and severity. METHODS: Eligible studies evaluating the association between admission fasting BG (FBG) and random BG (RBG) levels with COVID-19 outcomes were included and assessed for risk of bias with the Quality in Prognosis Studies tool. Random-effects dose-response meta-analysis was conducted to investigate potential linear or non-linear exposure-response gradient. RESULTS: The search yielded 35 studies involving a total of 14,502 patients. We discovered independent association between admission FBG and poor COVID-19 prognosis. Furthermore, we demonstrated non-linear relationship between admission FBG and severity (Pnon-linearity < 0.001), where each 1 mmol/L increase augmented the risk of severity by 33% (risk ratio 1.33 [95% CI: 1.26-1.40]). Albeit exhibiting similar trends, study scarcity limited the evidence strength on the independent prognostic value of admission RBG. GRADE assessment yielded high-quality evidence for the association between admission FBG and COVID-19 severity, and moderate-quality evidence for its association with mortality and poor outcomes. CONCLUSION: High admission FBG level independently predicted poor COVID-19 prognosis. Further research to confirm the prognostic value of admission RBG and to ascertain the estimated dose-response risk between admission FBG and COVID-19 severity are required.
