Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants.

We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Overall, in the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: The study has been registered to the South African National Clinical Trial Registry (SANCTR): DOH-27-012022-7841. The approval letter from SANCTR has been provided in the up-loaded documents.

Incidence and prevalence of hypertension among HIV-TB co-infected participants accessing treatment: A five-year prospective cohort analysis.

INTRODUCTION: Hypertension is a leading risk factor for cardiovascular disease among people living with human immunodeficiency virus (PLWH). This study determined incidence and prevalence of hypertension among PLWH receiving antiretroviral therapy (ART). METHOD: We prospectively followed-up 642 HIV and tuberculosis (TB) co-infected study participants from 2005-2013. We defined hypertension as two consecutive elevated systolic and/or diastolic blood pressure measurements above 139/89 mmHg or current use of antihypertensive therapy. RESULTS: Of 507 participants analyzed, 53% were women. Median [interquartile range (IQR)] age, body mass index (BMI), and CD4 count was 34 (28.0-40.0) years, 22.7 (20.5-25.4) kg/m2, and 145 (69.0-252.0) cells/mm3, respectively. Incidence [95% confidence interval (CI)] of both systolic and diastolic hypertension overall, in men, and in women over 40 years was 1.9 (1.4-2.6), 5.9 (3.6-9.6), and 5.0 (2.7-9.3) per 100 person-years (PY), respectively. Risk of developing hypertension was higher in men [(adjusted hazard ratio (aHR) 12.04, 95% CI: 4.35-33.32)] and women over 40 years (aHR 8.19, 95% CI 2.96-22.64), and in men below 40 years (aHR 2.79, 95% CI 0.95-8.23). CONCLUSION: Higher incidence rates of hypertension among older men and women accessing ART highlight opportunities to expand current integrated HIV-TB care models, to include cardiovascular disease risk screening and care to prevent premature death.

Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants.

Background: We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. Methods: A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. Results: No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Conclusion: In the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: South African National Clinical Trial Registry (SANCR): DOH-27-012022-7841. Funding: South African Medical Research Council (SAMRC) and South African Department of Health (SA DoH).

Novel optical coherence tomography angiography biomarkers in the diagnosis and assessment of diabetic macular edema and diabetic macular ischemia in patients with non-proliferative diabetic retinopathy.

Purpose: The present study aims to determine the macular and choroidal optical coherence tomography angiography (OCTA) biomarkers in the assessment and monitoring of diabetic macular edema (DME) and diabetic macular ischemia (DMI) in patients with non-proliferative diabetic retinopathy (NPDR). Methods: In this cohort study, a total of 176 eyes of 110 patients with NPDR were investigated at our institute over a period of 10 months. Eyes were divided into four groups based on the severity of NPDR. Each eye was subjected to OCTA (Topcon 3D OCT-1 Maestro2) macula 6 × 6 mm2 en face. It features IMAGEnet 6 software for dynamic viewing of OCTA and imaging data. Four OCTA biomarkers for the macula were identified: foveal avascular zone area (FAZ area), foveal avascular zone contour irregularity (FAZ-CI), capillary dropout areas (CDA), and perifoveal intercapillary areas (PICA). The choroidal OCTA biomarker was the number of choroidal circulation flow voids (CCFV). For all analyses, P < 0.05 was considered statistically significant. Results: Increase in FAZ area and number of CDA were statistically significant (p < 0.0001) with an increase in central foveal thickness, suggesting a correlation of ischemic changes with an increase in DME. FAZ-CI, enlarged PICA, and CCFV were significantly associated with more severe NPDR patients. Conclusion: A correlation between DME and DMI in a patient of NPDR and its progression can be evaluated in a single visit. A unique feature of our study is it revealed novel diagnostic biomarkers of OCTA for DMI and DME.

Cardiolipin-Mediated Alleviation of Mitochondrial Dysfunction Is a Neuroprotective Effect of Statin in Animal Model of Ischemic Stroke.

In clinical settings, the benefit of statin for stroke is debatable as regular statin users may suffer from myalgia, statin-associated myopathy (SAM), and rarely rhabdomyolysis. Studies suggest that patients on statin therapy show lesser vulnerability toward ischemic stroke and post-stroke frailty. Both pre- and post-treatment benefits of statin have been reported as evident by its neuroprotective effects in both cases. As mitochondrial dysfunction following stroke is the fulcrum for neuronal death, we hereby explore the role of statin in alleviating mitochondrial dysfunction by regulating the mitochondrial dynamics. In the present study, we intend to evaluate the role of statin in modulating cardiolipin-mediated mitochondrial functionality and further providing a therapeutic rationale for repurposing statins either as preventive or an adjunctive therapy for stroke.

Post-stroke depression: Chaos to exposition.

Cerebral ischemia contributes to significant disabilities worldwide, impairing cognitive function and motor coordination in affected individuals. Stroke has severe neuropsychological outcomes, the major one being a stroke. Stroke survivors begin to show symptoms of depression within a few months of the incidence that overtime progresses to become a long-term ailment. As the pathophysiology for the progression of the disease is multifactorial and complex, it limits the understanding of the disease mechanism completely. Meta-analyses and randomized clinical trials have shown that intervening early with tricyclic antidepressants and selective serotonin receptor inhibitors can be effective. However, these pharmacotherapies possess several limitations that have given rise to newer approaches such as brain stimulation, psychotherapy and rehabilitation therapy, which in today's time are gaining attention for their beneficial results in post-stroke depression (PSD). The present review highlights numerous factors like lesion location, inflammatory mediators and genetic abnormalities that play a crucial role in the development of depression in stroke patients. Further, we have also discussed various mechanisms involved in post-stroke depression (PSD) and strategies for early detection and diagnosis using biomarkers that may revolutionize treatment for the affected population. Towards the end, along with the preclinical scenario, we have also discussed the various treatment approaches like pharmacotherapy, traditional medicines, psychotherapy, electrical stimulation and microRNAs being utilized for effectively managing PSD.

Neuroimmune crosstalk and evolving pharmacotherapies in neurodegenerative diseases.

Neurodegeneration is characterized by gradual onset and limited availability of specific biomarkers. Apart from various aetiologies such as infection, trauma, genetic mutation, the interaction between the immune system and CNS is widely associated with neuronal damage in neurodegenerative diseases. The immune system plays a distinct role in disease progression and cellular homeostasis. It induces cellular and humoral responses, and enables tissue repair, cellular healing and clearance of cellular detritus. Aberrant and chronic activation of the immune system can damage healthy neurons. The pro-inflammatory mediators secreted by chief innate immune components, the complement system, microglia and inflammasome can augment cytotoxicity. Furthermore, these inflammatory mediators accelerate microglial activation resulting in progressive neuronal loss. Various animal studies have been carried out to unravel the complex pathology and ascertain biomarkers for these harmful diseases, but have had limited success. The present review will provide a thorough understanding of microglial activation, complement system and inflammasome generation, which lead the healthy brain towards neurodegeneration. In addition to this, possible targets of immune components to confer a strategic treatment regime for the alleviation of neuronal damage are also summarized.

Cerebro-renal interaction and stroke.

Stroke is an event causing a disturbance in cerebral function leading to death and disability worldwide. Both acute kidney injury and chronic kidney disease (CKD) are associated with an increased risk of stroke and cerebrovascular events. The underlying mechanistic approach between impaired renal function and stroke is limitedly explored and has attracted researchers to learn more for developing therapeutic intervention. Common risk factors such as hypertension, hyperphosphatemia, atrial fibrillation, arteriosclerosis, hyperhomocysteinemia, blood-brain barrier disruption, inflammation, etc. are observed in the general population, but are high in renal failure patients. Also, risk factors like bone mineral metabolism, uremic toxins, and anemia, along with the process of dialysis in CKD patients, eventually increases the risk of stroke. Therefore, early detection of risks associated with stroke in CKD is imperative, which may decrease the mortality associated with it. This review highlights mechanisms by which kidney dysfunction can lead to cerebrovascular events and increase the risk of stroke in renal impairment.

The Role of Inflammasomes in Atherosclerosis and Stroke Pathogenesis.

Inflammation is a devastating outcome of cerebrovascular diseases (CVD), namely stroke and atherosclerosis. Numerous studies over the decade have shown that inflammasomes play a role in mediating inflammatory reactions post cellular injury occurring after a stroke or a rupture of an atherosclerotic plaque. In view of this, targeting these inflammatory pathways using different pharmacological therapies may improve outcomes in patients with CVD. Here, we review the mechanisms by which inflammasomes drive the pathogenesis of stroke and atherosclerosis. Also, discussed here are the possible treatment strategies available for inhibiting inflammasomes or their up-stream/down-stream mediators.

Migraine and Ischemic Stroke: Deciphering the Bidirectional Pathway.

Migraine and stroke are common, disabling neurological conditions with several theories being proposed to explain this bidirectional relationship. Migraine is considered as a benign neurological disorder, but research has revealed a connection between migraine and stroke, predominantly those having migraine with aura (MA). Among migraineurs, females with MA are more susceptible to ischemic stroke and may have a migrainous infarction. Migrainous infarction mostly occurs in the posterior circulation of young women. Although there are several theories about the potential relationship between MA and stroke, the precise pathological process of migrainous infarction is not clear. It is assumed that cortical spreading depression (CSD) might be one of the essential factors for migrainous infarction. Other factors that may contribute to migrainous infarction may be genetic, hormonal fluctuation, hypercoagulation, and right to left cardiac shunts. Antimigraine drugs, such as ergot alkaloids and triptans, are widely used in migraine care. Still, they have been found to cause severe vasoconstriction, which may result in the development of ischemia. It is reported that patients with stroke develop migraines during the recovery phase. Both experimental and clinical data suggest that cerebral microembolism can act as a potential trigger for MA. Further studies are warranted for the treatment of migraine, which may lead to a decline in migraine-related stroke. In this present article, we have outlined various potential pathways that link migraine and stroke.