Clinical pharmacology of siRNA therapeutics: current status and future prospects.

INTRODUCTION: Small interfering RNA (siRNA) has emerged as a powerful tool for post-transcriptional downregulation of multiple genes for various therapies. Naked siRNA molecules are surrounded by several barriers that tackle their optimum delivery to target tissues such as limited cellular uptake, short circulation time, degradation by endonucleases, glomerular filtration, and capturing by the reticuloendothelial system (RES). AREAS COVERED: This review provides insights into studies that investigate various siRNA-based therapies, focusing on the mechanism, delivery strategies, bioavailability, pharmacokinetic, and pharmacodynamics of naked and modified siRNA molecules. The clinical pharmacology of currently approved siRNA products is also discussed. EXPERT OPINION: Few siRNA-based products have been approved recently by the Food and Drug Administration (FDA) and other regulatory agencies after approximately 20 years following its discovery due to the associated limitations. The absorption, distribution, metabolism, and excretion of siRNA therapeutics are highly restricted by several obstacles, resulting in rapid clearance of siRNA-based therapeutic products from systemic circulation before reaching the cytosol of targeted cells. The siRNA therapeutics however are very promising in many diseases, including gene therapy and SARS-COV-2 viral infection. The design of suitable delivery vehicles and developing strategies toward better pharmacokinetic parameters may solve the challenges of siRNA therapies.

Efficacy of therapeutic plasma exchange in severe COVID-19 disease: A meta-analysis.

BACKGROUND AND OBJECTIVES: Therapeutic plasma exchange (TPE) has been used in severe COVID-19 disease to eliminate the cytokine storm. This meta-analysis aims to assess the effectiveness of TPE in reducing mortality in severe COVID-19 disease compared to standard treatment. MATERIALS AND METHODS: A comprehensive literature search was performed in PubMed, the Cochrane database and the International Clinical Trial Registry Platform (ICTRP). The random-effect model was used to calculate the risk ratio and standardized mean difference (SMD) as pooled effect size for the difference in mortality and length of the intensive care unit (ICU) stay. The risk of bias and publication bias were assessed in R version 4.1.0. The certainty of the evidence was calculated using the GradePro tool. RESULTS: The database identified 382 participants from six studies, including one randomized control trial. Egger's test did not detect any publication bias (p = 0.178). The random model analysis for mortality evaluated a risk ratio of 0.38 (95% CI: 0.28-0.52) with a significant reduction in the TPE group. The certainty of the evidence was moderate, with a risk ratio of 0.34 (95% CI: 0.24-0.49). Length of ICU stays between TPE versus standard care showed an SMD of 0.08 (95% CI: -0.38, 0.55) and was not significant. CONCLUSION: The length of ICU stay in the TPE group was not different from standard care. However, this meta-analysis revealed a significant benefit of TPE in reducing mortality in severe COVID-19 disease compared to standard treatment.

Impact of COVID-19 on blood donor deferral patterns during the COVID-19 pandemic: A retrospective analysis.

BACKGROUND AND OBJECTIVES: Blood donor deferral is an essential tool for blood safety. The ongoing COVID-19 pandemic has adversely affected blood transfusion services all over the world. But its impact on donor deferral rate and the pattern is unclear in light of the new donor deferral policy due to the COVID-19 pandemic. MATERIALS AND METHODS: This retrospective study was divided into pre-COVID and COVID (15 March 2019-14 March 2021). All the deferred donors were divided into six different categories: (1) medical causes, (2) surgical causes, (3) drugs and vaccination, (4) risk of transfusion-transmitted diseases, (5) miscellaneous causes and (6) flu-like symptoms. In addition, COVID-related deferrals were also incorporated. All these above categories along with the donor demography were analysed by SPSS software version 25. RESULTS: The donor deferral rate was 17.03% and 12.74% during the pre-COVID and COVID periods, respectively. During the pre-COVID period, Category 3 deferrals and during COVID period, Category 6 deferrals were significantly higher. A reversal in pattern with increased blood pressure (40.2% vs. 24.04%) over-riding low haemoglobin (34.77% vs. 55.5%) was noted in the Category 1 deferral during the COVID period. Category 1 deferral was more in middle-aged adults as compared to young and old adults (p < 0.05). Among middle-aged adults, deferral due to flu-like symptoms was also significantly more during the COVID period (p < 0.05). CONCLUSION: COVID-19 significantly affected the donor pool and changed the pattern of donor deferral. Understanding donor deferral patterns may help in identifying targeted donor populations and planning donor recruitment strategies in future pandemic crises.

Analysis of responses of the health care workers recovered from COVID-19 on convalescent plasma donation by apheresis: A single-center survey study.

BACKGROUND: The COVID-19 convalescent plasma (CCP) has been tried as a therapy in moderate COVID-19 pneumonia. Donation of CCP requires motivation from recovered patients. This study evaluated the response of such recovered health care workers (HCWs) when they were motivated for CCP donation. METHODS: An interview-based survey was carried out with recovered HCWs as study participants between August 2020 and November 2020. A qualified social worker explained the details of CCP donation over a mobile call; he clarified all their doubts and motivated them for the plasma donation. Their responses were recorded as "interested" or "not interested" followed by analysis. RESULTS: We tried to call 624 recovered HCWs, but could not reach 213, and the final group available for the study was 411 participants. Of these 411, 186 were deferred. Finally, we analyzed a total of 225 responses. Eventually, 105 out of 225 HCWs (47%) were interested; there were no significant differences in responses among males and females and between different age groups (<.001) and the "doctors" designation category (P = .01) had a maximum number of "interested" responses. In multivariate logistic regression, only the "interested" responses of the doctors were significantly higher after adjusting the confounding effect of the "graduate and above" educational qualification category. CONCLUSION: This study found that nearly half of the eligible HCWs were interested in CCP donation. The educational qualification and designation among the recovered HCWs had an impact on CCP donation interest. The doctors were more interested in CCP donation compared to others.

Progress in understanding of Indian Ocean circulation, variability, air–sea exchange, and impacts on biogeochemistry

Over the past decade, our understanding of the Indian Ocean has advanced through concerted efforts toward measuring the ocean circulation and air–sea exchanges, detecting changes in water masses, and linking physical processes to ecologically important variables. New circulation pathways and mechanisms have been discovered that control atmospheric and oceanic mean state and variability. This review brings together new understanding of the ocean–atmosphere system in the Indian Ocean since the last comprehensive review, describing the Indian Ocean circulation patterns, air–sea interactions, and climate variability. Coordinated international focus on the Indian Ocean has motivated the application of new technologies to deliver higher-resolution observations and models of Indian Ocean processes. As a result we are discovering the importance of small-scale processes in setting the large-scale gradients and circulation, interactions between physical and biogeochemical processes, interactions between boundary currents and the interior, and interactions between the surface and the deep ocean. A newly discovered regional climate mode in the southeast Indian Ocean, the Ningaloo Niño, has instigated more regional air–sea coupling and marine heatwave research in the global oceans. In the last decade, we have seen rapid warming of the Indian Ocean overlaid with extremes in the form of marine heatwaves. These events have motivated studies that have delivered new insight into the variability in ocean heat content and exchanges in the Indian Ocean and have highlighted the critical role of the Indian Ocean as a clearing house for anthropogenic heat. This synthesis paper reviews the advances in these areas in the last decade.

Outcomes of multisystem inflammatory syndrome in children temporally related to COVID-19: a longitudinal study.

To study the clinical, laboratory characteristics and outcomes of multisystem inflammatory syndrome in children (MIS-C) temporally related to coronavirus disease 2019 (COVID-19) in a resource-limited setting. All children meeting the World Health Organization case definition of MIS-C were prospectively enrolled. Baseline clinical and laboratory parameters were compared between survivors and non-survivors. Enrolled subjects were followed up for 4-6 weeks for evaluation of cardiac outcomes using echocardiography. The statistical data were analyzed using the stata-12 software. Thirty-one children with MIS-C were enrolled in an 11-month period. Twelve children had preexisting chronic systemic comorbidity. Fever was a universal finding; gastrointestinal and respiratory manifestations were noted in 70.9% and 64.3%, respectively, while 57.1% had a skin rash. Fifty-eight percent of children presented with shock, and 22.5% required mechanical ventilation. HSP like rash, gangrene and arthritis were uncommon clinical observations.The median duration of hospital stay was 9 (6.5-18.5) days: four children with preexisting comorbidities succumbed to the illness. The serum ferritin levels (ng/ml) [median (IQR)] were significantly higher in non-survivors as compared to survivors [1061 (581, 2750) vs 309.5 (140, 720.08), p value = 0.045]. Six patients had coronary artery involvement; five recovered during follow-up, while one was still admitted. Twenty-six children received immunomodulatory drugs, and five improved without immunomodulation. The choice of immunomodulation (steroids or intravenous immunoglobulin) did not affect the outcome. Most children with MIS-C present with acute hemodynamic and respiratory symptoms.The outcome is favorable in children without preexisting comorbidities.Raised ferritin level may be a poor prognostic marker. The coronary outcomes at follow-up were reassuring.

Environmental impact of COVID-19 led lockdown: A satellite data-based assessment of air quality in Indian megacities.

The strategies to contain the spread of COVID-19 pandemic, including restricted human movement and economic activities, have shown positive impacts on the environment. Present research analysed the effects of COVID-19 led lockdown on air quality with special reference to major pollutants, namely nitrogen dioxide (NO2), carbon monoxide (CO), sulphur dioxide (SO2) and aerosol optical depth (AOD). The assessment has been conducted for megacities of India (Delhi, Mumbai, Bengaluru, Chennai and Kolkata) for four months, that is, March and April in 2019 and 2020 using Sentinel 5P and MCD19A2 data. A decrease in concentrations of air pollutants, specifically NO2 and SO2, has been observed during the lockdown period in all the cities; whereas CO and AOD have exhibited discrete pattern of spatio-temporal variation. Four megacities except Kolkata have revealed a positive correlation between NO2 concentration and population density. The results conclude overall improvement in air quality during COVID-19 led lockdown. The current situation provides a unique opportunity to implement a structural economic change that could help us move towards a city with low emission economy. Realizing the achievable improvement of air quality, the study suggests further in-depth research on source attribution of individual pollutants to assess the prospect of emission reduction actions.