ABSTRACT
The extent of gendered COVID-19 impact remains undetermined for the lack of sex-disaggregated data. The prevailing view puts males nearly twice as impacted as females. Globally, access to resources and their usage are gendered- mostly favoring males. Gender gaps widen during natural/man-made calamities and pandemics. Modeling estimates of impact for top 70 countries reporting >300 sex-disaggregated COVID-19 deaths (>80% of total), indicates average mortality sex (male:female) ratio (COVID-MSR) of 1.37{+/-}0.30 (95% confidence interval:1.30-1.44; range:0.85-2.47) against prevalent pre-pandemic MSR of 1.79{+/-}0.41 (1.70-1.89; range:0.93-2.99). Contrary to the prevailing view, widened gender gaps globally increased female mortality by 19.57{+/-}21.16% (14.62%-24.88%; range: -22.46 to +68.50%) causing an estimated 22.03% excess deaths (360 thousand by 30 December 2021). Identification of factors favoring gendered impacts is needed for equitable pandemic management. One-Sentence Summary Missing Females in COVID-19?
ABSTRACT
Endeavors to identify potentially protective variables for COVID-19 impact on certain populations have remained a priority. Multiple attempts have been made to attribute the reduced COVID-19 impact on populations to their bacillus Calmette-Guerin (BCG) vaccination coverage ignoring the fact that the effect of childhood BCG vaccination wanes within 5 years while most of the COVID-19 cases and deaths have occurred in aged with comorbidities. Since the supposed protection being investigated could come from heterologous trained immunity (TI) conferred by exposure to Mycobacterium spp. (i.e., environmental and BCG), it is argued that the estimates of the prevalence of TI of populations currently available as latent tuberculosis infection (LTBI) prevalence would be a better variable to evaluate such assertions. Indeed, when we analyze the European populations (twenty-four), and erstwhile East and West Germany populations completely disregarding their BCG vaccination coverage, the populations with higher TI prevalence consistently display reduced COVID-19 impact as compared to their lower TI prevalence neighbors. The TI estimates of the populations not the BCG coverage per se, negatively correlated with pandemic phase-matched COVID-19 incidences (r(24): - 0.79 to -0.57; p-value: <0.004), mortality (r(24): -0.63 to -0.45; p-value: <0.03), and interim case fatality rates(i-CFR) data. To decisively arrive at dependable conclusions about the potential protective benefit gained from BCG vaccination in COVID-19, the ongoing/planned randomized controlled trials should consciously consider including measures of TI as - a) all individuals immunized do not respond equally, b)small study groups from higher background TI could fail to indicate any protective effect. O_TEXTBOXSummary BoxO_ST_ABSWhat is already known?C_ST_ABSO_LIPreviously, COVID-19 incidence (SARS-CoV-2 infections) and mortality datasets of disparate populations with regard to phase of pandemic, demographics, medical infrastructure etc. have been modelled to negatively associate with highly transformed BCG vaccination coverage and policy of the countries. C_LIO_LIRecently BCG vaccination has been linked to risk of COVID-19 using vaccinated individuals from disparate populations (different underlying trained immunity) without any estimation of the underlying immune status or attempt to make the confounders for the groups being compared to be equal. C_LIO_LIAbout 8 out of 10 COVID-19 deaths have been in aged >65 years old. C_LIO_LIBCG vaccination is known to provide-cross protection from a number of unrelated diseases. C_LIO_LIBCG vaccination given in childhood protects children from milliary tuberculosis and the conferred protective trained-Immunity correlate or TIC (loosely equals tuberculin positivity) wanes away within 5 years from most in the absence of boosters or rechallenge from environmental Mycobacterium spp. C_LI New FindingsO_LIDisregarding BCG vaccination coverage or policy, the prevailing TIC correlate of populations predict protection from COVID-19 in socially similar European countries, i.e., the countries which are more similar to each other than other parts of the world with regard to various supposed confounders (e.g., exposure, phase of pandemic, health services, social support, food, genetic relatedness etc.). C_LI Recommendations for Policy and PracticeO_LIThe planned and ongoing studies or clinical trials assessing the effectiveness of BCG vaccination in protecting populations against COVID-19 or making them vulnerable to COVID-19 should include TIC correlates information of the participants (both controls and vaccinated) to arrive at dependable conclusions about potential benefit of BCG vaccination in controlling COVID-19 infections and mortality. C_LI C_TEXTBOX
ABSTRACT
The impact of Zinc (Zn) sufficiency/supplementation on COVID-19 associated mortality and incidence (SARS-CoV-2 infections) remains unknown. During an infection, the levels of free Zn are reduced as part of nutritional immunity to limit the growth and replication of pathogen and the ensuing inflammatory damage. Considering its key role in immune competency and frequently recorded deficiency in large sections of different populations, Zn has been prescribed for both prophylactic and therapeutic purposes in COVID-19 without any corroborating evidence for its protective role. Multiple trials are underway evaluating the effect of Zn supplementation on COVID-19 outcome in patients getting standard of care treatment. However, the trial designs presumably lack the power to identify negative effects of Zn supplementation, especially in the vulnerable groups of elderly and patients with comorbidities (contributing 9 out of 10 deaths; up to >8000-fold higher mortality). In this study, we have analyzed COVID-19 mortality and incidence (case) data from 23 socially similar European populations with comparable confounders (population: 522.47 million; experiencing up to >150 fold difference in death rates) and at the matching stage of the pandemic (12 March - 26 June 2020; 1st wave of COVID-19 incidence and mortality). Our results suggest a positive correlation between populations Zn-sufficiency status and COVID-19 mortality (r(23): 0.7893-0.6849, p-value<0.0003) as well as incidence [r(23):0.8084 to 0.5658; p-value<0.005]. The observed association is contrary to what would be expected if Zn sufficiency was protective in COVID-19. Thus, controlled trials or retrospective analyses of the adverse event patients data should be undertaken to correctly guide the practice of Zn supplementation in COVID-19.
ABSTRACT
Protective variables for COVID-19 are unknown. Trained immunity of the populace as a result of BCG immunization policy implementation and coverage had been suggested to be one of the factors responsible for the differential impact of COVID-19 on different countries. Several trials are underway to evaluate the potential protective role of BCG vaccination in COVID-19. However, the lack of clarity on the use of appropriate controls concerning the measures of trained immunity or the heterologous cell-mediated immunity conferred by BCG vaccination has been a cause of concern leading to more confusion as exemplified by a recently concluded trial in Israel that failed to find any protective correlation with regard to BCG vaccination. Whereas, when we analyze the COVID-19 data of European countries without any regard for BCG vaccination policy but with similar age distribution, comparable confounding variables, and the stage of the pandemic, the prevalence of tuberculin immunoreactivity - a measure of cell-mediated immunity persistence as a result of Mycobacterium spp. (including BCG vaccine) exposure of the populations, is found consistently negatively correlated with COVID-19 infections and mortality per million population, at all the time points evaluated. We propose that on-going and future studies evaluating the effect of BCG vaccination on COVID-19 outcomes may actively consider, if not already, the inclusion of controls for underlying trained immunity and heterologous cell-mediated immunity prevalence that may be pre-existing or resulting from the intervention (e.g., BCG vaccine) in such trials to arrive at more dependable conclusions concerning their potential benefit.
ABSTRACT
In the post-genomic era, various computational methods that predict protein-protein interactions at the genome level are available; however, each method has its own advantages and disadvantages, resulting in false predictions. Here we developed a unique integrated approach to identify interacting partner(s) of Semaphorin 5A (SEMA5A), beginning with seven proteins sharing similar ligand interacting residues as putative binding partners. The methods include Dwyer and Root-Bernstein/Dillon theories of protein evolution, hydropathic complementarity of protein structure, pattern of protein functions among molecules, information on domain-domain interactions, co-expression of genes and protein evolution. Among the set of seven proteins selected as putative SEMA5A interacting partners, we found the functions of Plexin B3 and Neuropilin-2 to be associated with SEMA5A. We modeled the semaphorin domain structure of Plexin B3 and found that it shares similarity with SEMA5A. Moreover, a virtual expression database search and RT-PCR analysis showed co-expression of SEMA5A and Plexin B3 and these proteins were found to have co-evolved. In addition, we confirmed the interaction of SEMA5A with Plexin B3 in co-immunoprecipitation studies. Overall, these studies demonstrate that an integrated method of prediction can be used at the genome level for discovering many unknown protein binding partners with known ligand binding domains.
