Among adults who develop coronavirus disease 2019 (COVID-19), those with rheumatic diseases (RDs) have similar hospitalization rates compared with those without RDs. Similar comparisons are lacking in children, due to the overall rarity of COVID-19-related hospitalization in this population. We aimed to examine the risk factors for COVID-19-related hospitalization in paediatric patients with RDs.

We conducted a systemic literature search in MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure from 1 December 2019, through 22 January 2024. We included observational studies based on inclusion and exclusion criteria. Odds ratios (ORs) with 95% CI were calculated.

Eight cohort studies capturing 1501 paediatric RD patients with SARS-CoV-2 and 118 COVID-19-related hospitalization were included. Odds of hospitalization was increased in children with RDs compared with healthy children. While the diagnosis of juvenile idiopathic arthritis (JIA) was associated with reduced odds of hospitalization overall (OR 0.43 [95% CI: 0.27, 0.68]), systemic JIA was associated with increased odds of hospitalization (OR 2.54 [95% CI: 1.01, 6.40]). The use of glucocorticoids (OR 5.36 [95% CI: 2.21, 13.04]), rituximab (OR 4.62 [95% CI: 1.87, 11.40]), mycophenolate mofetil (OR 4.17 [95% CI: 1.08, 16.16]), hydroxychloroquine (OR 2.97 [95% CI: 1.42, 6.21]), and IL-1 inhibitors (OR 2.28 [95% CI: 1.09, 4.78]) was associated with increased odds of hospitalization, while the use of TNFα inhibitors was associated with reduced odds (OR 0.35 [95% CI: 0.20, 0.66]).

Children with RDs are at risk of severe COVID-19 outcomes, while children with JIA taking TNFα inhibitors might be at a lower risk.

The rapid dissemination of scientific findings through media and social networks can profoundly impact public health policies and behaviors. However, the reliability of such data is crucial, as evidenced by significant cases like the retracted study on hydroxychloroquine (HCQ) during the COVID-19 pandemic. This paper examines the retraction of a widely publicized study by Pradelle et al., which concluded that HCQ was associated with an excess of 16,990 deaths during the pandemic's first wave. This finding was heavily influenced by a meta-analysis that did not robustly support its conclusions, particularly regarding the dose-response relationship of HCQ. Our analysis identified significant methodological flaws, including the misapplication of effect sizes and a lack of sensitivity analyses, rendering the study results unreliable. The retraction process, however, lacked transparency, failing to adequately describe in details the reasons for the study flaws to the public. This case underscores the broader challenges in scientific publishing, including the robustness of the peer-review process, the rise of fraudulent practices, and the erosion of trust in scientific institutions. We advocate for reforms to enhance transparency, improve data verification, and incentivize thorough peer review to maintain public trust and ensure the accuracy of scientific literature.

The preclinical work leading to the discovery of PF-07321332 (nirmatrelvir) is described in the Featured Article summarized in this Viewpoint. This work resulted in an Emergency Use Authorization (EUA) for Paxlovid within two years of the project's start. In addition to the medicinal chemistry approach taken, the authors describe how they achieved this remarkable speed.

Coronavirus disease-2019 was associated with significant mortality and morbidity in care homes in 2020-1. Repurposed antiviral drugs might reduce morbidity and mortality through reducing viral transmission, infection, replication and inflammation. We aimed to compare the safety and efficacy of potential antiviral drugs in care home residents.

We designed a cluster-randomised, open-label, blinded end-point platform trial to test drugs in a postexposure prophylaxis paradigm. Participants aged 65+ years from United Kingdom care homes, with or without nursing, were eligible for participation. Care homes were to be allocated at random by computer to administer 42 days of antiviral agent (ciclesonide or niclosamide) plus standard care versus standard care alone to residents. The primary outcome at 60 days after randomisation comprised the most serious outcome, which was defined as all-cause mortality, all-cause hospitalisation, severe acute respiratory syndrome coronavirus 2 infection or no infection. Analysis would be by intention to treat using ordinal logistic regression. Other outcomes included individual components of the primary outcome, transmission, plus health economic and process evaluation outcomes. The planned sample size was 300 care homes corresponding to 9600 residents. With ~40% of care homes predicted to develop an outbreak during the trial, we needed to recruit 750 homes/24,000 residents.

We initiated the trial including protocol, approvals, insurance, website, database, data algorithms, intervention selection and training materials. We built a network of principal investigators and staff (91) and care homes (299) to support the trial. However, we never contracted care homes or general practitioners since the trial was stopped in September 2021, as vaccination in care homes had significantly reduced infections. Multiple delays significantly delayed the start date, such as: (1) reduced prioritisation of pandemic trials in 2021; (2) cumbersome mechanisms for choosing the investigational medicinal products; (3) contracting between National Institute for Health and Care Research and the investigational medicinal product manufacturers; (4) publicising the investigational medicinal products; (5) identification of sufficient numbers of care homes; (6) identification and contracting with several thousand general practitioners; (7) limited research nurse availability and (8) identification of adequate insurance to cover care homes for research. Generic challenges included working across the four home nations with their different structures and regulations.

The feasibility of contracting between the sponsor and the principal investigators, general practitioners and care homes; screening, consent and treatment of care home residents; data acquisition and the potential benefit of postexposure prophylaxis were never tested.

The success of vaccination meant that the role of postexposure prophylaxis of coronavirus disease-2019 in care home residents was not tested. Significant progress was made in developing the infrastructure and expertise necessary for a large-scale clinical trial of investigational medicinal products in United Kingdom care homes.

The role of postexposure prophylaxis of coronavirus disease-2019 in care home residents remains undefined. Significant logistical barriers to conducting research in care homes need to be removed urgently before future studies are possible. Further work is required to develop the infrastructure for clinical trials of investigational medicinal products in care homes. Serious consideration should be given to building and then hibernating a pandemic-ready platform trial suitable for care home research.

This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR133443.

Canada's clinical research landscape is limited by minimal community hospital engagement. However, research participation in community hospitals may increase the speed of trial enrolment, enhance the generalizability of results and accelerate knowledge translation to community hospitals, where most Canadians receive care. Two identified barriers to community hospital participation are limited financial support and a lack of research mentorship.

This study is an intrinsic descriptive case study describing the impact of 1 year of research funding from the Canadian Critical Care Trials Group (CCCTG) and creation of a community of practice on research participation in 19 community hospitals. Thematic analysis was used to systematically identify themes from semistructured interviews and documents.

A total of nine individuals (physician research lead, n = 7; research staff, n = 2) participated in semistructured interviews between April and September 2023. Community of practice meeting minutes (n = 7), emails (n = 22), status reports (n = 21) and field notes (n = 7) were analysed alongside interview transcripts. Funding enabled community hospitals to hire research staff, sustain research programs, increase the number of clinical trials they were running and develop research policies. The community of practice facilitated reciprocal learning and networking that positively impacted research programs and produced a tangible output: a toolkit to help community hospitals build clinical research programs. Contextual influences on community hospital research activities were identified as: (1) system characteristics, (2) clinical trial design, (3) local context and (4) individual characteristics.

The perception of participants was that the CCCTG funding and community of practice positively influenced research activities in community hospitals. Lessons learned include the need to: (1) leverage the power of connections among community hospitals to expand linkages, enabling further knowledge transfer, (2) work with trialists on clinical trial design to facilitate implementation and (3) create resources to support community hospitals with building and sustaining research programs, including resources to foster engagement in hospitals without historic research participation. Our findings highlight the importance of context, including local populations, organizational research culture, provincial health systems and research funding structures, which need to be considered during research program implementation.

Estimating effects of interventions is a central task in perioperative and critical care outcomes research. While randomized trials remain the accepted standard for causal inference, trial data are not always available to inform clinical decisions, and some questions cannot be answered feasibly or efficiently with trials. In these settings, studies using observational healthcare data may be used to inform practice. Causal inference from observational data has been reconsidered in recent years, challenging the prevailing notion among clinical researchers that causal conclusions cannot be drawn from observational studies. The "target trial framework" is one contribution within a growing methodologic field that helps investigators avoid common pitfalls in observational study design and analysis. Importantly, researchers must understand which biases this framework can-and cannot-help avoid. The authors present an overview of target trial emulation and describe the promise and limitations of this framework for improving observational perioperative and critical care outcomes research.

The RECOVERY trial assessed the effectiveness of treatments on preventing severe outcomes from COVID-19 disease in hospitalised patients from 176 NHS hospitals. Clinical benefits of Dexamethasone were observed for hospitalised COVID-19 patients. About 15% of all eligible patients were recruited into the trial. Had patient recruitment been higher the study would have been completed more rapidly.

To estimate the cost-effectiveness of improving recruitment to the RECOVERY trial from 15% to 50%, by employing or redeploying two research nurses to each hospital participating in the RECOVERY trial. The analysis is restricted to the evaluation of Dexamethasone versus No Dexamethasone.

A decision tree model was developed to estimate the cost-effectiveness of Dexamethasone, against No Dexamethasone. Probability, utility, and cost inputs were used for each pathway and treatment. Then, a cost-utility analysis of clinical practice post-RECOVERY trial (83% Dexamethasone, 17% No Dexamethasone) versus previous clinical practice (100% No Dexamethasone) was undertaken; this analysis was aggregated at the population level and the cost of employing or redeploying two research nurses at each hospital was added, to estimate the cost-effectiveness of faster recruitment to the RECOVERY trial.

Faster recruitment to the RECOVERY trial could have generated an incremental net benefit of £13,955,476 related to the evaluation of Dexamethasone against No Dexamethasone, thus highlighting the magnitude of the foregone incremental net benefit due to not adopting a more cost-effective clinical practice (83% Dexamethasone, 17% No Dexamethasone) earlier. The findings remain robust following variations in the model's parameters, with a 85% and 94% probability of faster recruitment being cost-effective given a cost-effectiveness threshold of £20,000 and £30,000 per Quality Adjusted Life Year respectively.

Slow recruitment to randomised trials can have huge implications for healthcare systems as a result of not introducing a more cost-effective treatment earlier through faster patient recruitment.

SARS-CoV-2 can infect cells through endocytic uptake, a process that is targeted by inhibition of lysosomal proteases. However, clinically this approach to treat viral infections has afforded mixed results, with some studies detailing an oral regimen of hydroxychloroquine accompanied by significant off-target toxicities. We rationalized that an organelle-targeted approach will avoid toxicity while increasing the concentration of the drug at the target. Here, we describe a lysosome-targeted, mefloquine-loaded poly(glycerol monostearate-co-ε-caprolactone) nanoparticle (MFQ-NP) for pulmonary delivery via inhalation. Mefloquine is a more effective inhibitor of viral endocytosis than hydroxychloroquine in cellular models of COVID-19. MFQ-NPs are less toxic than molecular mefloquine, are 100-150 nm in diameter, and possess a negative surface charge, which facilitates uptake via endocytosis allowing inhibition of lysosomal proteases. MFQ-NPs inhibit coronavirus infection in mouse MHV-A59 and human OC43 coronavirus model systems and inhibit SARS-CoV-2 WA1 and its Omicron variant in a human lung epithelium model. Organelle-targeted delivery is an effective means to inhibit viral infection.

Steroids are used in management of coronavirus disease 2019 (COVID-19) patients with severe illness and their use has been demonstrated to decrease mortality. Although life-saving, steroids are well documented as risk factors for osteonecrosis. Osteonecrosis of the hip can be debilitating and surgery may be required to improve the quality of life. With the increasing number of COVID-19 cases, osteonecrosis of the hip and other joints resulting from steroid use is expected to show a sharp rise in the coming years. In this review we discuss the association between steroids and osteonecrosis, indications for steroid therapy in COVID-19 patients, and incidence, diagnosis, and treatment of osteonecrosis secondary to steroids in COVID-19.

The results of randomized clinical trials (RCTs) are frequently assessed with the fragility index (FI). Although the information provided by FI may supplement the p value, this indicator presents intrinsic weaknesses and shortcomings. In this article, we establish an analysis of fragility within a broader framework so that it can reliably complement the information provided by the p value. This perspective is named the analysis of strength. We first propose a new strength index (SI), which can be adopted in normal distribution settings. This measure can be obtained for both significance and nonsignificance and is straightforward to calculate, thus presenting compelling advantages over FI, starting from the presence of a threshold. The case of time-to-event outcomes is also addressed. Then, beyond the p value, we develop the analysis of strength using likelihood ratios from Royall's statistical evidence viewpoint. A new R package is provided for performing strength calculations, and a simulation study is conducted to explore the behavior of SI and the likelihood-based indicator empirically across different settings. The newly proposed analysis of strength is applied in the assessment of the results of three recent trials involving the treatment of COVID-19.

Leading up to the 2020 U.S. presidential elections, the scientific consensus on hydroxychloroquine's ineffectiveness in treating COVID-19 was dismissed by Executive branch scientists, who promoted it as both a therapeutic solution and a political tool. This article examines how experimental pharmaceuticals were rationalized even before the pandemic declaration, aligning with medical advocacy groups linked to Donald Trump, who criticized the crisis management capacity of existing health institutions. Framing the emergency as requiring extraordinary measures, White House researchers advocated for executive unilateralism and eventually sought to securitize public health by replacing key health authorities with operational medicine specialists. The most controversial case involved an attempt of planned pharmaceutical intervention aimed at saving lives and restoring public confidence in the administration's pandemic response before the 2020 election. The article draws on confidential documents released by the 2022 House Select Subcommittee on the Coronavirus Crisis.

The COVID-19 pandemic required the rapid and often widespread implementation of medical practices without robust data. Many of these practices have since been tested in large, randomised trials and were found to be in error. We sought to identify incorrect recommendations, or reversals, among National Institute of Health COVID-19 guidelines and Food and Drug Administration (FDA) approvals and authorisations.

Retrospective cross-sectional study.

Recommended medical practices and FDA authorisations or approvals for COVID-19 prevention, treatment and/or management.

The frequency and characteristics of COVID-19 medical reversals, defined as practices that were implemented and/or recommended during the pandemic, but were later tested in randomised trials that failed to find benefit.

We found 332 COVID-19 recommendations. 85 (25.6%) opposed a medical practice, 23 (6.9%) were to continue a pre-COVID standard of care without deviation and 224 (67.5%) reccommended a new medical practice. We found randomised trials assessing 72 of these practices (32.1%), among which 25 (35%) were found to be in error and deemed medical reversals. Among medical reversals, 21 (84%) were prescription medications and 1 (4%) was convalescent plasma. 17 (68%) were repurposed medications. Two (8%) were procedures or mechanical interventions and one (4%) was a device. 16 (64%) reversals pertained to the hospital setting (4 to intensive care units), 4 (16%) were non-specific (ie, applicable to any setting), 4 (16%) pertained to a non-hospital setting and 1 pertained to healthcare workers.

When faced with a novel pandemic, policymakers rapidly made hundreds of specific medical recommendations. More than two out of three were never robustly tested. Among practices tested in a randomised fashion, one in three was made in error. Pandemic recommendation errors were substantial. Early and coordinated efforts to initiate randomised trials, even during dire situations, may mitigate the perpetuation of ineffective practices.

Hydroxychloroquine paired with Azithromycin, Vitamin C, Vitamin D, and Zinc (HAZDPac), was used as a multidrug therapy method to treat COVID-19 illness and superimposed secondary bacterial pneumonia. Concerns have been raised though about such combinations regarding cardiac QTc interval prolongation and risks of arrhythmias, which we set out to address in this study.

We evaluated cardiac safety in a Phase II Double-Blind Randomized Placebo-Controlled Trial of Combination Therapy to Treat COVID-19 Infections study, conducted by ProgenaBiome. Acutely ill patients with COVID-19 had QTc intervals recorded in an outpatient setting utilizing a continuously worn EKG monitor for the duration of the 10 days treatment. QTc intervals were normally distributed. Two-sample t-tests were used to measure any significant differences in QTc intervals between treatment and placebo groups.

Between March 2020 and June 2021, 118 COVID-19 patients were recruited and signed informed consent, of which 83 were enrolled for a Double-Blind Randomized Placebo-Controlled Trial. Of the 83, 52 patients were randomly assigned to receive HAZDPac treatment, and 31 patients to receive placebo. Overall, and in stratified analysis by gender, maximum QTc values of patients in the treatment arm were normal and no differences were observed when compared to maximum QTc values from patients in the placebo arm (p ≥ 0.15). There were no adverse events related to HAZDPac treatment.

We found that the outpatient treatment of COVID-19 patients with HAZDPac which includes Hydroxychloroquine and Azithromycin, was not associated with prolongation of QTc compared to placebo and QTc remained within normal range.

Clinical Trial NCT04482686, clinicaltrials.gov, date of registration 07/21/2020.

Our objective was to investigate the temporal trends in baseline characteristics, interventions, and clinical outcomes in patients hospitalized with COVID-19 in Canada over five pandemic waves.

We conducted a multicentre prospective cohort study enrolling adults and children admitted with COVID-19 from 47 Canadian hospitals. We compared characteristics, interventions, and outcomes of patients across five distinct pandemic waves.

We enrolled 5,285 patients between 2 January 2020 and 8 February 2022. The mean (standard deviation) age was 62.6 (21.0) yr; 41.2% (n = 2,176) were female, and 48% (n = 2,539) required admission to an intensive care unit (ICU), of whom 60.3% (n = 1,530) underwent invasive mechanical ventilation. The proportion of vaccinated patients increased over time. The proportion of vaccinated hospitalized patients progressing to require ICU admission fell over pandemic waves while the proportion of unvaccinated hospitalized patients progressing to require ICU admission did not. Patients were most commonly treated with corticosteroids (48.7%; n = 2,575); use of corticosteroids and other evidence-based treatments increased over time. Hospital mortality was 22.1% (n = 1,166) among all patients, 30.2% (n = 766) among those admitted to an ICU, and 37.9% (n = 580) among those requiring invasive mechanical ventilation. Younger age, absence of chronic cardiac or pulmonary disease, severity of illness at admission, and prior vaccination was associated with a lower mortality; however, pandemic wave itself was not.

Among patients hospitalized in Canada with COVID-19, several clinical factors including prior vaccination were associated with lower mortality, but pandemic wave was not.

The Coronavirus disease 2019 (COVID-19) pandemic has brought a heavy burden to the world, interestingly, it shares many clinical symptoms with systemic lupus erythematosus (SLE). It is unclear whether there is a similar pathological process between COVID-9 and SLE. In addition, we don't know how to treat SLE patients with COVID-19. In this study, we analyse the potential similar pathogenesis between SLE and COVID-19 and explore their possible drug regimens using bioinformatics and systems biology approaches.

The common differentially expressed genes (DEGs) were extracted from the COVID-19 datasets and the SLE datasets for functional enrichment, pathway analysis and candidate drug analysis.

Based on the two transcriptome datasets between COVID-19 and SLE, 325 common DEGs were selected. Hub genes were identified by protein-protein interaction (PPI) analysis. few found a variety of similar functional changes between COVID-19 and SLE, which may be related to the pathogenesis of COVID-19. Besides, we explored the related regulatory networks. Then, through drug target matching, we found many candidate drugs for patients with COVID-19 only or COVID-19 combined with SLE.

COVID-19 and SLE patients share many common hub genes, related pathways and regulatory networks. Based on these common targets, we found many potential drugs that could be used in treating patient with COVID-19 or COVID-19 combined with SLE.

The proliferation of inaccurate and misleading information about COVID-19 on social media poses a significant public health concern. This study examines the impact of the infodemic and beneficial information on COVID-19 protective behaviors in an armed-conflict country. Using the protective action decision model (PADM), data were collected from 1439 participants through a questionnaire in Yemen between August 2020 and April 2021. Structural equation modeling tested hypotheses generated by the PADM. The findings indicate that the infodemic reduces the likelihood of individuals adopting protective measures against COVID-19. Surprisingly, official announcements by accountable authorities do not moderate the relationship between the infodemic and protective responses. These results highlight the need for further research on resilience in armed-conflict countries. This study contributes to understanding armed-conflict countries' unique challenges in combating health crises. Addressing the infodemic and promoting accurate information is crucial in enhancing protective behaviors and mitigating the negative impact of misinformation. Policymakers and public health authorities can utilize these insights to develop targeted interventions and communication strategies that ensure accurate information dissemination and encourage the adoption of adequate protective measures.

This study aimed to explore the effect of cyclosporine (CsA) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in systemic lupus erythematosus (SLE) patients to provide a valuable reference for clinical treatment strategies in the context of the long-term risk of SARS-CoV-2 infection. SLE patients who visited the Rheumatology Outpatient Department of Fujian Medical University Union Hospital between 1 May and 31 October 2022 were included. Data on SARS-CoV-2 infection in patients between 1 November 2022 and 31 July 2023 were obtained by telephone follow-up. Patients were divided into two groups according to whether CsA was used during the observation period: the glucocorticoid or hydroxychloroquine group and the CsA group. To assess the robustness of the results, Data sets 1 and 2 were established to be analyzed independently. Multivariate logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for symptomatic coronavirus disease (COVID-19). A total of 184 patients were included, among whom 129 were definite symptomatic COVID-19 patients; 29 were presumptive symptomatic COVID-19 patients; and 4 had signs and symptoms of COVID-19, but tested negative for SARS-CoV-2 in a virological test. According to the multivariable-adjusted models, CsA was associated with lower odds of symptomatic COVID-19 (P = 0.042, OR = 0.316, 95% CI: 0.104-0.959 in Data set 1 and P = 0.021, OR = 0.257, 95% CI: 0.081-0.812 in Data set 2). CsA is associated with lower odds of contracting symptomatic COVID-19. The use of CsA may be considered an appropriate therapeutic option for disease management in patients with rheumatic diseases who have severe disease activity and persistent SARS-CoV-2 infection.

Our study indicated that cyclosporine may reduce the risk of symptomatic COVID-19 in systemic lupus erythematosus patients in spite of its immunosuppressive effects. This study provides a reference for clinical treatment strategies for AIIRD patients in the context of the long-term risk of SARS-CoV-2 infection.

In the search for effective treatments for COVID-19, the initial emphasis has been on re-purposed treatments. To maximize the chances of finding successful treatments, novel treatments that have been developed for this disease in particular, are needed. In this article, we describe and evaluate the statistical design of the AGILE platform, an adaptive randomized seamless Phase I/II trial platform that seeks to quickly establish a safe range of doses and investigates treatments for potential efficacy. The bespoke Bayesian design (i) utilizes randomization during dose-finding, (ii) shares control arm information across the platform, and (iii) uses a time-to-event endpoint with a formal testing structure and error control for evaluation of potential efficacy. Both single-agent and combination treatments are considered. We find that the design can identify potential treatments that are safe and efficacious reliably with small to moderate sample sizes.

To evaluate the clinical efficacy of Langenlianqiao (LGLQ) oral liquid treatment and provide a reference basis for the clincal treatment of coronavirus disease 2019 (COVID-19).

An experimental clinical study was conducted on three groups with confirmed diagnoses of COVID-19. SITE: This study was conducted at Changde Hospital.

A total of 253 patients were enrolled in this study.

The patients were divided into the LGLQ treatment group (100 cases), the Lianhuaqingwen (LHQW) treatment group (100 cases) and the placebo control group (53 cases), according to the treatment each group received. The occurrence of major clinical symptoms, the duration of symptom disappearance, the number of days in hospitalisation and the duration of infection were compared among the three groups.

Compared with the placebo control group (10.0 [1.2] d, 9.4 [1.3] d), the duration of infection and hospitalisation effectively decreased in the LGLQ group (6.8 [0.6] d, 7.4 [0.8] d) and the LHQW group (6.8 [1.0] d, 7.3 [1.0] d). Furthermore, the incidence of fatigue in the LGLQ group (4.0%) was lower compared to the LHQW group (14.0%) and the placebo control group (15.1%), but this difference was not statistically significant (P = 0.580 for LGLQ vs. LHQW, P = 0.246 for LGLQ vs. placebo). In the treatment of cough, the LGLQ group showed a significantly different effect compared to both the LHQW group (P = 0.014) and the placebo group (P = 0.016). Additionally, for dry cough specifically, LHQW was effective in reducing its incidence compared to the placebo control group (P < 0.05), while LGLQ showed no statistically significant difference from either LHQW (P = 0.39) or the placebo group (P = 0.14). However, neither the LGLQ group nor the LHQW group showed a reduction in the duration of symptom disappearance in patients with pre-existing symptoms (P > 0.05).

Compared with the placebo control group, the LGLQ group showed an improvement in the clinical symptoms of COVID-19 and a decrease in the duration of hospitalisation and infection, which confirmed that the LGLQ treatment had the same antiviral effect as the LHQW treatment. This may provide in-depth insights for antiviral therapy research.

Background: During the coronavirus disease (COVID)-19 pandemic several drugs were used to manage the patients mainly those with a severe phenotype. Potential drugs were used off-label and major concerns arose from their applicability to managing the health crisis highlighting the importance of clinical trials. In this context, we described the mechanisms of the three repurposed drugs [Ivermectin-antiparasitic drug, Chloroquine/Hydroxychloroquine-antimalarial drugs, and Azithromycin-antimicrobial drug]; and, based on this description, the study evaluated the clinical efficacy of those drugs published in clinical trials. The use of these drugs reflects the period of uncertainty that marked the beginning of the COVID-19 pandemic, which made them a possible treatment for COVID-19. Methods: In our review, we evaluated phase III randomized controlled clinical trials (RCTs) that analyzed the efficacy of these drugs published from the COVID-19 pandemic onset to 2023. We included eight RCTs published for Ivermectin, 11 RCTs for Chloroquine/Hydroxychloroquine, and three RCTs for Azithromycin. The research question (PICOT) accounted for P-hospitalized patients with confirmed or suspected COVID-19; I-use of oral or intravenous Ivermectin OR Chloroquine/Hydroxychloroquine OR Azithromycin; C-placebo or no placebo (standard of care); O-mortality OR hospitalization OR viral clearance OR need for mechanical ventilation OR clinical improvement; and T-phase III RCTs. Results: While studying these drugs' respective mechanisms of action, the reasons for which they were thought to be useful became apparent and are as follows: Ivermectin binds to insulin-like growth factor and prevents nuclear transportation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), therefore preventing cell entrance, induces apoptosis, and osmotic cell death and disrupts viral replication. Chloroquine/Hydroxychloroquine blocks the movement of SARS-CoV-2 from early endosomes to lysosomes inside the cell, also, this drug blocks the binding between SARS-CoV-2 and Angiotensin-Converting Enzyme (ACE)-2 inhibiting the interaction between the virus spike proteins and the cell membrane and this drug can also inhibit SARS-CoV-2 viral replication causing, ultimately, the reduction in viral infection as well as the potential to progression for a higher severity phenotype culminating with a higher chance of death. Azithromycin exerts a down-regulating effect on the inflammatory cascade, attenuating the excessive production of cytokines and inducing phagocytic activity, and acts interfering with the viral replication cycle. Ivermectin, when compared to standard care or placebo, did not reduce the disease severity, need for mechanical ventilation, need for intensive care unit, or in-hospital mortality. Only one study demonstrated that Ivermectin may improve viral clearance compared to placebo. Individuals who received Chloroquine/Hydroxychloroquine did not present a lower incidence of death, improved clinical status, or higher chance of respiratory deterioration compared to those who received usual care or placebo. Also, some studies demonstrated that Chloroquine/Hydroxychloroquine resulted in worse outcomes and side-effects included severe ones. Adding Azithromycin to a standard of care did not result in clinical improvement in hospitalized COVID-19 participants. In brief, COVID-19 was one of the deadliest pandemics in modern human history. Due to the potential health catastrophe caused by SARS-CoV-2, a global effort was made to evaluate treatments for COVID-19 to attenuate its impact on the human species. Unfortunately, several countries prematurely justified the emergency use of drugs that showed only in vitro effects against SARS-CoV-2, with a dearth of evidence supporting efficacy in humans. In this context, we reviewed the mechanisms of several drugs proposed to treat COVID-19, including Ivermectin, Chloroquine/Hydroxychloroquine, and Azithromycin, as well as the phase III clinical trials that evaluated the efficacy of these drugs for treating patients with this respiratory disease. Conclusions: As the main finding, although Ivermectin, Chloroquine/Hydroxychloroquine, and Azithromycin might have mechanistic effects against SARS-CoV-2 infection, most phase III clinical trials observed no treatment benefit in patients with COVID-19, underscoring the need for robust phase III clinical trials.

Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use.

Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507.

In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs.

ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.

We review the latest screening and diagnostic techniques, and the most recent recommendations on the management of hydroxychloroquine retinopathy.

Hydroxychloroquine (HCQ) has been shown to cause retinal toxicity in a dose-dependent fashion. Early diagnosis is critical as the resultant retinopathy is not reversible. New imaging modalities, such as adaptive optics (AO), microperimetry, and retro-mode imaging, may show promise in the timely diagnosis of HCQ retinopathy.

Automated visual fields and spectral-domain optical coherence tomography (SD-OCT) are the primary tests used in routine screening for HCQ retinopathy, but fundus autofluorescence (FAF) and multifocal electroretinogram (mfERG) have also been shown to be useful. A baseline ophthalmologic examination is recommended in all patients beginning long-term hydroxychloroquine therapy within the first year of starting therapy. Automated visual fields and SD-OCT should be included during this baseline exam in patients with pre-existing macular conditions. Afterwards, annual screening can be deferred for the first 5 years of HCQ treatment unless the patient has a major risk factor.

Drug repurposing refers to the inference of therapeutic relationships between a clinical indication and existing compounds. As an emerging paradigm in drug development, drug repurposing enables more efficient treatment of rare diseases, stratified patient populations, and urgent threats to public health. However, prioritizing well-suited drug candidates from among a nearly infinite number of repurposing options continues to represent a significant challenge in drug development. Over the past decade, advances in genomic profiling, database curation, and machine learning techniques have enabled more accurate identification of drug repurposing candidates for subsequent clinical evaluation. This review outlines the major methodologic classes that these approaches comprise, which rely on (a) protein structure, (b) genomic signatures, (c) biological networks, and (d) real-world clinical data. We propose that realizing the full impact of drug repurposing methodologies requires a multidisciplinary understanding of each method's advantages and limitations with respect to clinical practice.

Background and Objectives: The coronavirus disease of 2019 (COVID-19) pandemic has posed a serious threat to humanity and is considered a global health emergency. Antimalarial drugs (ADs) have been used in the treatment of immuno-inflammatory arthritis (IIA) and coronavirus infection (COVID-19). The aim of this review is to analyze the current knowledge about the immunomodulatory and antiviral mechanisms of action, characteristics of use, and side effects of antimalarial drugs. Material and Methods: A literature search was carried out using PubMed, MEDLINE, SCOPUS, and Google Scholar databases. The inclusion criteria were the results of randomized and cohort studies, meta-analyses, systematic reviews, and original full-text manuscripts in the English language containing statistically confirmed conclusions. The exclusion criteria were summary reports, newspaper articles, and personal messages. Qualitative methods were used for theoretical knowledge on antimalarial drug usage in AIRDs and SARS-CoV-2 such as a summarization of the literature and a comparison of the treatment methods. Results: The ADs were considered a "candidate" for the therapy of a new coronavirus infection due to mechanisms of antiviral activity, such as interactions with endocytic pathways, the prevention of glycosylation of the ACE2 receptors, blocking sialic acid receptors, and reducing the manifestations of cytokine storms. The majority of clinical trials suggest no role of antimalarial drugs in COVID-19 treatment or prevention. These circumstances do not allow for their use in the treatment and prevention of COVID-19. Conclusions: The mechanisms of hydroxychloroquine are related to potential cardiotoxic manifestations and demonstrate potential adverse effects when used for COVID-19. Furthermore, the need for high doses in the treatment of viral infections increases the likelihood of gastrointestinal side effects, the prolongation of QT, and retinopathy. Large randomized clinical trials (RCTs) have refuted the fact that there is a positive effect on the course and results of COVID-19.

The coronavirus infectious disease-2019 (COVID-19) in Bangladesh is a paradigm for how one of the most densely populated countries in the world, with 1270 people per square kilometer, managed to cope with the COVID-19 pandemic under extraordinary circumstances. This review highlights the SARS-CoV-2 variants in Bangladesh and the timeline of their detection in the context of the global experience with the management of vaccination and natural SARS-CoV-2 infection. The motivation to overcome the COVID-19 vaccine dilemma and track Bangladeshi SARS-CoV-2 sub-variants underscores the potential for a low-income country to excel in international medical science, despite having stressed health care services and limited availability of resources for SARS-CoV-2 testing and gene sequencing.

Patients with acute critical illness require prompt interventions, yet high-quality evidence supporting many investigations and treatments is lacking. Clinical research in this setting is challenging due to the need for immediate treatment and the inability of patients to provide informed consent. Attempts to obtain consent from surrogate decision-makers can be intrusive and lead to unacceptable delays to treatment. These problems may be overcome by pragmatic approaches to study design and the use of supervised waivers of consent, which is ethical and appropriate in situations where there is high risk of poor outcome and a paucity of proven effective treatment.

An article published in this journal used a randomized controlled trial to evaluate the efficacy of combining chloroquine/hydroxychloroquine (CQ/HCQ) and zinc in the treatment of COVID-19 patients. Findings from this study indicate that zinc supplements did not enhance the clinical efficacy of hydroxychloroquine in improving COVID-19 treatment. Although this finding is consistent with many previous studies, several concerns regarding study protocol and trial registration, including interventions and primary outcomes, have been raised in which the protocol has been changed after the completion of the recruitment.

Previous studies in Pakistan have shown considerable over prescribing of antibiotics in patients hospitalized with COVID-19 despite very low prevalence of bacterial infections. Irrational use of antibiotics will worsen antimicrobial resistance (AMR).

Retrospective analysis of medical records of patients in the COVID-19 wards of three tertiary care hospitals to assess antibiotic use during the sixth COVID-19 wave.

A total of 284 patients were included, most were male (66.9%), aged 30-50 years (50.7%) with diabetes mellitus the most common comorbidity. The most common symptoms at presentation were cough (47.9%) and arthralgia-myalgia (41.5%). Around 3% were asymptomatic, 34.9% had mild, 30.3% moderate, and 23.6% had severe disease, with 8.1% critical. Chest X-ray abnormalities were seen in 43.3% of patients and 37% had elevated white cell counts, with 35.2% having elevated C-reactive protein levels. Around 91% COVID-19 patients were prescribed antibiotics during their hospital stay, with only a few with proven bacterial co-infections or secondary bacterial infections. Most antibiotics were from the 'Watch' category (90.8%) followed by the 'Reserve' category (4.8%), similar to previous COVID-19 waves.

There continued to be excessive antibiotics use among hospitalized COVID-19 patients in Pakistan. Urgent measures are needed to address inappropriate prescribing including greater prescribing of Access antibiotics where pertinent.

The safety of the COVID-19 vaccines has been a topic of concern globally. This issue of safety is associated with vaccine hesitancy due to concerns about the adverse effects of the vaccines. Consequently, this study determined the short-term safety profile of the Oxford/AstraZeneca COVID-19 vaccine in Ekiti State, Nigeria.

Descriptive cross-sectional study conducted between May and July 2021 among individuals who had received the first dose of the first batch of the Oxford/AstraZeneca COVID-19 vaccine at Ekiti State University Teaching Hospital (EKSUTH), Ado-Ekiti, Nigeria. A Google form was used to collect data on the adverse effects of the vaccine.

Out of over 1,000 individuals who were approached, 758 respondents completed the study. A large percentage (57.4%) of those who received the vaccines were healthcare workers. Adverse effects were reported in 70.8% of the participants with most manifesting on the first day of the vaccination. The predominant adverse effects were injection site soreness (28.5%), followed by fatigue (18.7%) and muscle pain (8.6%). There was no report of severe adverse effects such as anaphylactic reactions, thrombosis, myocarditis, transient myelitis, or Guillen-Barre syndrome.

This study found that self-reported adverse effects of the Oxford/AstraZeneca COVID-19 vaccine were mild and short in duration. This outcome has promising implications for improving COVID-19 vaccine uptake in the immediate environment and Nigeria.

This review reflects on the impact of the COVID-19 pandemic on the field of rheumatology, emphasizing resulting insights related to the risks of viral infections in immunosuppressed patients, vaccine immunogenicity in immunocompromised patients, and immune dysregulation in the setting of viral infection.

During the pandemic, global patient registries provided real-time insights into the risk factors associated with severe COVID-19 outcomes in rheumatology patients. Updated evidence-based recommendations from the American College of Rheumatology (ACR) guided rheumatology practice during a time of considerable uncertainty. Studies on COVID-19 vaccines in immunocompromised populations enhanced our understanding of specific immunosuppressive therapies on vaccine efficacy. The immune dysregulation seen in severe COVID-19 underscored a role for immunomodulation in this and other severe infections. Furthermore, novel post-infectious conditions, namely multisystem inflammatory syndrome in children (MIS-C) and Long COVID, reshaped our understanding of post-viral syndromes and revealed novel pathological mechanisms. Lessons from the COVID-19 pandemic demonstrate the power of collaborative research. The scientific revelations from this dreadful time will, nonetheless, benefit the practice of rheumatology for years to come.

In some medical indications, numerous interventions have a weak presumption of efficacy, but a good track record or presumption of safety. This makes it feasible to evaluate them simultaneously. This study evaluates a pragmatic fractional factorial trial design that randomly allocates a pre-specified number of interventions to each participant, and statistically tests main intervention effects. We compare it to factorial trials, parallel-arm trials and multiple head-to-head trials, and derive some good practices for its design and analysis.

We simulated various scenarios involving 4 to 20 candidate interventions among which 2 to 8 could be simultaneously allocated. A binary outcome was assumed. One or two interventions were assumed effective, with various interactions (positive, negative, none). Efficient combinatorics algorithms were created. Sample sizes and power were obtained by simulations in which the statistical test was either difference of proportions or multivariate logistic regression Wald test with or without interaction terms for adjustment, with Bonferroni multiplicity-adjusted alpha risk for both. Native R code is provided without need for compiling or packages.

Distributive trials reduce sample sizes 2- to sevenfold compared to parallel arm trials, and increase them 1- to twofold compared to factorial trials, mostly when fewer allocations than for the factorial design are possible. An unexpectedly effective intervention causes small decreases in power (< 10%) if its effect is additive, but large decreases (possibly down to 0) if not, as for factorial designs. These large decreases are prevented by using interaction terms to adjust the analysis, but these additional estimands have a sample size cost and are better pre-specified. The issue can also be managed by adding a true control arm without any intervention.

Distributive randomization is a viable design for mass parallel evaluation of interventions in constrained trial populations. It should be introduced first in clinical settings where many undercharacterized interventions are potentially available, such as disease prevention strategies, digital behavioral interventions, dietary supplements for chronic conditions, or emerging diseases. Pre-trial simulations are recommended, for which tools are provided.

The optimal strategy for initial respiratory support in patients with respiratory failure associated with COVID-19 is unclear, and the initial strategy may affect outcomes.

Which initial respiratory support strategy is associated with improved outcomes in patients with COVID-19 with acute respiratory failure?

All patients with COVID-19 requiring respiratory support and admitted to a large health care network were eligible for inclusion. We compared patients treated initially with noninvasive respiratory support (NIRS; noninvasive positive pressure ventilation by facemask or high-flow nasal oxygen) with patients treated initially with invasive mechanical ventilation (IMV). The primary outcome was time to in-hospital death analyzed using an inverse probability of treatment weighted Cox model adjusted for potential confounders. Secondary outcomes included unweighted and weighted assessments of mortality, lengths of stay (ICU and hospital), and time to intubation.

Nearly one-half of the 2,354 patients (47%) who met inclusion criteria received IMV first, and 53% received initial NIRS. Overall, in-hospital mortality was 38% (37% for IMV and 39% for NIRS). Initial NIRS was associated with an increased hazard of death compared with initial IMV (hazard ratio, 1.42; 95% CI, 1.03-1.94), but also an increased hazard of leaving the hospital sooner that waned with time (noninvasive support by time interaction: hazard ratio, 0.97; 95% CI, 0.95-0.98).

Patients with COVID-19 with acute hypoxemic respiratory failure initially treated with NIRS showed an increased hazard of in-hospital death.

The COVID-19 pandemic has had a significant and lasting impact on the world. Four years on, despite the existence of effective vaccines, the continuous emergence of new SARS-CoV-2 variants remains a challenge for long-term immunity. Additionally, there remain few purpose-built antivirals to protect individuals at risk of severe disease in the event of future coronavirus outbreaks. A promising mechanism of action for novel coronavirus antivirals is the inhibition of viral entry. To facilitate entry, the coronavirus spike glycoprotein interacts with angiotensin converting enzyme 2 (ACE2) on respiratory epithelial cells. Blocking this interaction and consequently viral replication may be an effective strategy for treating infection, however further research is needed to better characterize candidate molecules with antiviral activity before progressing to animal studies and clinical trials. In general, antiviral drugs are developed from purely synthetic compounds or synthetic derivatives of natural products such as plant secondary metabolites. While the former is often favored due to the higher specificity afforded by rational drug design, natural products offer several unique advantages that make them worthy of further study including diverse bioactivity and the ability to work synergistically with other drugs. Accordingly, there has recently been a renewed interest in natural product-derived antivirals in the wake of the COVID-19 pandemic. This review provides a summary of recent research into coronavirus entry inhibitors, with a focus on natural compounds derived from plants, honey, and marine sponges.

Hydroxychloroquine (HCQ) has been repurposed and used for the treatment of COVID-19 patients; however, its efficacy remains controversial, maybe partly due to the dosage, ranging from 200 to 800 mg/day, reported in different studies. Indeed, HCQ low dose (≤ 2.4 g/5 days) showed a lower risk of side effects compared to high doses. In this study, we performed a systematic review and meta-analysis to investigate the effect of low-dose HCQ used alone on three outcomes including in-hospital mortality, the need for mechanical ventilation, and ICU admission in COVID-19 patients. A systematic review of English literature was conducted from January 2020 to April 2022, in PubMed, Cochrane Library, and Google Scholar. Studies reporting a dosage of 400 mg twice the first day, followed by 200 mg twice for four days were included. Pooled odds ratios and 95% confidence intervals were calculated using random-effects models. Eleven studies (12,503 patients) were retained in the quantitative analysis, four observational cohort studies, and seven RCTs. When pooling both observational and RCTs, low-dose HCQ was associated with decreased mortality (OR = 0.73, 95% CI: [0.55-0.97], I2 = 58%), but not with mechanical ventilation need (OR = 1.03, 95% CI: [0.56-1.89], I2 = 67%) and ICU admission rate (OR = 0.70, 95% CI: [0.42-1.17], I2 = 47%). However, no effect was observed when pooling only RCTs. Despite RCTs limitations, treatment with low-dose HCQ was not associated with improvement in mortality, mechanical ventilation need and ICU admission rate in COVID-19 patients.

During the first wave of COVID-19, hydroxychloroquine (HCQ) was used off-label despite the absence of evidence documenting its clinical benefits. Since then, a meta-analysis of randomised trials showed that HCQ use was associated with an 11% increase in the mortality rate. We aimed to estimate the number of HCQ-related deaths worldwide.

We estimated the worldwide in-hospital mortality attributable to HCQ use by combining the mortality rate, HCQ exposure, number of hospitalised patients, and the increased relative risk of death with HCQ. The mortality rate in hospitalised patients for each country was calculated using pooled prevalence estimated by a meta-analysis of published cohorts. The HCQ exposure was estimated using median and extreme estimates from the same systematic review. The number of hospitalised patients during the first wave was extracted from dedicated databases. The systematic review included 44 cohort studies (Belgium: k = 1, France: k = 2, Italy: k = 12, Spain: k = 6, Turkey: k = 3, USA: k = 20). HCQ prescription rates varied greatly from one country to another (range 16-84%). Overall, using median estimates of HCQ use in each country, we estimated that 16,990 HCQ-related in-hospital deaths (range 6267-19256) occurred in the countries with available data. The median number of HCQ-related deaths in Belgium, Turkey, France, Italy, Spain, and the USA was 240 (range not estimable), 95 (range 92-128), 199 (range not estimable), 1822 (range 1170-2063), 1895 (range 1475-2094) and 12739 (3244- 15570), respectively.

Although our estimates are limited by their imprecision, these findings illustrate the hazard of drug repurposing with low-level evidence.

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome.