AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor (preprint)

Protein-protein interactions (PPIs) offer great opportunities to expand the druggable proteome and therapeutically tackle various diseases, but remain challenging targets for drug discovery. Here, we provide a comprehensive pipeline that combines experimental and computational tools to identify and validate PPI targets and perform early-stage drug discovery. We have developed a machine learning approach that prioritizes interactions by analyzing quantitative data from binary PPI assays and AlphaFold-Multimer predictions. Using the quantitative assay LuTHy together with our machine learning algorithm, we identified high-confidence interactions among SARS-CoV-2 proteins for which we predicted three-dimensional structures using AlphaFold Multimer. We employed VirtualFlow to target the contact interface of the NSP10-NSP16 SARS-CoV-2 methyltransferase complex by ultra-large virtual drug screening. Thereby, we identified a compound that binds to NSP10 and inhibits its interaction with NSP16, while also disrupting the methyltransferase activity of the complex, and SARS-CoV-2 replication. Overall, this pipeline will help to prioritize PPI targets to accelerate the discovery of early-stage drug candidates targeting protein complexes and pathways.

Effectiveness of early-treatment interventions on self-reported long COVID: A multi-arm, multi-stage adaptive platform control trial (preprint)

Approximately 20% of people infected with COVID-19 develop at least one persistent condition potentially attributable to their SARS-CoV-2 infection. We sought to determine the effectiveness of early COVID-19 treatment interventions on long COVID symptoms. We conducted a multi-arm multi-stage adaptive platform trial at 12 public health clinics in Brazil between June 2020 and July 2022. Participants were followed for 60. Patients received one of six interventions (doxazosin, fluvoxamine, fluvoxamine in combination with inhaled budesonide, interferon-lambda, ivermectin, or metformin) or matching placebo. The primary outcome was persistence of COVID-19 symptoms at 60 days after randomization. We analyzed data from 5,700 participants across study cohorts. Overall, approximately 22% of patients reported at least one ongoing symptom 60 days after randomization, regardless of the early treatment they received. At day 60, we did not find any statistical benefit of any intervention on recovery, cure fractions, or PROMIS scores (mental and physical).

Allergic contact cheilitis caused by propolis: case report.

Propolis is a lipophilic resin extracted from plants by bees. The purpose of this case report was to show the importance of this substance as cause of allergic contact cheilitis. A 21-year-old female patient complained of pruritic perioral eczema for 5 years. In the past months it also affected the neck. After diagnosing contact dermatitis, she was submitted to a patch test with a Latin American baseline series. The result was strongly positive for propolis (++) and weakly positive for perfume mix I (+). After the test, the patient revealed she had been using propolis drops, per oris, for 10 years. The worsening of the condition was due to increased dose, aiming "to improve immunity", during the coronavirus disease 2019 (COVID-19) pandemic. The contact allergy to propolis might be increasing due to the widespread use of natural products. Propolis is a sensitizer to be considered in patients with long-lasting cheilitis.

A Brazilian multicenter pilot case series on the efficacy of photobiomodulation therapy for COVID-19-related taste dysfunction.

BACKGROUND AND AIM: Among the most common symptoms of COVID-19 is taste dysfunction, which has a ranging clinical presentation. As well as its pathophysiology remains to be unclear, there is not enough information about the efficacy and safety of the available treatments. This study aims to report a series of cases using PBMT for the management of COVID-19-related taste impairment. CASE SERIES: 8 female and 2 male patients sought medical help for taste impairment (either partially or completely) after COVID-19 infection. Photobiomodulation therapy (PBMT) on the tongue mucosa was then proposed but with 3 different protocols. Taste perception at baseline and before every laser session was evaluated using a visual analog scale. Irrespective of the PBMT protocol, taste recovery was noted in all cases but with varying degrees of improvement. CONCLUSION: given the high prevalence rates of taste dysfunction in COVID-19 patients and the lack of information about the available treatments, PBMT seems to be a promising therapeutic modality but not dependent on the total number of laser sessions and the interval between them. The choice of the most suitable laser protocol as well as the knowledge of the exact photonic mechanisms, however, need to be better studied.

Intranasal photobiomodulation therapy for COVID-19-related olfactory dysfunction: A Brazilian multicenter case series.

Olfactory dysfunction is commonly seen in COVID-19 patients; however, little is known about the pathophysiology and management. The present study aimed to report a series of cases in which three protocols of intranasal photobiomodulation therapy (PBMT) were used for COVID-19-related olfactory dysfunction. Irrespective of the PBMT protocol, olfaction recovery was noted in all cases but with varying degrees of improvement. Although intranasal PBMT seems to be a promising therapeutic modality, more research is needed to better define effectiveness.

EFFECT OF EARLY TREATMENT WITH FLUVOXAMINE ON RISK OF EMERGENCY CARE AND HOSPITALIZATION AMONG PATIENTS WITH COVID-19: THE TOGETHER RANDOMIZED PLATFORM CLINICAL TRIAL (preprint)

BackgroundRecent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER randomized platform clinical trial for acutely symptomatic patients with COVID-19, we assessed the efficacy of fluvoxamine vs. placebo in preventing either extended emergency room observation or hospitalization due to COVID-19. Herein, we report the preliminary findings. MethodsThis placebo-controlled, randomized, adaptive, platform trial conducted among symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients with a known risk factor for progression to severe disease. Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) or placebo. The primary endpoint was a composite outcome of emergency room observation for >6 hours or hospitalization from COVID-19 up to 28 days post randomization using intention to treat. Modified intention to treat (mITT) explored patients receiving at least 24 hours of treatment before a primary outcome event. Secondary outcomes included viral clearance at day 7, time to hospitalization, mortality, and adverse drug reactions. We used a Bayesian analytic framework to determine effects along with probability of success of intervention compared to placebo. The trial is registered at clinicaltrials.gov (NCT04727424) and is ongoing. FindingsThe study team screened 9020 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomization from January 15, 2021 to August 6th 2021, when the trial arms were stopped for superiority. A total of 3238 patients were allocated to fluvoxamine (n=739), placebo (n=733) and other treatments (n=1766). Herein, we report the effectiveness of fluvoxamine vs. a concurrent placebo control. The average age of participants was 50 years (range 18-102 years); 57% were female. The proportion of patients observed in an emergency room for >6 hours or admitted to hospital due to COVID-19 was lower for the fluvoxamine group compared to placebo (77/739 vs 108/733; Relative Risk [RR]: 0.71; 95% Bayesian Credible Interval [95% BCI]: 0.54 - 0.93), with a probability of superiority of 99.4% surpassing the prespecified superiority threshold of 97.6% (risk difference 4.3%). Of the composite primary outcome events, 88% were hospitalizations. Findings were similar for the mITT analysis (RR0.68, 95% BCI : 0.50- 0.91). We found no significant relative effects between the fluvoxamine and placebo groups on viral clearance at day 7 (Odds ratio [OR]: 0.75; 95% Confidence Intervals [95% CI]: 0.53 - 1.07), mortality (OR: 0.70; 95% CI: 0.36 - 1.30), time to death (Hazard ratio [HR]: 0.79; 95% CI: 0.58 - 1.08), days hospitalized (Mean Difference (MD) 1.22 days; 95% CI: 0.98 - 1.53), number of days ventilated (MD 1.10; 95% CI: 0.70 - 1.73) or other secondary outcomes. Data capturing all 28 days of follow-up will be reported after August 26th, 2021. InterpretationTreatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19, reduced the need for extended emergency room observation or hospitalization. FundingThe trial was supported by FastGrants and The Rainwater Foundation.

Extracorporeal Respiratory Support During the First and Second Waves of the COVID-19 Pandemic in Spain and Portugal: An Observational, Multicenter, Cohort Study Including 334 Patients (preprint)

Background: The benefits of the use of extracorporeal membrane oxygenation (ECMO) in patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19 remain controversial.Methods: In this multicenter cohort study, we analyzed all the adult patients with ARDS due to COVID-19 who received extracorporeal respiratory support at 25 ECMO centers (23 in Spain and two in Portugal) during the first and second waves of the pandemic. Follow-up ended on December 1. Our primary aim was to describe this cohort taking into account its evolution during the pandemic. We also investigated hazard ratios for hospital mortality.Findings: A total of 334 patients were included. Patients supported during the second wave [176 (52.7%)] were older (54.6±9.7 vs 50.9±10.6,p=0.001), had more comorbidities, were more frequently coinfected at the start of ECMO [62 (35.2%) vs 37 (23.3%),p=0.028] and were less likely to be treated at a high-volume center [42 (23.9%) vs 54 (34.2%),p=0.008] than those supported during the first wave [158 (47.3%)]. At December 1, 134 (40.1%) patients had died and 49 (14.6%) were still on ECMO. Among patients supported during the first wave, 93 (58.8%) were discharged and all were alive at six months. Older age [HR 3.49 (1.94-6.28),p<0.001, for patients older than 65 years], low-volume center [HR 2.07 (1.19-3.59),p=0.009; for centers attending fewer than 15 cases] and coinfection at the start of ECMO [HR 1.49 (1.02-2.18),p=0.039] were associated with higher risk of hospital mortality, while a higher PEEP at day 3 of ECMO [HR 0.92 (0.86-0.98),p=0.019] was associated with a lower risk of death. Time on mechanical ventilation prior to ECMO was not associated with mortality [HR 1.01 (0.98-1.03),p=0.310].Interpretation: ECMO support provided at high volume centers should be considered in selected COVID-19 patients. Age and coinfection, but not mechanical ventilation days, should be taken into account at indication assessment.Funding Statement: No funding.Declaration of Interests: None.Ethics Approval Statement: The study protocol was approved by the local ethics committees at all the participating centers.