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Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose.ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing.Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36·0 (15·0-62·0) days. Vaccine efficacy was 75·2% (adjusted 95% CI 54·6-87·3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55·6%] of 3015 vs 896 [57·5%] of 1559, respectively; systemic adverse events, 1764 [58·5%] of 3015 vs 821 [52·7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity.A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed.Janssen ResearchDevelopment.

Odontogenic sinusitis (ODS) is distinct from non-odontogenic rhinosinusitis with regard to clinical features as well as diagnostic and therapeutic approaches. While numerous studies have explored immune profiles of chronic rhinosinusitis, very few studies have explored the inflammatory endotype of ODS.Odontogenic sinusitis was diagnosed by confirming infectious sinusitis adjacent to infectious maxillary odontogenic pathology. Maxillary sinus cultures and mucosal biopsies were obtained during endoscopic endonasal surgery in ODS and control patients. Controls were patients undergoing endoscopic skull base surgery with no sinus disease. Specimens were snap frozen in liquid nitrogen and stored at -80°C. Analysis was performed using a multiplex assay to measure Th-1 (TNFα, IFNγ, IL-2,12,18), Th-2 (IL-4,5,9,13), Th-17 (IL-17A,17F,22), and innate (CCL5,CXCL9,CXCL10, IL-6,8,10,12,23,27) immune pathways. Groups were compared via independent sample t-tests; if assumptions were violated, nonparametric Wilcoxon ranked sum tests were performed.Specimens from 22 ODS patients were compared to nine controls. ODS mucosal tissue was sampled in the setting of the following dental pathologies: post-dental extraction (n = 15), untreated apical periodontitis (n = 2), apical periodontitis after root canal therapy (n = 2), and maxillary sinus bone grafting with or without dental implantation (n = 3). The following cytokines were significantly elevated in ODS compared to controls: IFNγ, TNFα, IL-6, 8, 10, 27, and CXCL9. IL-17 levels were similar in both ODS and controls. Therefore, ODS demonstrated heightened innate and Th1 immune activity.ODS demonstrated both innate immune and Th1 inflammatory endotypes. Further studies are needed to explore ODS immunopathobiology and its potential impact on ODS management.

There are lots of Smartphone users data floating around which is not efficiently used for improving user experience and which can be used to provide a better user experience or enhance the current one. Enhancing user experience is a challenge as there are multiple competitors. A persons time spend on their Smartphone is an vast amount of time and everyone is trying to reduce this time by implementing efficient ways of android user experience. Starting with our work, which will focus on this user floating data? There are important segments of this user data one of them is facial data because humans are used to taking in non verbal cues from facial emotions. And also we are focusing on factors like user surrounding sound, user’s locations and patterns of application used history.

Objectives: Approximately 25% of patients with Clostridioides difficile infection (CDI) will experience recurrence, which is greater in immunocompromised patients. We report experience with an institutional guideline targeting high-risk immunocompromised patients. Methods: This was a retrospective cohort of consecutive patients with CDI who met institutional criteria for bezlotoxumab due to high risk for recurrent CDI between June 1, 2017, and November 30, 2018. The primary endpoint of recurrent CDI within 12 weeks was compared between patients who received the standard of care (SoC) plus or minus bezlotoxumab. Results: Twenty-three patients received bezlotoxumab infusion plus SoC and were compared to 30 SoC patients. 84% of patients were immunocompromised and 54.7% were transplant recipients. The primary endpoint occurred in 13% of bezlotoxumab patients compared to 23.3% of SoC patients. No serious adverse effects were identified. Conclusion: Bezlotoxumab was associated with a meaningful reduction in recurrent CDI in this cohort largely comprising immunocompromised and transplant patients. Larger studies are warranted to evaluate bezlotoxumab in this population.

Background Vancomycin (VAN) therapy for C. difficile infection (CDI) is effective with > 80% clinical response (CR) but is associated with 20–30% recurrence rate (rCDI). Secondary bile acids (2° BAs) inhibit C. difficile germination and help prevent rCDI. VAN depletes the gut microbiome decreasing the conversion of primary bile acids to 2° BAs. Ridinilazole (RDZ) is a highly selective anti-CDI, DNA-binding antibiotic in development for the treatment of CDI and prevention of rCDI. Methods A global, double-blinded, randomized Phase 3 trial assessed a 10-day treatment with RDZ 200 mg BID vs VAN 125 mg QID for CDI. The primary endpoint was sustained clinical response (SCR) defined as CR and no rCDI through 30 days post-end of treatment (EOT). Other endpoints included rCDI, microbiome diversity and composition, and microbiome-derived 2° BAs concentration. rCDI was defined as a new episode of diarrhea with confirmed positive free toxin test (FTT), requiring additional CDI therapy. All participants were monitored for treatment emergent adverse events (TEAE). Results Of the 759 patients (pts) enrolled, 745 were included in the mITT population (RDZ n=370, VAN n=375). RDZ achieved a numerically higher SCR rate than VAN (73.0% vs 70.7%) p=0.4672. RDZ resulted in a significant reduction in rCDI rate (8.1% vs 17.3%, p=0.0002) (Fig 1). In a pre-specified subpopulation, this was most notable in pts not receiving other antibiotics (rCDI 6.7% in RDZ vs 16.5% in VAN, p=0.0005). Microbiome alpha diversity was higher for RDZ vs VAN at EOT and EOT+30d (p< 0.0001 and p≤ 0.0007 respectively, Fig 2) as were relative abundance (p< 0.0001 and p=0.0203 respectively), and concentrations of 2° BAs (Fig 3). Higher microbiome diversity and concentrations of 2° BAs at EOT were associated with both lower rCDI and higher SCR rates. RDZ was well tolerated (pts with ≥ 1 TEAE: RDZ 36.4% vs VAN 35.5%, treatment discontinuation due to TEAE: RDZ 0.8% vs. VAN 2.9%). Conclusion RDZ was effective for sustained clinical response and safe for the treatment of patients with CDI. This was most notable in pts not receiving antibiotics. Compared to VAN, RDZ patients had faster recovery of fecal 2° BA, consistent with the preservation of microbiome diversity, resulting in a significantly lower rate of rCDI. Disclosures Pablo C. Okhuysen, MD, AstraZeneca: Stocks/Bonds|Beam Therapeutics: Stocks/Bonds|Biontech: Stocks/Bonds|Deinove: Grant/Research Support|Ferring: Advisor/Consultant|Glaxo Smith Kleine: Stocks/Bonds|Johnson and Johnson: Stocks/Bonds|Melinta: Grant/Research Support|Merck Sharp & Dohme Corp: Grant/Research Support|Moderna: Stocks/Bonds|Napo Pharmaceuticals: Advisor/Consultant|Napo Pharmaceuticals: Grant/Research Support|Novavax: Stocks/Bonds|Pfizer: Stocks/Bonds|Summit: Advisor/Consultant|Summit: Grant/Research Support Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|cidara: Advisor/Consultant|cidara: Grant/Research Support|Paratek: Grant/Research Support|Seres Health: Grant/Research Support|Summit: Grant/Research Support Thomas J. Louie, MD, adiso therapeutics: Advisor/Consultant|adiso therapeutics: Grant/Research Support|crestone: Advisor/Consultant|crestone: Grant/Research Support|Finch: Advisor/Consultant|Finch: Grant/Research Support|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Seres Therapeutics: Honoraria|summit plc: Grant/Research Support|vedanta biosciences: Advisor/Consultant|vedanta biosciences: Grant/Research Support Jianling LI, MS, Abbott: Stocks/Bonds|Abbvie: Stocks/Bonds|ALX Oncology: Stocks/Bonds|BioNTech: Stocks/Bonds|Bluebird Bio: Stocks/Bonds|Cytokinetics: Stocks/Bonds|I-Mab: Stocks/Bonds|Johnson & Johnson: Stocks/Bonds|Moderna: Stocks/Bonds|TG Therapeutics: Stocks/Bonds Esther Duperchy, PhD, Summit Plc: Employee Jose G. Montoya, MD, Summit: Honoraria|Summit: Stocks/Bonds Lori Styles, MD, Abbvie: Stocks/Bonds|Summit Therapeutics: employee|Summit Therapeutics: Stocks/Bonds Fong Clow, Sc. D, Summit Therapeutics: Employee Danelle James, MD, Summit Therapeutics: Employee.

Background Eravacycline (ERV) is a fluorocycline with in vitro activity against Clostridioides difficile infection (CDI). The purpose of this study was to evaluate the usage of ERV in the management of CDI. Methods IRB-approved, retrospective case series in a health system that added ERV to formulary in 9/2019. All patients between 9/2019 and 2/2020 treated with adjunctive ERV for > 24 hours for severe, recurrent, or fulminant CDI were included. Exclusion criteria: pregnant, age < 18 years. Primary outcome: all-cause mortality at 30 days (d) from start of ERV. Secondary outcomes: clinical cure, colectomy, and recurrence within 30 d. Data was reported using descriptive statistics and measures of central tendency. Results 14 patients included: severe (4, 29%), recurrent (4, 29%), and fulminant CDI (6, 43%) (table 1). Infectious diseases consult: 14/14, median time to consult 1 (1, 2) d. Surgery consult: 1 severe and 5 fulminant CDI cases, median time to consult 1 (1, 3) d. Prior to ERV initiation, 10 patients were on oral vancomycin (PO VAN) and intravenous metronidazole (IV MTZ), one was on PO VAN, two were on IV MTZ, and one was on no CDI therapy. After ERV was initiated, six patients were on ERV, PO VAN, and IV MTZ combination and eight patients were on ERV and PO VAN concurrently. The reason for using ERV was fulminant CDI (6, 42.8%), severe CDI (4, 29%), unable to tolerate other CDI medications (3, 21%), refractory CDI (3, 21%), and recurrent CDI (1, 7%). Time to eravacycline initiation 1.5 d (1, 3.75) with median duration of 6 d (4.5, 7.75). 30-day all-cause mortality 2 (14%), all were in-hospital; 1 (7%) hospice. Clinical cure occurred in 12 (86%). Two (14%) required colectomy; one received surgery on the same day of CDI diagnosis and ERV initiation and the other had surgery 4 days before ERV initiation. Two patients with recurrent CDI received fecal microbiota transplant outpatient, one of which also received bezlotoxumab. Zero recurrences and one readmission within 30 d. Table 1.Patient demographics, severity, and clinical outcomes Conclusion ERV appears to be a potential adjunctive therapy for severe, recurrent, or fulminant CDI. Prospective studies are needed to further investigate the safety and efficacy of ERV in serious CDI. Disclosures All Authors: No reported disclosures.

Background Universal PCR and Next Generation Sequencing (uPCR/NGS) is a major advancement in microbiology. It is a highly sensitive and specific test that amplifies ribosomal RNA in samples to detect bacterial and fungal pathogens. We investigated the uPCR/NGS tests sent from Henry Ford Health (HFH) and the effect obtaining this test had on patient care. Methods We completed a retrospective, observational study assessing all consecutive uPCR/NGS tests obtained from at HFH from 2016-2021. This included uPCR/NGS for detection of bacterial, fungal, mycobacterium tuberculosis (MTB), and non-tuberculosis mycobacterium (NTM). All samples were of non-blood fluids and tissue samples. Patients concurrent tissue cultures and blood cultures from day of uPCR/NGS, and within 6 months of obtaining the uPCR/NGS sample were evaluated. Primary outcomes included if uPCR/NGS testing resulted in a change of choice or duration of antibiotic therapy. Results At HFH, 226 uPCR/NGS tests from 111 samples were analyzed. This included 83 bacterial, 51 MTB, 51 NTM, and 41 fungal uPCR/NGS tests. Of the 226 uPCR/NGS tests, 31 tests (13.7%) resulted with positive result on uPCR/NGS. A total of 31 tests (13.7%) were ordered on a known culture positive sample, and 195 (86.3%) were ordered on a culture negative sample. Of samples sent from a culture positive sample, 7 (22.6%) resulted with positive uPCR/NGS results. 3 (42.9%) matched the tissue cultures, and 2 (28.6%) matched the patients’ blood cultures. None of the patients had any change in choice or duration of antibiotics based on uPCR/NGS results. Of the samples sent from a culture negative sample, 24 (12.3%) samples resulted with positive uPCR/NGS results. 2 (8.3%) matched a patient’s tissue cultures and none matched blood cultures. Change in antibiotic choice or duration occurred in 16 (17.6%) patients. The samples with the highest rates of change in management included cerebrospinal fluid (42.9%), brain tissue (36.4%), cardiac valvular tissue (27.3%), lymph nodes (25%), synovial fluid (20%). Figure 1:Flowchart of Results and Impact on Management Conclusion Our results show that uPCR/NGS has an overall low percent of impact in clinical outcomes, but it is a useful test in when used on a culture negative sample in certain sample types, along with a high index of suspicion for infection. Disclosures All Authors: No reported disclosures.

Background Prior studies evaluating the sensitivity blood cultures utilizing the Virtuo blood culture system versus the VersaTREK blood culture system have suggested increased sensitivity with the Virtuo system. Studies evaluating if this increased sensitivity effects patient outcomes are lacking. This study evaluates the effect of replacing the VersaTREK system with the Virtuo system on morbidity and mortality in patients with Staphylococcus aureus bacteremia. Methods This quasi-experimental study was performed at Henry Ford Health System in Southeast Michigan. We analyzed all patients with positive blood cultures for Staphylococcus aureus between 3/1/18 and 9/30/18 (VersaTREK system) and 3/1/19 and 9/30/19 (Virtuo system). The VersaTREK arm had 267 patients and the Virtuo arm 404. Patients transferred to or from outside facilities with ongoing bacteremia were excluded. Primary outcomes were differences in length of stay, mortality at 14, 30, and 90 days from completion of therapy, and hospitalization for recurrence of bacteremia within 30 days. Secondary outcomes were differences in length of therapy, rates of diagnostic imaging tests to assess for persistent foci of infection or an unknown source of persistent bacteremia, and length of bacteremia. Data were analyzed using SPSS for Macintosh using Pearson’s chi-square test and Student’s t-test. A p < 0.05 was considered statistically significant. Results Demographics of the study populations were equal however, the Charlson Comorbidity Index for VersaTREK arm compared to Virtuo (3.5 to 3.1) trended toward significance (p=0.05) (Table 1). There was no difference in length of bacteremia, lengths of antibiotic therapy, CT scans, or echocardiograms performed. More MRIs were performed in the Virtuo arm (p=< 0.001) (Table 2). There was no difference in recurrence of bacteremia, patient death due to bacteremia, length of hospital stay, or 30 day readmission for recurrence of bacteremia (Table 3). Conclusion This is the first study to evaluate how increased sensitivity of a blood culture system effects patient outcomes. Our results suggest that Staphylococcus aureus bacteremia may be over treated in blood cultures systems that are highly sensitive. Further prospective studies are needed to explore this further. Disclosures All Authors: No reported disclosures.

This study seeks to describe inpatient antimicrobial use (AU) utilizing the National Healthcare Safety Network-AU (NHSN-AU) framework among solid organ transplant recipients (SOTr) within 12 months after transplant.This cross-sectional study included SOTr ≥ 18 years of age who underwent transplantation from January 2015 to December 2016 at a Midwestern US transplant center. Inpatient AU was followed for 12 months post-transplant. Hospital days present up to 12 months post-transplant, AU variables, and Clostridioides difficile infection (CDI) occurrences were analyzed.The cohort of 530 SOTr included 225 kidney (42.5%), 171 liver (32.3%), 45 lung (8.5%), 40 heart (7.5%), 39 multivisceral (7.4%), seven small bowel (1.3%), and three pancreas (0.6%) transplants. Total days of therapy (DOT) were 22 782 among the cohort, with a median of 5 days [interquartile range [IQR], 1-12]. Lung and liver transplants had the most total DOT (6571 vs. 5569 days), while lungs and small bowels had the highest median DOT (13 [IQR, 2-56] vs. 12 [IQR, 2-31]). The facility-wide DOT/1000 days were lowest in pancreas and highest in lung transplants (5.3 vs. 428.1). Small bowel transplants received the most resistant-Gram-positive infection and hospital-onset infection agents for facility-wide DOT/1000 days present. Pancreas and kidney transplants accounted for the most high-risk CDI agents. CDI occurred in 34 patients, with kidney and liver transplants experiencing 13 each.This study represents one of the first reports of AU in SOTr utilizing the NHSN-AU framework. More studies are needed for further peer-to-peer comparison of AU in this complex patient population.

The utility of surveillance bronchoscopy (SB) for the clinical management of lung transplant recipients (LTRs) is undefined. This study evaluates the role of SB in the monitoring and care of LTRs.We retrospectively analyzed all LTRs who had SB at Henry Ford Hospital in Detroit, Michigan between August 2014 and August 2019. Bronchoscopies performed for clinical symptoms, new radiographic abnormalities, and to assess stents or acute rejection were excluded. A total of 107 LTRs and 449 bronchoscopies were analyzed. The primary outcome was the rate of change in clinical care based on microbiologic and pathologic test results. Secondary outcomes were rates of microbiologic and pathologic test positivity and rates of adverse effects.The most common microbiologic tests performed on bronchoalveolar lavage were bacterial (96.9%), fungal (95.3%), and acid-fast bacillus (95.1%) stains and cultures. Of 2560 microbiologic tests, 22.0% were positive and resulted in therapy changes for 2.9%. Positive galactomannan, acid-fast bacillus tests, and Pneumocystis jirovecii antigen/polymerase chain reaction did not result in therapy changes. Of the 370 transbronchial biopsies performed, 82.2% were negative for acute rejection and 13% were positive for A1/A2 rejection. Immunosuppressive therapy changes occurred after 15.8% with reduction in immunosuppression due to positive microbiologic tests in 16.9%. Adverse events occurred in 8.0% of patients.Diagnostic stewardship is warranted when performing SB in LTRs.

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

Background Characterization of disease progression and outcomes after coronavirus disease 2019 (COVID-19)–related hospitalization in vaccinated compared with unvaccinated individuals is limited. Methods This was a retrospective case–control study of symptomatic vaccinated (cases) and unvaccinated (controls) participants hospitalized for COVID-19 between December 30, 2020, and September 30, 2021, in Southeast Michigan. Hospitalized adult patients with lab-confirmed COVID-19 were identified through daily census report. Breakthrough infection was defined as detection of severe acute respiratory syndrome coronavirus 2 ≥14 days after completion of the primary vaccination series. The association between prior vaccination and critical COVID-19 illness (composite of intensive care unit [ICU] admission, invasive mechanical ventilation [IMV], 28-day mortality) was examined. Results Two hundred ten (39%) fully vaccinated and 325 (61%) unvaccinated patients were evaluated. Compared with controls, cases were older, had more comorbidities (4 [3–7] vs 2 [1–4]; P Conclusions COVID-19-vaccinated patients were less likely to develop critical COVID-19 illness and more likely to survive. Disease severity at presentation was a predictor of adverse outcomes regardless of vaccination status.

We completed a real-world analysis of 498 consecutive high-risk nonimmunocompromised and immunocompromised patients who received sotrovimab during the B.1.1.529 surge. Emergency department visits/hospitalizations and 30-day all-cause mortality between the 2 groups were similar. When administered early, sotrovimab is effective at preventing coronavirus disease 2019 progression in immunocompromised and nonimmunocompromised patients.

Background Characterizations of coronavirus disease 2019 (COVID-19) vaccine breakthrough infections are limited. We aim to characterize breakthrough infections and identify risk factors associated with outcomes. Methods This was a retrospective case series of consecutive fully vaccinated patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a multicenter academic center in Southeast Michigan, between December 30, 2020, and September 15, 2021. Results A total of 982 patients were identified; the mean age was 57.9 years, 565 (59%) were female, 774 (79%) were White, and 255 (26%) were health care workers (HCWs). The median number of comorbidities was 2; 225 (23%) were immunocompromised. BNT162b2 was administered to 737 (75%) individuals. The mean time to SARS-CoV-2 detection was 135 days. The majority were asymptomatic or exhibited mild to moderate disease, 154 (16%) required hospitalization, 127 (13%) had severe–critical illness, and 19 (2%) died. Age (odds ratio [OR], 1.14; 95% CI, 1.04–1.07; P  Conclusions COVID-19 vaccines remain effective at attenuating disease severity. However, patients with breakthrough infections necessitating hospitalization may benefit from early treatment modalities and COVID-19-mitigating strategies, especially in areas with substantial or high transmission rates.

Solid organ transplant recipients (SOTr) with coronavirus disease 2019 (COVID‐19) are expected to have poorer outcomes compared to nontransplant patients because of immunosuppression and comorbidities. The clinical characteristics of 47 SOTr (38 kidneys and 9 nonkidney organs) were compared to 100 consecutive hospitalized nontransplant controls. Twelve of 47 SOTr managed as outpatients were subsequently excluded from the outcome analyses to avoid potential selection bias. Chronic kidney disease (89% vs 57% P = .0007), diabetes (66% vs 33% P = .0007), and hypertension (94% vs 72% P = .006) were more common in the 35 hospitalized SOTr compared to controls. Diarrhea (54% vs 17%, P

Significance The United States is in an acceleration phase of the COVID-19 pandemic. Currently there is no known effective therapy or vaccine for treatment of SARS-CoV-2, highlighting urgency around identifying effective therapies. Objective The purpose of this study was to evaluate the role of hydroxychloroquine therapy alone and in combination with azithromycin in hospitalized patients positive for COVID-19. Design Multi-center retrospective observational study. Setting The Henry Ford Health System (HFHS) in Southeast Michigan: large six hospital integrated health system; the largest of hospitals is an 802-bed quaternary academic teaching hospital in urban Detroit, Michigan. Participants Consecutive patients hospitalized with a COVID-related admission in the health system from March 10, 2020 to May 2, 2020 were included. Only the first admission was included for patients with multiple admissions. All patients evaluated were 18 years of age and older and were treated as inpatients for at least 48 h unless expired within 24 h. Exposure Receipt of hydroxychloroquine alone, hydroxychloroquine in combination with azithromycin, azithromycin alone, or neither. Main outcome The primary outcome was in-hospital mortality. Results Of 2,541 patients, with a median total hospitalization time of 6 days (IQR: 4–10 days), median age was 64 years (IQR:53–76 years), 51% male, 56% African American, with median time to follow-up of 28.5 days (IQR:3–53). Overall in-hospital mortality was 18.1% (95% CI:16.6%–19.7%); by treatment: hydroxychloroquine + azithromycin, 157/783 (20.1% [95% CI: 17.3%–23.0%]), hydroxychloroquine alone, 162/1202 (13.5% [95% CI: 11.6%–15.5%]), azithromycin alone, 33/147 (22.4% [95% CI: 16.0%–30.1%]), and neither drug, 108/409 (26.4% [95% CI: 22.2%–31.0%]). Primary cause of mortality was respiratory failure (88%); no patient had documented torsades de pointes. From Cox regression modeling, predictors of mortality were age > 65 years (HR:2.6 [95% CI:1.9–3.3]), white race (HR:1.7 [95% CI:1.4–2.1]), CKD (HR:1.7 [95%CI:1.4–2.1]), reduced O2 saturation level on admission (HR:1.5 [95%CI:1.1–2.1]), and ventilator use during admission (HR: 2.2 [95%CI:1.4–3.3]). Hydroxychloroquine provided a 66% hazard ratio reduction, and hydroxychloroquine + azithromycin 71% compared to neither treatment (p Conclusions and relevance In this multi-hospital assessment, when controlling for COVID-19 risk factors, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality. Prospective trials are needed to examine this impact.

The surge of coronavirus disease 2019 (COVID-19) hospitalizations at our 877-bed quaternary care hospital in Detroit led to an emergent demand for Infectious Diseases (ID) consultations. The traditional 1-on-1 consultation model was untenable. Therefore, we rapidly restructured our ID division to provide effective consultative services. We implemented a novel unit-based group rounds model that focused on delivering key updates to teams and providing unit-wide consultations simultaneously to all team members. Effectiveness of the program was studied using Likert-scale survey data. The survey captured data from the first month of the Detroit COVID-19 pandemic. During this period there were approximately 950 patients hospitalized for treatment of COVID-19. The survey of trainees and faculty reported an overall 95% positive response to delivery of information, new knowledge acquisition, and provider confidence in the care of COVID-19 patients. This showed that the unit-based consult model is a sustainable effort to provide care during epidemics.

Background. Fecal microbiota transplantation (FMT) is a well-established therapeutic option for patients with antibiotic resistant Clostridioides difficile infection (CDI). However, the efficacy of FMT in patients with chronic liver disease remains elusive. Aims. We studied the effect of FMT on chronic liver disease (CLD) patients with CDI at our tertiary medical center. Methods. A cohort of all patients who received FMT from December 2012 to May 2014 for refractory or recurrent CDI was identified. Patients were monitored for a year after FMT. Descriptive analysis was conducted to compare the effect of FMT in patients with and without CLD. Results. A total of 201 patients with CDI received FMT, 14 of which had a history of CLD. Nine of these patients exhibited cirrhosis of the liver with a mean Child-Turcotte-Pugh score of 8. CDI development in these patients was associated with recent exposure to antibiotics and was observed to be significantly different between both groups (17% of CLD patients vs. 58% in the general cohort, p=0.01). Four patients with CLD received >1 FMT, of which 2 did not respond to treatment. There was no significant difference between patients with liver disease and the rest of the cohort with regard to FMT response (12/14 (87%) vs. 164/187 (88%), p=0.68). Conclusion. FMT is a safe and effective therapy against CDI for patients with CLD and cirrhosis.

Background Corticosteroids use in severe coronavirus disease 2019 (COVID-19) improves survival; however, the optimal dose is not established. We aim to evaluate clinical outcomes in patients with severe COVID-19 receiving high-dose corticosteroids (HDC) versus low-dose corticosteroids (LDC). Methods This was a quasi-experimental study conducted at a large, quaternary care center in Michigan. A corticosteroid dose change was implemented in the standardized institutional treatment protocol on November 17, 2020. All patients admitted with severe COVID-19 that received corticosteroids were included. Consecutive patients in the HDC group (September 1 to November 15, 2020) were compared to the LDC group (November 30, 2020 to January 20, 2021). High-dose corticosteroids was defined as 80 mg of methylprednisolone daily in 2 divided doses, and LDC was defined as 32–40 mg of methylprednisolone daily in 2 divided doses. The primary outcome was all-cause 28-day mortality. Secondary outcomes included progression to mechanical ventilation, hospital length of stay (LOS), discharge on supplemental oxygen, and corticosteroid-associated adverse events. Results Four-hundred seventy patients were included: 218 (46%) and 252 (54%) in the HDC and LDC groups, respectively. No difference was observed in 28-day mortality (14.5% vs 13.5%, P = .712). This finding remained intact when controlling for additional variables (odds ratio, 0.947; confidence interval, 0.515–1.742; P = .861). Median hospital LOS was 6 and 5 days in the HDC and LDC groups, respectively (P Conclusions Low-dose methylprednisolone had comparable outcomes including mortality to high-dose methylprednisolone for the treatment of severe COVID-19.

This collaborative meta-analysis was supported by the Swiss National Science Foundation and the Laura and John Arnold Foundation (grant supporting the post-doctoral fellowship at the Meta-Research Innovation Center at Stanford (METRICS), Stanford University). The funders had no role in the design of this collaborative meta-analysis; in the collection, analysis, and interpretation of data; or in the report writing., We would like to express our warm gratitude to all participating patients and convalescent plasma donors. We thank Katja Suter and Sina Ullrich, University of Basel, for their administrative assistance. For their helpful contribution to individual trials, we thank Erica Wood, Iain Gosbell, Richard Charlewood, Thomas Hills, Veronica Hoad, Kristina Kairaitis, Aikaj Jindal, John Gerrard, Hong Foo, Adam Stewart, and Nanette Trask (ASCOT trial); Amalia Bravo-Lindoro, Ral Carrillo-Esper, Karla Maldonado-Silva, Catalina Casillas-Suárez, Orlando Carrillo-Torres, Sandra Murrieta, Elizabeth Diaz-Padilla, Eli Omar Zavaleta, Yadira Bejar-Ramirez, and Evelyn Cortina-de la Rosa (CPC-SARS trial); Sheri Renaud, Roel Rolando-Almario, and Jacqueline Day (NCT04385199 trial); Sandra Tingsgrd, MD, Karen Brorup Heje Pedersen, MD, Michaela Tinggaard, MD, Louise Thorlacius-Ussing, MD, Clara Lundetoft Clausen, MD, Nichlas Hovmand, MD, Simone Bastrup Israelsen, MD, Cecilie Leding, MD, Katrine Iversen, MD, Maria Engel Miller, MD, Hkon Sandholdt, MSc biostatistician (CCAP-2 trial). On behalf of the IRCT20200310046736N1 trial, we thank the Khuzestan Blood Transfusion Organization for specialized assistance in the preparation and maintenance of plasma samples. On behalf of the NCT04332835 trial, we thank all the members of the "PC-COVID-19 Group" at the Clinica del Occidente and Hospital Universitario Mayor Mederi in Bogota, and Clinica CES in Medellin. On behalf of the NCT04403477 trial, we thank Miles Carroll for his support regarding the antibody testing in Bangladesh. The Co-CLARITY team would like to extend their gratitude to the Department of Science and Technology Philippine Council for Health Research and Development and the UP-Philippine General Hospital for all their support in the setting up and conduct of the trial. For helpfully communicating details of their trial, we thank members of the PlasmAr trial, NCT04359810 trial (Max O´Donnell), NCT04468009 trial, and CTRI/2020/05/025299 trial. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute (https://www.cancer.gov/)., During the conduct of the study, the following is reported: Dr. Berry reports being employee with ownership role at Berry Consultants (receives payments for statistical modeling and design of REMAP-CAP). Dr. Castillo reports grants from DOST PCHRD. Dr. Daly reports grants from Medical Research Future Fund (Australian Govt) and RBWH. Dr. Denkinger reports grants from German Ministry for Education and Research. Dr. Dumagay reports grants from Philippine Council for Health Research and Development. Dr. Dunachie reports grants from UK Department of Health and Social Care, grants from UK National Institute of Health Research. Dr. Gauiran reports grants from Department of Science and Technology—Philippine Council for Health Research and Development. Dr. Gordon reports grants from NIHR, grants from NIHR Research Professorship (RP-2015-06-18), and non-financial support from NIHR Clinical Research Network. Dr. Higgins reports grants from NHMRC and from the Minderoo Foundation. Dr. Hills reports grants from Health Research Council of New Zealand. Dr. Holm reports grants from Swedish Government Funds for Clinical Research (ALF). Dr. Janssen and Dr. Müller-Tidow report grants from the Federal Ministry of Education and Research in Germany (BMBF) to the RECOVER clinical trial. Dr. Krapp reports grants from Department of Foreign Affairs, Trade, and Development of Canada, grants from Fundación Telefónica del Perú. Dr. J. Lim reports grants from the Department of Science and Technology, Philippine Council for Health Research and Development. Dr. Lucero reports grants from Philippine Council for Health Research and Development. Dr Manrique reports economic support from Grupo ISA Intercolombia for the project development of trial NCT04332835. Drs. McQuilten and Wood report grants from Medical Research Future Fund. Dr. McVerry reports grants from The Pittsburgh Foundation, Translational Breast Cancer Research Consortium, and from UPMC Learning While Doing Program. Mr. Mouncey reports grants from National Institute for Health Research and from the European Union FP7: PREPARE. Dr. Najdovski reports payment from KUL Leuven to Belgian Red Cross for supply of convalescent plasma. Dr. Nichol reports grants from Health Research Board of Ireland. Dr. D. Roberts reports grants from the National Institute for Health (UKRIDHSC COVID-19 Rapid Response Rolling Call—Grant Reference Number COV19-RECPLAS) and the European Commission (SUPPORT-E #101015756). Dr. Rowan reports grants from the European Commission and from the UK National Institute for Health Research. Dr. Shankar-Hari reports grants from National Institute for Health Research UK, grants from UKRI-National Institute for Health Research UK. Dr. Turgeon reports grants from Canadian Institutes of Health Research. Dr. Venkatesh reports grants from Baxter. Dr. Webb reports grants from National Health and Medical Research Council, grants from Minderoo Foundation. Dr. Zacharowski reports grants from EU Horizon 2020. The ASCOT trial team (Drs Bowen, Daly, Davis, Denholm, Hammond, Jha, L. Lim, McQuilten, Molton, Morpeth, O’Sullivan, Paterson, Perry, Price, Rees, Roberts, Rogers, Sasadeusz, Snelling, Tong, Venkatesh, Wood) is funded by grants from from Royal Brisbane and Women’s Hospital Foundation, Pratt Foundation, Minderoo Foundation, BHP Foundation, Hospital Research Foundation, Macquarie Group Foundation, Health Research Council of New Zealand, Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE), and the collection and supply of convalescent plasma was conducted within Lifeblood’s funding arrangements. The CONFIDENT trial is funded by the Belgian KCE (blood establishments received payment for the convalescent plasma supplied in the clinical trial). REMAP-CAP was supported in part by funding from UKRIDHSC COVID-19 Rapid Response Rolling Call (Grant Reference Number COV19-RECPLAS). Collection of convalescent plasma for REMAP-CAP was funded by the Department of Health and Social Care, UK. The IRCT20200310046736N1 trial was supported by the Ahvaz Jundishapur University of Medical Sciences (Grant No. R.AJUMS.REC.1399.003, Dr. Pouladzadeh). The PC-COVID-19 Group is supported by the Universidad del Rosario, IDCBIS, ISA Group and Suramericana (Colombia). Outside the submitted work, the following is reported: Dr. Axfors reports postdoctoral grants from the Knut and Alice Wallenberg Foundation, Uppsala University, the Swedish Society of Medicine, the Blanceflor Foundation, and the Sweden-America Foundation. Dr. Aomar reports personal fees from SOBI, GEDEON RICHTER, and GSK. Dr. Benfield reports grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Hansen Foundation, Erik and Susanna Olesen’s Charitable Fund; grants and personal fees from GSK, Pfizer, Gilead; and personal fees from Boehringer Ingelheim, MSD, and Pentabase ApS. Dr. Estcourt reports being an investigator on the RECOVERY trial. Dr. Gordon reports personal fees from GlaxoSmithKline, Bristol Myers Squibb, and 30 Respiratory. Dr. Jha reports grants and personal fees from Baxter Healthcare, personal fees from Astra Zeneca, grants from NephroPlus. Dr. Laterre reports personal fees from Adrenomed. Dr. McVerry reports grants from NIH/NHLBI and Bayer Pharmaceuticals, Inc. Dr. Mondragon reports financial activities outside the submitted work (employment at Johnson & Johnson). Dr. Perry reports partner being employed at CSL and owning shares in CSL. Dr. Paterson reports involvement with ALLIANCE trial of COVID-19 treatments. Dr. J. Roberts reports other COVID-19 related trials (in different patient groups): tocilizumab in ICU patients; hydroxychloroquine dosing in ICU patients; planned study of remdesivir pharmacokinetics in patients during expanded access program; and in silico evaluation of ivermectin dosing. Dr Sasadeusz reports grants from various Pharma companies including Gilead Sciences, Abvvie, Merck, and Takeda. Dr. Zacharowski reports personal fees from Biotest AG, CSL Behring, GE Heathcare, and is President of the ESAIC., Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care., Amalia Bravo-Lindoro, BHP Foundation, Blanceflor Foundation, Department of Foreign Affairs, Trade, and Development of Canada, Eli Omar Zavaleta, Erik and Susanna Olesen’s Charitable Fund, Federal Ministry of Education and Research in Germany, Fundación Telefónica del Perú, IDCBIS, ISA Group and Suramericana, Kai Hansen Foundation, Katja Suter and Sina Ullrich, Khuzestan Blood Transfusion Organization, Macquarie Group Foundation, Medical Research Future Fund, NephroPlus, RBWH, Roel Rolando-Almario NCT04385199, Royal Brisbane, Sheri Renaud, Simonsen Foundation, UKRI-National Institute for Health Research UK, UKRIDHSC COV19-RECPLAS, UP-Philippine General Hospital CTRI/2020/05/025299, NCT04359810, NCT04468009, Women’s Hospital Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, Pittsburgh Foundation, Pfizer, Baxter International, Stanford University, Gilead Sciences, National Institute on Handicapped Research RP-2015-06-18, Meso Scale Diagnostics, Universität Basel, Laura and John Arnold Foundation, Health Research Board, Pratt Foundation, Canadian Institutes of Health Research, National Institute for Health Research, Department of Health and Social Care, European Commission 101015756, National Health and Medical Research Council, Department of Science and Technology, Ministry of Science and Technology, India, Health Research Council of New Zealand, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Sweden-America Foundation, Bundesministerium für Bildung und Forschung, Lundbeckfonden, Knut och Alice Wallenbergs Stiftelse, Seventh Framework Programme, Ahvaz Jundishapur University of Medical Sciences, Université Pierre et Marie Curie, Uppsala Universitet, Horizon 2020, Svenska Läkaresällskapet, Universidad del Rosario, Pharmaceuticals Bayer, Novo Nordisk Fonden, Department of Science and Technology, Philippines, Philippine Council for Health Research and Development, Minderoo Foundation

Summary Background Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. Methods In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov , NCT04421027 . Findings Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of −2·7 percentage points (95% CI −7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41–0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47–0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. Interpretation Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. Funding Eli Lilly and Company. Translations For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

The 3rd Annual Symposium on Hidradenitis Suppurativa Advances (SHSA) took place on 12-14 October 2018 at the Women's College Hospital in Toronto, Ontario, Canada. This symposium was a joint meeting of the Hidradenitis Suppurativa Foundation (HSF) founded in the USA and the Canadian Hidradenitis Suppurativa Foundation (CHSF). This cross-disciplinary meeting with experts from around the world was an opportunity to discuss the most recent advances in the study of hidradenitis suppurativa pathogenesis, epidemiology, classification, scoring systems, radiologic diagnosis, treatment approaches and psychologic assessment. Two special sessions this year were HS as a systemic disease and HS management guidelines. There were focused workshops on wound healing and ultrasound. There were two sessions primarily for patients and their families in the HS School programme: One workshop focused on mindfulness, and the second involved discussion among clinicians and patients about various disease aspects and the latest management. To facilitate networking between clinical and research experts and those early in their career, a mentoring breakfast was held.

Motivation COVID-19 has several distinct clinical phases: a viral replication phase, an inflammatory phase and in some patients, a hyper-inflammatory phase. High mortality is associated with patients developing cytokine storm syndrome. Treatment of hyper-inflammation in these patients using existing approved therapies with proven safety profiles could address the immediate need to reduce mortality. Results We analyzed the changes in the gene expression, pathways and putative mechanisms induced by SARS-CoV2 in NHBE, and A549 cells, as well as COVID-19 lung versus their respective controls. We used these changes to identify FDA approved drugs that could be repurposed to help COVID-19 patients with severe symptoms related to hyper-inflammation. We identified methylprednisolone (MP) as a potential leading therapy. The results were then confirmed in five independent validation datasets including Vero E6 cells, lung and intestinal organoids, as well as additional patient lung sample versus their respective controls. Finally, the efficacy of MP was validated in an independent clinical study. Thirty-day all-cause mortality occurred at a significantly lower rate in the MP-treated group compared to control group (29.6% versus 16.6%, P = 0.027). Clinical results confirmed the in silico prediction that MP could improve outcomes in severe cases of COVID-19. A low number needed to treat (NNT = 5) suggests MP may be more efficacious than dexamethasone or hydrocortisone. Availability and implementation iPathwayGuide is available at https://advaitabio.com/ipathwayguide/. Supplementary information Supplementary data are available at Bioinformatics online.

Importance Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed. Objective To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. Design, Setting, and Participants This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. Interventions Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). Main Outcomes and Measures The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. Results Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). Conclusions and Relevance Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults. Trial Registration ClinicalTrials.gov:NCT04332991

BACKGROUND Three companion randomized pragmatic trials were recently published assessing the effect of hydroxychloroquine (HCQ) on pre- exposure prophylaxis (PrEP - “Rajasingham,” NCT04328467), post- exposure prophylaxis (PEP - “Boulware,” NCT04308668) and treatment of early COVID-19 (“Skipper,” NCT04308668). Respectively, they found non-statistically significant reductions in development or persistence of COVID of 17%, 27% and 20% and concluded that HCQ did not reduce, prevent or substantially treat COVID-19 illness. With a likely Type 2 error and over ambitious powering (50% effect), these effects may impact trajectory and resource models that drive decisions on lockdowns. All three studies have signals mostly found in the data appendices that suggest useful effects of HCQ in sub-groups worthy of re-analysis and prospective exploration. HCQ appeared to benefit younger rather than older patients in both the PrEP and PEP studies with respective reductions in COVID-19 of 45% and 36%. There was a strong benefit (40%) of HCQ in women (PrEP). Response to HCQ appeared to vary by type of exposure, with a large benefit (64%) in first responders (PrEP) and in household contacts (31%, PEP). Further confounding the data was the undefined, ex-protocol use of zinc and ascorbic acid. INTERIM FINDINGS A major impediment in interpreting the PEP and treatment studies concerns the estimation of the time from exposure or symptom onset to treatment. Our initial analysis of the PEP study as published revealed a negative correlation between treatment lag and disease reduction, reaching 49% when HCQ was initiated within one day (RR 0.51, CI 0.176-1.46, p=0.249). However, our initial review (pursuant to this protocol, v1.1) of the publicly released PEP dataset revealed that, contrary to the study’s conclusion, this four-day period referred not to the time from exposure to treatment as we (and others) had understood, but to the time from exposure and enrollment, a difference of up to 3.5 days. Our re-stratification of new data we had requested revealed that HCQ may reduce the development of COVID-19 by as much as 65% (RR 0.35, CI 0.13-0.93, p=0.044) when received within 3 days of exposure (RR 0.83 at 3-5 days; RR 1.37 at 5-7 days). There remains ambiguity in these estimates addressable by further data we have requested. This same issue appears shared by the Treatment study. Further, patients in the PEP study were likely exposed to a series, rather than a single, “index” exposure, an issue possibly shared with the PrEP study. In the treatment study, there may be a bimodal effect of responders and non-responders, in whom symptoms may actually worsen. All three studies share the confounding effect of a possibly active folate placebo. OBJECTIVES To conduct a post hoc exploratory re-analyses of the de-identified raw datasets from randomized studies of the use of HCQ for pre- and post-exposure prophylaxis, and treatment of early of COVID-19 with view to further defining: (a) The time dependent effect of HCQ, on post exposure prophylaxis and treatment of COVID-19; (b) The age dependent effect of HCQ, on pre- and post- exposure prophylaxis and treatment of COVID-19; (c) The sub-stratification of gender, time- and age-dependent effects by exposure type and risk level, as well as by the use of zinc and ascorbic acid; (d) The design of prospective clinical trials designed to test the hypotheses generated by this study. These analyses will be expanded should datasets from similarly designed Spanish studies involving PEP or treatment of (both NCT04304053) COVID-19, with directionally similar results, become available. This protocol was devised using the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) incorporating the WHO Trial Registration Data Set. Study Status: Protocol version 1.2 (September 27 2020): registered at: OSF Registries September 27 2020 https://osf.io/fqtnw https://doi.org/10.17605/OSF.IO/FQTNW First submitted to medrxiv 9/30/20 as version1.2a, with format revisions requested by medrxiv Supplemental file: Detailed background and rationale Wiseman2020Synechion2001-v1-2aReanalysisHydroxychloroquine092720medrxivREV2-SUPPL.pdf Plain Language Summary Three companion clinical studies from the University of Minnesota examined the effect of hydroxychloroquine (HCQ) when given to treat early cases of COVID-19 or to prevent it from occurring either before or just after exposure to someone with coronavirus. Although reductions in COVID-19 between 17% and 27% were found when HCQ was used before or just after exposure to COVID-19, because the studies had too few patients in them and because they were designed to find larger differences, these effects were not statistically significant, even though, they may have been clinically meaningful. Furthermore, larger reductions of COVID-19 were found within sub-groups, reaching for example in one study 45% for younger patients ( In our initial review of the publicly released data from one of the studies, we discovered an issue that fundamentally alters its interpretation as well as one of its companion studies. According to their published reports, and understood by many others citing this work (including NIH), treatment with HCQ began within four days of either exposure or onset of symptoms. Because shipping schedules were not considered, this delay could have been 7.5 days and many patients may not have received drug in time to have an effect, if there was one. After we requested additional data, we found that HCQ may reduce COVID-19 by as much as 65% when given within 3 days of exposure and we have requested more data to clarify this figure further. We plan therefore to conduct a re-analysis of all three studies to explore how the effects of HCQ, if any, might be dependent on time, age, gender, and type of exposure to COVID-19. This will enable us to conduct clinical studies to confirm or refute what we think we have learned from this work.

Key Points Question What are the clinical characteristics and outcomes of patients with coronavirus disease 2019 evaluated at Henry Ford Health System in Southeast Michigan during the early phase of the outbreak? Findings In this case series involving 463 consecutive patients with confirmed coronavirus disease 2019 evaluated at a 5-hospital system serving metropolitan Detroit, 72.1% of patients were African American and 94.0% had at least 1 comorbidity. Among the 355 patients who were hospitalized, 39.7% required intensive care unit admission, of whom 80.8% underwent invasive mechanical ventilation and 40.4% died within 30 days. Meaning In this series of patients with coronavirus disease 2019 in metropolitan Detroit, a high proportion were admitted and required intensive care unit admission and invasive mechanical ventilation with a mortality rate of 40.4% among patients in the intensive care unit., This case series describes the clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) at a health system in metropolitan Detroit, Michigan, and provides a comparative analysis of hospitalized and ambulatory patient populations., Importance In late December 2019, an outbreak caused by a novel severe acute respiratory syndrome coronavirus 2 emerged in Wuhan, China. Data on the clinical characteristics and outcomes of infected patients in urban communities in the US are limited. Objectives To describe the clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) and to perform a comparative analysis of hospitalized and ambulatory patient populations. Design, Setting, and Participants This study is a case series of 463 consecutive patients with COVID-19 evaluated at Henry Ford Health System in metropolitan Detroit, Michigan, from March 9 to March 27, 2020. Data analysis was performed from March to April 2020. Exposure Laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection. Main Outcomes and Measures Demographic data, underlying comorbidities, clinical presentation, complications, treatment, and outcomes were collected. Results Of 463 patients with COVID-19 (mean [SD] age, 57.5 [16.8] years), 259 (55.9%) were female, and 334 (72.1%) were African American. Most patients (435 [94.0%]) had at least 1 comorbidity, including hypertension (295 patients [63.7%]), chronic kidney disease (182 patients [39.3%]), and diabetes (178 patients [38.4%]). Common symptoms at presentation were cough (347 patients [74.9%]), fever (315 patients [68.0%]), and dyspnea (282 patients [60.9%]). Three hundred fifty-five patients (76.7%) were hospitalized; 141 (39.7%) required intensive care unit management and 114 (80.8%) of those patients required invasive mechanical ventilation. Male sex (odds ratio [OR], 2.0; 95% CI, 1.3-3.2; P = .001), severe obesity (OR, 2.0; 95% CI, 1.4-3.6; P = .02), and chronic kidney disease (OR, 2.0; 95% CI, 1.3-3.3; P = .006) were independently associated with intensive care unit admission. Patients admitted to the intensive care unit had longer length of stay and higher incidence of respiratory failure and acute respiratory distress syndrome requiring invasive mechanical ventilation, acute kidney injury requiring dialysis, shock, and mortality (57 patients [40.4%] vs 15 patients [7.0%]) compared with patients in the general practice unit. Twenty-nine (11.2%) of those discharged from the hospital were readmitted and, overall, 20.0% died within 30 days. Male sex (OR, 1.8; 95% CI, 1.1-3.1; P = .03) and age older than 60 years (OR, 5.3; 95% CI, 2.9-9.7; P