Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: The TOGETHER randomized platform clinical trial.

BACKGROUND: Observational studies have postulated a therapeutic role of metformin in treating COVID-19. We conducted an adaptive platform clinical trial to determine whether metformin is an effective treatment for high-risk patients with early COVID-19 in an outpatient setting. METHODS: The TOGETHER Trial is a placebo-controled, randomized, platform clinical trial conducted in Brazil. Eligible participants were symptomatic adults with a positive antigen test for SARS-CoV-2. We enroled eligible patients over the age of 50 years or with a known risk factor for disease severity. Patients were randomly assigned to receive either placebo or metformin (750 mg twice daily for 10 days or placebo, twice daily for 10 days). The primary outcome was hospitalization defined as either retention in a COVID-19 emergency setting for > 6 h or transfer to tertiary hospital due to COVID-19 at 28 days post randomization. Secondary outcomes included viral clearance at day 7, time to hospitalization, mortality, and adverse drug reactions. We used a Bayesian framework to determine probability of success of the intervention compared to placebo. FINDINGS: The TOGETHER Trial was initiated June 2, 2020. We randomized patients to metformin starting January 15, 2021. On April 3, 2021, the Data and Safety Monitoring Committee recommended stopping enrollment into the metformin arm due to futility. We recruited 418 participants, 215 were randomized to the metformin arm and 203 to the placebo arm. More than half of participants (56.0%) were over the age of 50 years and 57.2% were female. Median age was 52 years. The proportion of patients with the primary outcome at 28 days was not different between the metformin and placebo group (relative risk [RR] 1.14[95% Credible Interval 0.73; 1.81]), probability of superiority 0.28. We found no significant differences between the metformin and placebo group on viral clearance through to day 7 (Odds ratio [OR], 0.99, 95% Confidence Intervals 0.88-1.11) or other secondary outcomes. INTERPRETATION: In this randomized trial, metformin did not provide any clinical benefit to ambulatory patients with COVID-19 compared to placebo, with respect to reducing the need for retention in an emergency setting or hospitalization due to worsening COVID-19. There were also no differences between metformin and placebo observed for other secondary clinical outcomes.

Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.

BACKGROUND: Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19. METHODS: This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing. FINDINGS: The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18-102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0·68; 95% Bayesian credible interval [95% BCI]: 0·52-0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53-0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21-0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36-1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01-0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups. INTERPRETATION: Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital. FUNDING: FastGrants and The Rainwater Charitable Foundation. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Subspecialty Fellowship Training Is Not Associated With Better Outcomes in Fixation of Low-Energy Femoral Neck Fractures-An Analysis of the Fixation Using Alternative Implants for the Treatment of Hip Fractures Database.

OBJECTIVES: To compare risk of reoperation for femoral neck fracture patients undergoing fixation with cancellous screws (CSs) or sliding hip screws based on surgeon fellowship (trauma-fellowship-trained vs. non-trauma-fellowship-trained). DESIGN: Retrospective review of Fixation using Alternative Implants for the Treatment of Hip fractures data. SETTING: Eighty-one centers across 8 countries. PATIENTS/PARTICIPANTS: Eight hundred nineteen patients ≥50 years old with low-energy hip fractures requiring surgical fixation. INTERVENTION: Patients were randomized to CS or sliding hip screw group in the initial dataset. MAIN OUTCOME MEASUREMENTS: The primary outcome was risk of reoperation. Secondary outcomes included death, serious adverse events, radiographic healing, discharge disposition, and use of ambulatory devices postoperatively. RESULTS: There was no difference in risk of reoperation between the 2 surgeon groups (P > 0.05). Patients treated by orthopaedic trauma surgeons were more likely to be overweight/obese and have major medical comorbidities (P < 0.05). There was a higher risk of serious adverse events, higher likelihood of radiographic healing, and higher odds of discharge to a facility for patients treated by trauma-fellowship-trained surgeons (P < 0.05). CONCLUSIONS: Based on these data, risk of reoperation for low-energy femoral neck fracture fixation is equivalent regardless of fellowship training. The higher likelihood of radiographic healing noted in the trauma-trained group does not seem to have a major clinical implication because it did not affect risk of reoperation between the 2 groups. Patient-specific factors present preinjury, such as body habitus and medical comorbidities, may account for the lower odds of discharge to home and higher risk of postoperative medical complications for patients treated by orthopaedic trauma surgeons. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Orthopaedic Trauma Care Specialist Program for Developing Countries.

The dire challenges faced in Haiti, both preearthquake and postearthquake, highlight the need for developing surgical infrastructure to care for traumatic musculoskeletal injuries. The proposed Orthopaedic Trauma Care Specialist (OTCS) residency program aims to close the critical human resource gap that limits the appropriate care of musculoskeletal trauma in Haiti. The OTCS program is a proposal for a 2-year residency program that will focus primarily on the management of orthopaedic trauma. The proposed program will be a comprehensive approach for implementing affordable and sustainable strategies to improve orthopaedic trauma care. Its curriculum will be tailored to the injuries seen in Haiti, and the treatments that can be delivered within their health care system. Its long-term sustainability will be based on a "train-the-trainers" approach for developing local faculty to continue the program. This proposal outlines the OTCS framework specifically for Haiti; however, this concept is likely applicable to other low- and middle-income environments in a similar need for improved trauma and fracture care.

Current practice in the intramedullary nailing of tibial shaft fractures: an international survey.

BACKGROUND: Tibial fractures are the most common of all long bone fractures. Although many tibial fractures may be managed conservatively, a certain subset, including unstable fractures and open fractures, require operative stabilization. Intramedullary nails have become the popular choice of implant in the treatment of tibial shaft fractures. The variability in outcomes with tibial shaft fractures may reflect technical aspects of the surgical procedure and perioperative care regimens among surgeons. Identifying the distribution of surgeons' preferences in nailing technique, and the rationale for their choices, will aid in focusing educational activities for the orthopedic community and planning future clinical trials. Our objectives were to clarify surgeons' opinions regarding technical aspects of surgery and perioperative care after intramedullary nailing of closed and open tibial shaft fractures, and to identify predictors of surgeons' preferences in technique and perioperative care. METHODS: This study was a cross-sectional survey using focus groups, key informants, and sampling to redundancy strategies to develop a survey to examine surgeons' preferences in the treatment of tibial shaft fractures. The survey was pilot tested for clarity and content validity. We mailed this survey in July 2000 to 577 orthopedic surgeons who have an interest in trauma care. These were members of the Orthopaedic Trauma Association, American Academy of Orthopaedic Surgeons, or European AO International affiliated trauma centers. We used several strategies to improve response rates including personalized cover letters, stamped return envelopes, follow-up telephone calls, and repeat mailing of questionnaires. Main outcome measures included technical issues such as reduction, exposure, intramedullary reaming, and interlocking screws; and factors associated with surgeons' preferences such as age, fellowship, academic practice, and geographic location. RESULTS: Four hundred forty-four surgeons (77%) responded. Sixty percent of respondents had an academic practice, 84% supervised residents, and 65.1% had fellowship training in trauma. Approximately half (51.5%) of surgeons used a tourniquet. The odds that a surgeon in Asia or Africa used tourniquets was 10 times that of a North American surgeon (p = 0.004 and p = 0.002, respectively). Patellar tendon retraction and an inferior-based entry portal was the popular choice among surgeons (70.1% and 70.8%, respectively). Surgeons from Australia (odds ratio [OR] = 50, p < 0.001), South America (OR = 9.0, p < 0.001), Europe (OR = 3.7, p = 0.001), and Asia (OR = 3.8, p = 0.006) were significantly more likely to use a patellar splitting approach compared with North American surgeons. In the perioperative care of open tibial shaft fractures, there was consensus in the use of intravenous antibiotics and wound irrigation (96.5% and 95.6%, respectively). However, we found considerable variability in surgeons' preference in wound irrigation pressures (high, 38.7%; low, 45.4%). Surgeons in South America were 10 times more likely to use low-pressure irrigation than North American surgeons (p = 0.0005). In grade IIIB open tibial shaft fractures, 94% of surgeons believed wound closure should be obtained within the first 7 days after the injury. A surgeon's geographic location was a significant predictor of the timing of soft tissue coverage (p = 0.001). CONCLUSION: Consensus in the use of irrigation and intravenous antibiotics in open fractures was achieved among surgeons. However, there remains considerable variability in the surgical technique of intramedullary nailing, the duration of antibiotic use, and the timing of wound closure in open tibial fracture care. Continued education and large multicenter trials are needed to establish best practice in the operative treatment of tibial shaft fracture.