Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 × 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19.

BACKGROUND: Early antiviral treatment is effective for Coronavirus Disease 2019 (COVID-19) but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral load trajectory when administered early. METHODS AND FINDINGS: We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2 × 2 factorial, double-blind trial of ambulatory outpatients with early COVID-19 (within 7 days of symptom onset) at 2 sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1,800 mg twice daily on Day 1 followed by 400 mg 4 times daily on Days 2 to 7) plus lopinavir-ritonavir (400 mg/100 mg twice daily on Day 1, followed by 200 mg/50 mg 4 times daily on Days 2 to 7), favipiravir plus lopinavir-ritonavir placebo, lopinavir-ritonavir plus favipiravir placebo, or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. Between 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo, and placebo-only arms, we recruited 61, 59, 60, and 60 participants and analysed 55, 56, 55, and 58 participants, respectively, who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had changed by -0.57 log10 (95% CI -1.21 to 0.07, p = 0.08) and in the lopinavir-ritonavir+placebo arm by -0.18 log10 (95% CI -0.82 to 0.46, p = 0.58) compared to the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log10, 95% CI -0.32 to 1.50, p = 0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% versus 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p = 0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm, possibly due to poor absorption. The major limitation was that the study population was relatively young and healthy compared to those most affected by the COVID-19 pandemic. CONCLUSIONS: At the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations. TRIAL REGISTRATION: Clinicaltrials.gov NCT04499677 EudraCT: 2020-002106-68.

News and failures from recent treatment trials in systemic sclerosis.

There have been many recent trials in systemic sclerosis (SSc) that have explored treatment for skin or lung. Some have been encouraging, but there has also been disappointment reflecting potential limitations of treatment effect of study design. These trials are discussed and reviewed. Studies conducted in SSc are described and discussed with a focus on endpoint selection and trial design as well as potential mechanism of action and treatment effect. Studies have included very encouraging trials of interleukin 6 blockade, immunosuppression, and broad-spectrum tyrosine kinase inhibition. Other trials including recent studies of peroxisome proliferator-activated receptor agonists and specific intracellular signaling inhibitors such as imatinib or anti-transforming growth factor beta blocking strategies have been more disappointing. Trial design is improving, and overall, there are now almost positive trials using agents with great promise, and studies are also providing important biological insight into SSc. It is hoped that ongoing studies will further progress the field and move it toward better treatments for SSc that still represent a major unmet medical need.

The Differential Effect of Antibodies on Radiographic Progression in Rheumatoid Arthritis.

BACKGROUND/OBJECTIVES: The presence of bony erosions in patients with RA is a marker of disease severity and once present they are largely irreversible. Previous studies have shown that the presence of both rheumatoid factor (RF) and anti-cyclic citrullinated peptide (ACPA) antibodies is associated with erosive burden. The aim of our study is to determine the strength of relationship between antibody status and the presence of radiographic erosions at diagnosis. METHODS: A retrospective study of patients diagnosed with RA at a large university teaching hospital between January 1981 and December 2018. Clinical records were reviewed to determine antibody status, diagnosis date, duration of symptoms, DAS-28, age, ethnicity and whether the 1987 RA criteria was met. The presence of erosions at diagnosis were determined from plain film radiographs reports of hands and feet of patients. Statistical analysis was done using a Chi Square Model and Mann Whitney two-tailed U test. RESULTS: There were 774 patients diagnosed with RA in our cohort. 367 (47%) of them were RF+/ACPA+, 87 (11%) were RF+/ACPA-, 66 (9%) were RF-/ACPA+ and 254 (33%) were antibody negative. 127 patients had erosions at the time of diagnosis. Patients in the double positive group had a significantly higher (p=0.003) erosion burden compared to the double negative group i.e. 21.5% in RF+/ACPA+ versus 11.0% in RF-/ACPA- group. The erosion burdens in RF+/ACPA- and RF-/ACPA+ groups were 13.7% and 12.1% respectively. CONCLUSIONS: Our results show that patients RF+/ACPA+ have nearly two-fold higher incidence of radiographic erosions than patients who are RF-/ACPA-.

Barriers to Neurosurgical Training in Sub-Saharan Africa: The Need for a Phased Approach to Global Surgery Efforts to Improve Neurosurgical Care.

BACKGROUND: Neurosurgery in low-income countries is faced with multiple challenges. Although the most common challenges include infrastructure and physical resource deficits, an underemphasized barrier relates to the methods and components of surgical training. The role of important aspects, including didactic surgical training, surgical decision-making, workshops, conferences, and assessment methods, has not been duly studied. Knowledge of these issues is a crucial step to move closer to strengthening surgical capacity in low-income countries. METHODS: We designed an online survey to assess self-perceived and objectively measured barriers to neurosurgical training in various Sub-Saharan African countries. Key outcomes included perception toward adequacy of neurosurgery training and barriers to neurosurgical training at each individual site. RESULTS: Only 37% of responders felt that their training program adequately prepared them for handling incoming neurosurgical cases. Top perceived limitations of neurosurgery training included lack of physical resources (25% of all responses), lack of practical workshops (22%), lack of program structure (18%), and lack of topic-specific lectures (10%). CONCLUSIONS: Our results show that most responders believe their training program is inadequate and are interested in improving it through international collaborations. This implies that activities directed at strengthening surgical capacity must address this important necessity. One important strategy is the use of online educational tools. In consideration of the observed limitations in care, resources, and training, we recommend a phased approach to neurosurgical growth in low-income settings.

Assessing Barriers to Neurosurgical Care in Sub-Saharan Africa: The Role of Resources and Infrastructure.

BACKGROUND: Quantitative estimates of surgical capacity and infrastructure and perceived care limitations in low-resource countries are essential baseline measures that can provide strategies for improving access to surgical care. Information about these barriers in Africa is scarce, particularly with respect to neurosurgery. We conducted a survey to better understand the unmet surgical need and resources available for the care of neurosurgery patients in Sub-Saharan Africa. METHODS: Using SurveyMonkey, we administered a neurosurgery-specific survey to neurosurgery attending surgeons and residents in Sub-Saharan African countries. Key outcome measures included workforce, access to imaging modalities and instruments, volume and breakdown of neurosurgical cases, and perceived limitations of care. RESULTS: We obtained a 41% survey response (129/314 sent). In addition to the expected large gap in workforce between low- and high-income countries, we found a dramatic paucity of neurosurgical resources in Central Africa, whereas specific pockets in West and South Africa have better neurosurgical care. Access to neuroimaging was not a major limitation in Sub-Saharan African countries. The most commonly perceived limitations of care included infrastructure, anesthesia/nursing availability, wait times, and strength of training. CONCLUSIONS: This large survey defines important self-perceived limitations to care within neurosurgery and highlights the importance of infrastructure and allied professions in this role. A clear understanding of areas of focus will enable a more efficient and sustainable response to the limitations in surgical care in low-resource areas.

Diffusion tensor imaging assessment of microstructural brainstem integrity in Chiari malformation Type I.

OBJECTIVE The diagnosis of Chiari malformation Type I (CM-I) is primarily based on the degree of cerebellar tonsillar herniation even though it does not always correlate with symptoms. Neurological dysfunction in CM-I presumably results from brainstem compression. With the premise that conventional MRI does not reveal brain microstructural changes, this study examined both structural and microstructural neuroimaging metrics to distinguish patients with CM-I from age- and sex-matched healthy control subjects. METHODS Eight patients with CM-I and 16 controls were analyzed. Image postprocessing involved coregistration of anatomical T1-weighted with diffusion tensor images using 3D Slicer software. The structural parameters included volumes of the posterior fossa, fourth ventricle, and tentorial angle. Fractional anisotropy (FA) was calculated separately in the anterior and posterior compartments of the lower brainstem. RESULTS The mean age of patients in the CM-I cohort was 42.6 ± 10.4 years with mean tonsillar herniation of 12 mm (SD 0.7 mm). There were no significant differences in the posterior fossa volume (p = 0.06) or fourth ventricular volume between the 2 groups (p = 0.11). However, the FA in the anterior brainstem compartment was significantly higher in patients with CM-I preoperatively (p = 0.001). The FA values normalized after Chiari decompression except for persistently elevated FA in the posterior brainstem compartment in patients with CM-I and syrinx. CONCLUSIONS In this case-control study, microstructural alterations appear to be reliably associated with the diagnosis of CM-I, with a significantly elevated FA in the lower brainstem in patients with CM-I compared with controls. More importantly, the FA values normalized after decompressive surgery. These findings should be validated in future studies to determine the significance of diffusion tensor imaging-based assessment of brainstem microstructural integrity as an adjunct to the clinical assessment in patients with CM-I.