Citations

Summary Background Ivermectin became a popular choice for COVID-19 treatment among clinicians and the public following encouraging results from pre-print trials and in vitro studies. Early reviews recommended the use of ivermectin based largely on non-peer-reviewed evidence, which may not be robust. This systematic review and meta-analysis assessed the efficacy and safety of ivermectin for treating COVID-19 based on peer-reviewed randomized controlled trials (RCTs) and observational studies (OSs). Methods MEDLINE, EMBASE and PubMed were searched from 1 January 2020 to 1 September 2021 for relevant studies. Outcomes included time to viral clearance, duration of hospitalization, mortality, incidence of mechanical ventilation and incidence of adverse events. RoB2 and ROBINS-I were used to assess risk of bias. Random-effects meta-analyses were conducted. GRADE was used to evaluate quality of evidence. Results Three OSs and 14 RCTs were included in the review. Most RCTs were rated as having some concerns in regards to risk of bias, while OSs were mainly rated as having a moderate risk of bias. Based on meta-analysis of RCTs, the use of ivermectin was not associated with reduction in time to viral clearance, duration of hospitalization, incidence of mortality and incidence of mechanical ventilation. Ivermectin did not significantly increase incidence of adverse events. Meta-analysis of OSs agrees with findings from RCT studies. Conclusions Based on very low to moderate quality of evidence, ivermectin was not efficacious at managing COVID-19. Its safety profile permits its use in trial settings to further clarify its role in COVID-19 treatment. Protocol registration The review was prospectively registered in PROSPERO (CRD42021275302).

Current guidelines recommend cardiac resynchronization therapy (CRT-D) in appropriate patients undergoing ICD implantation. However, not all physicians who implant ICDs are trained to perform CRT-D. We examined the ICD Registry to assess whether use of CRT-D implantation varied by physician certification. We determined the certification of 2128 physicians who had submitted >=10 cases between April 2006 and June 2007. We excluded patients with a prior ICD, an epicardial lead, or aged ≤18 years, leaving 111,293 patients. Physicians were grouped into mutually exclusive categories reflecting highest current certification- Electrophysiology (EP), Cardiovascular Disease (CVD), Thoracic Surgery (TS), Internal Medicine (IM), Heart Rhythm Society alternative pathway (HRS), and Other. Patients were considered eligible for CRT-D if they met the following criteria: QRS duration >=120ms, LVEF ≪26>35%, and NYHA Class III-IV. We examined crude rates of CRT-D across physician categories and developed a logistic regression model to assess the association of physician certification and CRT-D implantation. Candidate variables included demographics, cardiac status, comorbidities, and physician volume. Odds ratios were converted to relative risks. 35,851 patients met all three eligibility criteria for CRT-D, and 28,932 (80.7%) had a CRT-D implanted. EP physicians implanted the majority of CRT-D (73.6%), with fewer CRT-D placed by CVD (20.6%), TS (0.9%), IM (0.8%), HRS (1.1%), or Other (3.1%). The crude rate of CRT-D implantation was highest among EP physicians and lower in all other categories: EP- 83.1%, CVD-75.8%, TS- 57.9%, IM- 76.5%, HRS- 77.1%, Other- 73.5% (p<0.001). In multivariable analysis, CVD and TS physicians were less likely to implant CRT-D in eligible patients compared with EP physicians (EP: Ref; CVD: RR 0.92 (0.90 – 0.94); TS: RR 0.76 (0.71– 0.85)). CRT-D rates were comparable for other physician groups (IM RR 0.95 (0.87–1.01); HRS: RR 0.97 (0.90 –1.02); Other RR 0.97 (0.93–1.00)). Among eligible patients, use of CRT-D varies by physician certification. Given the benefits of CRT-D, clinicians should consider referring eligible patients to physicians with familiarity and expertise in CRT-D implantation.

A nano-resolution PDMS sensor simultaneously measures cell force and matrix stiffening dynamics in 3D.

ObjectiveDuring PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin‐4 immunoglobulin G‐positive neuromyelitis optica spectrum disorder (AQP4‐IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open‐label extension (OLE; NCT02003144) evaluating eculizumab's long‐term safety and efficacy.MethodsPatients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.ResultsAcross PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1–276.9 weeks), for a combined total of 362.3 patient‐years (PY). Treatment‐related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab‐treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6–97.3) of patients remained adjudicated relapse‐free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013–0.048) in all eculizumab‐treated patients versus 0.350 (95% CI = 0.199–0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use.InterpretationThis analysis demonstrates that eculizumab's long‐term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long‐term eculizumab treatment to reduce relapse risk in patients with AQP4‐IgG+ NMOSD. ANN NEUROL 2021;89:1088–1098

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

10062 Background: 17-AAG is a benzoquinone ansamycin that binds to and inhibits the HSP90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0–2, and adequate hematologic, hepatic, renal and cardiac functions received CNF1010 by 1 h intravenous infusion, twice-a-week, three weeks out of four, starting at 6 mg/m2 per dose. Doses were escalated sequentially in single pts (6 and 12 mg/m2) and 3–6 pts (≥ 25 mg/m2) cohorts according to a modified Fibonacci’s schema. Plasma pharmacokinetic (PK) profiles were obtained on days 1 and 18. Biomarkers were measured in PBMC’s (HSP70) and plasma (HER-2 ectodomain (HER-2 ECD)). Results: 30 pts (M/F: 14/16; median age 63, range 48–78) with colorectal cancer (11), pancreatic cancer (5), melanoma (5), ovarian (2), others (7) were treated with a median of 2 courses (range: 1–10). There was no dose-limiting toxicity up to 175 mg/m2. One pt at 175 mg/m2 died on study, but drug relation was unclear. Grade 1–2 gastrointestinal toxicities (nausea, vomiting, diarrhea) and serum creatinine elevation were observed. Severe toxicities (grade 3 but no grade 4) consisted of reversible hepatic enzyme elevation, hyperbilirubinemia, fatigue, anemia and hyperglycemia. There were no hematological toxicities. Plasma 17-AAG PK appeared dose-proportional (AUC, Cmax); CL (17 L/h/m2) and t1/2 (5.2 h) were dose independent and unchanged after repeated dosing (day 18). Post-treatment increases in HSP70 were observed in PBMCs and decreases in plasma HER-2 ECD were observed at doses ≥ 83 mg/m2. Minor tumor regressions were seen in 1 pt with duodenal cancer (83 mg/m2), 1 pt with gastric carcinoid (175 mg/m2) and 1 pt with melanoma (175 mg/m2). Conclusion: The threshold of biologic activity for CNF1010 administered by a twice a week schedule appears to be 83 mg/m2. This dosing regimen appears to be optimal and supported by the pharmacokinetic and pharmacodynamic data. The MTD has not yet been determined. Dose escalation of CNF1010 continues at 225 mg/m2. [Table: see text]