VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency ...virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed.
HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens. Additionally, this study aimed to assess the effect that the human body has on the functional activities of VRC01 as measured by several in vitro assays. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range, 18-50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic), 11% were Hispanic, and 11% were non-Hispanic people of diverse origins. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 T1, n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 T3, n = 20); placebo (placebo group 3 P3, n = 4) doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 T2, n = 20). Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities, nor evidence for anti-VRC01 antibodies observed. Serum VRC01 levels were detected through 12 weeks after final administration in all participants who received all scheduled doses. Mean peak serum VRC01 levels of 1,177 μg/ml (95% CI: 1,033, 1,340) and 420 μg/ml (95% CI: 356, 494) were achieved 1 hour after the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively. Mean trough levels at week 24 in the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively, were 16 μg/ml (95% CI: 10, 27) and 6 μg/ml (95% CI: 5, 9) levels, which neutralize a majority of circulating strains in vitro (50% inhibitory concentration IC50 > 5 μg/ml). Post-infusion/injection serum VRC01 retained expected functional activity (virus neutralization, antibody-dependent cellular cytotoxicity, phagocytosis, and virion capture). The limitations of this study include the relatively small sample size of each VRC01 administration regimen and missing data from participants who were unable to complete all study visits.
VRC01 administered as either an IV infusion (10-40 mg/kg) given monthly or bimonthly, or as an SC injection (5 mg/kg) every 2 weeks, was found to be safe and well tolerated. In addition to maintaining drug concentrations consistent with neutralization of the majority of tested HIV strains, VRC01 concentrations from participants' sera were found to avidly capture HIV virions and to mediate antibody-dependent cellular phagocytosis, suggesting a range of anti-HIV immunological activities, warranting further clinical trials.
Clinical Trials Registration: NCT02165267.
Background The hospital volume–outcome relationship for complex procedures has led to the suggestion that care should be centralized. This study was performed to investigate whether centralization is ...occurring for pancreatoduodenectomy (PD) and to examine its effect on short-term postoperative outcomes. Methods We queried the New York State Statewide Planning and Research Cooperative System database ( n = 6,185, 2002–2011) and the California and Florida State Inpatient Databases ( n = 6,766 and 4,810, respectively, 2002–2011) for PD. Hospitals were divided into low (≤10), medium (11–25), high (25–60), and very high (≥61) groups depending on annual volume. Hierarchical logistic modeling accounted for patient clustering within hospitals. Results A migration of cases from low-volume to medium, high, and very high-volume (MHVH) hospitals occurred in these 3 states ( P < .01). There was an increase in the number of MHVH hospitals and a decrease in the number of low-volume hospitals performing PD across all states over time, with a large number of hospitals ceasing to perform PD cases entirely. Comorbidities such as congestive heart failure and diabetes were more prevalent in low-volume hospitals. After we adjusted for all predictors, MHVH hospitals had less rates of mortality and morbidity and shorter durations of stay than low-volume hospitals ( P < .05); 30-day readmission rates were similar across all volume groups. Conclusion Centralization of PD is occurring in these 3 states and probably across the nation. After PD, MHVH hospitals had statistically better outcomes (mortality, morbidity, and duration of stay) than low-volume hospitals. Readmission rates were not affected by volume.
BACKGROUND:Fixation in total hip replacements remains a controversial topic, despite the high level of its success. Data obtained from major orthopaedic registries indicate that there are large ...differences among preferred fixation and survival results.
METHODS:Using a distributed registry data network, primary total hip arthroplasties performed for osteoarthritis from 2001 to 2010 were identified from six national and regional total joint arthroplasty registries. A multivariate meta-analysis was performed using linear mixed models with the primary outcome revision for any reason. Survival probabilities and their standard errors were extracted from each registry for each unique combination of the covariates. Fixation strategies were compared with regard to age group, sex, bearing, and femoral-head diameter. All comparisons were based on the random-effects model and the fixed-effects model.
RESULTS:In patients who were seventy-five years of age and older, uncemented fixation had a significantly higher risk of revision (p < 0.001) than hybrid fixation, with a hazard ratio of 1.575 (95% confidence interval, 1.389 to 1.786). We found a similar, if lesser, effect in the intermediate age group of sixty-five to seventy-four years (hazard ratio, 1.16 95% confidence interval, 1.023 to 1.315; p = 0.021) and in the younger age group of forty-five to sixty-four years (hazard ratio, 1.205 95% confidence interval, 1.008 to 1.442; p = 0.041). There were no significant differences between hybrid and cemented bearings across age groups.
CONCLUSIONS:We conclude that cementless fixation should be avoided in older patients (those seventy-five years of age or older), although this evidence is less strong in patients of intermediate and younger ages.
Objective In this study, the effectiveness of peripheral vascular intervention (PVI) was compared with surgical bypass grafting (BPG) for critical limb ischemia (CLI) in the Vascular Study Group of ...Greater New York (VSGGNY). Methods Patients undergoing BPG or PVI for CLI at VSGGNY centers (2011-2013) were included. The Society for Vascular Surgery objective performance goals for CLI were used to directly compare the safety and effectiveness of PVI and BPG. Propensity score matching was used for risk-adjusted comparisons of PVI with BPG. Results A total of 414 patients (268 PVI, 146 BPG) were treated for tissue loss (69%) or rest pain (31%). Patients undergoing PVI were more likely to have tissue loss (74.6% vs 57.5%; P < .001) and comorbidities such as diabetes (69.3% vs 57.5%; P = .02), heart failure (22% vs 13.7%; P = .04), and severe renal disease (13.1% vs 4.1%; P = .004). No significant differences were found between the groups across a panel of safety objective performance goals. In unadjusted analyses at 1 year, BPG was associated with higher rates of freedom from reintervention, amputation, or restenosis (90.4% vs 81.7%; P = .02) and freedom from reintervention or amputation (92.5% vs 85.8%, P = .045). After propensity score matching, PVI was associated with improved freedom from major adverse limb events and postoperative death at 1 year (95.6% vs 88.5%; P < .05). Conclusions By unadjusted comparison, early reintervention and restenosis are more prevalent with PVI. However, risk-adjusted comparison underscores the safety and effectiveness of PVI in the treatment of CLI.
Objective The purpose of this study is to characterize the evolution in perioperative outcomes and costs of endovascular abdominal aortic aneurysm (AAA) repair (EVAR) by detailing changes in adjusted ...outcomes and costs over time. Methods National Inpatient Sample (2000-2011) data were used to evaluate patient characteristics, outcomes, and perioperative costs for elective EVAR performed for intact AAA. Outcomes were adjusted for patient demographics and comorbidities, and hospital factors by multivariate analysis. Costs were calculated from hospital cost to charge ratio files and adjusted to 2011 dollars. Results From 2000 to 2011, 185,249 patients underwent elective EVAR for intact AAA. The absolute rates of in-hospital major morbidity, mortality, and procedural costs all decreased significantly over time ( P < .0001). The prevalence of major comorbidities in patients undergoing EVAR, including obesity, diabetes, and dyslipidemia, all increased significantly over time. After adjusting for multiple demographics, comorbidities, and hospital-level factors, recent outcomes of EVAR (2009-2011) remain superior to the early experience (2000-2002) with respect to mortality and major complications. Conclusions From 2000-2011, the perioperative outcomes of EVAR improved significantly despite a higher prevalence of comorbidities among patients undergoing repair. Concurrently, procedure-associated costs declined. Advanced technology is often implicated in escalating healthcare spending, and the value of novel techniques is often questioned. These findings highlight that, in the case of EVAR, procedural outcomes have improved while the initial costs of repair have declined over time. EVAR offers an interesting example for stakeholders to consider in the era of cost-containment pressures and criticism of nascent, expensive technology in healthcare.
Recall and social desirability bias undermine self-report of paper-and-pencil questionnaires. Mobile phone questionnaires may overcome these challenges. We assessed and compared sexual risk behavior ...reporting via in-clinic paper-and-pencil and mobile phone questionnaires. HVTN 915 was a prospective cohort study of 50 adult women in Soweto, who completed daily mobile phone, and eight interviewer-administered in-clinic questionnaires over 12 weeks to assess sexual risk. Daily mobile phone response rates were 82% (n = 3486/4500); 45% (n = 1565/3486) reported vaginal sex (median sex acts 2 (IQR: 1–3)) within 24 h and 40% (n = 618/1565) consistent condom. Vaginal sex reporting was significantly higher via mobile phone across all visits (p < 0.0001). There was no significant difference in condom use reporting by mobile phone and in-clinic paper-based questionnaires across all visits (p = 0.5134). The results show high adherence and reporting of sex on the mobile phone questionnaire. We demonstrate feasibility in collecting mobile phone sexual risk data.
The International Consortium for Orthopaedic Registries is a multinational initiative established by the United States Food and Drug Administration to develop a health data network aimed at providing ...a robust infrastructure to facilitate evidence-based decision-making on performance of medical devices. Through the International Consortium for Orthopaedic Registries, individual data holders have complete control of their data and can choose to participate in studies of their choice. In this article, we present an overview of the data extraction process and the analytic strategy employed to answer several device performance-related questions in total hip arthroplasty and total knee arthroplasty. In the process, we discuss some nuances pertinent to International Consortium for Orthopaedic Registries data that pose certain statistical challenges, and we briefly suggest strategies to be adopted to address them.
BACKGROUND:Posterior-stabilized total knee prostheses were introduced to address instability secondary to loss of posterior cruciate ligament function, and they have either fixed or mobile bearings. ...Mobile bearings were developed to improve the function and longevity of total knee prostheses. In this study, the International Consortium of Orthopaedic Registries used a distributed health data network to study a large cohort of posterior-stabilized prostheses to determine if the outcome of a posterior-stabilized total knee prosthesis differs depending on whether it has a fixed or mobile-bearing design.
METHODS:Aggregated registry data were collected with a distributed health data network that was developed by the International Consortium of Orthopaedic Registries to reduce barriers to participation (e.g., security, proprietary, legal, and privacy issues) that have the potential to occur with the alternate centralized data warehouse approach. A distributed health data network is a decentralized model that allows secure storage and analysis of data from different registries. Each registry provided data on mobile and fixed-bearing posterior-stabilized prostheses implanted between 2001 and 2010. Only prostheses associated with primary total knee arthroplasties performed for the treatment of osteoarthritis were included. Prostheses with all types of fixation were included except for those with the rarely used reverse hybrid (cementless tibial and cemented femoral components) fixation. The use of patellar resurfacing was reported. The outcome of interest was time to first revision (for any reason). Multivariate meta-analysis was performed with linear mixed models with survival probability as the unit of analysis.
RESULTS:This study includes 137,616 posterior-stabilized knee prostheses; 62% were in female patients, and 17.6% had a mobile bearing. The results of the fixed-effects model indicate that in the first year the mobile-bearing posterior-stabilized prostheses had a significantly higher hazard ratio (1.86) than did the fixed-bearing posterior-stabilized prostheses (95% confidence interval, 1.28 to 2.7; p = 0.001). For all other time intervals, the mobile-bearing posterior-stabilized prostheses had higher hazard ratios; however, these differences were not significant.
CONCLUSIONS:Mobile-bearing posterior-stabilized prostheses had an increased rate of revision compared with fixed-bearing posterior-stabilized prostheses. This difference was evident in the first year.
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