A pilot study of pNGVL4a-CRT/E7(detox) for the treatment of patients with HPV16+ cervical intraepithelial neoplasia 2/3 (CIN2/3).

OBJECTIVE: The purpose of this study was to evaluate the safety, efficacy, and immunogenicity of a plasmid vaccine, pNGVL4a-CRT-E7(detox), administered either intradermally, intramuscularly, or directly into the cervical lesion, in patients with HPV16-associated CIN2/3. METHODS: Eligible patients with HPV16(+) CIN2/3 were enrolled in treatment cohorts evaluating pNGVL4a-CRT-E7(detox), administered by either particle-mediated epidermal delivery (PMED), intramuscular injection (IM), or cervical intralesional injection, at study weeks 0, 4, and 8. Patients were monitored for local injection site and systemic toxicity. A standard therapeutic resection was performed at week 15. The primary endpoints were safety and tolerability. Secondary endpoints included histologic regression and change in cervical HPV viral load. Exploratory endpoints included immune responses in the blood and in the target tissue. RESULTS: Thirty-two patients with HPV16(+) CIN2/3 were enrolled onto the treatment phase of the study, and were vaccinated. Twenty-two of 32 patients (69%) experienced vaccine-specific related adverse events. The most frequent vaccine-related events were constitutional and local injection site in nature, and were grade 1 or less in severity. Histologic regression to CIN 1 or less occurred in 8 of 27 (30%) patients who received all vaccinations and underwent LEEP. In subject-matched comparisons, intraepithelial CD8+ T cell infiltrates increased after vaccination in subjects in the intralesional administration cohort. CONCLUSION: pNGVL4a-CRT-E7(detox) was well-tolerated, elicited the most robust immune response when administered intralesionally, and demonstrated preliminary evidence of potential clinical efficacy.

Referral Efficiency for Veterans with Osteoarthritis: A Quality Improvement Project.

Management of osteoarthritis, a common disease among veterans, includes referrals to orthopedic specialists. This requires an effective referral system. The aim of this study was to evaluate a quality improvement project addressing inefficiencies in the osteoarthritis referral process between primary care providers and orthopedic specialists. A pre- and post-intervention evaluation using medical record review and provider surveys was conducted to measure the process improvement of a primary care to orthopedic referral template. There was a 3.5% increase in the referral acceptance rate following the intervention. In addition, primary care providers perceived that role clarity and perception on making referrals had significantly improved. The largest perceived improved change among orthopedic specialists was in communication. A simple process change, such as improving the referral template, can help with communication, data transfer, and referral acceptance rates between primary care providers and orthopedic specialists. This in turn will benefit the large population of veterans needing orthopedic referrals for management of osteoarthritis.

Cost-effectiveness of Humanitarian Pediatric Cardiac Surgery Programs in Low- and Middle-Income Countries.

Importance: Endorsement of global humanitarian interventions is based on either proven cost-effectiveness or perceived public health benefits. The cost-effectiveness and long-term benefits of global humanitarian pediatric cardiac surgery are unknown, and funding for this intervention is insufficient. Objectives: To determine the cost-effectiveness of the intervention (multiple 2-week-long humanitarian pediatric cardiac surgery program assistance trips to various low- and middle-income countries [LMICs]) and to produce a measure of the long-lasting effects of global humanitarian programs. Design, Setting, and Participants: International, multicenter cost-effectiveness analysis of a cohort of children (aged <16 years) undergoing surgical treatment of congenital heart disease during 2015 in LMICs, including China, Macedonia, Honduras, Iran, Iraq, Libya, Nigeria, Pakistan, Russia, and Ukraine. The study also assessed estimated improvement in the United Nations Human Development Indicators (life expectancy, years of schooling, and gross national income) for each individual survivor, as a proxy for long-term benefits of the intervention. Main Outcomes and Measures: The primary outcome was cost-effectiveness of the intervention. The secondary outcomes were potential gains in life expectancy, years of schooling, and gross national income per capita for each survivor. Results: During 2015, 446 patients (192 [43%] female; mean [SD] age, 3.7 [5.4] years) were served in 10 LMICs at an overall cost of $3 210 873. Of them, 424 were children. The cost-effectiveness of the intervention was $171 per disability-adjusted life-year averted. Each survivor in the cohort (390 of 424) potentially gained 39.9 disability-adjusted life-years averted, 3.5 years of schooling, and $159 533 in gross national income per capita during his or her extended lifetime at purchasing power parity and 3% discounting. Conclusions and Relevance: Humanitarian pediatric cardiac surgery in LMICs is highly cost-effective. It also leaves behind a lasting humanitarian footprint by potentially improving individual development indices.