Neurologic Acyclovir Toxicity in the Absence of Kidney Injury.

BACKGROUND: Herpes zoster (zoster) also commonly known as "shingles," occurs following re-activation of the varicella zoster virus. It contributes a large cost burden to the U.S. health care system, with an estimated 1 million cases costing $1 billion annually. The current gold standard treatment is acyclovir, which limits viral replication. However, acyclovir has been reported to cause neurotoxicity in patients with acute or chronic kidney disease. CASE REPORT: This case presents an occurrence of acyclovir-induced toxic encephalopathy in a patient with normal renal function. A 63-year-old male presented to the emergency department with ataxia, tremors, fluctuating aphasia, confusion, agitation, and fatigue. Results of imaging, lumbar puncture, and laboratory studies directed clinicians toward acyclovir toxicity, despite a normal creatinine level. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians will likely be the first point of contact in the health care system following the onset of acyclovir toxicity. With an increasing incidence of zoster disease, such atypical toxic manifestations may increase. Early recognition is important to avoid permanent neurologic compromise.

Kinetics of tumor destruction by chimeric antigen receptor-modified T cells.

The use of chimeric antigen receptor (CAR)-modified T cells as a therapy for hematologic malignancies and solid tumors is becoming more widespread. However, the infusion of a T-cell product targeting a single tumor-associated antigen may lead to target antigen modulation under this selective pressure, with subsequent tumor immune escape. With the purpose of preventing this phenomenon, we have studied the impact of simultaneously targeting two distinct antigens present on tumor cells: namely mucin 1 and prostate stem cell antigen, both of which are expressed in a variety of solid tumors, including pancreatic and prostate cancer. When used individually, CAR T cells directed against either tumor antigen were able to kill target-expressing cancer cells, but tumor heterogeneity led to immune escape. As a combination therapy, we demonstrate superior antitumor effects using both CARs simultaneously, but this was nevertheless insufficient to achieve a complete response. To understand the mechanism of escape, we studied the kinetics of T-cell killing and found that the magnitude of tumor destruction depended not only on the presence of target antigens but also on the intensity of expression-a feature that could be altered by administering epigenetic modulators that upregulated target expression and enhanced CAR T-cell potency.

A Package of Sexual and Reproductive Health and Rights Interventions-What Does It Mean for Adolescents?

This article analyzes the relevance of the comprehensive definition of sexual and reproductive health and rights (SRHR) to adolescents and identifies adolescent-specific implications for the implementation of an essential package of SRHR interventions. The delivery of a comprehensive approach to SRHR targeting adolescents is underpinned by five principles-equity, quality, accountability, multisectorality, and meaningful engagement. All SRHR interventions included in the package are relevant to adolescents, given the diversity of adolescents' SRHR needs and considering their specific attributes, circumstances, and experiences. Ensuring that this package is available, accessible, and acceptable to adolescents requires an approach that looks at adolescents as being biologically and socially distinct from other age groups and acknowledges that they face some specific barriers when accessing SRHR services. This article provides cross-cutting strategies for the implementation of a comprehensive approach to SRHR for adolescents and specific considerations in delivering each intervention in the package of essential SRHR interventions. To further implement the International Conference on Population and Development Programme of Action, a prerequisite for achieving the Sustainable Development Goals, SRHR interventions must be adolescent responsive, delivered through multiple platforms, leveraging multisectoral collaboration, and strengthening accountability and participation.

Forward, Together: A Collaborative Path to Comprehensive Adolescent Sexual and Reproductive Health and Rights in Our Time.

The 1994 International Conference on Population and Development established a basis for the advancement of adolescent sexual and reproductive health and rights (ASRHR) that endures today. Twenty-five years later, our vision for the future warrants reflection based on a clear understanding of the opportunities and challenges before us. Inclusion of adolescents on global, regional, and national agendas; increased investment in ASRHR policies and programs; renewed commitments to universal health coverage; increased school enrollment; and advances in technology are all critical opportunities we can and must leverage to catalyze progress for adolescents. At the same time, a range of significant challenges remain, have newly emerged, or can be seen on the horizon, including persistent denial of adolescent sexuality; entrenched gender inequality; resistance to meaningfully engaging adolescents and young people in political and programmatic processes; weak systems, integration, and multisectoral coordination; changes in population dynamics; humanitarian and climate crises; and changes in family and community structures. To achieve as much progress toward our vision for ASRHR as possible, the global ASRHR community must take strategic and specific steps in the next 10 years within five areas for action: (1) mobilize and make full use of political and social support for ASRHR policies and programs; (2) increase and make effective use of external and domestic funding for ASRHR; (3) develop, communicate, apply, and monitor enabling and protective laws and policies for ASRHR; (4) use and improve available ASRHR data and evidence to strengthen advocacy, policies, and programs; and (5) manage the implementation of ASRHR strategies at scale with quality and equity.

Increasing Access to Family Planning Choices Through Public-Sector Social Franchising: The Experience of Marie Stopes International in Mali.

BACKGROUND: Mali has one of the world's lowest contraceptive use rates and a high rate of unmet need for family planning. In order to increase access to and choice of quality family planning services, Marie Stopes International (MSI) Mali introduced social franchising in public-sector community health centers (referred to as CSCOMs in Mali) in 3 regions under the MSI brand BlueStar. PROGRAM DESCRIPTION: Potential franchisees are generally identified from CSCOMs who have worked with MSI outreach teams; once accredited as franchisees, CSCOMs receive training, supervision, family planning consumables and commodities, and support for awareness raising and demand creation. To ensure availability and affordability of services, franchisees are committed to providing a wide range of contraceptive methods at low fixed prices. METHODS AND RESULTS: The performance of the BlueStar network from inception in March 2012 until December 2015 was examined using information from routine monitoring data, clinical quality audits, and client exit interviews. During this period, the network grew from 70 to 135 franchisees; an estimated 123,428 clients received voluntary family planning services, most commonly long-acting reversible methods of contraception. Franchisee efficiency and clinical quality of services increased over time, and client satisfaction with services remained high. One-quarter of clients in 2015 were under 20 years old, and three-quarters were adopters of family planning (that is, they had not been using a modern method during the 3 months prior to their visit). CONCLUSION: Applying a social franchising support package, originally developed for for-profit private-sector providers, to public-sector facilities in Mali has increased access, choice, and use of family planning in 3 regions of Mali. The experience of BlueStar Mali suggests that interventions that support quality supply of services, while simultaneously addressing demand-side barriers such as service pricing, can successfully create demand for a broad range of family planning services, even in settings with low contraceptive prevalence.

Private-Sector Social Franchising to Accelerate Family Planning Access, Choice, and Quality: Results From Marie Stopes International.

BACKGROUND: To achieve the global Family Planning 2020 (FP2020) goal of reaching 120 million more women with voluntary family planning services, rapid scale-up of services is needed. Clinical social franchising, a service delivery approach used by Marie Stopes International (MSI) in which small, independent health care businesses are organized into quality-assured networks, provides an opportunity to engage the private sector in improving access to family planning and other health services. METHODS: We analyzed MSI's social franchising program against the 4 intended outputs of access, efficiency, quality, and equity. The analysis used routine service data from social franchising programs in 17 African and Asian countries (2008-2014) to estimate number of clients reached, couple-years of protection (CYPs) provided, and efficiency of services; clinical quality audits of 636 social franchisees from a subset of the 17 countries (2011-2014); and exit interviews with 4,844 clients in 14 countries (2013) to examine client satisfaction, demographics (age and poverty), and prior contraceptive use. The MSI "Impact 2" model was used to estimate population-level outcomes by converting service data into estimated health outcomes. RESULTS: Between 2008 and 2014, an estimated 3,753,065 women cumulatively received voluntary family planning services via 17 national social franchise programs, with a sizable 68% choosing long-acting reversible contraceptives (LARCs). While the number of social franchisee outlets increased over time, efficiency also significantly improved over time, with each outlet delivering, on average, 178 CYPs in 2008 compared with 941 CYPs in 2014 (P = .02). Clinical quality audit scores also significantly improved; 39.8% of social franchisee outlets scored over 80% in 2011 compared with 84.1% in 2014. In 2013, 40.7% of the clients reported they had not been using a modern method during the 3 months prior to their visit (95% CI = 37.4, 44.0), with 46.1% (95% CI = 40.9, 51.2) of them reporting having never previously used family planning at all. Analysis of age and poverty levels of clients indicate mixed results in bridging equity gaps: 57.4% of clients lived on under US$2.50/day in 2013 (95% CI = 54.9, 60.0) and 26.1% were 15-24 years old (95% CI = 23.8, 28.4), but only 15.1% lived on less than $1.25/day (95% CI = 13.8, 16.4) and 5.0% were 15-19 years old (95% CI = 3.9, 6.1). The services provided via social franchising are estimated to avert 4,958,000 unintended pregnancies and 7,150 maternal deaths. CONCLUSION: Social franchising through the existing private sector has the ability to rapidly scale-up access to high-quality family planning services, including LARCs, for the general population as well as young women and the poor, providing a promising model to help achieve the global FP2020 goal.

Establishing and Scaling-Up Clinical Social Franchise Networks: Lessons Learned From Marie Stopes International and Population Services International.

In many low- and middle-income countries, a majority of people seek health care from the private sector. However, fragmentation, poor economies of scale, inadequate financing, political opposition, a bias toward curative services, and weak regulatory and quality control systems pose serious challenges for the private sector. Social franchising addresses a number of these challenges by organizing small, independent health care businesses into quality-assured networks. Global franchisors Marie Stopes International (MSI) and Population Services International (PSI) have rapidly scaled their family planning social franchising programs in recent years, jointly delivering over 10.8 million couple-years of protection (CYPs) in 2014-up 26% from 8.6 million CYPs just 1 year prior. Drawing on experience across MSI's 17 and PSI's 25 social franchise networks across Africa, Asia, and Latin America and the Caribbean, this article documents the organizations' operational approaches, challenges faced, and solutions implemented. The organizations provide intensive capacity building and support for private-sector providers, including clinical training, branding, monitoring quality of franchised services, and commodity support. In addition, franchising programs engage providers and clients through behavior change communication (BCC) and demand generation activities to raise awareness and to attract clients, and they implement initiatives to ensure services are affordable for the lowest-income clients. Social franchise programs offer the private sector a collective platform to better engage government in health policy advocacy and for integrating into new public health care financing and procurement mechanisms. The future of social franchising will require developing approaches to scale-up and sustain the model cost-effectively, selectively integrating other health services into the franchise package, and being responsive to evolving health care financing approaches with the potential to contribute to universal health coverage.

Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner.

PURPOSE: Activating Q209L/P mutations in GNAQ or GNA11 (GNAQ/11) are present in approximately 80% of uveal melanomas. Mutant GNAQ/11 are not currently therapeutically targetable. Inhibiting key down-stream effectors of GNAQ/11 represents a rational therapeutic approach for uveal melanomas that harbor these mutations. The mitogen-activated protein/extracellular signal-regulated kinase/mitogen-activated protein kinase (MEK/MAPK) and PI3K/AKT pathways are activated in uveal melanoma. In this study, we test the effect of the clinically relevant small molecule inhibitors GSK1120212 (MEK inhibitor) and GSK2126458 (pan class I PI3K inhibitor) on uveal melanoma cells with different GNAQ/11 mutation backgrounds. EXPERIMENTAL DESIGN: We use the largest set of genetically annotated uveal melanoma cell lines to date to carry out in vitro cellular signaling, cell-cycle regulation, growth, and apoptosis analyses. RNA interference and small molecule MEK and/or PI3K inhibitor treatment were used to determine the dependency of uveal melanoma cells with different GNAQ/11 mutation backgrounds on MEK/MAPK and/or PI3K/AKT signaling. Proteomic network analysis was done to unveil signaling alterations in response to MEK and/or PI3K small molecule inhibition. RESULTS: GNAQ/11 mutation status was not a determinant of whether cells would undergo cell-cycle arrest or growth inhibition to MEK and/or phosphoinositide 3-kinase (PI3K) inhibition. A reverse correlation was observed between MAPK and AKT phosphorylation after MEK or PI3K inhibition, respectively. Neither MEK nor PI3K inhibition alone was sufficient to induce apoptosis in the majority of cell lines; however, the combination of MEK + PI3K inhibitor treatment resulted in the marked induction of apoptosis in a GNAQ/11 mutant-dependent manner. CONCLUSIONS: MEK + PI3K inhibition may be an effective combination therapy in uveal melanoma, given the inherent reciprocal activation of these pathways within these cells.