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Abstract Background Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel®) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. Methods Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. Results Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). Conclusion These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV.

Many women risk unintended pregnancy because of medical contraindications or dissatisfaction with contraceptive methods, including real and perceived side effects associated with the use of exogenous hormones. We pursued direct vaginal delivery of sperm-binding monoclonal antibodies (mAbs) that can limit progressive sperm motility in the female reproductive tract as a strategy for effective nonhormonal contraception. Here, motivated by the greater agglutination potencies of polyvalent immunoglobulins but the bioprocessing ease and stability of immunoglobulin G (IgG), we engineered a panel of sperm-binding IgGs with 6 to 10 antigen-binding fragments (Fabs), isolated from a healthy immune-infertile woman against a unique surface antigen universally present on human sperm. These highly multivalent IgGs (HM-IgGs) were at least 10- to 16-fold more potent and faster at agglutinating sperm than the parent IgG while preserving the crystallizable fragment (Fc) of IgG that mediates trapping of individual spermatozoa in mucus. The increased potencies translated into effective (>99.9%) reduction of progressively motile sperm in the sheep vagina using as little as 33 μg of the 10-Fab HM-IgG. HM-IgGs were produced at comparable yields and had identical thermal stability to the parent IgG, with greater homogeneity. HM-IgGs represent not only promising biologics for nonhormonal contraception but also a promising platform for engineering potent multivalent mAbs for other biomedical applications., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

This study examines the impacts arising from neuroscience and mental health research going back 20-25 years, and identifies attributes of the research, researchers or research setting that are associated with translation into patient benefit, in the particular case of schizophrenia. The study combined two methods: forward-tracing case studies to examine where scientific advances of 20 years ago have led to impact today; and backward-tracing perspectives to identify the research antecedents of today's interventions in schizophrenia. These research and impact trails are followed principally in Canada, the UK and the USA. The headline findings are as follows: The case studies and perspectives support the view that mental health research has led to a diverse and beneficial range of academic, health, social and economic impacts over the 20 years since the research was undertaken.Clinical research has had a larger impact on patient care than basic research has over the 20 years since the research was undertaken.Those involved in mental health research who work across boundaries are associated with wider health and social benefits.Committed individuals, motivated by patient need, who effectively champion research agendas and/or translation into practice are key in driving the development and implementation of interventions.This study provides an overview of the methods and presents the full set of findings, with the policy provocations they raise, and an emerging research agenda. It has been written for funders of biomedical and health research and health services, health researchers, and policymakers in those fields. It will also be of interest to those involved in research and impact evaluation.

The Army manages the Department of Defense Serum Repository (DoDSR) of over 43 million serum samples and the associated Defense Medical Surveillance System (DMSS) database that links individual service member characteristics to these biological samples. The main mission and use of these resources has been for military health surveillance. The Army turned to RAND Arroyo Center to systematically examine current requirements and capabilities of the DoDSR and DMSS, identify gaps, and suggest strategies to improve their ability to meet current and potential future military health needs, including surveillance, outbreak investigation, research, and clinical support, particularly as these relate to influenza and other infectious disease threats. The research drew information from written documents and interviews with military and civilian experts. The study identified a number of opportunities to improve the management, content, and use of the serum repository and associated database. There were six main recommendations: (1) clarify and communicate the missions of the DoDSR and DMSS both within and beyond the Department of Defense; (2) empower, structure, and resource the organizational oversight of DoDSR and DMSS so that they can fulfill the full range of their missions; (3) create an integrative data plan for comprehensive health surveillance; (4) enhance the utility of specimens; (5) plan for the next repository facility; and (6) raise awareness of and expand access to DoDSR and DMSS.

Objectives: Tracking vaccine reactions and adverse events during a large-scale vaccination program such as the recent smallpox program or a pandemic flu outbreak will be a challenge. We report on vaccine reaction data collected using a novel telephone- and web-based electronic reporting system. The system was used to monitor vaccinees during the U.S. Army's smallpox vaccination campaign, which was part of the national program to prepare against biological attack. In addition, we report on the time course of events after smallpox vaccination based on the self-reported data and evaluate the validity and reliability of self-reported take information after smallpox vaccination., Methods: A prospective cohort of subjects receiving the smallpox vaccination volunteered to use an electronic monitoring system to track and report their vaccination reactions., Results: Users made 6.8 +/- 6.2 (mean +/- SD) reports using the electronic monitoring system. The sensitivity and positive predictive value of self-reported takes were high, 98.8% and 99.6%, respectively. The vaccination-site reactions progressed faster for revaccinees than first-time vaccinees., Conclusions: Simple-to-use telephone/Internet-based technology allowed detailed self-recording of response to smallpox vaccination among outpatients. Self-reports on site appearance were sufficient to determine vaccine takes in most vaccinees. During a mass vaccination event, an electronic monitoring system could facilitate tracking of vaccine reactions, including providing an early warning system for adverse events, and might reduce the burden associated with follow-up visits with healthcare professionals.