Engineering of HIV-1 neutralizing antibody CAP256V2LS for manufacturability and improved half life.

The broadly neutralizing antibody (bNAb) CAP256-VRC26.25 has exceptional potency against HIV-1 and has been considered for clinical use. During the characterization and production of this bNAb, we observed several unusual features. First, the antibody appeared to adhere to pipette tips, requiring tips to be changed during serial dilution to accurately measure potency. Second, during production scale-up, proteolytic cleavage was discovered to target an extended heavy chain loop, which was attributed to a protease in spent medium from 2-week culture. To enable large scale production, we altered the site of cleavage via a single amino acid change, K100mA. The resultant antibody retained potency and breadth while avoiding protease cleavage. We also added the half-life extending mutation LS, which improved the in vivo persistence in animal models, but did not impact neutralization activity; we observed the same preservation of neutralization for bNAbs VRC01, N6, and PGDM1400 with LS on a 208-virus panel. The final engineered antibody, CAP256V2LS, retained the extraordinary neutralization potency of the parental antibody, had a favorable pharmacokinetic profile in animal models, and was negative in in vitro assessment of autoreactivity. CAP256V2LS has the requisite potency, developability and suitability for scale-up, allowing its advancement as a clinical candidate.

Safety, tolerability, and immunogenicity of the respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: a phase 1, randomised, open-label, dose-escalation clinical trial.

BACKGROUND: Multiple active vaccination approaches have proven ineffective in reducing the substantial morbidity and mortality caused by respiratory syncytial virus (RSV) in infants and older adults (aged ≥65 years). A vaccine conferring a substantial and sustainable boost in neutralising activity is required to protect against severe RSV disease. To that end, we evaluated the safety and immunogenicity of DS-Cav1, a prefusion F subunit vaccine. METHODS: In this randomised, open-label, phase 1 clinical trial, the stabilised prefusion F vaccine DS-Cav1 was evaluated for dose, safety, tolerability, and immunogenicity in healthy adults aged 18-50 years at a single US site. Participants were assigned to receive escalating doses of either 50 µg, 150 µg, or 500 µg DS-Cav1 at weeks 0 and 12, and were randomly allocated in a 1:1 ratio within each dose group to receive the vaccine with or without aluminium hydroxide (AlOH) adjuvant. After 71 participants had been randomised, the protocol was amended to allow some participants to receive a single vaccination at week 0. The primary objectives evaluated the safety and tolerability at every dose within 28 days following each injection. Neutralising activity and RSV F-binding antibodies were evaluated from week 0 to week 44 as secondary and exploratory objectives. Safety was assessed in all participants who received at least one vaccine dose; secondary and exploratory immunogenicity analysis included all participants with available data at a given visit. The trial is registered with ClinicalTrials.gov, NCT03049488, and is complete and no longer recruiting. FINDINGS: Between Feb 21, 2017, and Nov 29, 2018, 244 participants were screened for eligibility and 95 were enrolled to receive DS-Cav1 at the 50 µg (n=30, of which n=15 with AlOH), 150 µg (n=35, of which n=15 with AlOH), or 500 µg (n=30, of which n=15 with AlOH) doses. DS-Cav1 was safe and well tolerated and no serious vaccine-associated adverse events deemed related to the vaccine were identified. DS-Cav1 vaccination elicited robust neutralising activity and binding antibodies by 4 weeks after a single vaccination (p<0·0001 for F-binding and neutralising antibodies). In analyses of exploratory endpoints at week 44, pre-F-binding IgG and neutralising activity were significantly increased compared with baseline in all groups. At week 44, RSV A neutralising activity was 3·1 fold above baseline in the 50 µg group, 3·8 fold in the 150 µg group, and 4·5 fold in the 500 µg group (p<0·0001). RSV B neutralising activity was 2·8 fold above baseline in the 50 µg group, 3·4 fold in the 150 µg group, and 3·7 fold in the 500 µg group (p<0·0001). Pre-F-binding IgG remained significantly 3·2 fold above baseline in the 50 µg group, 3·4 fold in the 150 µg group, and 4·0 fold in the 500 µg group (p<0·0001). Pre-F-binding serum IgA remained 4·1 fold above baseline in the 50 µg group, 4·3 fold in the 150 µg group, and 4·8 fold in the 500 µg group (p<0·0001). Although a higher vaccine dose or second immunisation elicited a transient advantage compared with lower doses or a single immunisation, neither significantly impacted long-term neutralisation. There was no long-term effect of dose, number of vaccinations, or adjuvant on neutralising activity. INTERPRETATION: In this phase 1 study, DS-Cav1 vaccination was safe and well tolerated. DS-Cav1 vaccination elicited a robust boost in RSV F-specific antibodies and neutralising activity that was sustained above baseline for at least 44 weeks. A single low-dose of pre-F immunisation of antigen-experienced individuals might confer protection that extends throughout an entire RSV season. FUNDING: The National Institutes of Allergy and Infectious Diseases.

A proof of concept for structure-based vaccine design targeting RSV in humans.

Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.

Trauma, Family Factors and the Mental Health of Homeless Adolescents.

Family factors, such as poor family functioning and trauma, have been associated with negative outcomes for homeless adolescents. Further study is needed to better understand how family factors and trauma jointly relate to mental health problems and externalizing behaviors among homeless adolescents. Structural equation modeling was used to examine the influence of trauma (encompassing traumatic events experienced prior to, and after, becoming homeless) and family factors (poor family functioning and family conflict) on mental health problems and externalizing behaviors (substance use, delinquent behaviors, and sexual risk) among 201 homeless adolescents, ages 12 to 17 years. Trauma, poor family functioning, and family conflict significantly predicted greater mental health problems, delinquent behaviors, high-risk sexual behaviors and substance use. Overall, the findings suggest that family factors appear to be key to understanding mental health problems and externalizing behaviors among homeless adolescents. Implications, limitations and future directions are addressed.

Group 1 Innate Lymphoid Cell Lineage Identity Is Determined by a cis-Regulatory Element Marked by a Long Non-coding RNA.

Commitment to the innate lymphoid cell (ILC) lineage is determined by Id2, a transcriptional regulator that antagonizes T and B cell-specific gene expression programs. Yet how Id2 expression is regulated in each ILC subset remains poorly understood. We identified a cis-regulatory element demarcated by a long non-coding RNA (lncRNA) that controls the function and lineage identity of group 1 ILCs, while being dispensable for early ILC development and homeostasis of ILC2s and ILC3s. The locus encoding this lncRNA, which we termed Rroid, directly interacted with the promoter of its neighboring gene, Id2, in group 1 ILCs. Moreover, the Rroid locus, but not the lncRNA itself, controlled the identity and function of ILC1s by promoting chromatin accessibility and deposition of STAT5 at the promoter of Id2 in response to interleukin (IL)-15. Thus, non-coding elements responsive to extracellular cues unique to each ILC subset represent a key regulatory layer for controlling the identity and function of ILCs.

Role of Protein Kinase C and Nox2-Derived Reactive Oxygen Species Formation in the Activation and Maturation of Dendritic Cells by Phorbol Ester and Lipopolysaccharide.

Aims. Activation/maturation of dendritic cells (DCs) plays a central role in adaptive immune responses by antigen processing and (cross-) activation of T cells. There is ongoing discussion on the role of reactive oxygen species (ROS) in these processes and with the present study we investigated this enigmatic pathway. Methods and Results. DCs were cultured from precursors in the bone marrow of mice (BM-DCs) and analyzed for ROS formation, maturation, and T cell stimulatory capacity upon stimulation with phorbol ester (PDBu) and lipopolysaccharide (LPS). LPS stimulation of BM-DCs caused maturation with moderate intracellular ROS formation, whereas PDBu treatment resulted in maturation with significant ROS formation. The NADPH oxidase inhibitors apocynin/VAS2870 and genetic gp91phox deletion both decreased the ROS signal in PDBu-stimulated BM-DCs without affecting maturation and T cell stimulatory capacity of BM-DCs. In contrast, the protein kinase C inhibitors chelerythrine/Gö6983 decreased PDBu-stimulated ROS formation in BM-DCs as well as maturation. Conclusion. Obviously Nox2-dependent ROS formation in BM-DCs is not always required for their maturation or T cell stimulatory potential. PDBu/LPS-triggered BM-DC maturation rather relies on phosphorylation cascades. Our results question the role of oxidative stress as an essential "danger signal" for BM-DC activation, although we cannot exclude contribution by other ROS sources.

Patient factors associated with non-attendance at colonoscopy after a positive screening faecal occult blood test.

Background Screening participants with abnormal faecal occult blood test results who do not attend further testing are at high risk of colorectal cancer, yet little is known about their reasons for non-attendance. Methods We conducted a medical record review of 170 patients from two English Bowel Cancer Screening Programme centres who had abnormal guaiac faecal occult blood test screening tests between November 2011 and April 2013 but did not undergo colonoscopy. Using information from patient records, we coded and categorized reasons for non-attendance. Results Of the 170 patients, 82 were eligible for review, of whom 66 had at least one recorded reason for lack of colonoscopy follow-up. Reasons fell into seven main categories: (i) other commitments, (ii) unwillingness to have the test, (iii) a feeling that the faecal occult blood test result was a false positive, (iv) another health issue taking priority, (v) failing to complete bowel preparation, (vi) practical barriers (e.g. lack of transport), and (vii) having had or planning colonoscopy elsewhere. The most common single reasons were unwillingness to have a colonoscopy and being away. Conclusions We identify a range of apparent reasons for colonoscopy non-attendance after a positive faecal occult blood test screening. Education regarding the interpretation of guaiac faecal occult blood test findings, offer of alternative confirmatory test options, and flexibility in the timing or location of subsequent testing might decrease non-attendance of diagnostic testing following positive faecal occult blood test.

Pathways of Risk and Resilience: Impact of a Family Resilience Program on Active-Duty Military Parents.

Over the past decade, studies into the impact of wartime deployment and related adversities on service members and their families have offered empirical support for systemic models of family functioning and a more nuanced understanding of the mechanisms by which stress and trauma reverberate across family and partner relationships. They have also advanced our understanding of the ways in which families may contribute to the resilience of children and parents contending with the stressors of serial deployments and parental physical and psychological injuries. This study is the latest in a series designed to further clarify the systemic functioning of military families and to explicate the role of resilient family processes in reducing symptoms of distress and poor adaptation among family members. Drawing upon the implementation of the Families Overcoming Under Stress (FOCUS) Family Resilience Program at 14 active-duty military installations across the United States, structural equation modeling was conducted with data from 434 marine and navy active-duty families who participated in the FOCUS program. The goal was to better understand the ways in which parental distress reverberates across military family systems and, through longitudinal path analytic modeling, determine the pathways of program impact on parental distress. The findings indicated significant cross-influence of distress between the military and civilian parents within families, families with more distressed military parents were more likely to sustain participation in the program, and reductions in distress among both military and civilian parents were significantly mediated by improvements in resilient family processes. These results are consistent with family systemic and resilient models that support preventive interventions designed to enhance family resilient processes as an important part of comprehensive services for distressed military families.

The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan.

Neutrophils, eosinophils and 'classical' monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice. To control the lifespan of these cells, Morrbid regulates the transcription of the neighbouring pro-apoptotic gene, Bcl2l11 (also known as Bim), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis, enabling allele-specific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.

Developing Valid Measures of Emergency Management Capabilities within US Department of Veterans Affairs Hospitals.

UNLABELLED: Introduction Hospitals play a critical role in providing health care in the aftermath of disasters and emergencies. Nonetheless, while multiple tools exist to assess hospital disaster preparedness, existing instruments have not been tested adequately for validity. Hypothesis/Problem This study reports on the development of a preparedness assessment tool for hospitals that are part of the US Department of Veterans Affairs (VA; Washington, DC USA). METHODS: The authors evaluated hospital preparedness in six "Mission Areas" (MAs: Program Management; Incident Management; Safety and Security; Resiliency and Continuity; Medical Surge; and Support to External Requirements), each composed of various observable hospital preparedness capabilities, among 140 VA Medical Centers (VAMCs). This paper reports on two successive assessments (Phase I and Phase II) to assess the MAs' construct validity, or the degree to which component capabilities relate to one another to represent the associated domain successfully. This report describes a two-stage confirmatory factor analysis (CFA) of candidate items for a comprehensive survey implemented to assess emergency preparedness in a hospital setting. RESULTS: The individual CFAs by MA received acceptable fit statistics with some exceptions. Some individual items did not have adequate factor loadings within their hypothesized factor (or MA) and were dropped from the analyses in order to obtain acceptable fit statistics. The Phase II modified tool was better able to assess the pre-determined MAs. For each MA, except for Resiliency and Continuity (MA 4), the CFA confirmed one latent variable. In Phase I, two sub-scales (seven and nine items in each respective sub-scale) and in Phase II, three sub-scales (eight, four, and eight items in each respective sub-scale) were confirmed for MA 4. The MA 4 capabilities comprise multiple sub-domains, and future assessment protocols should consider re-classifying MA 4 into three distinct MAs. CONCLUSION: The assessments provide a comprehensive and consistent, but flexible, approach for ascertaining health system preparedness. This approach can provide an organization with a clear understanding of areas for improvement and could be adapted into a standard for hospital readiness. Dobalian A , Stein JA , Radcliff TA , Riopelle D , Brewster P , Hagigi F , Der-Martirosian C . Developing valid measures of emergency management capabilities within US Department of Veterans Affairs hospitals. Prehosp Disaster Med. 2016;31(5):475-484.

AMP!: A Cross-site Analysis of the Effects of a Theater-based Intervention on Adolescent Awareness, Attitudes, and Knowledge about HIV.

AMP! (Arts-based, Multiple component, Peer-education) is an HIV intervention developed for high school adolescents. AMP! uses interactive theater-based scenarios developed by trained college undergraduates to deliver messages addressing HIV/STI prevention strategies, healthy relationships, and stigma reduction towards people living with HIV/AIDS. We used a pre-test/post-test, control group study design to simultaneously assess intervention effect on ninth grade students in an urban county in California (N = 159) and a suburban county in North Carolina (N = 317). In each location, the control group received standard health education curricula delivered by teachers; the intervention group received AMP! in addition to standard health education curricula. Structural equation modeling was used to determine intervention effects. The post-test sample was 46 % male, 90 % self-identified as heterosexual, 32 % reported receiving free or reduced lunch, and 49 % White. Structural models indicated that participation in AMP! predicted higher scores on HIV knowledge (p = 0.05), HIV awareness (p = 0.01), and HIV attitudes (p = 0.05) at the post-test. Latent means comparison analyses revealed post-test scores were significantly higher than pre-test scores on HIV knowledge (p = 0.001), HIV awareness (p = 0.001), and HIV attitudes (p = 0.001). Further analyses indicated that scores rose for both groups, but the post-test scores of intervention participants were significantly higher than controls (HIV knowledge (p = 0.01), HIV awareness (p = 0.01), and HIV attitudes (p = 0.05)). Thus, AMP!'s theater-based approach shows promise for addressing multiple adolescent risk factors and attitudes concerning HIV in school settings.

Generation of Genetically Modified Mice Using the CRISPR-Cas9 Genome-Editing System.

Genetically modified mice are extremely valuable tools for studying gene function and human diseases. Although the generation of mice with specific genetic modifications through traditional methods using homologous recombination in embryonic stem cells has been invaluable in the last two decades, it is an extremely costly, time-consuming, and, in some cases, uncertain technology. The recently described CRISPR-Cas9 genome-editing technology significantly reduces the time and the cost that are required to generate genetically engineered mice, allowing scientists to test more precise and bold hypotheses in vivo. Using this revolutionary methodology we have generated more than 100 novel genetically engineered mouse strains. In the current protocol, we describe in detail the optimal conditions to generate mice carrying point mutations, chromosomal deletions, conditional alleles, fusion tags, or endogenous reporters.

T Cell Receptor Mediated Calcium Entry Requires Alternatively Spliced Cav1.1 Channels.

The process of calcium entry in T cells is a multichannel and multi-step process. We have studied the requirement for L-type calcium channels (Cav1.1) α1S subunits during calcium entry after TCR stimulation. High expression levels of Cav1.1 channels were detected in activated T cells. Sequencing and cloning of Cav1.1 channel cDNA from T cells revealed that a single splice variant is expressed. This variant lacks exon 29, which encodes the linker region adjacent to the voltage sensor, but contains five new N-terminal exons that substitute for exons 1 and 2, which are found in the Cav1.1 muscle counterpart. Overexpression studies using cloned T cell Cav1.1 in 293HEK cells (that lack TCR) suggest that the gating of these channels was altered. Knockdown of Cav1.1 channels in T cells abrogated calcium entry after TCR stimulation, suggesting that Cav1.1 channels are controlled by TCR signaling.

Depression, Abuse, Relationship Power and Condom Use by Pregnant and Postpartum Women with Substance Abuse History.

Substance-abusing pregnant and postpartum women are less likely to maintain consistent condom use and drug and alcohol abstinence, which is particularly concerning in high HIV-prevalence areas. Data from 224 pregnant and postpartum women in substance abuse treatment were analyzed to examine effects of history of substance use, child abuse, and mental health problems on current substance use and condom-use barriers. Mediators were depression, relationship power and social support. Most participants (72.9 %) evidenced current depression. Less social support (-0.17, p < 0.05) and relationship power (-0.48, p < 0.001), and greater depression (-0.16, p < 0.05) predicted more condom-use barriers. History of mental health problems predicted condom-use barriers, mediated by recent depression and relationship power (0.15, p < 0.001). These findings suggest depression and diminished relationship power limit highest-risk women's ability to negotiate condom use and abstain from substance use, increasing their risk of acute HIV infection and vertical transmission.

Alcohol Use, Partner Violence, and Depression: A Cluster Randomized Controlled Trial Among Urban South African Mothers Over 3 Years.

INTRODUCTION: Pregnant South African women with histories of drinking alcohol, abuse by violent partners, depression, and living with HIV are likely to have their post-birth trajectories over 36 months significantly influenced by these risks. DESIGN: All pregnant women in 24 Cape Town neighborhoods were recruited into a cluster RCT by neighborhood to either: (1) a standard care condition (n=12 neighborhoods, n=594 mothers); or (2) a home-visiting intervention condition (n=12 neighborhoods, n=644 mothers). SETTING/PARTICIPANTS: Pregnant women residing in urban, low-income neighborhoods in Cape Town, South Africa. INTERVENTION: Home visiting included prenatal and postnatal visits by community health workers (Mentor Mothers) focusing on general maternal and child health, HIV/tuberculosis, alcohol use, and nutrition. MAIN OUTCOME MEASURES: Mothers were assessed in pregnancy and at 18 and 36 months post birth: 80.6% of mothers completed all assessments between 2009 and 2014 and were included in these analyses performed in 2014. Longitudinal structural equation modeling examined alcohol use, partner violence, and depression at the baseline and 18-month interviews as predictors of maternal outcomes at 36 months post birth. RESULTS: Relative to standard care, intervention mothers were significantly less likely to report depressive symptoms and more positive quality of life at 36 months. Alcohol use was significantly related to use over time, but was also related to depression and HIV status at each assessment and partner violence at 36 months. CONCLUSIONS: Alcohol, partner violence, and depression are significantly related over time. A home-visiting intervention improved the emotional health of low-income mothers even when depression was not initially targeted.

A Longitudinal Investigation of Race, Socioeconomic Status, and Psychosocial Mediators of Allostatic Load in Midlife Women: Findings From the Study of Women's Health Across the Nation.

OBJECTIVES: This research sought to assess racial and socioeconomic status (SES) differences in level and change in allostatic load (AL) over time in midlife women and to test whether psychosocial factors mediate these relationships. These factors were discrimination, perceived stress, and hostility. METHODS: Longitudinal data obtained from the Study of Women's Health Across the Nation were used (n = 2063; mean age at baseline = 46.0 years). Latent growth curve models evaluated the impact of demographic, menopausal, and psychosocial variables on level and change in AL for 8 years. RESULTS: Direct effects: high levels of discrimination and hostility significantly predicted higher AL (path coefficients = 0.05 and 0.05, respectively). High perceived stress significantly predicted a faster rate of increase of AL (path coefficient = 0.06). Racial and SES differentials were present, with African American race (path coefficient = 0.23), low income (path coefficient = -0.15), and low education (path coefficient = -0.08) significantly predicting high AL level. Indirect effects: significant indirect effects were found for African American race, less income, and lower education through higher discrimination, perceived stress, and hostility on level and rate of AL. CONCLUSIONS: This was one of the first studies that investigated AL over multiple periods, and results supported AL as a cumulative phenomenon, affected by multiple psychosocial and demographic factors. The results suggest the complex ways in which race, SES, and psychosocial factors operate to influence AL.

Regulation of IgE production and airway reactivity by CD4⁻CD8⁻ regulatory T cells.

The mechanisms of tolerance induction occurring in the course of allergen-specific immunotherapy have not been elucidated in full detail. Our study aimed to characterize high zone tolerance in mouse models of type I allergy and of allergic airway inflammation induced by subcutaneous sensitization of mice with high doses of the model allergen ovalbumin (OVA) without the use of adjuvant. Mice were immunized by subcutaneous injection of high doses (HD) of OVA or, for comparison, low doses (LD) of OVA in saline. HD-mice showed lower specific IgE, but augmented IgG in sera than LD-mice. Pre-treatment of mice with HD-OVA antigen-specifically inhibited IgE production subsequently induced by LD-OVA. OVA-restimulated splenocytes from HD-mice revealed hypoproliferation and impaired production of Th2-associated cytokines. HD-mice exhibited lower airway reactivity, goblet cell hyperplasia and mucus production, as well as IL-5 and IL-13 production in the lungs than LD-mice following local provocation. Recruitment of inflammatory cells into the airways was comparable, while the number of eosinophils in the bronchoalveolar lavage was substantially higher in HD-mice. Adoptive transfer of dnTC from HD-mice into naïve mice, which were subsequently sensitized with LD-OVA, suppressed IgE production in the recipients. The number of dnTC was higher in the spleens of HD-mice than LD-mice. In conclusion, our study demonstrates that subcutaneous sensitization of mice with high doses of allergen in the absence of adjuvant results in attenuated airway reactivity as compared with LD-sensitization and induces CD4(-)CD8(-) dnTC with regulatory function on IgE production.

The impact of paraprofessional home visitors on infants' growth and health at 18 months.

Paraprofessional home visitors trained to improve multiple outcomes (HIV, alcohol, infant health, and malnutrition) have been shown to benefit mothers and children over 18 months in a cluster randomised controlled trial (RCT). These longitudinal analyses examine the mechanisms which influence child outcomes at 18 months post-birth in Cape Town, South Africa. The results were evaluated using structural equation modelling, specifically examining the mediating effects of prior maternal behaviours and a home visiting intervention post-birth. Twelve matched pairs of neighbourhoods were randomised within pairs to: 1) the control condition, receiving comprehensive healthcare at community primary health care clinics (n=12 neighbourhoods; n=594 pregnant women), or 2) the Philani Intervention Program, which provided home visits by trained, paraprofessional community health workers, here called Mentor Mothers, in addition to clinic care (n=12 neighbourhoods; n=644 pregnant women). Recruitment of all pregnant neighbourhood women was high (98%) with 88% reassessed at six months and 84% at 18 months. Infants' growth and diarrhoea episodes were examined at 18 months in response to the intervention condition, breastfeeding, alcohol use, social support, and low birth weight, controlling for HIV status and previous history of risk. We found that randomisation to the intervention was associated with a significantly lower number of recent diarrhoea episodes and increased rates and duration of breastfeeding. Across both the intervention and control conditions, mothers who used alcohol during pregnancy and had low birth weight infants were significantly less likely to have infants with normal growth patterns, whereas social support was associated with better growth. HIV-infection was significantly associated with poor growth and less breastfeeding. Women with more risk factors had significantly smaller social support networks. The relationships among initial and sustained maternal risk behaviours and the buffering impact of home visits and social support are demonstrated in these analyses.

Intervening on conflict, parental bonds, and sexual risk acts among adolescent children of mothers living with HIV.

OBJECTIVE: In 1993-1994, a psychosocial intervention conducted in New York City significantly improved outcomes for parents living with HIV and their adolescent children over six years. We examine if the intervention benefits are similar for adolescents of mothers living with HIV (MLH) in 2004-2005 in Los Angeles when MLH's survival had increased substantially. METHODS: Adolescents of MLH in Los Angeles (N = 256) aged 12-20 years old were randomized with their MLH to either: 1) a standard care condition (n = 120 adolescent-MLH dyads); or 2) an intervention condition consisting of small group activities to build coping skills (n = 136 adolescent-MLH dyads, 78% attended the intervention). At 18 months, 94.7% of adolescents were reassessed. Longitudinal structural equation modeling examined if intervention participation impacted adolescents' relationships with parents and their sexual risk behaviors. RESULTS: Compared to the standard care, adolescents in the intervention condition reported significantly more positive family bonds 18 months later. Greater participation by MLH predicted fewer family conflicts, and was indirectly associated with less adolescent sexual risk behavior at the 18 month follow-up assessment. Anticipated developmental patterns were observed--sexual risk acts increased with age. Reports were also consistent with anticipated gender roles; girls reported better bonds with their mothers at 18 months, compared to boys. CONCLUSIONS: Adolescents of MLH have better bonds with their mothers as a function of participating in a coping skills intervention and reduced sexual risk-taking as a function of MLH intervention involvement.

Factors influencing readiness to deploy in disaster response: findings from a cross-sectional survey of the Department of Veterans Affairs Disaster Emergency Medical Personnel System.

BACKGROUND: The Disaster Emergency Medical Personnel System (DEMPS) program provides a system of volunteers whereby active or retired Department of Veterans Affairs (VA) personnel can register to be deployed to support other VA facilities or the nation during national emergencies or disasters. Both early and ongoing volunteer training is required to participate. METHODS: This study aims to identify factors that impact willingness to deploy in the event of an emergency. This analysis was based on responses from 2,385 survey respondents (response rate, 29%). Latent variable path models were developed and tested using the EQS structural equations modeling program. Background demographic variables of education, age, minority ethnicity, and female gender were used as predictors of intervening latent variables of DEMPS Volunteer Experience, Positive Attitude about Training, and Stress. The model had acceptable fit statistics, and all three intermediate latent variables significantly predicted the outcome latent variable Readiness to Deploy. RESULTS: DEMPS Volunteer Experience and a Positive Attitude about Training were associated with Readiness to Deploy. Stress was associated with decreased Readiness to Deploy. Female gender was negatively correlated with Readiness to Deploy; however, there was an indirect relationship between female gender and Readiness to Deploy through Positive Attitude about Training. CONCLUSIONS: These findings suggest that volunteer emergency management response programs such as DEMPS should consider how best to address the factors that may make women less ready to deploy than men in order to ensure adequate gender representation among emergency responders. The findings underscore the importance of training opportunities to ensure that gender-sensitive support is a strong component of emergency response, and may apply to other emergency response programs such as the Medical Reserve Corps and the American Red Cross.