Project ASPIRE: A feasibility randomized controlled trial of a brief intervention for reducing risk of depression and alcohol-related harms among South African adolescents.

OBJECTIVE: Brief interventions could reduce adolescents' risk of depression and alcohol-related harms, but evidence of their feasibility and acceptability for low-and middle-income countries is lacking. To address this gap, we conducted a feasibility trial of the ASPIRE intervention, a four-session multi-component counselling intervention for South African adolescents. METHOD: We recruited 117 adolescents who met our inclusion criteria. Participants were randomly assigned to the ASPIRE intervention or a comparison condition. Outcomes were assessed at baseline, six-week, and three-month post-randomization time points. Primary outcomes were based on feasibility of study procedures and intervention delivery (assessed on seven predetermined progression criteria). Clinical outcomes (risk of depression and alcohol harms) were secondary. RESULTS: Despite modifications to all study procedures arising from Covid-19 restrictions, five of the seven key progression criteria were fully met, including: feasibility of data collection and outcome measures, counsellor competencies, randomization and blinding, adverse advents, and acceptability of the intervention. The progression criterion for recruitment and intervention retention were not fully met. CONCLUSION: Findings suggest that the ASPIRE intervention was generally feasible to deliver and acceptable to adolescents. However, modifications to the trial design and intervention delivery are needed to optimize the validity of a definitive randomized controlled trial of the ASPIRE intervention.

Human Pharmacokinetics of LYS006, an Oral Leukotriene A4 Hydrolase Inhibitor Displaying Target-Mediated Drug Disposition.

LYS006 is a potent leukotriene A4 hydrolase inhibitor currently in clinical development for long-term treatment of various neutrophil-driven inflammatory conditions. Here, we present pharmacokinetics from the first-in-human study with complementary metabolism and transporter profiling data. The randomized first-in-human study included nine cohorts receiving 5-2*100 mg of LYS006 or placebo, a crossover food-effect part, and a multiple-dose part consisting of two fasted (5 mg and 15 mg once daily) and three fed cohorts (20-80 mg twice a day) of LYS006 or placebo. LYS006 and metabolites were assessed in plasma and urine, and transporters involved in LYS006 disposition were analyzed in vitro. Systemic plasma exposure increased with dose; steady-state exposure was dose proportional up to 40 mg twice a day. Steady state was achieved after ∼3 days, with mean accumulation of 2.1-fold for 5 mg once daily and ≤1.4-fold for all higher doses. Despite limited accumulation, a long terminal half-life (T1/2) was observed. The long T1/2 and saturable binding to blood cells, which causes a highly nonlinear blood-to-plasma distribution, reflect a strong impact of target binding on drug distribution at lower concentrations. Skin biopsy and blister fluid concentration data indicated saturable binding in the former but not the latter, suggesting saturable binding in tissues beyond blood. Major excretion of LYS006 (∼90% of dose) through urine at steady state triggered renal transporter investigations that identified LYS006 as a substrate of organic anion transporter (OAT)3, OAT4, breast cancer resistance protein, and multidrug resistance-associated protein 4. Seven metabolites were identified in human plasma and urine, comprising only 4% of the dose recovered in urine at steady state. SIGNIFICANCE STATEMENT: Pharmacokinetic data from a first-in-human study combined with in vitro work support dose and regimen selection for patient studies with LYS006 and provide guidance on drug interaction investigations and other clinical pharmacology work needed for further development. Mass balance information at steady state without the use of a radiolabel, skin concentrations, and identification of the major clearance pathway, as well as the transporters driving elimination, make this a particularly conclusive early study despite nonlinear pharmacokinetics impacted by target binding.

Clinical Investigation of Metabolic and Renal Clearance Pathways Contributing to the Elimination of Fevipiprant Using Probenecid as Perpetrator.

Fevipiprant, an oral, nonsteroidal, highly selective, reversible, and competitive prostaglandin D2 receptor 2 antagonist, is eliminated by glucuronidation and by direct renal excretion predominantly via organic anion transporter (OAT) 3. This study aimed to assess the effect of simultaneous UDP-glucuronosyltransferase (UGT) and OAT3 inhibition by probenecid on the pharmacokinetics of fevipiprant and its acyl glucuronide (AG) metabolite to support the dosing recommendation of fevipiprant in the presence of drugs inhibiting these pathways; however, phase III clinical trial results did not support its submission. This was a single-center, open-label, single-sequence, two-period crossover study in healthy subjects. Liquid chromatography with tandem mass spectrometry was used to measure concentrations of fevipiprant and its AG metabolite in plasma and urine. In the presence of probenecid, the mean maximum concentrations of fevipiprant increased approximately 1.7-fold, and the area under the concentration-time curve in plasma increased approximately 2.5-fold, whereas the mean apparent volume of distribution and the AG metabolite:fevipiprant ratio decreased. The apparent systemic clearance decreased by approximately 60% and the renal clearance decreased by approximately 88% in the presence of probenecid. Using these data and those from previous studies, the relative contribution of OAT and UGT inhibition to the overall effect of probenecid was estimated. Furthermore, a general disposition scheme for fevipiprant was developed, showing how a perpetrator drug such as probenecid, which interferes with two key elimination pathways of fevipiprant, causes only a moderate increase in exposure and allows estimation of the drug-drug inhibition when only one of the two pathways is inhibited. SIGNIFICANCE STATEMENT: In this drug-drug interaction (DDI) study, probenecid was used as a tool to inhibit both glucuronidation and active renal secretion of fevipiprant. The combination of plasma and urine pharmacokinetic data from this study with available data allowed the development of a quantitative scheme to describe the fate of fevipiprant in the body, illustrating why the DDI effect on fevipiprant is weak-to-moderate even if a perpetrator drug inhibits several elimination pathways.

A Study of the Effect of Cyclosporine on Fevipiprant Pharmacokinetics and its Absolute Bioavailability Using an Intravenous Microdose Approach.

This drug-drug interaction study determined the effect of cyclosporine, an inhibitor of organic anion transporting polypeptide (OATP) 1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant as well as mechanistic insights into its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios [90% confidence interval (CI)] for oral fevipiprant with or without cyclosporine were 3.02 (2.38, 3.82) for C max, 2.50 (2.17, 2.88) for AUClast, and 2.35 (1.99, 2.77) for AUCinf The geometric mean ratios (90% CI) for fevipiprant intravenous microdose with or without cyclosporine were 1.04 (0.86, 1.25) for C max, 2.04 (1.83, 2.28) for AUClast, and 1.95 (1.76, 2.16) for AUCinf The absolute bioavailability for fevipiprant was approximately 0.3 to 0.4 in the absence and 0.5 in the presence of cyclosporine. The intravenous microdose allowed differentiation between systemic and presystemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) presystemic effect of cyclosporine and a larger (approximately twofold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant, whereas P-gp does not have a relevant effect on oral absorption. SIGNIFICANCE STATEMENT: The drug interaction investigated here with cyclosporine, an inhibitor of several drug transporters, provides a refined quantitative understanding of the role of active transport processes in liver and intestine for the absorption and elimination of fevipiprant as well as the basis to assess the need for dose adjustment in the presence of transporter inhibitors. The applied intravenous microdose approach presents a strategy to maximize learnings from a trial, limit the number and duration of clinical trials, and enhance mechanistic drug-drug interaction understanding.

Effects of Maternal Suicidal Ideation on Child Cognitive Development: A Longitudinal Analysis.

This study aimed to assess the association between suicidal ideation among mothers living with HIV in Zimbabwe and the cognitive development of their children. Participants were mother-child dyads recruited from two rural districts in Zimbabwe. Data were collected at baseline and 12 months follow-up. Suicidal ideation was assessed using item-10 from the Edinburgh postnatal depression scale. Mixed-effects linear regression was used to assess the association of child cognitive outcomes at follow-up (using the Mullen scales of early learning) with maternal suicidal ideation. Mothers with suicidal ideation at baseline (n = 171) tended to be younger, unmarried, experienced moderate to severe hunger, had elevated parental stress and depression symptoms compared with non-suicidal mothers (n = 391). At follow-up, emerging maternal suicidal ideation was associated with poorer child cognitive outcomes (adjusted mean difference - 6.1; 95% CI - 10.3 to - 1.8; p = 0.03). Suicidal ideation affects child cognitive development and should be addressed, particularly in HIV positive mothers.

Effect of Concentration on the Interfacial and Bulk Structure of Ionic Liquids in Aqueous Solution.

Bio and aqueous applications of ionic liquids (IL) such as catalysis in micelles formed in aqueous IL solutions or extraction of chemicals from biologic materials rely on surface-active and self-assembly properties of ILs. Here, we discuss qualitative relations of the interfacial and bulk structuring of a water-soluble surface-active IL ([C8MIm][Cl]) on chemically controlled surfaces over a wide range of water concentrations using both force probe and X-ray scattering experiments. Our data indicate that IL structuring evolves from surfactant-like surface adsorption at low IL concentrations, to micellar bulk structure adsorption above the critical micelle concentration, to planar bilayer formation in ILs with <1 wt % of water and at high charging of the surface. Interfacial structuring is controlled by mesoscopic bulk structuring at high water concentrations. Surface chemistry and surface charges decisively steer interfacial ordering of ions if the water concentration is low and/or the surface charge is high. We also demonstrate that controlling the interfacial forces by using self-assembled monolayer chemistry allows tuning of interfacial structures. Both the ratio of the head group size to the hydrophobic tail volume as well as the surface charging trigger the bulk structure and offer a tool for predicting interfacial structures. Based on the applied techniques and analyses, a qualitative prediction of molecular layering of ILs in aqueous systems is possible.

Evaluating the effectiveness of a multi-component intervention on early childhood development in paediatric HIV care and treatment programmes: a randomised controlled trial.

BACKGROUND: HIV infection in a family may affect optimum child development. Our hypothesis is that child development outcomes among HIV-exposed infants will be improved through a complex early childhood stimulation (ECS) programme, and income and loans saving programme for HIV positive parents. METHODS: The study was a cluster-randomized controlled trial in 30 clinic sites in two districts in Zimbabwe. Clinics were randomised in a 1:1 allocation ratio to the Child Health Intervention for Development Outcomes (CHIDO) intervention or Ministry of Health standard care. The CHIDO intervention comprises three elements: a group ECS parenting programme, an internal savings and lending scheme (ISALS) and case-management home visits by village health workers. The intervention was aimed at caregiver-child dyads (child aged 0-24 months) where the infant was HIV exposed or infected. The primary outcomes were cognitive development (assessed by the Mullen Scales of Early Learning) and retention of the child in HIV care, at 12 months after enrolment. A comprehensive process evaluation was conducted. DISCUSSION: The results of this cluster-randomised trial will provide important information regarding the effects of multi-component interventions in mitigating developmental delays in HIV-exposed infants living in resource-limited environments. TRIAL REGISTRATION: This trial is registered with the Pan African Clinical Trials Registry ( www.pactr.org ), registration number PACTR201701001387209; the trial was registered on 16th January 2017 (retrospectively registered).

Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro.

Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [14C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multidrug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.

ECSPECT prospective multicentre registry for single-port laparoscopic colorectal procedures.

BACKGROUND: The international multicentre registry ECSPECT (European Consensus of Single Port Expertise in Colorectal Treatment) was established to evaluate the general feasibility and safety of single-port colorectal surgery with regard to preoperative risk assessment. METHODS: Consecutive patients undergoing single-port colorectal surgery were enrolled from 11 European centres between March 2010 and March 2014. Data were analysed to assess patient-, technique- and procedure-dependent parameters. A validated sex-adjusted risk chart was developed for prediction of single-port colorectal surgery-related conversion and complications. RESULTS: Some 1769 patients were enrolled, 937 with benign and 832 with malignant conditions. Procedures were completed without additional trocars in 1628 patients (92·0 per cent). Conversion to open surgery was required in 75 patients (4·2 per cent) and was related to male sex and ASA fitness grade exceeding I. Conversions were more frequent in pelvic procedures involving the rectum compared with abdominal procedures (8·1 versus 3·2 per cent; odds ratio 2·69, P < 0·001). Postoperative complications were observed in a total of 224 patients (12·7 per cent). Independent predictors of complications included male sex (P < 0·001), higher ASA grade (P = 0·006) and rectal procedures (P = 0·002). The overall 30-day mortality rate was 0·5 per cent (8 of 1769 patients); three deaths (0·2 per cent; 1 blood loss, 2 leaks) were attributable to surgical causes. CONCLUSION: The feasibility and safety, conversion and complication profile demonstrated here provides guidance for patient selection.

Effects of a carbohydrase complex added in different inclusion rates in feeds for broilers on growth performance, digesta viscosity and foot pad health.

Foot pad dermatitis (FPD) is a widespread disease in poultry and important for economic and animal welfare reasons. It is well recognized that using non-starch polysaccharide (NSP)-degrading enzymes can affect excreta/litter quality (not only in terms of moisture content but also regarding water evaporation) at high stocking densities and might help to prevent FPD and further negative effects of NSP. This study aimed to evaluate effects of a carbohydrase complex (CC) in different dietary inclusion rates on performance, digesta viscosity and foot pad health in broilers from 9 to 37 days of life. In total, 240 broilers were divided into 12 floor pens of 20 birds and received one of four different experimental diets. The four wheat- and soyabean meal-based diets only differed in the inclusion rate of CC: 0%, 50%, 100% and 500% of the recommended dose of CC (Endo-1,4-ß-xylanase and Endo-1,3(4)-ß-glucanase; 50 g/t). The addition of CC led to a significant decrease of digesta viscosity in the proximal small intestine, a tendency of improved feed conversion ratio, and significantly favoured FPD-scores (Treatment 2). At the higher tested inclusion rate of CC (500% of recommended dose), the FPD score was worser than in the treatments with 50% and 100% of the recommended enzyme dosage. No improvements among treatments were observed in terms of body weight and dry matter content of excreta and litter at the end of trial. The low positive effects on foot pad health in this study were presumably associated with the low NSP content in the experimental diets (soluble arabinoxylans: 7.38 g/kg as fed). In conclusion, the addition of the evaluated CC reduced digesta viscosity. An improvement of foot pad health could only be seen in the treatment with 50% of the recommended enzyme dosage in the diet.

The incidence of psychoses in diverse settings, INTREPID (2): a feasibility study in India, Nigeria, and Trinidad.

BACKGROUND: There are striking global inequities in our knowledge of the incidence, aetiology, and outcome of psychotic disorders. For example, only around 10% of research on incidence of psychotic disorders originates in low- and middle-income countries. We established INTREPID I to develop, implement, and evaluate, in sites in India (Chengalpet), Nigeria (Ibadan), and Trinidad (Tunapuna-Piarco), methods for identifying and recruiting untreated cases of psychosis, as a basis for investigating incidence and, subsequently, risk factors, phenomenology, and outcome. In this paper, we compare case characteristics and incidence rates across the sites. METHOD: In each site, to identify untreated cases of psychoses in defined catchment areas, we established case detection systems comprising mental health services, traditional and spiritual healers, and key informants. RESULTS: Rates of all untreated psychoses were 45.9 (per 1 00 000 person-years) in Chengalpet, 31.2 in Ibadan, and 36.9 in Tunapuna-Piarco. Duration of psychosis prior to detection was substantially longer in Chengalpet (median 232 weeks) than in Ibadan (median 13 weeks) and Tunapuna-Piarco (median 38 weeks). When analyses were restricted to cases with a short duration (i.e. onset within preceding 2 years) only, rates were 15.5 in Chengalpet, 29.1 in Ibadan, and 26.5 in Tunapuna-Piarco. Further, there was evidence of age and sex differences across sites, with an older average age of onset in Chengalpet and higher rates among women in Ibadan. CONCLUSION: Our findings suggest there may be differences in rates of psychoses and in the clinical and demographic profiles of cases across economically and socially distinct settings.

Duplex sonography of the mesenteric vessels--a critical evaluation of inter-observer variability.

INTRODUCTION: The number of publications concerning mesenteric Doppler sonography (mesDS) is immense and does not correlate with the frequency of its use in clinical practice. This is astonishing since it provides real time blood flow (perfusion) information without side effects. Despite uncontrollable parameters like the technical limitations in some situations the optimization of (possibly) controllable parameters like standardization, production of normal values and reduction of the investigator variability by evaluating stable parameters could change the situation. PATIENTS AND METHODS: 10 investigators experienced in abdominal sonography ("DEGUM-Seminarleiter") performed mesenteric Doppler sonography in 5 healthy subjects with 5 different machines. RESULTS: The portal vein at the confluence and the common hepatic artery provide a significant portion of investigations with intromission angles of more than 60°. Values of diameter, resistance index and pulsatility index of the celiac trunc could be obtained with inter-observer variability values below 25 %. The proper and the common hepatic artery show no differences in inter-observer variability values, whereas the intrahepatic measure point of the portal vein showed a higher reproducibility. DISCUSSION: We define frame conditions for future mesenteric Doppler studies: the portal vein should be investigated at the intrahepatic measure point. Pathophysiological studies should refrain from velocity parameters except in the case of larger vessels running in a straight course towards the probe.

Laparoscopy following peritoneal entry during transanal endoscopic microsurgery may increase the safety and maximize the benefits of the transanal excision.

BACKGROUND: Peritoneal entry (PE) during transanal endoscopic microsurgery (TEM) for tumors of the upper rectum is not an uncommon complication. The suture line of the rectal defect performed for PE is not devoid of leaks. Diagnostic laparoscopy after PE enables visualization and testing of the suture line. Here, we report the outcome of patients undergoing laparoscopy for PE following TEM. METHODS: Data pertaining to patients undergoing laparoscopy for PE following TEM between 2004 and 2013 were retrospectively collected. RESULTS: One hundred and forty-one TEM procedures were performed, and 19 (13 %) with PE were included. The mean age was 68.1 ± 10.6 years, mean distance from the anal verge 12.5 ± 2 cm, and mean tumor size 2 cm. Lesions were located in the lateral wall (n = 14), anteriorly (n = 4), and posteriorly (n = 1). Indications for TEM were: adenoma (n = 13), indeterminate margins after polypectomy (n = 4, a submucosal lesion (n = 1), and a T1N0 adenocarcinoma (n = 1). In all patients, the rectal wall defect was closed primarily. Twelve patients underwent additional laparoscopy and suture line leak testing. In one patient, a small leak was detected which was repaired laparoscopically. In another, a hematoma of the suture line was observed and a drain was left in place. The mean operative time was 109 min (range 80-135 min) for TEM and 33 min (range 22-45 min) for laparoscopy. A diverting ileostomy was fashioned in one patient on postoperative day 3 after TEM without laparoscopy. No other major complications were observed. CONCLUSIONS: Laparoscopy after PE during TEM permits visualization and testing of the suture line. It is not associated with increased morbidity, and it may increase the safety of TEM.

Hemostatic effects of two desogestrel-containing combined oral contraceptive regimens: a multinational, multicenter, randomized, open-label study.

PURPOSE OF INVESTIGATION: To compare the effects of desogestrel (DSG) 150 mcg/ethinyl estradiol (EE) 20 mcg for 21 days followed by either seven days of EE ten mcg (21/7-active) or no treatment (DSG/EE+no Tx) on hemostatic markers. MATERIALS AND METHODS: This was a randomized, multicenter, open-label study that enrolled healthy premenopausal women. Non-inferiority of 21/7-active to DSG/EE+no Tx was determined if the upper limit of the two-sided 95% CI of the mean treatment difference in prothrombin fragment 1+2 (F1+2) over 24 weeks between groups was < 130 pmol/L. RESULTS: 246 subjects (n = 125, 21/7-active; n = 121, DSG/EE+no Tx) comprised the primary analysis. Mean F1+2 levels increased in both 21/7-active and DSG/EE+no Tx regimens (least square [LS] mean changes +45 pmol/L and +56.8 pmol/L, respectively). LS mean treatment difference was -11.8 pmol/L (95% CI: -54.8, 31.2). CONCLUSION: The effect of adding EE ten mcg to the seven-day hormone-free interval of DSG/EE on F1+2 levels was non-inferior to traditional DSG/EE.

Factors associated with HIV-testing and acceptance of an offer of home-based testing by men in rural Zambia.

The objective of this study is to describe HIV-testing among men in rural Lusaka Province, Zambia, using a population-based survey for a cluster-randomized trial. Households (N = 120) were randomly selected from each of the 42 clusters, defined as a health facility catchment area. Individuals aged 15-60 years were invited to complete questionnaires regarding demographics and HIV-testing history. Men testing in the last year were defined as recent-testers. After questionnaire completion adults were offered home-based rapid HIV-testing. Of the 2,828 men, 53 % reported ever-testing and 25 % recently-testing. Factors independently associated with ever- and recent-testing included age 20+ years, secondary/higher education, being married or widowed, a history of TB-treatment and higher socioeconomic position. 53 % of never-testers and 57 % of men who did not report a recent-test accepted home-based HIV-testing. Current HIV-testing approaches are inadequate in this high prevalence setting. Alternative strategies, including self-testing, mobile- or workplace-testing, may be required to complement facility-based services.

Frequency of HIV-testing and factors associated with multiple lifetime HIV-testing among a rural population of Zambian men.

BACKGROUND: Across sub-Saharan Africa, men's levels of HIV-testing remain inadequate relative to women's. Men are less likely to access anti-retroviral therapy and experience higher levels of morbidity and mortality once initiated on treatment. More frequent HIV-testing by men at continued risk of HIV-infection is required to facilitate earlier diagnosis. This study explored the frequency of HIV-testing among a rural population of men and the factors associated with more frequent HIV-testing. METHODS: We conducted a secondary analysis of a population-based survey in three rural district in Zambia, from February-November, 2013. Households (N = 300) in randomly selected squares from 42 study sites, defined as a health facility and its catchment area, were invited to participate. Individuals in eligible households were invited to complete questionnaires regarding demographics and HIV-testing behaviours. Men were defined as multiple HIV-testers if they reported more than one lifetime test. Upon questionnaire completion, individuals were offered rapid home-based HIV-testing. RESULTS: Of the 2376 men, more than half (61%) reported having ever-tested for HIV. The median number of lifetime tests was 2 (interquartile range = 1-3). Just over half (n = 834; 57%) of ever-testers were defined as multiple-testers. Relative to never-testers, multiple-testers had higher levels of education and were more likely to report an occupation. Among the 719 men linked to a spouse, multiple-testing was higher among men whose spouse reported ever-testing (adjusted prevalence ratio = 3.02 95% CI: 1.37-4.66). Multiple-testing was higher in study sites where anti-retroviral therapy was available at the health facility on the day of a health facility audit. Among ever-testers, education and occupation were positively associated with multiple-testing relative to reporting one lifetime HIV-test. Almost half (49%) of ever-testers accepted the offer of home-based HIV-testing. DISCUSSION: Reported HIV-testing increased among this population of men since a 2011/12 survey. Yet, only 35% of all men reported multiple lifetime HIV-tests. The factors associated with multiple HIV-testing were similar to factors associated with ever-testing for HIV. Men living with HIV were less likely to report multiple HIV-tests and employment and education were associated with multiple-testing. The offer of home-based HIV-testing increased the frequency of HIV-testing among men. CONCLUSION: Although men's levels of ever-testing for HIV have increased, strategies need to increase the lifetime frequency of HIV-testing among men at continued risk of HIV-infection.

Sexual risk behavior, alcohol use, and social media use among secondary school students in informal settlements in Cape Town and Port Elizabeth, South Africa.

South Africa's HIV prevalence among young people remains among the highest in the world. A cross-sectional study was carried out in 2012 to estimate prevalences of sexual risk behavior and hazardous alcohol use (HAU) (via the Alcohol Use Disorder Identification Test) as well as to investigate potential associations between these outcomes and social media use. In all, 4485 students (mean age 15.66 years, SD 1.39) at 46 secondary schools in informal settlements in Cape Town and Port Elizabeth completed mobile-phone-assisted, self-administered baseline questionnaires within a cluster-randomized trial. In all, 312 females (12.5 %) and 468 males (23.5 %) screened positive for HAU (AOR = 1.98, 95 % CI 1.69-2.34). 730 males (39.9 %) and 268 females (11.8 %) reported having had two or more partners in the last year (AOR = 3.46, 95 % CI 2.87-4.16). Among females, having a Facebook account was associated with reported multiple partnerships in the last year (AOR = 1.81, 95 % CI 1.19-2.74), age-disparate sex in the last year (AOR = 1.96, 95 % CI 1.16-3.32) and HAU (AOR = 1.97, 95 % CI 1.41-2.74). Using Mxit-a popular mobile instant messaging application-was associated with higher odds of reported multiple partnerships in the last year among both males (AOR = 1.70, 95 % CI 1.35-2.14) and females (AOR = 1.45, 95 % CI 1.07-1.96) and with HAU among both males (AOR = 1.47, 95 % CI 1.14-1.90) and females (AOR = 1.50, 95 % CI 1.18-1.90). Further longitudinal and qualitative research should explore in more depth the observed links between social media and risk behavior.

Volatile organic compounds effective diffusion coefficients and fluxes estimation through two types of construction material.

UNLABELLED: Accumulation of volatile organic compounds (VOCs) that migrate inside buildings from underlying contaminated soils and groundwater poses human health risks. VOCs intrusion into buildings driven only by diffusion was reproduced by a laboratory-scale experiment. Effective diffusion coefficients and fluxes of a group of selected chlorinated solvents and BTEX through two types of isolation material - that is, concrete (anhydrite screed) and geo-membrane - were estimated. The laboratory experiment indicated that the diffusive transfer of pollutants through sediments into indoor air of buildings cannot be prevented by building sealing material, but it could be attenuated to a certain degree by concrete and up to non-detectable levels by the geo-membrane. Effective diffusion coefficients through concrete and geo-membrane ranged from 3.17 × 10(-2) to 5.90 × 10(-5) cm(2) /s and from 5.47 × 10(-6) to 5.50 × 10(-8) cm(2) /s, respectively. PRACTICAL IMPLICATIONS: The vapor intrusion of volatile organic compounds (VOCs) into buildings has special relevance in human health risk assessment. Prediction of indoor air VOCs concentration by applying numerical or analytical models eventually fails due to the lack of input parameters, such as the VOCs effective diffusion coefficient through building material used as foundation or isolation material. Passive migration of VOCs from contaminated sites into indoor air through construction and isolation materials has not been extensively investigated. Our findings showed that the mass flux through building material is not negligible, but it could be reduced partly, and to a minimum, with the utilization of concrete and geo-membranes, respectively. As a result of our investigation, effective diffusion coefficients of BTEX and chlorinated solvents, as well as the correlation between specific compounds' parameters and the estimated effective diffusion coefficient, are provided.

LTA4H inhibitor LYS006: Clinical PK/PD and safety in a randomized phase I clinical trial.

LYS006 is a novel, highly potent and selective, new-generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil-driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006-treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re-distribution from target expressing cells resulted in a long terminal half-life and a long-lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well-tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose-limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil-driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.