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In this article, a dataset from a collaborative non-target screening trial organised by the NORMAN Association is used to review the state-of-the-art and discuss future perspectives of non-target screening using high-resolution mass spectrometry in water analysis. A total of 18 institutes from 12 European countries analysed an extract of the same water sample collected from the River Danube with either one or both of liquid and gas chromatography coupled with mass spectrometry detection. This article focuses mainly on the use of high resolution screening techniques with target, suspect, and non-target workflows to identify substances in environmental samples. Specific examples are given to emphasise major challenges including isobaric and co-eluting substances, dependence on target and suspect lists, formula assignment, the use of retention information, and the confidence of identification. Approaches and methods applicable to unit resolution data are also discussed. Although most substances were identified using high resolution data with target and suspect-screening approaches, some participants proposed tentative non-target identifications. This comprehensive dataset revealed that non-target analytical techniques are already substantially harmonised between the participants, but the data processing remains time-consuming. Although the objective of a "fully-automated identification workflow" remains elusive in the short term, important steps in this direction have been taken, exemplified by the growing popularity of suspect screening approaches. Major recommendations to improve non-target screening include better integration and connection of desired features into software packages, the exchange of target and suspect lists, and the contribution of more spectra from standard substances into (openly accessible) databases. Graphical Abstract Matrix of identification approach versus identification confidence.

Eight organic UV filters and stabilizers were quantitatively determined in wastewater sludge and effluent, landfill leachate, sediments, and marine and freshwater biota. Crab, prawn and cod from Oslofjord, and perch, whitefish and burbot from Lake Mjøsa were selected in order to evaluate the potential for trophic accumulation. All of the cod livers analysed were contaminated with at least 1 UV filter, and a maximum concentration of almost 12 μg/g wet weight for octocrylene (OC) was measured in one individual. 80% of the cod livers contained OC, and approximately 50% of cod liver and prawn samples contained benzophenone (BP3). Lower concentrations and detection frequencies were observed in freshwater species and the data of most interest is the 4 individual whitefish that contained both BP3 and ethylhexylmethoxycinnamate (EHMC) with maximum concentrations of almost 200 ng/g wet weight. The data shows a difference in the loads of UV filters entering receiving water dependent on the extent of wastewater treatment. Primary screening alone is insufficient for the removal of selected UV filters (BP3, Padimate, EHMC, OC, UV-234, UV-327, UV-328, UV-329). Likely due in part to the hydrophobic nature of the majority of the UV filters studied, particulate loading and organic carbon content appear to be related to concentrations of UV filters in landfill leachate and an order of magnitude difference in these parameters correlates with an order of magnitude difference in the effluent concentrations of selected UV filters (Fig. 2). From the data, it is possible that under certain low flow conditions selected organic UV filters may pose a risk to surface waters but under the present conditions the risk is low, but some UV filters will potentially accumulate through the trophic food chain., (Copyright © 2015. Published by Elsevier Ltd.)

Objectives: To evaluate electrodermal activity (EDA) as a prospective biomarker of treatment response, to determine whether patterns of EDA are altered by treatment, and to assess oppositional defiant disorder (ODD) as a possible moderator of trajectories in EDA after an empirically supported behavioral intervention for attention-deficit hyperactivity disorder (ADHD) in preschool., Method: Nonspecific fluctuations (NSFs) in skin conductance, which index sympathetic nervous system activity, were assessed among 4-6 year old children with ADHD (n = 99) before they participated with their parents in 1 of 2 versions of the Incredible Years intervention. All were reassessed at posttreatment, and a subgroup (n = 49) were assessed again at 1-year follow-up., Results: No difference in pretreatment NSFs was observed between ADHD participants and a group of normal control children (n = 41). Nevertheless, among those with ADHD, fewer NSFs at pretest predicted poorer treatment response on 4 of 7 externalizing outcomes. Furthermore, treatment was associated with increasing NSFs across time, but not for those who scored high on ODD at pretest., Conclusions: Low EDA appears to mark resistance to treatment among preschoolers with ADHD. Furthermore, although our study was not experimental, treatment was associated with longitudinal increases in EDA, which were not observed in a normal control group. This may suggest increased sensitivity to discipline, with positive implications for long term outcome. In contrast to treated participants as a whole, however, those who scored high on ODD at pretest exhibited reduced EDA over time. (PsycINFO Database Record, ((c) 2015 APA, all rights reserved).)

A case of false-negative serum latex agglutination cryptococcal antigen (CRAG) test in a 45-year-old HIV-positive male with Cryptococcus-positive culture is described. The patient was presented to a hospital in Botswana, with breathlessness and a diffuse papular rash. His CD4 count was 25 cells/μL. Despite the suspicion for disseminated cryptococcal disease, an initial serum CRAG latex test was negative. Results of subsequent Indian ink staining, culture of cerebrospinal fluid and skin scrapings, and serum lateral flow immunoassay (LFA) were all positive for Cryptococcus neoformans. There are several possible explanations for the false-negative CRAG latex test. Given the positive LFA result, we speculate that disease may have been caused by Cryptococcus gattii, which is estimated to be responsible for between 15% and 30% of all cryptococcal diseases in Botswana. Reduced sensitivity of CRAG latex assays for detecting C gattii may lead to underdiagnosis of cryptococcal infection., (© The Author(s) 2014.)

Background: There is a concern about methamphetamine use in Europe. Methamphetamine fatalities have recently occurred in Southern European countries. The aim of this study is to examine Norwegian methamphetamine trends in recent years, comparing different data sources., Material and Methods: Data about amphetamines were collected from five different sources; blood samples from drivers suspected of driving under the influence of drugs and apprehended by the police (during the years 2000-2012), urine samples from inmates in Norwegian prisons (during 2000-2012), post-mortem blood samples from medico-legal autopsies (2000-2012), drug seizures (1994-2012) and wastewater samples from a metropolitan/suburban population (2010-2012)., Results: The number of cases where methamphetamine was detected has increased during the period studied for the driving under the influence cases, the samples from inmates and from forensic autopsies. The increase seems to be linear up to 2009-2010, with a subsequent stabilisation or even a decline in the market share of methamphetamine for the next few years. The number of methamphetamine seizures has risen from less than 1% in 2000 to approximately 66% in 2009, and a steady share around 60% have been seen between 2010 and 2012. Wastewater samples showed that the share of methamphetamine peaked in 2010-11, before falling., Interpretation: It is difficult to obtain reliable data on illicit drugs. Data from different populations might give indications of changes and trends, but are always prone to different biases. By comparing results from different data sources, a better knowledge of the illicit drug market might be obtained. All our data sources confirmed that methamphetamine became a more prevalent drug during the first decade of the new millennium in Norway, but since approximately 2009 the share of methamphetamine stabilised., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: A method to quantify emixustat (an investigational drug agent) in human blood collected using volumetric absorptive microsampling (VAMS) could be more practical for sample collection at sites with limited facilities for processing and storage of plasma., Methods: A LC-MS/MS method was developed and evaluated for accuracy and precision, linearity, carryover, selectivity, recovery, matrix effects, hematocrit effects and stability., Results: Core validation parameters met acceptance criteria within the normal ranges of hematocrit levels for adults (30-55%). Stability of emixustat in blood collected with and without anticoagulant (NaF/KOx) on the VAMS device at ambient, refrigerated and frozen conditions was established., Conclusion: The method has been validated and is suitable for the bioanalysis of emixustat in human blood collected by VAMS.

This study assessed the impact of several interventions, including predeparture simulation training and procedure logs, on incidence needlestick injuries (NSIs) among U.S. medical students on global health (GH) elective in Botswana. Review of NSI incident reports before and after introduction of these interventions demonstrated a reduction in the number of splash and body fluid exposures (n = 5 [6%] vs n = 21 [23%]; P < .001), respectively. Simple predeparture training is highly effective in reducing NSIs among students participating in GH electives., (Copyright © 2014 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Because of its proximity and its youth, the Pleiades open cluster of stars has been extensively studied and serves as a cornerstone for our understanding of the physical properties of young stars. This role is called into question by the "Pleiades distance controversy," wherein the cluster distance of 120.2 ± 1.5 parsecs (pc) as measured by the optical space astrometry mission Hipparcos is significantly different from the distance of 133.5 ± 1.2 pc derived with other techniques. We present an absolute trigonometric parallax distance measurement to the Pleiades cluster that uses very long baseline radio interferometry (VLBI). This distance of 136.2 ± 1.2 pc is the most accurate and precise yet presented for the cluster and is incompatible with the Hipparcos distance determination. Our results cement existing astrophysical models for Pleiades-age stars., (Copyright © 2014, American Association for the Advancement of Science.)

Background and Aim: Scientific literature offers few measurements of the quantities consumed by individual drug users. Such measurements are used for calculating the total drug consumption by the quantity-frequency method, and are extremely important for the comparison with waste water derived consumption estimates. The aim of this study was to measure quantities of amphetamines, cocaine and heroin consumed by marginalized drug users, using a multi-city questionnaire survey design. Variation by gender, age, frequency of use, main drug used and city was explored., Results: The self-reported quantity used on the last day of use was for amphetamines on average 800 mg, for cocaine 1,014 mg and for heroin 682 mg. The self-reported usual dose was on average 297 mg, 487 mg and 297 mg respectively, while the median value was 250 mg for all three drugs. Overall, gender and age group were less important than frequency of use and the main drug used for establishing differences regarding the outcome variables. There were some differences regarding cities. No measure of purity was carried out at the interview sites, so the calculation of pure quantities was based on aggregate results from analyses of seizures by police and customs., Conclusions: The self-reported quantities of drugs consumed in three cities in Norway was equal to or somewhat higher among marginalized users than earlier assumed, where assumptions were based on limited literature and anecdotal information., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Data obtained from the analysis of wastewater from large-scale sewage treatment plants has been successfully applied to study trends in the use of classical illicit drugs such as cocaine, but the dynamic nature of the new psychoactive substances (NPS) market presents a unique set of challenges to epidemiologists. In an attempt to overcome some of the challenges, this paper presents a framework whereby a collection of tools and alternative data-sources can be used to support the design and implementation of wastewater-based studies on NPS use. Within this framework the most likely and most suitable biomarkers for a given NPS are predicted via in-silico metabolism, biotransformation and sorption models. Subsequent detection and confirmation of the biomarkers in samples of wastewater are addressed via high-resolution mass spectrometry (HRMS). The proposed framework is applied to a set of test substances including synthetic cannabinoids and cathinones. In general, the in-silico models predict that transformation via N-dealkylation and hydroxylation is likely for these compounds, and that adsorption is expected to be significant for cannabinoids in wastewater. Screening via HRMS is discussed with examples from the literature, and common-fragment searching and mass-defect filtering are successfully performed on test samples such that spectral noise is removed to leave only the information that is most likely to be related to the NPS biomarkers. HRMS screening is also applied to a set of pissoir-sourced wastewater samples and a total of 48 pharmaceuticals and drugs including 1-(2-methoxyphenyl)piperazine (oMeOPP) are identified. The framework outlined in this paper can provide an excellent means of maximizing the chances of success when identifying and detecting biomarkers of NPS in wastewater., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: The aim of the study was to extend research on the potential benefits of adding ongoing feedback, coaching, and consultation to initial therapist training workshops to ensure fidelity of delivery of evidence-based practices, specifically for the Incredible Years parenting program., Methods: A randomized controlled trial compared two models for training therapists to deliver the parenting program for children at high risk of developing conduct problems. Therapists (N=56) from ten community-based mental health service organizations in California were trained in either a three-day workshop model (N=25), based on active, experiential, self-reflective, principle-based learning, video modeling, and manuals, or an enhanced training model (N=31) that included all elements of the workshop model plus ongoing expert coaching, video review of and feedback on group sessions, and consultation for therapists and agency supervisors., Results: Overall fidelity across both conditions was rated >3 on a 5-point scale in seven of eight domains measured. Therapists in the condition that received ongoing coaching and consultation were significantly stronger in four of the domains: practical support, collaboration, knowledge, and skill at mediating vignettes., Conclusions: Consultation and expert coaching for training therapists beyond the standard three-day training enhanced skills and therapists' adherence to the model.

There is a paucity of research demonstrating how HIV-funded services in Africa have improved equity and access to non-HIV services for both HIV-infected and uninfected patients. In this short communication, we describe the impact of an airborne outreach program to provide HIV services to high-HIV burden health facilities in rural Botswana. The analysis demonstrates how this HIV-funded program enhanced access to essential subspecialist services at several rural health facilities across Botswana.

We conducted a retrospective cohort study assessing the association between diabetes mellitus (DM) and immune recovery in HIV-infected adults. Immune reconstitution after initiating antiretroviral therapy was more rapid in DM patients (120.4 cells/year) compared to non-DM patients (94.2 cells/year, p<0.023). Metformin use was associated with improved CD4 recovery (p=0.034)., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Proponents of minimally invasive total knee arthroplasty argue that retracting rather than everting the patella results in quicker postoperative recovery and improved function. We aimed to investigate this in patients undergoing knee arthroplasty through a standard medial parapatellar approach., Methods: In a prospective randomized double-blinded study, sixty-eight patients undergoing total knee arthroplasty through a standard medial parapatellar approach were assigned to either retraction or eversion of the patella. Postoperatively, at three months, and at one year after surgery, an independent observer assessed the primary outcome measure (i.e., knee flexion) and secondary outcome measures (i.e., Oxford knee score, Short Form-12 [SF-12] score, visual analog scale pain score, knee motion, and alignment and patellar height as measured on radiographs with use of the Insall-Salvati ratio)., Results: Early (three-month) follow-up showed no significant difference between patellar eversion and subluxation in flexion (mean and 95% confidence interval [CI], 101° ± 5.37° versus 102° ± 4.14°, respectively), Oxford knee scores (25 ± 3 versus 27 ± 2.69, respectively), SF-12, or visual analog scale pain scores (1.9 ± 0.54 versus 1.1 ± 0.44, respectively). A significant improvement in extension was found (-3.9° ± 1.12° versus -2.0° ± 0.91°, respectively [p = 0.034]), but this was not clinically significant. There was no significant difference in any of the outcomes at one year. There was a significant difference in implant malpositioning between the eversion group and the subluxation group, with an increased percentage of lateral tibial overhang in the subluxation group (0.45 ± 0.39 versus 1.84 ± 0.82, respectively [p = 0.005]), but this did not correlate with functional outcome. There was no significant difference in alignment between the two groups (178.29° ± 0.84° versus 178.18° ± 0.78°). At one year after surgery, there was no difference between the two groups in Insall-Salvati ratio (1.15 ± 0.06 versus 1.12 ± 0.06) although there was a correlation between the percentage reduction in the ratio and functional outcome. There were two partial divisions of the patella tendon in the subluxation group, but no patella-related complications in the eversion group., Conclusions: The results of this trial showed that retracting rather than everting the patella during total knee arthroplasty resulted in no significant clinical benefit in the early to medium term. We observed no increase in patellar tendon shortening as a result of eversion rather than subluxation. Our findings did suggest that, with subluxation, there may be an increased risk of damage to the patellar tendon and reduced visualization of the lateral compartment, leading to an increase in implant malpositioning with lateral tibial overhang.

The analysis of sewage for the residues of commonly used illicit drugs has successfully been applied as a suitable approach for estimating community illicit drug use. The drug market is increasingly dynamic with new substances continually being marketed for recreational purposes. In this study, ultra-high pressure liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) was used to simultaneously and quantitatively detect the exogenous biomarkers of new classes of recreational drugs in sewage collected from three different Norwegian cities (Oslo, Bergen, Hamar). The samples were screened for the presence of khat (d-norpseudoephedrine and cathinone), mephedrone, pseudoephedrine, 7-aminoflunitrazepam, para-methoxyamphetamine (PMA), para-methoxy-N-methylamphetamine (PMMA) and a selection of urinary metabolites of synthetic cannabinoids collectively termed ´Spice´ (5-3-1-naphthoyl-1H-indol-1-yl-pentanoic acid (JWH 018 N-pentanoic acid), 1-5-hydroxypentyl-1H-indol-3-ylnaphthalen-1-yl-methanone (JWH 018 N-5-hydroxypentyl), 4-3-1-naphthoyl-1H-indol-1-yl-butanoic acid (JWH 073 N-butanoic acid), 1-4-hydroxybutyl-1H-indol-3-ylnaphthalen-1-yl-methanone (JWH 073 N-4-hydroxybutyl), 1-5-hydroxypentyl-1H-indol-3-yl4-methylnaphthalen-1-yl-methanone (JWH 122 N-5-hydroxypentyl), 1-5-fluoro-4-hydroxypentyl-1H-indol-3-ylnaphthalen-1-ylmethanone (AM2201 N-4-hydroxypentyl), and 1-5-hydroxypentyl-1H-indol-3-yl4-methoxyphenyl-methanone (RCS-4 N-5-hydroxypentyl)). Limits of detection were 1 ng/L for amphetamine like compounds and 5 ng/L for the metabolites of synthetic cannabinoids while the limits of quantification were 3 and 15 ng/L, respectively. Three of the fourteen selected biomarkers (cathine, pseudoephedrine and the synthetic cannabinoid metabolite JWH-018 N-5-hydroxypentyl) were detected in sewage, alongside the illicit drugs (and/or metabolites) typically found in sewage (cocaine, benzoylecognine, methamphetamine, MDMA, and THC-COOH). The khat biomarker d-norpseudoephedrine was detected in Oslo sewage at a mean concentration of 93 ng/L that represents a daily load of 54 mg/day/1000 inhabitants. Pseudoephedrine was present at mean concentrations of between 27 and 67 ng/L representing normalized daily loads of between 10 (Hamar) and 24 mg/day/1000 inhabitants (Bergen). The daily normalized loads of JWH-018 N-5-hydroxypentyl were between 49 (Oslo) and 62 mg/day/1000 inhabitants (Hamar). This study demonstrates for the first time that sewage biomarker analysis can be applied to evaluate not only the use the traditional illicit drugs (cocaine, cannabis and amphetamines), but also the use of certain new synthetic drugs., (Copyright © 2013 John Wiley & Sons, Ltd.)

There is a paucity of research demonstrating how best to address inequalities in health and access to specialist care faced by rural disadvantaged populations in high HIV-prevalent settings in Sub Saharan Africa. Delivering equitable and cost-effective specialist clinical services in many parts of Africa is challenging, given human resource shortages, poor transport infrastructure and competing health priorities. In this report we describe how an airborne outreach program to provide HIV services to high HIV burden health facilities in rural Botswana has been an important catalyst for improving specialist service delivery across the spectrum of clinical care. The success of Botswana's airborne program is a consequence of many country-specific determinants as well as external funding support. We argue that lessons learned from the experience in Botswana are normative for other African settings. Specialist medical airborne outreach to rural hospitals can improve access to and quality of care, when part of a multifaceted, multidisciplinary intervention. Furthermore, we demonstrate how an HIV funded program can be a vehicle for enhanced access to essential sub-specialist clinicians in rural Botswana.

Background: There is little in the literature on HIV and diabetes mellitus (DM) in sub-Saharan Africa., Objective: To assess the characteristics of HIV and DM in patients receiving antiretroviral therapy (ART) in Botswana., Methods: A retrospective case-control study was conducted at 4 sites. Each HIV-infected patient with DM (n=48) was matched with 2 HIV-infected controls (n=108) by age (±2 years) and sex. Primary analysis was conditional logistic regression to estimate univariate odds and 95% confidence intervals (CIs) for each characteristic., Results: There was no significant association between co-morbid diseases, tuberculosis, hypertension or cancer and risk of diabetes. DM patients were more likely to have higher pre-ART weight (odds ratio (OR) 1.09; 95% CI 1.04 - 1.14). HIV-infected adults >70 kg were significantly more likely to have DM (OR 12.30; 95% CI 1.40 - 107.98). Participants receiving efavirenz (OR 4.58; 95% CI 1.44 - 14.57) or protease inhibitor therapy (OR 20.7; 95% CI 1.79 - 240.02) were more likely to have DM. Neither mean pre-ART CD4 cell count (OR 1.0; 95% CI 0.99 - 1.01) nor pre-ART viral load >100 000 copies/ml (OR 0.71; 95% CI 0.21 - 2.43) were associated with a significant risk of diabetes., Conclusions: These findings suggest a complex interrelation among traditional host factors and treatment-related metabolic changes in the pathogenesis of DM inpatients receiving ART. Notably, pre-ART weight, particularly if >70 kg, is associated with the diagnosis of diabetes in HIV-infected patients in Botswana.

Objective: To evaluate measures of cardiac activity and reactivity as prospective biomarkers of treatment response to an empirically supported behavioral intervention for attention-deficit/hyperactivity disorder (ADHD)., Method: Cardiac preejection period (PEP), an index of sympathetic-linked cardiac activity, and respiratory sinus arrhythmia (RSA), an index of parasympathetic-linked cardiac activity, were assessed among 99 preschool children (ages 4-6 years) with ADHD both at rest and in response to behavioral challenge, before participants and their parents completed 1 of 2 versions of the Incredible Years parent and child interventions., Results: Main effects of PEP activity and reactivity and of RSA activity and reactivity were found. Although samplewide improvements in behavior were observed at posttreatment, those who exhibited lengthened cardiac PEP at rest and reduced PEP reactivity to incentives scored higher on measures of conduct problems and aggression both before and after treatment. In contrast, children who exhibited lower baseline RSA and greater RSA withdrawal scored lower on prosocial behavior before and after treatment. Finally, children who exhibited greater RSA withdrawal scored lower on emotion regulation before and after treatment., Conclusions: We discuss these findings in terms of (a) individual differences in underlying neurobiological systems subserving appetitive (i.e., approach) motivation, emotion regulation, and social affiliation and (b) the need to develop more intensive interventions targeting neurobiologically vulnerable children.

The quantitative analysis of human urinary metabolites as biomarkers in wastewater streams has been used to estimate the rates of illicit drug use in the wider community. The primary underlying assumption in such studies is that a sample of wastewater is equivalent to a cumulative sample of urine. Drug metabolism in humans is predominantly enzymatically mediated, but these processes are not exclusive to the human body, and are found to occur in the environment and the sewer network. Understanding what happens to drugs and their urinary metabolites in the sewer system between the point of excretion and sampling is particularly important since it is possible that in-sewer transformation may influence final biomarker concentration. The present study uses batch experiments to measure and assess the biotransformation processes of cocaine and its two major human metabolites, benzoylecgonine and ecgonine methyl ester. The activated sludge modelling framework for xenobiotic organic micro-pollutants (ASM-X) is used for model structure identification and calibration. Biotransformation was observed to follow pseudo first-order kinetics. The biodegradation kinetics of cocaine, benzoylecgonine and ecgonine methyl ester is not significantly affected by the availability of dissolved oxygen. Results obtained in this study show that omitting in-pipe biotransformation affects the accuracy of back-calculated cocaine use estimates. This varies markedly depending on the in-sewer hydraulic retention time, total biomass concentration and the relative concentration of each metabolite. However, back-calculated cocaine use estimates derived from wastewater concentrations of benzoylecgonine and ecgonine methyl ester do show very close agreement if ex-vivo biotransformation of these compounds is considered., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Efficacies of the Incredible Years (IY) interventions are well-established in children with oppositional defiant disorder (ODD) but not among those with a primary diagnosis of attention-deficit/hyperactivity disorder (ADHD). We sought to evaluate 1-year follow-up outcomes among young children with ADHD who were treated with the IY interventions. Four- to 6-year-olds with ADHD (n = 49, 73% male) participated in 6 months of treatment using the IY parent and child interventions. Immediate posttreatment results indicated improvements in parenting, children's externalizing and attention problems, and social contact at school. At 1-year follow up, 22 of 27 variables that showed significant posttreatment effects demonstrated maintenance to 1-year follow up. Children with higher ODD symptoms at baseline showed more improvement in oppositionality and total behavior problems, and their mothers showed more improvement on harsh discipline scores. Approximately 70 to 75% of children were reported by their parents and teachers to fall below clinical cutoffs on measures of externalizing symptoms at the 1-year follow up (compared to 50% at baseline), and more than 50% fell below clinical cutoffs on measures of hyperactivity and inattentiveness (all were in the clinical range at baseline). Children with ADHD who were treated with the IY parent and child treatment programs showed maintenance of treatment effects 1 year after treatment.

Setting: A total of 663 human immunodeficiency virus (HIV) care and treatment sites in nine tuberculosis (TB) affected African countries, serving over 900,000 persons living with HIV., Objective: To determine the implementation of infection control (IC) measures and whether program and facility characteristics were associated with implementation of these measures., Design: A survey was conducted to assess the presence of a TB IC plan, triage practices for TB suspects, location of sputum collection and availability of particulate respirators. The association of facility characteristics with IC measures was examined using bivariate and multivariate methods., Results: Forty-seven per cent (range across countries [RAC] 2-77%) of sites had written TB IC plans; 60% (RAC 5-93%) practiced triage; of those with access to microscopy, 83% (RAC 59-91%) performed sputum collection outdoors and 13% (RAC 0-36%) in ventilated indoor rooms; 16% (RAC 1-87%) had particulate respirators available. Sites providing anti-tuberculosis treatment were more likely to have written IC plans (54% vs. 12%, P < 0.0001) and particulate respirators (18% vs. 8%, P = 0.0126), and to perform TB triage (65% vs. 40%, P = 0.0001) than those without anti-tuberculosis treatment services., Conclusions: To protect HIV-infected patients and health care workers, there is an urgent need to scale up IC practices at HIV care and treatment sites, particularly at sites without anti-tuberculosis treatment services.

Objectives: A range of approaches are now available to estimate the level of drug use in the community so it is desirable to critically compare results from the differing techniques. This paper presents a comparison of the results from three methods for estimating the level of cocaine use in the general population., Design: The comparison applies to; a set of regional-scale sample survey questionnaires, a representative sample survey on drug use among drivers and an analysis of the quantity of cocaine-related metabolites in sewage., Setting: 14 438 participants provided data for the set of regional-scale sample survey questionnaires; 2341 drivers provided oral-fluid samples and untreated sewage from 570 000 people was analysed for biomarkers of cocaine use. All data were collected in Oslo, Norway., Results: 0.70 (0.36-1.03) % of drivers tested positive for cocaine use which suggest a prevalence that is higher than the 0.22 (0.13-0.30) % (per day) figure derived from regional-scale survey questionnaires, but the degree to which cocaine consumption in the driver population follows the general population is an unanswered question. Despite the comparatively low-prevalence figure the survey questionnaires did provide estimates of the volume of consumption that are comparable with the amount of cocaine-related metabolites in sewage. Per-user consumption estimates are however highlighted as a significant source of uncertainty as little or no data on the quantities consumed by individuals are available, and much of the existing data are contradictory., Conclusions: The comparison carried out in the present study can provide an excellent means of checking the quality and accuracy of the three measurement techniques because they each approach the problem from a different viewpoint. Together the three complimentary techniques provide a well-balanced assessment of the drug-use situation in a given community and identify areas where more research is needed.

As HIV care services continue to scale-up in sub-Saharan Africa, adequate tuberculosis diagnostic capacity is vital to reduce mortality among HIV-infected persons. A structured survey was administered at 663 health facilities providing HIV care to 908,043 patients in across 9 sub-Saharan African countries to estimate the proportion of facilities and HIV patients at these facilities with access TB-related diagnostic tests. Sputum smear microscopy was available at 87% of facilities (representing 97% of patients), chest x-ray at 26% of facilities (representing 56% of patients), tuberculin skin tests were available at 12% of facilities (representing 33% of patients). Acid-fast bacillus culture was available on-/off-site at 53% of facilities (representing 77% of patients). Primary health facilities had lower availability of tuberculosis diagnostic tests compared with secondary and tertiary health facilities. As HIV care continues to decentralize to primary health facilities, a corresponding expansion of diagnostic capacity to lower levels of the health system will be essential.

Botswana has the second highest prevalence of human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS) in the world, and yet it has built one of Africa's most progressive and comprehensive HIV programs. While public health infrastructure has responded remarkably to the HIV epidemic, the prevalence of non-communicable diseases (NCDs), particularly diabetes mellitus and cardiovascular disease, in both HIV-infected and non-infected individuals, is increasing rapidly. Applying lessons learned from the scale-up of HIV/AIDS services may help with the implementation of an effective response to the challenges of the emerging NCD epidemic. We suggest that a successful response should include integrated service delivery, capacity building to provide disease-specific care, and strong partnerships to mobilize communities.

Background: Healthcare workers in Africa managing human immunodeficiency virus (HIV)-infected patients often receive inadequate HIV-specific medical education. The acceptability and feasibility of Web-based distance learning tools to enhance HIV training in Africa have not been extensively evaluated., Materials and Methods: In this prospective observational study, we assessed the feasibility of Web-conferencing to deliver HIV-specific medical training to clinicians supporting HIV care and treatment across 12 Sub-Saharan African countries over a 10-month period. Webinar attendance, technical quality, and participant satisfaction were measured for each Webinar. Demographic details about participants were recorded., Results: Attendance increased from 40 participants in Month 1 to over 160 in Month 10. Thirty-six percent of participants were physicians, and 21% were in allied health professions. A mean of 95% of respondents found the content to be relevant. Participants reported that the opportunity to interact with HIV clinicians from other countries and expert teaching from leading scientists were major reasons for attendance. Audio quality was variable across countries and over time. Barriers to attendance included lack of information technology (IT) literacy and Internet connectivity., Conclusions: This analysis demonstrates that Webinars are feasible and acceptable to support HIV training. Significant impediments to scale up in use of Web-conferencing for HIV education in resource-limited settings include lack of IT hardware and limited IT literacy. Strengthening IT capacity and Internet infrastructure is necessary to support expanded use of Webinars as a tool for continuing HIV education.

Research on the prevalence of pediatric-specific tuberculosis (TB) diagnostics in sub-Saharan Africa is scarce. We assessed the availability of pediatric TB diagnostic tests at 651 pediatric human immunodeficiency virus care and treatment sites across nine African countries: 54% of the sites had access to sputum culture capacity and 51% to chest X-ray services. While 87% of sites had access to smear microscopy, only 6% had the capacity to perform sputum induction and 5% to perform gastric aspirate. These findings confirm that diagnostic resources for the accurate diagnosis of pediatric TB are limited. Capacity-building initiatives to improve sputum collection in children are urgently required.

Background: Recent findings of Plasmodium in African apes have changed our perspectives on the evolution of malarial parasites in hominids. However, phylogenetic analyses of primate malarias are still missing information from Southeast Asian apes. In this study, we report molecular data for a malaria parasite lineage found in orangutans., Methodology/principal Findings: We screened twenty-four blood samples from Pongo pygmaeus (Kalimantan, Indonesia) for Plasmodium parasites by PCR. For all the malaria positive orangutan samples, parasite mitochondrial genomes (mtDNA) and two antigens: merozoite surface protein 1 42 kDa (MSP-1(42)) and circumsporozoite protein gene (CSP) were amplified, cloned, and sequenced. Fifteen orangutans tested positive and yielded 5 distinct mitochondrial haplotypes not previously found. The haplotypes detected exhibited low genetic divergence among them, indicating that they belong to one species. We report phylogenetic analyses using mitochondrial genomes, MSP-1(42) and CSP. We found that the orangutan malaria parasite lineage was part of a monophyletic group that includes all the known non-human primate malaria parasites found in Southeast Asia; specifically, it shares a recent common ancestor with P. inui (a macaque parasite) and P. hylobati (a gibbon parasite) suggesting that this lineage originated as a result of a host switch. The genetic diversity of MSP-1(42) in orangutans seems to be under negative selection. This result is similar to previous findings in non-human primate malarias closely related to P. vivax. As has been previously observed in the other Plasmodium species found in non-human primates, the CSP shows high polymorphism in the number of repeats. However, it has clearly distinctive motifs from those previously found in other malarial parasites., Conclusion: The evidence available from Asian apes indicates that these parasites originated independently from those found in Africa, likely as the result of host switches from other non-human primates.

Background: Accurate and timely information on the scale and dynamics of drug consumption is important for assessing the needs of law enforcement and public health services in a community., Aims: This paper presents a detailed examination of a comprehensive sewage-sampling campaign for the purposes of increasing an understanding of the dynamics of drug-flows in sewage streams, and developing new methodology by which this technique can support traditional drug-use surveys., Methods: A total of 104 sewage samples were collected from a treatment plant servicing approximately 500000 people and analysed for levels of methamphetamine, cocaine and cocaine metabolites. Careful examination of the kinetics of drug-flow profiles was then performed in order to identify trends or patterns of use within the community., Results: Results were validated against identical measurements of pharmaceutical reference compounds. Consumption profiles for cocaine and methamphetamine were found to differ in terms of frequency and timing of use. The majority of cocaine consumption occurs during the evening hours and 45% of consumption of this drug occurs in weekend periods. The flow of methamphetamine in the sewage system appears more evenly spread throughout the week., Conclusions: This result is consistent with both an extended excretion half-life and a pattern of use that is more evenly balanced across all days of the week. Comprehensive investigation in to the scale and kinetics of drug flow in a sewage stream can therefore provide valuable information, not only in terms of the volume of drug consumed, but also in terms of identifying differing usage-patterns over daily and weekly time-scales., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: The quantitative measurement of urinary metabolites in sewage streams and the subsequent estimation of consumption rates of the parent compounds have previously been demonstrated for pharmaceuticals and narcotics. Ethyl sulfate and ethyl glucuronide are excreted in urine following the ingestion of alcohol, and are useful biomarkers for the identification of acute alcohol consumption. This study reports a novel ion-exchange-mediated chromatographic method for the quantitative measurement of ethyl sulfate and ethyl glucuronide in sewage effluent, and presents a novel calculation method for the purposes of relating the resulting sewage concentrations with rates of alcohol consumption in the region., Methods: A total of 100 sewage samples covering a 25-day period were collected from a treatment plant servicing approximately 500,000 people, and analyzed for levels of ethyl sulfate and ethyl glucuronide. The resulting data were then used to estimate combined alcohol consumption rates for the region, and the results were compared with alcohol related sales statistics for the same region., Results: Ethyl glucuronide was found to be unstable in sewage effluent. Ethyl sulfate was stable and measurable in all samples at concentrations ranging from 16 to 246 nM. The highest concentrations of the alcohol biomarker were observed during weekend periods. Sixty one percent of the total mass of ethyl sulfate in sewage effluent corresponds to alcohol consumption on Friday and Saturday. Sales statistics for alcohol show that consumption in the region is approximately 6,750 kg/d. The quantity of ethyl sulfate passing through the sewage system is consistent with consumption of 4,900 to 7,800 kg/d., Conclusions:   Sewage epidemiology assessments of ethyl sulfate can provide accurate estimates of community alcohol consumption, and detailed examination of the kinetics of this biomarker in sewage streams can also identify time-dependent trends in alcohol consumption patterns., (2011 by the Research Society on Alcoholism.)

Nonhuman primates are potentially good sentinels of environmental toxicants because they share a similar physiology and life history with humans. In this report we present the results of an analysis of lead concentrations in hair from long-tailed macaques in Singapore. We hypothesized that because Singapore is highly urbanized, its macaque population may be exposed to higher levels of lead. The results of our study indicated that Singapore's macaque population has not been exposed to high levels of environmental lead. Compared with previous studies of lead levels in human and nonhuman primate hair, the results of our analysis indicate a low level of exposure of monkeys to environmental lead (n = 27, arithmetic mean = 2.51 ppm, max = 6.45, min = 0.21 ppm). Hair lead concentrations varied both within social groups and by geographic location, with the highest concentrations observed in monkeys residing within an area containing a small-arms firing range and a manufacturing facility. Although lead exposure in this area seems to be low, additional monitoring and possible remediation may be warranted. Our study is among the first to illustrate how primates can serve as potential sentinels of environmental toxicants such as lead. Future research examining the efficacy of primates as sentinels of lead exposure should include monitoring of environmental lead levels, and comparison of hair lead levels with levels measured in blood samples.

The efficacy of the Incredible Years parent and child training programs is established in children diagnosed with oppositional defiant disorder but not among young children whose primary diagnosis is attention-deficit/hyperactivity disorder (ADHD). We conducted a randomized control trial evaluating the combined parent and child program interventions among 99 children diagnosed with ADHD (ages 4-6). Mother reported significant treatment effects for appropriate and harsh discipline, use of physical punishment, and monitoring, whereas fathers reported no significant parenting changes. Independent observations revealed treatment effects for mothers' praise and coaching, mothers' critical statements, and child total deviant behaviors. Both mothers and fathers reported treatment effects for children's externalizing, hyperactivity, inattentive and oppositional behaviors, and emotion regulation and social competence. There were also significant treatment effects for children's emotion vocabulary and problem-solving ability. At school teachers reported treatment effects for externalizing behaviors and peer observations indicated improvements in treated children's social competence.

Clear cell renal cell carcinoma (ccRCC), a tubular epithelial cell (TEC) malignancy, frequently secretes tumor necrosis factor (TNF). TNF signals via two distinct receptors (TNFRs). TNFR1, expressed in normal kidney primarily on endothelial cells, activates apoptotic signaling kinase 1 and nuclear factor-kappaB (NF-kappaB) and induces cell death, whereas TNFR2, inducibly expressed on endothelial cells and on TECs by injury, activates endothelial/epithelial tyrosine kinase (Etk), which trans-activates vascular endothelial growth factor receptor 2 (VEGFR2) to promote cell proliferation. We investigated TNFR expression in clinical samples and function in short-term organ cultures of ccRCC tissue treated with wild-type TNF or specific muteins selective for TNFR1 (R1-TNF) or TNFR2 (R2-TNF). There is a significant increase in TNFR2 but not TNFR1 expression on malignant TECs that correlates with increasing malignant grade. In ccRCC organ cultures, R1-TNF increases TNFR1, activates apoptotic signaling kinase and NF-kappaB, and promotes apoptosis in malignant TECs. R2-TNF increases TNFR2, activates NF-kappaB, Etk, and VEGFR2 and increases entry into the cell cycle. Wild-type TNF induces both sets of responses. R2-TNF actions are blocked by pretreatment with a VEGFR2 kinase inhibitor. We conclude that TNF, acting through TNFR2, is an autocrine growth factor for ccRCC acting via Etk-VEGFR2 cross-talk, insights that may provide a more effective therapeutic approach to this disease.

Tumor necrosis factor (TNF) utilizes two receptors, TNFR1 and 2, to initiate target cell responses. We assessed expression of TNF, TNFRs and downstream kinases in cardiac allografts, and compared TNF responses in heart organ cultures from wild-type ((WT)C57BL/6), TNFR1-knockout ((KO)), TNFR2(KO), TNFR1/2(KO) mice. In nonrejecting human heart TNFR1 was strongly expressed coincidentally with inactive apoptosis signal-regulating kinase-1 (ASK1) in cardiomyocytes (CM) and vascular endothelial cells (VEC). TNFR2 was expressed only in VEC. Low levels of TNF localized to microvessels. Rejecting cardiac allografts showed increased TNF in microvessels, diminished TNFR1, activation of ASK1, upregulated TNFR2 co-expressed with activated endothelial/epithelial tyrosine kinase (Etk), increased apoptosis and cell cycle entry in CM. Neither TNFR was expressed significantly by cardiac fibroblasts. In (WT)C57BL/6 myocardium, TNF activated both ASK1 and Etk, and increased both apoptosis and cell cycle entry. TNF-treated TNFR1(KO) myocardium showed little ASK1 activation and apoptosis but increased Etk activation and cell cycle entry, while TNFR2(KO) myocardium showed little Etk activation and cell cycle entry but increased ASK1 activation and apoptosis. These observations demonstrate independent regulation and differential functions of TNFRs in myocardium, consistent with TNFR1-mediated cell death and TNFR2-mediated repair.

The ADAMTS enzymes (a disintegrin and metalloproteinase with thrombospondin type 1-like motifs) have important roles in central nervous system (CNS) physiology and pathology. This current study aimed to analyse the expression of ADAMTS-9 following transient middle cerebral artery occlusion (tMCAo) in the rat, a model of focal cerebral ischaemia. Using real-time RT-PCR, ADAMTS-9 mRNA was demonstrated to be significantly up-regulated in tMCAo brain tissue compared to sham-operated at 24h post-ischaemia. The mature form of the ADAMTS-9 protein was only detected by Western blotting in brains subjected to tMCAo at 24h. In situ hybridisation demonstrated that ADAMTS-9 mRNA was expressed by neurones in tMCAo tissue. This study indicates that ADAMTS-9 expression is modulated in response to cerebral ischaemia in vivo and further research will resolve whether it plays a role in the subsequent degenerative or repair processes.

Tuberculosis is the main cause of morbidity and mortality in people living with HIV/AIDS worldwide. Early diagnosis and treatment is essential to addressing the dual epidemic of tuberculosis and HIV. Increasing recognition of the importance of integrating tuberculosis services--including screening--into HIV care has led to global policies and the beginnings of implementation of joint activities at the national level. However, debate remains about the best methods of screening for pulmonary tuberculosis among people living with HIV/AIDS in resource-limited settings. Mycobacterial culture, the gold standard for tuberculosis diagnosis, is too slow and complex to be a useful screening test in such settings. More widely available methods, such as symptom screening, sputum smear microscopy, chest radiography, and tuberculin skin testing have important shortcomings, especially in people living with HIV/AIDS. However, until simpler, cheaper, and more sensitive diagnostics for tuberculosis are available in peripheral healthcare settings, a strategy must be developed that uses current evidence to combine available screening tools.

The remarkable sensitivity of accelerator mass spectrometry (AMS) is finding many new applications in pharmacology. In this study AMS was used to measure [(14)C]-Zidovudine (ZDV) concentrations at the drug's site of action (peripheral blood mononuclear cells, PBMCs) following a dose of 520 ng (less than one-millionth of the standard daily dose) to a healthy volunteer. In addition, the pharmacokinetics of this microdose were determined and compared to previously published parameters for therapeutic doses. Microdose ZDV pharmacokinetic parameters fell within reported 95% confidence intervals or standard deviations of most previously published values for therapeutic doses. Blood, urine, stool, saliva, and isolated PBMCs were collected periodically through 96 h postdose and analyzed for ZDV and metabolite concentrations. The results showed that ZDV is rapidly absorbed and eliminated, has one major metabolite, and is sequestered in PBMCs. (14)C mass balance assessments indicated a significant portion of ZDV remained after 96 h with a much prolonged elimination half-life. Results of this study demonstrate the usefulness of microdosing and AMS as a tool for studying the pharmacokinetic characteristics, including PBMC concentrations, of ZDV and underscore the value of AMS as a tool with which to perform pharmacokinetic and mass balance studies using trace amounts of radiolabeled compound.

The Incredible Years parent and classroom interventions were evaluated for the first time in elementary schools. Culturally diverse, socioeconomically disadvantaged schools were randomly assigned to intervention or control (CON). In intervention schools, all children received a 2-year classroom intervention beginning in kindergarten. In addition, indicated children were randomly assigned to also receive parent training (PT + CR) or only the classroom intervention (CR). PT + CR mothers reported that, following intervention, children showed fewer externalizing problems and more emotion regulation than CR or CON children. Observations showed that child-mother bonding was stronger in the PT + CR condition than in the CON condition, and PT + CR mothers were significantly more supportive and less critical than CR or CON mothers. Teachers reported that PT + CR mothers were significantly more involved in school and that children in the PT + CR and the CR conditions had significantly fewer externalizing problems than in the CON condition.

Data are lacking on the specific diseases to which great apes are susceptible and the transmission dynamics and overall impact of these diseases. We examined the prevalence of Plasmodium spp. infections in semicaptive orangutans housed at the Orangutan Care Center and Quarantine, Central Kalimantan, Indonesia, by using a combination of microscopic and DNA molecular techniques to identify the Plasmodium spp. in each animal. Previous studies indicated 2 orangutan-specific Plasmodium spp., but our data show 4 Plasmodium spp. These findings provide evidence for P. vivax transmission between humans and orangutans and for P. cynomolgi transmission between macaques and orangutans. These data have potential implications for the conservation of orangutans and also for the bidirectional transmission of parasites between orangutans and humans visiting or living in the region.

We have measured the distance to the massive star-forming region W3OH in the Perseus spiral arm of the Milky Way to be 1.95 +/- 0.04 kiloparsecs (5.86 x10(16) km). This distance was determined by triangulation, with Earth's orbit as one segment of a triangle, using the Very Long Baseline Array. This resolves the long-standing problem that there is a discrepancy of a factor of 2 between different techniques used to determine distances. The reason for the discrepancy is that this portion of the Perseus arm has anomalous motions. The orientation of the anomalous motion agrees with spiral density-wave theory, but the magnitude of the motion is somewhat larger than most models predict.

Several child conduct problem interventions have been classified as either efficacious or well established. Nevertheless, much remains to be learned about predictors of treatment response and mechanisms of behavioral change. In this study, the authors combine data from 6 randomized clinical trials and 514 children, ages 3.0-8.5 years, to evaluate moderators, mediators, and predictors of outcome. Among other findings, latent growth curve models of mother-report and observational measures of child externalizing behaviors suggested that marital adjustment, maternal depression, paternal substance abuse, and child comorbid anxiety/depression each moderated treatment response. Moreover, critical, harsh, and ineffective parenting both predicted and mediated outcome, with the most favorable responses observed when parents scored relatively low on each construct at intake yet improved during treatment. Implications for treatment nonresponders are discussed., ((c) 2005 APA, all rights reserved.)

We measured the angular rotation and proper motion of the Triangulum Galaxy (M33) with the Very Long Baseline Array by observing two H2O masers on opposite sides of the galaxy. By comparing the angular rotation rate with the inclination and rotation speed, we obtained a distance of 730 +/- 168 kiloparsecs. This distance is consistent with the most recent Cepheid distance measurement. M33 is moving with a velocity of 190 +/- 59 kilometers per second relative to the Milky Way. These measurements promise a method to determine dynamical models for the Local Group and the mass and dark-matter halos of M31, M33, and the Milky Way.

We examined parent and child moderators of outcome, program engagement effects, and predictors of engagement in the Incredible Years Parent Training Program. Head Start classrooms (N = 882 children) were randomly assigned to an intervention condition (that received the Incredible Years program) or to a control condition (that received usual Head Start services). Structural equation modeling (SEM) was used to model the effects of the training program on child outcomes. The analyses showed differential program effects depending on children's initial levels of conduct problems and mothers' initial levels of critical parenting. Children with high baseline levels of conduct problems and children of mothers with high initial levels of critical parenting benefited most from the program. Changes in children's conduct problems were also related to maternal engagement in the program and to intervention mothers' success at reducing their critical parenting.