SARS-CoV-2 Transmission Risk in the School Environment: a pilot case-ascertained prospective study to inform future school-based surveillance.

BACKGROUND: There is no current active or passive disease surveillance programme focused on schools in South Africa. As such the country is missing an opportunity to rapidly and effectively flag and address pathogen outbreaks, for example SARS-CoV-2, in a key closed setting. Furthermore, the role of school transmission in the spread of the SARS-CoV-2 virus within communities is uncertain.  Objective. This pilot study, conducted during March 2022 in Cape Town, aimed to indicate the feasibility of conducting intense active contact-tracing in a school environment prior to a large national study to compare school versus community SARS-CoV-2 transmission risk.  Methods. We conducted a pilot school-level case-ascertained prospective study with a component of enhanced surveillance. Following study initiation, the first learner at a participating school who tested SARS-CoV-2 positive (via Polymerase Chain Reaction (PCR) or a Rapid Antigen Test (RAT)) was invited to join the study as the index case and all their school-based close contacts were followed up telephonically, monitored for symptoms for 14 days, and tested using a PCR if any symptoms were reported.  Results. On 8th March 2022, a student with RAT laboratory-confirmed COVID-19 was identified and they and their guardian consented to participate as the index case. Of the 11 eligible close contacts, six provided consent/assent and completed symptom monitoring calls until the end of the 14-day study period. The Secondary Attack Rate (SAR) was 2/11 (18.18%) of all close contacts who were at risk of infection, 2/4 (50.0%) of all those close contacts who developed symptoms, and 2/4 (50.0%) of all those close contacts who developed symptoms and were tested for SARS-CoV-2. During the same period, the school reported that nine of the 926 learner body tested COVID-19 positive (0.97%). Total hours spent conducting monitoring for 6 learners was 27 hours, with each learner requiring approximately 4.5 hours of contact time during the study period.  Conclusion. This is the first South African school-based COVID-19 transmission study, the results of which can inform national discussions regarding the role of schools and school-based active and passive surveillance in pathogen prevention and control.

Rapid review of the effects of cloth and medical masks for preventing transmission of SARS-CoV-2 in community and household settings.

BACKGROUND: Evidence on mask use in the general population is needed to inform SARS-CoV-2 responses. OBJECTIVES: To assess the effectiveness of cloth and medical masks for preventing SARS-CoV-2 transmission in community settings. METHODS: Two rapid reviews were conducted searching three electronic databases (PubMed, Embase, Cochrane Library) and two clinical trials registries on 30 and 31 March 2020. RESULTS: We screened 821 records and assessed nine full-text articles for eligibility. One and seven RCTs were included for cloth and medical mask reviews, respectively. No SARS-CoV-2-specific RCTs and no cloth mask RCTs in community settings were identified. A single hospital-based RCT provided indirect evidence that, compared with medical masks, cloth masks probably increase clinical respiratory illnesses (relative risk (RR) 1.56; 95% confidence interval (CI) 0.98 - 2.49) and laboratory-confirmed respiratory virus infections (RR 1.54; 95% CI 0.88 - 2.70). Evidence for influenza-like illnesses (ILI) was uncertain (RR 13.00; 95% CI 1.69 - 100.03). Two RCTs provide low-certainty evidence that medical masks may make little to no difference to ILI infection risk versus no masks (RR 0.98; 95% CI 0.81 - 1.19) in the community setting. Five RCTs provide low-certainty evidence that medical masks may slightly reduce infection risk v. no masks (RR 0.81; 95% CI 0.55 - 1.20) in the household setting. CONCLUSIONS: Direct evidence for cloth and medical mask efficacy and effectiveness in the community is limited. Decision-making for mask use may consider other factors such as feasibility and SARS-CoV-2 transmission dynamics; however, well-designed comparative effectiveness studies are required.

Moving towards universal health coverage: Strengthening the evidence ecosystem for the South African health system.

Health policy and systems research (HPSR) guides health system reforms and is essential for South Africa (SA)'s progress towards universal coverage of high-quality healthcare. For HPSR evidence to inform and strengthen health systems, it needs to flow efficiently between evidence producers, evidence synthesisers, evidence processers and disseminators and evidence implementors in an evidence ecosystem. A substantial body of evidence for health systems strengthening is generated in SA, and this informs national and international health system guidelines and guidance. In this manuscript, in celebration of the 50th anniversary of the SA Medical Research Council, we apply an evidence ecosystem lens to the SA health system, and discuss its current functioning in support of the achievement of a high-quality health system that is able to achieve universal health coverage. We use three case studies to describe successes, challenges and gaps in the functioning of the evidence ecosystem. The first case study focuses on using evidence to strengthen health-system governance and support for community health worker programmes. The second case focuses on managing the growing epidemic of drug-resistant tuberculosis, while the third case focuses on social protection, the child support grant and its impact on health. SA scientists are part of global initiatives to strengthen the health-systems evidence ecosystem, specifically through pioneering methods to synthesise evidence and produce evidence-informed guidelines to facilitate evidence use in health-system decision-making. SA institutes of health policy analysis facilitate involvement of evidence producers and synthesisers in the national health system policy-making process. A future priority is to further strengthen national initiatives to translate evidence into policy and practice and to sustain capacity for continuous technical support to health-systems policy development and implementation.

Looking back, moving forward: 50 years of South African Medical Research Council alcohol-related publications.

BACKGROUND: Alcohol is one of the highest risk factors for death and disability in South Africa (SA). Objective. To explore the trajectory of empirical research on alcohol in SA between 1969 and 2019, with an emphasis on South African Medical Research Council (SAMRC) authored publications. Methods. We reviewed published research (Pubmed and Africa-Wide Information) using systematic methods, clear inclusion and exclusion criteria, and defined search terms. The search was not limited by language. Data synthesis was carried out by the first and last authors. Results. A total of 867 journal articles met the inclusion criteria, with 243 (28.0%) authored or co-authored by SAMRC researchers. For the latter group, three-quarters had an SAMRC researcher as first or last author. Over three-quarters (78.6%) of the SAMRC author positions ('first', 'last' or 'other, counting researchers from a unit only once, but counting authors across different units on a single publication) were from intramural units. Over half the articles authored by SAMRC researchers focused on non-communicable diseases (55.9%), 23.8% focused on communicable diseases, and 10% on crime, violence or injury. Few articles focused on alcohol and tuberculosis (TB), alcohol and cancer, or alcohol policy. Over three-quarters (76.9%) were epidemiological in nature, and 65.3% were cross-sectional studies. There were 17 reviews (7 systematic) and 11 randomised controlled trials (RCTs). There was an increase in the annual number of publications over the 50-year period for both SAMRC and non-SAMRC researchers. Over time, there has been a trend towards publishing on alcohol research in journals published outside SA, but the SAMJ still remains a popular journal choice. Conclusion. The SAMRC has contributed substantially to the growing field of alcohol research in SA, but gaps in areas such as alcohol policy evaluation, alcohol and its association with TB and cancer, and interventional research, are evident.

A contextualisation approach to health promotion guideline development in South Africa.

BACKGROUND: Risk factors for chronic illness contribute significantly to the disease burden in South Africa. The National Department of Health (NDoH) commissioned the development of a toolkit of health promotion guidelines for use by healthcare professionals working in the primary care setting to address this burden. OBJECTIVES: To (i) demonstrate the contextualisation approach to evidence-based health promotion recommendations; and (ii) present the development process of a contextually sensitive and illustrated fit-for-purpose product. METHODS: A contextualised approach was used whereby evidence from rigorous guidelines produced elsewhere was tailored to local conditions. The scope of the toolkit included five risk factors and 22 conditions identified by the NDoH and was underpinned by the Theory of Planned Behaviour. Potential health promotion messages relevant to risks, conditions or both were formulated as population, intervention, comparison and outcome (PICO) questions. The team searched for and selected evidence for each PICO question in a stepwise hierarchical manner and categorised sources as: (i) World Health Organization (WHO) guidelines; (ii) Cochrane systematic reviews; and (iii) non-Cochrane systematic reviews. Those messages supported by source-based evidence were included in the toolkit with culturally appropriate illustrations. Regular engagement with stakeholders included an initial health department stakeholder consultation, a focus group with national programme managers on the appearance and content of a draft toolkit, and a presentation of the final draft at a forum of provincial managers. Final approval of the toolkit rested with programme representatives. RESULTS: A total of 152 PICO questions were formulated. Supporting evidence was identified from 42 current WHO guidelines and 45 Cochrane systematic reviews to answer 147 PICO questions with several guidelines relevant to more than one risk or condition. Evidence for a further five PICO questions was obtained from non-Cochrane systematic reviews. Six additional service delivery messages and four 'no harm' messages were included to align the toolkit with current national guidelines. The illustrated toolkit was well received by stakeholders nationally and provincially, with programme managers expressing a high degree of willingness to adopt a preventive approach in the primary care clinic setting. CONCLUSIONS: Use of a tailored contextualised approach to health promotion guidelines resulted in a culturally appropriate tool based on evidence gathered from rigorous sources and probably reduced development time and costs. Adherence to a robust framework to identify evidence ensured that the toolkit conforms to international guideline development standards.

Large-scale preparation of (13) C-labeled 2-(phenylthio)acetic acid and the corresponding labeled sulfoxides and sulfones.

We have developed large-scale efficient procedures for the conversion of commercially available [(13) C]- or [(2) H3 ,(13) C]methanol and (13) CO2 or (13) C-labeled bromoacetic acid to 2-(phenylthio)[1,2-(13) C2 ]-, [1-(13) C]-, and [2-(13) C]acetic acid. The resulting derivatives are versatile, chemically stable, and nonvolatile two-carbon labeling precursors. We have used the (13) C-isotopomers of 2-(phenylthio)acetic acid in the synthesis of (13) C-labeled acrylic acid, methacrylic acid, and trans-crotonic acid.

Does South Africa need a national clinical trials support unit?

BACKGROUND: No national South African institution provides a coherent suite of support, available skills and training for clinicians wishing to conduct randomised controlled trials (RCTs) in the public sector. We report on a study to assess the need for establishing a national South African Clinical Trials Support Unit. OBJECTIVES: To determine the need for additional training and support for conduct of RCTs within South African institutions; identify challenges facing institutions conducting RCTs; and provide recommendations for enhancing trial conduct within South African public institutions. DESIGN: Key informant interviews of senior decision-makers at institutions with a stake in the South African public sector clinical trials research environment. RESULTS: Trial conduct in South Africa faces many challenges, including lack of dedicated funding, the burden on clinical load, and lengthy approval processes. Strengths include the high burden of disease and the prevalence of treatment-naïve patients. Participants expressed a significant need for a national initiative to support and enhance the conduct of public sector RCTs. Research methods training and statistical support were viewed as key. There was a broad range of views regarding the structure and focus of such an initiative, but there was agreement that the national government should provide specific funding for this purpose. CONCLUSIONS: Stakeholders generally support the establishment of a national clinical trials support initiative. Consideration must be given to the sustainability of such an initiative, in terms of funding, staffing, expected research outputs and permanence of location.

Psychosocial interventions for people with both severe mental illness and substance misuse.

BACKGROUND: Even low levels of substance misuse by people with a severe mental illness can have detrimental effects. OBJECTIVES: To assess the effects of psychosocial interventions for substance reduction in people with a serious mental illness. SEARCH STRATEGY: For this update (2007) we searched the Cochrane Schizophrenia Group Trials Register (May 2006) which is based on regular searches of major databases. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing psychosocial interventions for substance misuse with standard care in people with serious mental illness. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where data were homogeneous. For continuous data, we calculated weighted mean differences (WMD) again based on a random effects model. MAIN RESULTS: Evaluation of long-term integrated care included 4 RCTs (total n=735). We found no significant difference on measures of substance use (n=85, 1 RCT, RR 0.89 CI 0.6 to 1.3) or loss to treatment (n=603, 3 RCTs, RR 1.09 CI 0.8 to 1.5). For the non-integrated intensive case management trials (4 RCTs, total n=151) we also found no significant difference for loss (n=134, 3 RCTs, RR 1.35 CI 0.8 to 2.2). Motivational interviewing plus cognitive behavioural therapy (3 RCTs, total n=276) did not reveal any advantage for retaining participants (n=36, 1 RCT, RR lost to treatment 0.50 CI 0.1 to 5.0) or for relapse (n=36, 1 RCT, RR 0.58 CI 0.3 to 1.1), and no benefit for reducing substance use (n=119, 1 RCT, RR 0.19 CI -0.2 to 0.6). Cognitive behavioural therapy alone (4 trials, total n=260) showed fewer participants lost from treatment (n=260, 4 RCTs, p=0.02, RR 0.61 CI 0.4 to 0.9). No benefits were observed on measures of lessening cannabis use (n=47, 1 RCT, RR 1.30 CI 0.8 to 2.2) or on the number of participants using substances (alcohol; n=46, 1 RCT, RR 5.88 CI 0.8 to 44.0, drugs; n=46, 1 RCT, RR 2.02 CI 0.9 to 4.8) and no differences were observed on measures of mental state (n=105, 1 RCT, RR 0.52 CI -0.8 to 1.8). We found no advantage for motivational interviewing alone (5 trials, total n=338) in reducing 'lost to evaluation' (n=338, 5 RCTs, RR 0.96 CI 0.6 to 1.5) compared with treatment as usual, although significantly more participants in the motivational interviewing group reported for their first aftercare appointment (n=93, 1 RCT, RR 0.69 CI 0.5 to 0.9, NNT 4 CI 3 to 12). Some differences were observed in abstaining from alcohol favouring treatment (n=28, 1 RCT, RR 0.36 CI 0.2 to 0.8, NNT 2 CI 2 to 5), but not other substances (n=89, 1 RCT, RR -0.07 CI -0.6 to 0.4) and no differences were observed in mental state (n=30, 1 RCT, WMD -4.20 CI -18.7 to 10.3). Finally, we found no significant differences for skills training in the numbers lost to treatment by 12 months (n=94, 2 RCTs, RR 0.70 CI 0.4 to 1.1). AUTHORS' CONCLUSIONS: We included 25 RCTs and found no compelling evidence to support any one psychosocial treatment over another to reduce substance use (or improve mental state) by people with serious mental illnesses. Furthermore, methodological difficulties exist which hinder pooling and interpreting results; high drop out rates, varying fidelity of interventions, varying outcome measures, settings and samples and comparison groups may have received higher levels of treatment than standard care. Further studies are required which address these concerns and improve the evidence in this important area.

Psychosocial treatment programs for people with both severe mental illness and substance misuse.

Over 50% of people with a severe mental illness also use illicit drugs and/or alcohol at hazardous levels. This review is based on the findings of 25 randomized controlled trials which assessed the effectiveness of psychosocial interventions, offered either as one-off treatments or as an integrated or nonintegrated program, to reduce substance use by people with a severe mental illness. The findings showed that there was no consistent evidence to support any one psychosocial treatment over another. Differences across trials with regard to outcome measures, sample characteristics, type of mental illness and substance used, settings, levels of adherence to treatment guidelines, and standard care all made pooling results difficult. More quality trials are required that adhere to proper randomization methods; use clinically valuable, reliable, and validated measurement scales; and clearly report data, including retention in treatment, relapse, and abstinence rates. Future trials of this quality will allow a more thorough assessment of the efficacy of psychosocial interventions for reducing substance use in this challenging population.

Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection.

BACKGROUND: Antiretroviral drugs (ARV) reduce viral replication and can reduce mother-to-child transmission of HIV either by lowing plasma viral load in pregnant women or through post-exposure prophylaxis in their newborns. In rich countries, highly active antiretroviral therapy (HAART) has reduced the vertical transmission rates to around 1-2%, but HAART is not yet widely available in low and middle income countries. In these countries, various simpler and less costly antiretroviral regimens have been offered to pregnant women or to their newborn babies, or to both. OBJECTIVES: To determine whether, and to what extent, antiretroviral regimens aimed at decreasing the risk of mother-to-child transmission of HIV infection achieve a clinically useful decrease in transmission risk, and what effect these interventions have on maternal and infant mortality and morbidity. SEARCH STRATEGY: We sought to identify all relevant studies regardless of language or publication status by searching the Cochrane HIV/AIDS Review Group Trials Register, The Cochrane Library, Medline, EMBASE and AIDSearch and relevant conference abstracts. We also contacted research organizations and experts in the field for unpublished and ongoing studies. The original review search strategy was updated in 2006. SELECTION CRITERIA: Randomised controlled trials of any antiretroviral regimen aimed at decreasing the risk of mother-to-child transmission of HIV infection compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two authors independently selected relevant studies, extracted data and assessed trial quality. For the primary outcomes, we used survival analysis to estimate the probability of infants being infected with HIV (the observed proportion) at various specific time-points and calculated efficacy at a specific time as the relative reduction in the proportion infected. Efficacy, at a specific time, is defined as the preventive fraction in the exposed group compared to the reference group, which is the relative reduction in the proportion infected: 1-(Re/Rf). For those studies where efficacy and hence confidence intervals were not calculated, we calculated the approximate confidence intervals for the efficacy using recommended methods. For analysis of results that are not based on survival analyses we present the relative risk for each trial outcome based on the number randomised. No meta-analysis was conducted as no trial assessed the identical drug regimens. MAIN RESULTS: Eighteen trials including 14,398 participants conducted in 16 countries were eligible for inclusion in the review. The first trial began in April 1991 and assessed zidovudine (ZDV) versus placebo and since then, the type, dosage and duration of drugs to be compared has been modified in each subsequent trial. Antiretrovirals versus placebo In breastfeeding populations, three trials found that:ZDV given to mothers from 36 to 38 weeks gestation, during labour and for 7 days after delivery significantly reduced HIV infection at 4-8 weeks (Efficacy 32.00%; 95% CI 0.64 to 63.36), 3 to 4 months (Efficacy 34.00%; 95% CI 6.56 to 61.44), 6 months (Efficacy 35.00%; 95% CI 9.52 to 60.48), 12 months (Efficacy 34.00%; 95% CI 8.52 to 59.48) and 18 months (Efficacy 30.00%; 95% CI 2.56 to 57.44).ZDV given to mothers from 36 weeks gestation and during labour significantly reduced HIV infection at 4 to 8 weeks (Efficacy 44.00%; 95% CI 8.72 to 79.28) and 3 to 4 months (Efficacy 37.00%; 95% CI 3.68 to 70.32) but not at birth.ZDV plus lamivudine (3TC) given to mothers from 36 weeks gestation, during labour and for 7 days after delivery and to babies for the first 7 days of life (PETRA 'regimen A') significantly reduced HIV infection (Efficacy 63.00%; 95% CI 41.44 to 84.56) and a combined endpoint of HIV infection or death (Efficacy 61.00%; 95% CI 41.40 to 80.60) at 4 to 8 weeks but these effects were not sustained at 18 months.ZDV plus 3TC given to mothers from the start of labour until 7 days after delivery and to babies for the first 7 days of life (PETRA 'regimen B') significantly reduced HIV infection (Efficacy 42.00%; 95% CI 12.60 to 71.40) and HIV infection or death at 4 to 8 weeks (Efficacy 36.00%; 95% CI 8.56 to 63.44) but the effects were not sustained at 18 months.ZDV plus 3TC given to mothers during labour only (PETRA 'regimen C') with no treatment to babies did not reduce the risk of HIV infection at either 4 to 8 weeks or 18 months. In non-breastfeeding populations, three trials found that:ZDV given to mothers from 14 to 34 weeks gestation and during labour and to babies for the first 6 weeks of life significantly reduced HIV infection in babies at 18 months (Efficacy 66.00%; 95% CI 34.64 to 97.36).ZDV given to mothers from 36 weeks gestation and during labour with no treatment to babies ('Thai-CDC regimen') significantly reduced HIV infection at 4 to 8 weeks (Efficacy 50.00%; 95% CI 12.76 to 87.24) but not at birthZDV given to mothers from 38 weeks gestation and during labour with no treatment to babies did not influence HIV transmission at 6 months. Longer versus shorter regimens using the same antiretrovirals One trial in a breastfeeding population found that:ZDV given to mothers during labour and to their babies for the first 3 days of life compared with ZDV given to mothers from 36 weeks and during labour (similar to 'Thai-CDC') resulted in HIV infection rates that were not significantly different at birth, 4-8 weeks, 3 to 4 months, 6 months and 12 months. Three trials in non-breastfeeding populations found that:ZDV given to mothers from 28 weeks gestation during labour and to infants for the first 3 days after birth compared with ZDV given to mothers from 35 weeks gestation through labour and to infants from birth to 6 weeks significantly reduced HIV infection rate at 6 months (Efficacy 45.00%; 95% CI 1.88 to 88.12) but compared with the same regimen ZDV given to mothers from 28 weeks gestation through labour and to infants from birth to 6 weeks did not result in a statistically significant difference in HIV infection at 6 months. ZDV given to mothers from 35 weeks gestation during labour and to infants for the first 3 days after birth was considered ineffective for reducing transmission rates and this regimen was discontinued.An antenatal/intrapartum course of ZDV used for a median of 76 days compared with an antenatal/intrapartum ZDV regimen used for a median 28 days with no treatment to babies in either group did not result in HIV infection rates that were significantly different at birth and at 3 to 4 months. In a programme where mothers were routinely receiving ZDV in the third trimester of pregnancy and babies were receiving one week of ZDV therapy, a single dose of nevirapine (NVP) given to mothers in labour and to their babies soon after birth compared with a single dose of NVP given to mothers only resulted in HIV infection rates that were not significantly different at birth and 6 months. However the reduction in risk of HIV infection or death at 6 months was marginally significant (Efficacy 45.00%; 95% CI -4.00 to 94.00). Antiretroviral regimens using different drugs and durations of treatment In breastfeeding populations, three trials found that:A single dose of NVP given to mothers at the onset of labour plus a single dose of NVP given to their babies immediately after birth ('HIVNET 012 regimen') compared with ZDV given to mothers during labour and to their babies for a week after birth resulted in lower HIV infection rates at 4-8 weeks (Efficacy 41.00%; 95% CI 11.60 to 70.40), 3-4 months (Efficacy 39.00%; 95% CI 11.56 to 66.44), 12 months (Efficacy 36.00%; 95% CI 8.56 to 63.44) and 18 months (Efficacy 39.00%; 95% CI 13.52 to 64.48). In addition, the NVP regimen significantly reduced the risk of HIV infection or death at 4-8 weeks (Efficacy 42.00%; 95% CI 14.56 to 69.44), 3 to 4 months (Efficacy 40.00%; 95% CI 14.52 to 65.48), 12 months (Efficacy 32.00%; 95% CI 8.48 to 55.52) and 18 months (Efficacy 33.00%; 95% CI 9.48 to 56.52). The 'HIVNET 012 regimen' plus ZDV given to babies for 1 week after birth compared with the 'HIVNET 012 regimen' alone did not result in a statistically significant difference in HIV infection at 4 to 8 weeks.A single dose of NVP given to babies immediately after birth plus ZDV given to babies for 1 week after birth compared with a single dose of NVP given to babies only significantly reduced the HIV infection rate at 4 to 8 weeks (Efficacy 37.00%; 95% CI 3.68 to 70.32). Five trials in non-breastfeeding populations found that:In a population in which mothers were receiving 'standard' ARV for HIV infection a single dose of NVP given to mothers in labour plus a single dose of NVP given to babies immediately after birth ('HIVNET 012 regimen') compared with placebo did not result in a statistically significant difference in HIV infection rates at birth and at 4 to 8 weeks. The 'Thai CDC regimen' compared with the 'HIVNET 012 regimen' did not result in a significant difference in HIV infection at 4 to 8 weeks.A single dose of NVP given to babies immediately after birth compared to ZDV given to babies for the first 6 weeks of life did not result in a significant difference in HIV infection rates at 4-8 weeks and 3 to 4 months.ZDV plus 3TC given to mothers in labour and for a week after delivery and to their infants for a week after birth (similar to 'PETRA regimen B') compared with NVP given to mothers in labour and immediately after delivery plus a single dose of NVP to their babies immediately after birth (similar to 'HIVNET 012 regimen') did not result in a significant difference in the HIV infection rate at 4 to 8 weeks. (ABSTRACT TRUNCATED)

Determination of lysine pK values using [5-13C]lysine: application to the lyase domain of DNA Pol beta.

Determination of the protonation state of titratable protein residues is of critical importance for the interpretation of active site chemistry, as well as for understanding the role of electrostatic interactions in protein folding and stability. However, protein titration studies are limited by the fact that, at extreme pH values, increasing fractions of unfolded or partially unfolded structures may be present. This problem is particularly acute for lysine residues which have high pK values. In the present study, we point out that the use of the 13C resonance of lysine C-5 as a reporter for titration of the epsilon-amino group is preferable to the use of C-6 due to the 5-fold greater titration shift, so that reasonable results can be obtained using a two parameter fit of data obtained over a more limited pH range. A new synthetic procedure for [5-13C]lysine is described, and the pK value for Lys72 in the lyase domain of DNA polymerase beta has been determined using the [5-13C]lysine-labeled enzyme. The results agree well with recent studies of the Pol lambda lyase domain, demonstrating that the pK value for this residue is not optimized for Schiff base chemistry (Gao et al., Biochemistry 2006, 45, 1785-1794). We also have re-evaluated data for the pK of Lys73 in the TEM-1 beta-lactamase.

Stavudine, lamivudine and nevirapine combination therapy for treatment of HIV infection and AIDS in adults.

BACKGROUND: A favourable regimen for people infected with HIV/AIDS is one that provides optimal efficacy, durability of antiretroviral activity, tolerability, and has low adverse effects and drug-drug interactions. The combination of the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), and two nucleoside reverse transcriptase inhibitors, stavudine (d4T) and lamivudine (3TC), is widely used as first-line therapy, especially in low-resource countries. Analysis of the efficacy, durability and tolerability of the regimen is thus important to clinicians, consumers and policy-makers living in both rich and poor countries. OBJECTIVES: To examine the efficacy of the stavudine, lamivudine and nevirapine regimen for the treatment of HIV infection and AIDS in adults. SEARCH STRATEGY: We used the comprehensive search strategy developed specifically by the Cochrane HIV/AIDS Review Group to identify HIV/AIDS randomised controlled trials, and searched the following electronic databases: MEDLINE (searched July 2004); Embase (searched October 2004); and CENTRAL (July 2004). This search was supplemented with a search of AIDSearch (April 2005) to identify relevant conference abstracts, as well as searching reference lists of all eligible articles. The search was not limited by language or publication status. SELECTION CRITERIA: Randomised controlled trials of the stavudine, lamivudine and nevirapine regimen, compared with any other regimens for treating HIV/AIDS, in antiretroviral treatment-naive or antiretroviral treatment-experienced adults. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the methodological quality of the trials and extracted data. MAIN RESULTS: Our search resulted in 1,148 records, of which two studies described trials that met our inclusion criteria. One trial was a small single-centre Australian trial of 70 antiretroviral-naive participants, while the other trial was a large, multicentre trial, conducted in 14 countries, of 1,216 antiretroviral-naive participants. In both trials over 60% of participants were male. As the therapeutic combinations compared in both trials were not identical, it was not possible to conduct a meta-analysis to increase the power of the results. The main findings, therefore, are from the much larger trial, which was of a high quality. This trial found that there was no statistically significant difference in the efficacy (measured by treatment failure) between nevirapine and efavirenz (EFZ), when used in combination with 3TC and d4T (RR = 1.16; 95%CI: 0.95, 1.41). There was no statistically significant difference between once daily or twice-daily dosing of NVP, when used in combination with 3TC and d4T (RR = 1.00; 95%CI: 0.83; 1.21). It also showed that, compared with NVP plus EFZ, 3TC and d4T, a once-daily dosing of NVP, in combination with 3TC and d4T, performs better in averting treatment failure (RR = 0.82; 95%CI: 0.67, 1.00) than does twice-daily dosing of NVP with 3TC and d4T (RR = 0.82; 95%CI: 0.69; 0.97). Frequency of toxicity was higher in participants receiving NVP, compared with EFZ. AUTHORS' CONCLUSIONS: The combination of nevirapine, 3TC and d4T is as efficacious as a combination of efavirenz, 3TC and d4T. Once-daily NVP with twice-daily 3TC and d4T is as efficacious as twice-daily NVP, 3TC and d4T. However, toxicity may be increased in the once-daily NVP regime. Additional trials of sufficient duration are required to provide better evidence for the use of this combination as a first line therapy. Ideally, trials should use standardised assessment measures especially with respect to measuring viral load, so that results can be compared and combined in meta-analyses.

Micronutrient supplementation in children and adults with HIV infection.

BACKGROUND: The scale and impact of the HIV/AIDS pandemic has made the search for simple, affordable, safe, and effective public health interventions all the more urgent. Micronutrient supplements hold the promise of meeting these criteria, but their widespread use needs to be based on sound scientific evidence of effectiveness and safety. OBJECTIVES: To assess whether micronutrient supplements are effective in reducing morbidity and mortality in adults and children with HIV infection. SEARCH STRATEGY: The Cochrane Library (CENTRAL), EMBASE, MEDLINE, AIDSearch, CINAHL, and conference proceedings were searched, and pharmaceutical manufacturers and researchers in the field were contacted to locate any ongoing or unpublished trials. SELECTION CRITERIA: Randomised controlled trials comparing the effects of micronutrient supplements (vitamins, trace elements, and combinations of these) with placebo or no treatment on mortality and morbidity in HIV-infected individuals. DATA COLLECTION AND ANALYSIS: Two reviewers independently appraised trial quality and extracted data. Study authors were contacted for additional data where necessary. A meta-analysis was not deemed appropriate due to significant heterogeneity between trials. MAIN RESULTS: Fifteen trials were included. Six trials comparing vitamin A/beta-carotene with placebo in adults failed to show any effects on mortality, morbidity, CD4 and CD8 counts, or on viral load. Four trials of other micronutrients in adults did not affect overall mortality, although there was a reduction in mortality in a low CD4 subgroup. In a large Tanzanian trial in pregnant and lactating women, daily multivitamin supplementation was associated with a number of benefits to both mothers and children: a reduction in maternal mortality from AIDS-related causes; a reduced risk of progression to stage four disease; fewer adverse pregnancy outcomes; less diarrhoeal morbidity; and a reduction in early-child mortality among immunologically- and nutritionally-compromised women. Vitamin A alone reduced all-cause mortality and improved growth in a small sub-group of HIV-infected children in one hospital-based trial, and reduced diarrhoea-associated morbidity in a small HIV-infected sub-group of infants in another trial. AUTHORS' CONCLUSIONS: There is no conclusive evidence at present to show that micronutrient supplementation effectively reduces morbidity and mortality among HIV-infected adults. It is reasonable to support the current WHO recommendations to promote and support adequate dietary intake of micronutrients at RDA levels wherever possible. There is evidence of benefit of vitamin A supplementation in children. The long-term clinical benefits, adverse effects, and optimal formulation of micronutrient supplements require further investigation.

Treatment for methaqualone dependence in adults.

BACKGROUND: Methaqualone is a potent quinazoline, a class of sedative-hypnotics, that has a high potential for abuse. While the oral use of methaqualone (Quaalude, Mandrax) has waned in western countries since the mid-late 1980's, the practice of smoking methaqualone is a serious public health problem in South Africa, other parts of Africa and India. In the context of diminishing resources devoted to substance abuse treatment in regions affected by methaqualone abuse, it would be desirable to base treatment on the best evidence available. This review aimed to provide health care workers, policy-makers and consumers with the necessary information to make decisions regarding effective treatment of this highly dependence-producing drug. OBJECTIVES: To compare the effectiveness of any type of pharmacological or behavioural treatment administered in either an in-patient or out-patient setting compared with either a placebo or no treatment or a waiting list, or with another form of treatment administered in either an in- or out-patient setting. SEARCH STRATEGY: The authors searched the following databases: Cochrane Drugs and Alcohol Group'Register of Trials (February 2004); Cochrane Central Register of Controlled Trials (CENTRAL-The Cochrane Library, Issue 2, 2004); MEDLINE (OVID - January 1966 to february 2004), PsycInfo (OVID - January 1967 to february 2004). Relevant conference proceedings and reference lists of relevant articles were hand-searched. Broad internet searches were conducted and contact made with experts in the field. SELECTION CRITERIA: All randomised controlled trials and quasi-randomised trials of the effectiveness of treatment programmes (in- or out-patient) for methaqualone dependence and abuse were considered for inclusion in this review. DATA COLLECTION AND ANALYSIS: The authors independently assessed study eligibility and quality. MAIN RESULTS: No studies were found that met the inclusion criteria. AUTHORS' CONCLUSIONS: To date, no randomized controlled trials appear to have been conducted. Consequently, the effectiveness of inpatient versus outpatient treatment, psychosocial treatment versus no treatment, and pharmacological treatments versus placebo for methaqualone abuse or dependence has yet to be established.

HIV and male circumcision--a systematic review with assessment of the quality of studies.

This Cochrane systematic review assesses the evidence for an interventional effect of male circumcision in preventing acquisition of HIV-1 and HIV-2 by men through heterosexual intercourse. The review includes a comprehensive assessment of the quality of all 37 included observational studies. Studies in high-risk populations consisted of four cohort studies, 12 cross-sectional studies, and three case-control studies; general population studies consisted of one cohort study, 16 cross-sectional studies, and one case-control study. There is evidence of methodological heterogeneity between studies, and statistical heterogeneity was highly significant for both general population cross-sectional studies (chi(2)=132.34; degrees of freedom [df]=15; p<0.00001) and high-risk cross-sectional studies (chi(2)=29.70; df=10; p=0.001). Study quality was very variable and no studies measured the same set of potential confounding variables. Therefore, conducting a meta-analysis was inappropriate. Detailed quality assessment of observational studies can provide a useful visual aid to interpreting findings. Although most studies show an association between male circumcision and prevention of HIV, these results may be limited by confounding, which is unlikely to be adjusted for.

Male circumcision for prevention of heterosexual acquisition of HIV in men.

BACKGROUND: The findings from observational studies, reviews and meta-analyses, supported by biological theories, that circumcised men appear less likely to acquire human immunodeficiency virus (HIV) has contributed to the recent ground swell of support for considering male circumcision as a strategy for preventing sexually acquired infection. We sought to elucidate and appraise the global evidence from published and unpublished studies that circumcision can be used as an intervention to prevent HIV infection. OBJECTIVES: 1) To assess the evidence of an interventional effect of male circumcision for preventing acquisition of HIV-1 and HIV-2 by men through heterosexual intercourse 2) To examine the feasibility and value of performing individual person data (IPD) meta-analysis SEARCH STRATEGY: We searched online for published and unpublished studies in The Cochrane Library (issue 2, 2002), MEDLINE (April 2002), EMBASE (February 2002) and AIDSLINE (August 2001). We also searched databases listing conference abstracts, scanned reference lists of articles and contacted authors of included studies. SELECTION CRITERIA: We searched for randomized and quasi-randomized controlled trials of male circumcision or, in their absence, observational studies that compare acquisition rates of HIV-1 and HIV-2 infection in circumcised and uncircumcised heterosexual men. DATA COLLECTION AND ANALYSIS: Independent reviewers selected studies, assessed study quality and extracted data. We stratified studies based on study design and on whether they included participants from the general population or high-risk groups (such as patients treated for sexually transmitted infections). We expressed findings as crude and adjusted odds ratios (OR) together with their 95% confidence intervals (CI) and conducted a sensitivity analysis to explore the effect of adjustment on study results. We investigated whether the method of circumcision ascertainment influenced study outcomes. MAIN RESULTS: We identified no completed randomized controlled trials. Three randomized controlled trials are currently underway or commencing shortly. We found 34 observational studies: 16 conducted in the general population and 18 in high-risk populations. It seems unlikely that potential confounding factors were completely accounted for in any of the included studies. In particular, important risk factors, such as religion and sexual practices, were not adequately accounted for in many of the included studies. General population study results:The single cohort study (N = 5516) showed a significant difference in HIV transmission rates between circumcised and uncircumcised men [OR = 0.58; 95% CI: 0.36 to 0.96]. Results for the 14 cross-sectional studies were inconsistent, with point estimates for unadjusted odds ratios varying between 0.28 and 1.73. Six studies had statistically significant results, four in the direction of benefit and two in the direction of harm. The test for heterogeneity between the cross-sectional studies was highly significant (chi-square = 77.59; df = 13; P-value < 0.00001). Nine studies reported adjusted odds ratios with eight in the direction of benefit, ranging from 0.26 to 0.80. Use of adjusted results tended to show stronger evidence of an association although they remained heterogenous (chi-square = 75.2; df = 13; P-value < 0.00001). Only one case-control study was found (N = 51) which had a non-significant result [OR = 1.90; 95% CI: 0.50 to 7.20]. High-risk group study results:The four cohort studies identified found a protective effect from circumcision with point estimates for unadjusted odds ratios varying from 0.10 to 0.39. Two of these studies had statistically significant results. Two studies reported adjusted odds ratios, both protective with one being significant. The chi-square test for between-study heterogeneity was not significant (chi-square = 5.21; df = 3; P-value = 0.16). All eleven cross-sectional studies reporting unadjusted results found benefit from circumcision, eight of which had statistically significant results. Estimates of effnal studies reporting unadjusted results found benefit from circumcision, eight of which had statistically significant results. Estimates of effect varied from an unadjusted odds ratio of 0.10 to 0.66. Between-study heterogeneity was significant with the chi-square = 29.77; df = 10; P-value = 0.0009. Four of these studies reported adjusted odds ratios ranging from 0.20 to 0.59 and all were significant. One additional cross-sectional study only reported an adjusted odds ratio in the direction of benefit which was statistically significant. All three case-control studies found a protective effect of circumcision on HIV status, two being statistically significant. Point estimates varied from unadjusted odds ratios of 0.37 to 0.88. One reported an adjusted odds ratio showing a significant protective effect. Adverse effects:No studies reported on the adverse effects of circumcision. In most studies, circumcision had taken place during childhood or adolescence before the studies commenced. REVIEWER'S CONCLUSIONS: We found insufficient evidence to support an interventional effect of male circumcision on HIV acquisition in heterosexual men. The results from existing observational studies show a strong epidemiological association between male circumcision and prevention of HIV, especially among high-risk groups. However, observational studies are inherently limited by confounding which is unlikely to be fully adjusted for. In the light of forthcoming results from RCTs, the value of IPD analysis of the included studies is doubtful. The results of these trials will need to be carefully considered before circumcision is implemented as a public health intervention for prevention of sexually transmitted HIV.