The Cochrane 2018 Review on Brief Interventions in Primary Care for Hazardous and Harmful Alcohol Consumption: A Distillation for Clinicians and Policy Makers.

AIMS: An updated Cochrane systematic review assessed effectiveness of screening and brief intervention to reduce hazardous or harmful alcohol consumption in general practice or emergency care settings. This paper summarises the implications of the review for clinicians. METHODS: Cochrane methods were followed. Reporting accords with PRISMA guidance. We searched multiple resources to September 2017, seeking randomised controlled trials of brief interventions to reduce hazardous or harmful alcohol consumption in people attending general practice, emergency care or other primary care settings for reasons other than alcohol treatment. Brief intervention was defined as a conversation comprising five or fewer sessions of brief advice or brief lifestyle counselling and a total duration of less than 60 min. Our primary outcome was alcohol consumption, measured as or convertible to grams per week. We conducted meta-analyses to assess change in consumption, and subgroup analyses to explore the impact of participant and intervention characteristics. RESULTS: We included 69 studies, of which 42 were added for this update. Most studies (88%) compared brief intervention to control. The primary meta-analysis included 34 studies and provided moderate-quality evidence that brief intervention reduced consumption compared to control after one year (mean difference -20 g/wk, 95% confidence interval -28 to -12). Subgroup analysis showed a similar effect for men and women. CONCLUSIONS: Brief interventions can reduce harmful and hazardous alcohol consumption in men and women. Short, advice-based interventions may be as effective as extended, counselling-based interventions for patients with harmful levels of alcohol use who are presenting for the first time in a primary care setting.

Systems Pharmacology Approach Toward the Design of Inhaled Formulations of Rifampicin and Isoniazid for Treatment of Tuberculosis.

Conventional oral therapies for the treatment of tuberculosis are limited by poor antibiotic distribution in granulomas, which contributes to lengthy treatment regimens and inadequate bacterial sterilization. Inhaled formulations are a promising strategy to increase antibiotic efficacy and reduce dose frequency. We develop a multiscale computational approach that accounts for simultaneous dynamics of a lung granuloma, carrier release kinetics, pharmacokinetics, and pharmacodynamics. Using this computational platform, we predict that a rationally designed inhaled formulation of isoniazid given at a significantly reduced dose frequency has better sterilizing capabilities and reduced toxicity than the current oral regimen. Furthermore, we predict that inhaled formulations of rifampicin require unrealistic carrier antibiotic loadings that lead to early toxicity concerns. Lastly, we predict that targeting carriers to macrophages has limited effects on treatment efficacy. Our platform can be extended to account for additional antibiotics and provides a new tool for rapidly prototyping the efficacy of inhaled formulations.

A state-time epidemiology model of tuberculosis: importance of re-infection.

An epidemiological model is presented that considers five possible states of a population: susceptible (S), exposed (W), infectious (Y), in treatment (Z) and recovered (R). In certain instances transition rates (from one state to another) depend on the time spent in the state; therefore the states W, Y and Z depend on time and length of stay in that state - similar to age-structured models. The model is particularly amenable to describe delays of exposed persons to become infectious and re-infection of exposed persons. Other transitions that depend on state time include the case finding and diagnosis, increased death rate and treatment interruption. The mathematical model comprises of a set of partial differential and ordinary differential equations. Non-steady state solutions are first presented, followed by a bifurcation study of the stationary states.

A Kinetic Study of In Vitro Lysis of Mycobacterium smegmatis.

The traditional diagnostic tests for tuberculosis consist of an acid fast stain and a culture test from a sputum sample. With the emergence of drug resistant strains of tuberculosis, nucleic acid amplification has become the diagnostic test of choice. The nucleic acid amplification test consists of four steps: sputum sample collection, lysis of bacilli to release DNA, DNA amplification by PCR and detection of PCR products. The DNA extraction step has been largely overlooked and this study describes a systematic approach to measure the kinetics of cell lysis in a Tris-EDTA buffer. Mycobacterium smegmatis is a saphorytic, fast-growing mycobacterium that is often used as a surrogate of Mycobacterium tuberculosis in laboratory studies. M. smegmatis cells have been transformed with green fluorescent protein (GFP) genes. Transformed cells are lysed in a temperature-controlled cuvette that is equipped with optical input/output. The fluorescence signal increases when the GFP is released from lysed cells, and the extent of lysis of the loaded cells can be followed in real time. The experimental results are complemented by two theoretical models. The first model is based on a Monte Carlo simulation of the lysis process and the accompanying probability density function as described by the Fokker-Planck equation. The second model follows a chemical reaction engineering approach: the cell wall is modeled as layers, where each layer is made up of 'blocks'. Blocks can only be removed if they are exposed to the lysis solution and the model describes the rate of block exposure and removal. Both models are consistent with the experimental results. The main findings are: (1) the activation energy for M. smegmatis lysis by Tris-EDTA buffer is 22.1kcal/mole, (2) cells lyse on the average after 14-17% loss in cell wall thickness locally, (3) with the help of the models, the initial distribution in cell wall thickness of the population can be resolved, (4) near complete lysis of the cells is accomplished in 200 seconds at 80°C (90 seconds at 90°C). The results can be used to design an optimal lysis protocol that compromises between shorter processing times at higher temperature and reduced thermal damage to DNA at lower temperature.

A fundamental study of the PCR amplification of GC-rich DNA templates.

A theoretical analysis is presented with experimental confirmation to conclusively demonstrate the critical role that annealing plays in efficient PCR amplification of GC-rich templates. The analysis is focused on the annealing of primers at alternative binding sites (competitive annealing) and the main result is a quantitative expression of the efficiency (eta) of annealing as a function of temperature (T(A)), annealing period (t(A)), and template composition. The optimal efficiency lies in a narrow region of T(A) and t(A) for GC-rich templates and a much broader region for normal GC templates. To confirm the theoretical findings, the following genes have been PCR amplified from human cDNA template: ARX and HBB (with 78.72% and 52.99% GC, respectively). Theoretical results are in excellent agreement with the experimental findings. Optimum annealing times for GC-rich genes lie in the range of 3-6s and depend on annealing temperature. Annealing times greater than 10s yield smeared PCR amplified products. The non-GC-rich gene did not exhibit this sensitivity to annealing times. Theory and experimental results show that shorter annealing times are not only sufficient but can actually aid in more efficient PCR amplification of GC-rich templates.

Effectiveness of brief alcohol interventions in primary care populations.

BACKGROUND: Many trials reported that brief interventions are effective in reducing excessive drinking. However, some trials have been criticised for being clinically unrepresentative and unable to inform clinical practice. OBJECTIVES: To assess the effectiveness of brief intervention, delivered in general practice or based primary care, to reduce alcohol consumption SEARCH STRATEGY: We searched the Cochrane Drug and Alcohol Group specialised register (February 2006), MEDLINE (1966 to February 2006), EMBASE (1980 to February 2006), CINAHL (1982 to February 2006), PsycINFO (1840 to February 2006), Science Citation Index (1970 to February 2006), Social Science Citation Index (1970 to February 2006), Alcohol and Alcohol Problems Science Database (1972 to 2003), reference lists of articles. SELECTION CRITERIA: Randomised controlled trials, patients presenting to primary care not specifically for alcohol treatment; brief intervention of up to four sessions. DATA COLLECTION AND ANALYSIS: Two authors independently abstracted data and assessed trial quality. Random effects meta-analyses, sub-group, sensitivity analyses, and meta-regression were conducted. MAIN RESULTS: The meta-analysis included 21 RCTs (7,286 participants), showing that participants receiving brief intervention reduced their alcohol consumption compared to the control group (mean difference: -41 grams/week, 95% CI: -57 to -25), although there was substantial heterogeneity between trials (I2 = 52%). Sub-group analysis (8 studies, 2307 participants) confirmed the benefit of brief intervention in men (mean difference: -57 grams/week, 95% CI: -89 to -25, I2 = 56%), but not in women (mean difference: -10 grams/week, 95% CI: -48 to 29, I2 = 45%). Meta-regression showed a non-significant trend of an increased reduction in alcohol consumption of 1.1, 95%CI: -0.05 to 2.2 grams/week, p=0.06, for each extra minute of treatment exposure, but no relationship between the reduction in alcohol consumption and the efficacy score of the trial. Extended intervention when compared with brief intervention was associated with a non-significantly greater reduction in alcohol consumption (mean difference = -28, 95%CI: -62 to 6 grams/week, I2 = 0%) AUTHORS' CONCLUSIONS: Brief interventions consistently produced reductions in alcohol consumption. When data were available by gender, the effect was clear in men at one year of follow up, but unproven in women. Longer duration of counselling probably has little additional effect. The lack of differences in outcomes between efficacy and effectiveness trials suggests that the current literature had clear relevance to routine primary care. Future trials should focus on women and on delineating the most effective components of interventions.

Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children.

BACKGROUND: Oral candidiasis (OC) associated with human immunodeficiency virus (HIV) infection occurs commonly and recurs frequently, often presenting as an initial manifestation of the disease. Left untreated these lesions contribute considerably to the morbidity associated with HIV infection. Interventions aimed at preventing and treating HIV-associated oral candidal lesions form an integral component of maintaining the quality of life for affected individuals. OBJECTIVES: To determine the effects of any intervention in preventing or treating OC in children and adults with HIV infection. SEARCH STRATEGY: The search strategy was based on that of the HIV/AIDS Cochrane Review Group. The following electronic databases were searched for randomised controlled trials for the years 1982 to 2005: Medline; AIDSearch; EMBASE and CINAHL. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Central Register of Controlled Trials (CENTRAL) was also searched through May 2005. The abstracts of relevant conferences, including the International Conferences on AIDS and the Conference on Retroviruses and Opportunistic Infections, as indexed by AIDSLINE, were also reviewed. The strategy was iterative, in that references of included studies were searched for additional references. All languages were included. SELECTION CRITERIA: Randomised controlled trials (RCTs) of palliative, preventative or curative therapy were considered, irrespective of whether the control group received a placebo. Participants were HIV positive adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the methodological quality of the trials and extracted data. Study authors were contacted for additional data where necessary. MAIN RESULTS: Four trials were conducted in developing countries with eleven of the trials conducted in the United States of America. Twenty eight trials (n=3225) were included. Nineteen trials investigated treatment and nine trials the prevention of OC. One trial, comparing fluconazole and ketoconazole, investigated the treatment of OC in children. Eighteen of the included studies reported CD4 cell counts. None of the included studies investigated the effects of HAART or any other form of antiretroviral treatment on OC treatment or prevention.TreatmentTreatment was assessed in the majority of trials looking at both clinical and mycological cures. In the majority of comparisons there was only one trial. Compared to nystatin, fluconazole favoured clinical cure in adults(1 RCT; n=167; RR 1.69; 95% CI 1.27 to 2.23). There was no difference with regard to clinical cure between fluconazole compared to ketoconazole (2 RCTs; n=83; RR 1.27; 95% CI 0.97 to 1.66), itraconazole (2 RCTs; n=434; RR 1.05; 95% CI 0.94 to 1.16) or clotrimazole (2 RCTs; n=358; RR 1.14; 95% CI 0.92 to 1.42). When compared with clotrimazole, both fluconazole (2 RCTs; n=358; RR 1.47; 95% CI 1.16 to 1.87) and itraconazole (1 RCT; n=123; RR 2.20; 95% CI 1.43 to3.39) proved to be better for mycological cure. Both gentian violet (1 RCT; n=96; RR 5.28; 95% CI 1.23 to 22.55) and ketoconazole (1 RCT; n=92; RR 5.22; 95% CI 1.21 to 22.53) were superior to nystatin in bringing about clinical cure. PreventionSuccessful prevention was defined as the prevention of a relapse while receiving prophylaxis. Fluconazole was compared with placebo in one trial (5 RCTs; n=599; RR 0.61; 95% CI 0.5 to 0.74) and with no treatment in another (1 RCT; n=65; RR 0.16; 95% CI 0.08 to 0.34). In both instances the prevention of clinical episodes was favoured by fluconazole. Comparing continuous fluconazole treatment with intermittent treatment (1 RCT; n=62; RR 0.37; 95% CI 0.15 to 0.92), prevention is favoured by the continuous treatment. AUTHORS' CONCLUSIONS: Implications for practiceDue to only one study in children it is not possible to make recommendations for treatment or prevention of OC in children. Amongst adults, there were few studies per comparison. Due to insufficient evidence no conclusion could be made about the effectiveness of clotrimazole, nystatin, amphotericin B, itraconazole or ketoconazole with regard to OC prophylaxis. In comparison to placebo, fluconazole is an effective preventative intervention. However, the potential for resistant Candida organisms to develop, as well as the cost of prophylaxis, might impact the feasibility of implementation. No studies were found comparing fluconazole with other interventions. Direction of findings suggests that ketoconazole, fluconazole, itraconazole and clotrimazole improved the treatment outcomes. Implications for researchThere is an urgent need for gentian violet and other less expensive anti-fungal drugs for OC treatment to be evaluated in larger studies. More well designed treatment trials with larger sample size are needed to allow for sufficient power to detect differences in not only clinical, but also mycological response and relapse rates. There is also a strong need for more research to be done on the treatment and prevention of OC in children as it is reported that OC is the most frequent fungal infection in children and adolescents who are HIV positive. More research on the effectiveness of less expensive interventions also needs to be done in resource-poor settings. Currently few trials report outcomes related to quality of life, nutrition, or survival. Future researchers should consider measuring these when planning trials. Development of resistance remains under-studied and more work must be done in this area. It is recommended that trials be more standardised and conform more closely to CONSORT as this will improve research and also clinical practice.

A quantitative model of error accumulation during PCR amplification.

The amplification of target DNA by the polymerase chain reaction (PCR) produces copies which may contain errors. Two sources of errors are associated with the PCR process: (1) editing errors that occur during DNA polymerase-catalyzed enzymatic copying and (2) errors due to DNA thermal damage. In this study a quantitative model of error frequencies is proposed and the role of reaction conditions is investigated. The errors which are ascribed to the polymerase depend on the efficiency of its editing function as well as the reaction conditions; specifically the temperature and the dNTP pool composition. Thermally induced errors stem mostly from three sources: A+G depurination, oxidative damage of guanine to 8-oxoG and cytosine deamination to uracil. The post-PCR modifications of sequences are primarily due to exposure of nucleic acids to elevated temperatures, especially if the DNA is in a single-stranded form. The proposed quantitative model predicts the accumulation of errors over the course of a PCR cycle. Thermal damage contributes significantly to the total errors; therefore consideration must be given to thermal management of the PCR process.

Randomised trials in the South African Medical Journal, 1948-1997.

OBJECTIVE: To describe randomised controlled trials (RCTs) published in the South African Medical Journal (SAMJ) over a 50-year period from 1948 to 1997 with regard to number, topic and quality. METHODS: We hand searched all issues of the SAMJ published during the study period to identify all published RCTs. OUTCOME MEASURES: Number, topic and quality of RCTs published from 1948 to 1997. RESULTS: Eight hundred and fifty-eight clinical trials were published during the period reviewed. Eighty-four per cent of RCTs were published as full articles. During the 1980s the number of RCTs published increased rapidly, with a peak of 35 in 1985, but then declined to only 5 in 1997. The majority (92%) of RCTs were conducted in a hospital setting. A varied range of subjects was covered, with gastroenterology taking the lead and no trials in public health. The sample size in more than 50% of RCTs was smaller than 50 patients. Fifty-one per cent (435 trials) used random allocation and 49% (423) quasi-random methods of allocation. Concealment of treatment allocation was judged to be adequate in 46% of studies (N = 200), blinding of observers assessing outcomes was adequate in 28% (123), and all the allocated test subjects were included in the primary analysis in 28% (123). The follow-up period was more than 1 year in 4% (17) and less than 6 days in 16% (71). CONCLUSIONS: Compared with other international journals the SAMJ is highly regarded in terms of the number of trials published. There are, however, a number of deficiencies in the quality of the trials.

Multicenter study on reproducibility of sperm morphology assessments.

Sperm morphology has always been considered an important tool in evaluating a man's fertilizing potential. The objective of this multicentric study was to evaluate intra- and interindividual variability and between-laboratory variation using the same or different criteria of sperm morphology assessment. Semen samples were obtained from 20 males and 32 smears were made of all samples. Eighty coded smears (4 per patient) were sent to 8 laboratories for morphology assessment. The centers applied different classification systems (strict criteria, WHO 1987, Düsseldorf criteria) and participants were asked to analyze the 80 smears twice, with an interval of 1 week between each participant's two analyses. Intraclass correlations between repeats showed that sperm morphology can be assessed with acceptable within observer reproducibility. Expected increases in imprecision were observed up to coefficients of variation of >30% with decreasing morphology scores, regardless of the classification system used. Agreement in correct classification of samples as normal/abnormal was obtained in 80% of cases. Differences in reproducibility between slides may reflect an important source of heterogeneity due to smear preparation. These results emphasize the importance of external quality control systems to improve the value of sperm morphology assessments in the investigation of the male partner in a subfertile couple.

Semen quality and fertility of men employed in a South African lead acid battery plant.

Previous studies of the associations of measures of occupational lead exposure with measures of semen quality and infertility among male workers have produced conflicting results. The current study was undertaken to examine these associations among a population of workers with a broad range of measures of current and historical lead exposure. Ninety-seven lead-exposed workers from a South African lead acid battery facility provided semen samples that were analyzed for sperm density, sperm count, sperm motility, sperm morphology, and presence of antisperm antibodies. Questionnaire data were collected for reported histories of sub- or infertility. Current blood leads ranged from 28 to 93 micrograms/dl. Semen lead ranged from 1 to 87 micrograms/dl. Reasonably consistent and significant associations were found between an increased percentage of sperm with abnormal morphology and higher measures of current blood lead, cumulative blood lead, and duration of exposure. An increased percent of immotile sperm was associated only with zinc protoporphyrin (ZPP) among the lead exposure measures. There were no associations of sperm density or sperm count with any of the lead exposure measures. A weak association of increased percent of sperm with antisperm antibodies with increased semen lead was present. There were no consistent associations of measures of lead exposure with measures of fertility or procreativity. This study, while supporting the association of lead exposure with increased risk of abnormal sperm morphology seen in some previous studies, does not lend support to previously reported associations of sperm density or count or infertility with measures of lead exposure. However, the relatively high range of current blood leads, high prevalence of abnormalities in semen quality, and the lack of a control population, suggest that these negative findings should be interpreted with caution.

The availability of health information in South Africa.

The South African Medical Research Council (MRC) has provided access to on-line health and biomedical information since 1976, when the MRC became an international partner of NLM. This was done to support research and health care when the Institute of Biomedical Communication was established. The institute has since reorganized and is now the Information Systems Division in the Research Systems Support Group MRC. he MRC and medical libraries in South Africa are able to access various automated services via telecommunication. The major systems available are MEDLARS, DIALOG, DATASTAR and BRS, with ECRI being the latest addition; most used are MEDLARS and DIALOG. New technologies (e.g., CD-ROM) have given more people access. This technology is not available to many people working in Primary Health Care (PHC), as they do not have access to computer networks. Beyond on-line is statistical and printed information, called "Gray Literature," not accessible through on-line systems as it is not published in conventional sources used to build databases. With a shift to Essential National Health Research and the focus on PHC and preventative medicine, demand for health information and "gray literature" is growing. The MRC collects and produces this material and has its own database called SAMED, which is to be made available to others as our contribution to health. It is hoped to make this available for inclusion in the proposed African Index Medicus presently investigated by the World Health Organization. Africa as a continent, and South Africa as a country, are experiencing major changes in health care and medical practice, and inevitably, provision of health information services. With South Africa's re-entry into the global village and its acceptance by the rest of Africa, it can be a key player in information provision to the rest of the continent. The MRC, as a major provider of Health information, can play a vital role in the information flow throughout Africa by continuously improving and expanding its services. A large proportion of South Africans live in rural areas where health care is provided by clinics not linked to information networks. This does not mean these clinics are excluded from the use of information. The major challenge is to find the ways and means of getting the relevant information to these clinics. Information is needed to help with patient care and continuing education. With this in mind, the MRC is evaluating different formats in which information can be supplied. Due to the lack of computer literacy, facilities, and financial constraints, it is better to supply printed information. With the spread of technology through the country and continent, it can be assumed that information flow and transfer will be more rapid. Repackaging of information means that it is possible to get the relevant information to the right people at the right time. The first such package developed is for hospital managers. With the help from experts in the field of PHC, it is hoped to develop packages aimed specifically at the CHWs and other workers in the field. All packages developed by the MRC are backed by a document provision service, using the most cost-effective route to obtain documents. A printed product must comply with certain criteria; these are: 1) purpose for which the information is needed; 2) kind of information needed and the format in which it is needed; 3) when the information is needed; 4) is the information to be supplied on an ongoing basis i.e., updated with latest information; 5) cost involved; and 6) how to get the information to the relevant user.