Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection.

Salmonella Typhi activates the host DNA damage response through the typhoid toxin, facilitating typhoid symptoms and chronic infections. Here we reveal a non-canonical DNA damage response, which we call RING (response induced by a genotoxin), characterized by accumulation of phosphorylated histone H2AX (γH2AX) at the nuclear periphery. RING is the result of persistent DNA damage mediated by toxin nuclease activity and is characterized by hyperphosphorylation of RPA, a sensor of single-stranded DNA (ssDNA) and DNA replication stress. The toxin overloads the RPA pathway with ssDNA substrate, causing RPA exhaustion and senescence. Senescence is also induced by canonical γΗ2ΑΧ foci revealing distinct mechanisms. Senescence is transmitted to non-intoxicated bystander cells by an unidentified senescence-associated secreted factor that enhances Salmonella infections. Thus, our work uncovers a mechanism by which genotoxic Salmonella exhausts the RPA response by inducing ssDNA formation, driving host cell senescence and facilitating infection

RevManHAL: towards automatic text generation in systematic reviews

Background: Systematic reviews are a key part of healthcare evaluation. They involve important painstaking but repetitive work. A major producer of systematic reviews, the Cochrane Collaboration, employs Review Manager (RevMan) programme—a software which assists reviewers and produces XML-structured files. This paper describes an add-on programme (RevManHAL) which helps auto-generate the abstract, results and discussion sections of RevMan-generated reviews in multiple languages. The paper also describes future developments for RevManHAL. Methods: RevManHAL was created in Java using NetBeans by a programmer working full time for 2 months. Results: The resulting open-source programme uses editable phrase banks to envelop text/numbers from within the prepared RevMan file in formatted readable text of a chosen language. In this way, considerable parts of the review’s ‘abstract’, ‘results’ and ‘discussion’ sections are created and a phrase added to ‘acknowledgements’. Conclusion: RevManHAL’s output needs to be checked by reviewers, but already, from our experience within the Cochrane Schizophrenia Group (200 maintained reviews, 900 reviewers), RevManHAL has saved much time which is better employed thinking about the meaning of the data rather than restating them. Many more functions will become possible as review writing becomes increasingly automated

Storage of lyophilized cultures of Lactobacillus bulgaricus under different relative humidities and atmospheres

The viability of lyophilized cultures of Lactobacillus bulgaricus in skim milk, during storage at different temperatures, relative humidities, and atmospheres was investigated. Survival was greatest at 11% relative humidity and at 5°C. Indirect and direct evidence is presented supporting the hypothesis that membrane damage occurs during storage. Experiments on the lipid composition of the cell membrane demonstrate that changes occur with time that are probably the result of oxidation. A study on the lipid composition of the cell membrane by gas chromatography showed that the unsaturated/saturated fatty acid index changes with time during storage

Comparative 3D QSAR study on β1-, β2-, and β3-adrenoceptor agonists

A quantitative structure–activity relationship study of tryptamine-based derivatives of β1-, β2-, and β3-adrenoceptor agonists was conducted using comparative molecular field analysis (CoMFA). Correlation coefficients (cross-validated r2) of 0.578, 0.595, and 0.558 were obtained for the three subtypes, respectively, in three different CoMFA models. All three CoMFA models have different steric and electrostatic contributions, implying different requirements inside the binding cavity. The CoMFA coefficient contour plots of the three models and comparisons among these plots provide clues regarding the main chemical features responsible for the biological activity variations and also result in predictions which correlate very well with the observed biological activity. Based on the analysis, a summary regeospecific description of the requirements for improving β-adrenoceptor subtype selectivity is given

A critical analysis of Child and Adolescent Mental Health Services policy in England

Policy in Child and Adolescent Mental Health (CAMH) in England has undergone radical changes in the last 15 years, with far reaching implications for funding models, access to services and service delivery. Using corpus analysis and critical discourse analysis, we explore how childhood, mental health, and CAMHS are constituted in 15 policy documents, 9 pre-2010, and 6 post 2010. We trace how these constructions have changed over time, and consider the practice implications of these changes. We identify how children’s distress is individualised, through medicalising discourses and shifting understandings of the relationship between socioeconomic context and mental health. This is evidenced in a shift from seeing children’s mental health challenges as produced by social and economic inequities, to a view that children’s mental health must be addressed early to prevent future socio-economic burden. We consider the implications CAMHS policies for the relationship between children, families, mental health services and the state. The paper concludes by exploring how concepts of ‘parity of esteem’ and ‘stigma reduction’ may inadvertently exacerbate the individualisation of children’s mental health

Minimal Intervention Needed for Change: Definition, Use, and Value for Improving Health and Health Research

Much research focuses on producing maximal intervention effects. This has generally not resulted in interventions being rapidly or widely adopted or seen as feasible given resources, time, and expertise constraints in the majority of real-world settings. We present a definition and key characteristics of a minimum intervention needed to produce change (MINC). To illustrate use of a MINC condition, we describe a computer-assisted, interactive minimal intervention, titled Healthy Habits, used in three different controlled studies and its effects. This minimal intervention produced modest to sizable health behavior and psychosocial improvements, depending on the intensity of personal contacts, producing larger effects at longer-term assessments. MINC comparison conditions could help to advance both health care and health research, especially comparative effectiveness research. Policy and funding implications of requiring an intervention to be demonstrated more effective than a simpler, less costly MINC alternative are discussedYe

Collaborative research between clinicians and researchers: a multiple case study of implementation

<p>Abstract</p> <p>Background</p> <p>Bottom-up, clinician-conceived and directed clinical intervention research, coupled with collaboration from researcher experts, is conceptually endorsed by the participatory research movement. This report presents the findings of an evaluation of a program in the Veterans Health Administration meant to encourage clinician-driven research by providing resources believed to be critical. The evaluation focused on the extent to which funded projects: maintained integrity to their original proposals; were methodologically rigorous; were characterized by collaboration between partners; and resulted in sustained clinical impact.</p> <p>Methods</p> <p>Researchers used quantitative (survey and archival) and qualitative (focus group) data to evaluate the implementation, evaluation, and sustainability of four clinical demonstration projects at four sites. Fourteen research center mentors and seventeen clinician researchers evaluated the level of collaboration using a six-dimensional model of participatory research.</p> <p>Results</p> <p>Results yielded mixed findings. Qualitative and quantitative data suggested that although the process was collaborative, clinicians' prior research experience was critical to the quality of the projects. Several challenges were common across sites, including subject recruitment, administrative support and logistics, and subsequent dissemination. Only one intervention achieved lasting clinical effect beyond the active project period. Qualitative analyses identified barriers and facilitators and suggested areas to improve sustainability.</p> <p>Conclusions</p> <p>Evaluation results suggest that this participatory research venture was successful in achieving clinician-directed collaboration, but did not produce sustainable interventions due to such implementation problems as lack of resources and administrative support.</p

Long-term declines in ADLs, IADLs, and mobility among older Medicare beneficiaries

<p>Abstract</p> <p>Background</p> <p>Most prior studies have focused on short-term (≤ 2 years) functional declines. But those studies cannot address aging effects inasmuch as all participants have aged the same amount. Therefore, the authors studied the extent of long-term functional decline in older Medicare beneficiaries who were followed for varying time lengths, and the authors also identified the risk factors associated with those declines.</p> <p>Methods</p> <p>The analytic sample included 5,871 self- or proxy-respondents who had complete baseline and follow-up survey data that could be linked to their Medicare claims for 1993-2007. Functional status was assessed using activities of daily living (ADLs), instrumental ADLs (IADLs), and mobility limitations, with declines defined as the development of two of more new difficulties. Multiple logistic regression analysis was used to focus on the associations involving respondent status, health lifestyle, continuity of care, managed care status, health shocks, and terminal drop.</p> <p>Results</p> <p>The average amount of time between the first and final interviews was 8.0 years. Declines were observed for 36.6% on ADL abilities, 32.3% on IADL abilities, and 30.9% on mobility abilities. Functional decline was more likely to occur when proxy-reports were used, and the effects of baseline function on decline were reduced when proxy-reports were used. Engaging in vigorous physical activity consistently and substantially protected against functional decline, whereas obesity, cigarette smoking, and alcohol consumption were only associated with mobility declines. Post-baseline hospitalizations were the most robust predictors of functional decline, exhibiting a dose-response effect such that the greater the average annual number of hospital episodes, the greater the likelihood of functional status decline. Participants whose final interview preceded their death by one year or less had substantially greater odds of functional status decline.</p> <p>Conclusions</p> <p>Both the additive and interactive (with functional status) effects of respondent status should be taken into consideration whenever proxy-reports are used. Encouraging exercise could broadly reduce the risk of functional decline across all three outcomes, although interventions encouraging weight reduction and smoking cessation would only affect mobility declines. Reducing hospitalization and re-hospitalization rates could also broadly reduce the risk of functional decline across all three outcomes.</p

Regional disparities in infant mortality in Canada: a reversal of egalitarian trends

<p>Abstract</p> <p>Background</p> <p>Although national health insurance plans and social programs introduced in the 1960s led to reductions in regional disparities in infant mortality in Canada, it is unclear if such patterns prevailed in the 1990s when the health care and related systems were under fiscal duress. This study examined regional patterns of change in infant mortality in Canada in recent decades.</p> <p>Methods</p> <p>We analysed regional changes in crude infant mortality rates and in infant mortality rates among live births with a birth weight ≥ 500 g and ≥ 1,000 g in Canada from 1945 to 2002. Associations between baseline infant mortality rates in the provinces and territories (e.g., in 1985–89) and the change observed in infant mortality rates over the subsequent period (e.g., between 1985–89 and 1995–99) were assessed using Spearman's rank correlation coefficient. Trends in regional disparities were also assessed by calculating period-specific rate ratios between provinces/territories with the highest versus the lowest infant mortality.</p> <p>Results</p> <p>Provincial/territorial infant mortality rates in 1945–49 were not correlated with changes in infant mortality over the next 10 years (rho = 0.01, P = 0.99). However, there was a strong negative correlation between infant mortality rates in 1965–69 and the subsequent decline in infant mortality (rho = - 0.85, P = 0.002). Provinces/territories with higher infant mortality rates in 1965–69 (Northwest Territories 64.7 vs British Columbia 20.7 per 1,000 live births) experienced relatively larger reductions in infant mortality between 1965–69 and 1975–79 (53.7% decline in the Northwest Territories vs a 36.6% decline in British Columbia). This pattern was reversed in the more recent decades. Provinces/territories with higher infant mortality rates ≥ 500 g in 1985–89 experience relatively smaller reductions in infant mortality between 1985–89 and 2000–02 (rho = 0.82, P = 0.004). The infant mortality ≥ 500 g rate ratio (contrasting the province/territory with the highest versus lowest infant mortality) was 3.2 in 1965–69, 2.4 in 1975–79, 2.2 in 1985–89, 3.1 in 1995–99 and 4.1 in 2000–02.</p> <p>Conclusion</p> <p>Fiscal constraints in the 1990s led to a reversal of provincial/territorial patterns of change in infant mortality in Canada and to an increase in regional health disparities.</p

Individualizing therapy – in search of approaches to maximize the benefit of drug treatment (II)

Adjusting drug therapy to the individual, a common approach in clinical practice, has evolved from 1) dose adjustments based on clinical effects to 2) dose adjustments made in response to drug levels and, more recently, to 3) dose adjustments based on deoxyribonucleic acid (DNA) sequencing of drug-metabolizing enzyme genes, suggesting a slow drug metabolism phenotype. This development dates back to the middle of the 20(th )century, when several different drugs were administered on the basis of individual plasma concentration measurements. Genetic control of drug metabolism was well established by the 1960s, and pharmakokinetic-based individualized therapy was in use by 1973