The crystal structure of Pneumolysin at 2.0 Å resolution reveals the molecular packing of the pre-pore complex

Pneumolysin is a cholesterol-dependent cytolysin (CDC) and virulence factor of Streptococcus pneumoniae. It kills cells by forming pores assembled from oligomeric rings in cholesterol-containing membranes. Cryo-EM has revealed the structures of the membrane-surface bound pre-pore and inserted-pore oligomers, however the molecular contacts that mediate these oligomers are unknown because high-resolution information is not available. Here we have determined the crystal structure of full-length pneumolysin at 1.98 Å resolution. In the structure, crystal contacts demonstrate the likely interactions that enable polymerisation on the cell membrane and the molecular packing of the pre-pore complex. The hemolytic activity is abrogated in mutants that disrupt these intermolecular contacts, highlighting their importance during pore formation. An additional crystal structure of the membrane-binding domain alone suggests that changes in the conformation of a tryptophan rich-loop at the base of the toxin promote monomer-monomer interactions upon membrane binding by creating new contacts. Notably, residues at the interface are conserved in other members of the CDC family, suggesting a common mechanism for pore and pre-pore assembly

Videos of sipuleucel-T programmed T cells lysing cells that express prostate cancer target antigens

Sipuleucel-T, an autologous cellular immunotherapy, was approved to treat metastatic castration-resistant prostate cancer in 2010 in the United States. Treatment with sipuleucel-T primes the immune system to target prostate acid phosphatase, which is expressed by prostate cancer cells, potentially leading to lysis of cancer cells. Expanding on previously reported indirect evidence of cell killing with sipuleucel-T treatment, we sought to provide direct evidence of cell lysis through visualization. We used advanced video technology and available samples of peripheral blood mononuclear cells from subjects enrolled in the STAMP trial (NCT01487863). Isolated CD8+ T cells were used as effector cells and cocultured with autologous monocytes pulsed with control or target antigens. Differentially stained effector and target cells were then video recorded during coculture. Here, we present video recordings and analyses of T cells from sipuleucel-T-treated subjects showing-for the first time-direct lysis of cells that express prostate cancer target antigens, prostate acid phosphatase, or prostate-specific antigen

Predictors of long-term function in older community-dwelling people who have presented to an emergency department after a fall: A cohort study

Aim: To identify factors predictive of function 12 months after a fall and emergency department (ED) presentation. Methods: This was a prospective cohort study with 608 older people who had a fall. After presentation and discharge from the ED, a baseline assessment was initially undertaken and then repeated after 12 months. The Human Activity Profile Adjusted Activity Score (HAP-AAS) at the 12-month follow-up assessment was the functional outcome measure. Results: Over the follow-up period, 37.3% (95% CI 33.4, 41.2) of participants declined in their HAP-AAS score. Increased age, pre-index fall functional impairment, poorer mobility/balance, and sustaining falls and severe injuries over the 12-month follow-up period were some of the factors predictive of a lower HAP-AAS score. Conclusion: This study highlights the importance of preventing falls in the 12 months after discharge from an ED. Some of the factors identified as being predictive of lower function are the same as those previously found to be predictive of falls

Building the Field of Health Policy and Systems Research: Social Science Matters

In the second in a series of articles addressing the current challenges and opportunities for the development of Health Policy and Systems Research (HPSR), Lucy Gilson and colleagues argue the importance of insights from the social sciences

Knowledge, attitudes and practices of healthcare professionals toward the novel coronavirus during the early stage of COVID-19 in a lower-and-middle income country, Bangladesh

Healthcare workers (HCWs) are at an increased risk of COVID-19 infection because of their direct exposure to suspected and confirmed coronavirus patients in healthcare facilities. This condition is even more acute in low-and lower-middle-income countries (LMICs). Given the poor healthcare settings of Bangladesh, it is challenging to halt the spread of infection without proper knowledge, attitudes, and good behavioral practices (KAPs). Therefore, this study conducted a cross-sectional study from May 5 to 31, 2020, with 203 healthcare professionals to determine the knowledge, attitudes, and practices (KAP) toward COVID-19. Participants were doctors, nurses, dentists, and allied health professionals. A self-administered questionnaire including several KAP-related items aligned with the World Health Organization (WHO) guidelines was distributed over various online platforms to collect data. Bivariate and multivariable logistic regression analyses were conducted to determine the factors influencing KAP levels. The majority of participants were male (52.22%). The prevalence of high knowledge levels, positive attitudes, and good practices were 51.23, 45.81, and 49.75%, respectively. Social media was the most common source for seeking coronavirus information. Workers at private institutions were less likely (OR = 0.56, 95% CI = 0.30–0.95, p < 0.05) to be knowledgeable than workers at public institutions. Doctors had more positive attitudes than other healthcare professionals. Older participants showed high rates of good behavioral practices (OR = 1.05, 95% CI = 1.06–1.32, p < 0.05) than younger ones. Workers at private institutions had a better practice level toward COVID-19 (OR = 2.11, 95% CI = 1.17–3.83) than those at public institutions. These results point to the necessity for proper training programs for medical professionals that help them gain confidence to deliver the correct treatment to their patients and the need to implement preventative steps during pandemics

Mental health literacy: a cross-cultural approach to knowledge and beliefs about depression, schizophrenia and generalized anxiety disorder

Many families worldwide have at least one member with a behavioral or mental disorder, and yet the majority of the public fails to correctly recognize symptoms of mental illness. Previous research has found that Mental Health Literacy (MHL)—the knowledge and positive beliefs about mental disorders—tends to be higher in European and North American cultures, compared to Asian and African cultures. Nonetheless quantitative research examining the variables that explain this cultural difference remains limited. The purpose of our study was fourfold: (a) to validate measures of MHL cross-culturally, (b) to examine the MHL model quantitatively, (c) to investigate cultural differences in the MHL model, and (d) to examine collectivism as a predictor of MHL. We validated measures of MHL in European American and Indian samples. The results lend strong quantitative support to the MHL model. Recognition of symptoms of mental illness was a central variable: greater recognition predicted greater endorsement of social causes of mental illness and endorsement of professional help-seeking as well as lesser endorsement of lay help-seeking. The MHL model also showed an overwhelming cultural difference; namely, lay help-seeking beliefs played a central role in the Indian sample, and a negligible role in the European American sample. Further, collectivism was positively associated with causal beliefs of mental illness in the European American sample, and with lay help-seeking beliefs in the Indian sample. These findings demonstrate the importance of understanding cultural differences in beliefs about mental illness, particularly in relation to help-seeking beliefs

Development and validation of a new algorithm for improved cardiovascular risk prediction

QRISK algorithms use data from millions of people to help clinicians identify individuals at high risk of cardiovascular disease (CVD). Here, we derive and externally validate a new algorithm, which we have named QR4, that incorporates novel risk factors to estimate 10-year CVD risk separately for men and women. Health data from 9.98 million and 6.79 million adults from the United Kingdom were used for derivation and validation of the algorithm, respectively. Cause-specific Cox models were used to develop models to predict CVD risk, and the performance of QR4 was compared with version 3 of QRISK, Systematic Coronary Risk Evaluation 2 (SCORE2) and atherosclerotic cardiovascular disease (ASCVD) risk scores. We identified seven novel risk factors in models for both men and women (brain cancer, lung cancer, Down syndrome, blood cancer, chronic obstructive pulmonary disease, oral cancer and learning disability) and two additional novel risk factors in women (pre-eclampsia and postnatal depression). On external validation, QR4 had a higher C statistic than QRISK3 in both women (0.835 (95% confidence interval (CI), 0.833–0.837) and 0.831 (95% CI, 0.829–0.832) for QR4 and QRISK3, respectively) and men (0.814 (95% CI, 0.812–0.816) and 0.812 (95% CI, 0.810–0.814) for QR4 and QRISK3, respectively). QR4 was also more accurate than the ASCVD and SCORE2 risk scores in both men and women. The QR4 risk score identifies new risk groups and provides superior CVD risk prediction in the United Kingdom compared with other international scoring systems for CVD risk

The serotonin transporter linked polymorphic region and brain-derived neurotrophic factor valine to methionine at position 66 polymorphisms and maternal history of depression: Associations with cognitive vulnerability to depression in childhood

Preliminary work indicates that cognitive vulnerability to depression may be associated with variants of the serotonin transporter promoter polymorphism (5-HTTLPR) and the valine to methionine at position 66 (val66met) polymorphism of the brain-derived neurotrophic factor (BDNF) gene; however, existing reports come from small samples. The present study sought to replicate and extend this research in a sample of 375 community-dwelling children and their parents. Following a negative mood induction, children completed a self-referent encoding task tapping memory for positive and negative self-descriptive traits. Consistent with previous work, we found that children with at least one short variant of the 5-HTTLPR had enhanced memory for negative self-descriptive traits. The BDNF val66met polymorphism had no main effect but was moderated by maternal depression, such that children with a BDNF methionine allele had a heightened memory for negative self-descriptive traits when mothers had experienced depression during children\u27s lifetimes; in contrast, children with a methionine allele had low recall of negative traits when mothers had no depression history. The findings provide further support for the notion that the 5-HTTLPR is associated with cognitive markers of depression vulnerability and that the BDNF methionine allele moderates children\u27s sensitivity to contextual factors. Copyright © Cambridge University Press 2013

Understanding and evaluating the effects of implementing an electronic paediatric prescribing system on care provision and hospital work in paediatric hospital ward settings:A qualitatively driven mixed-method study protocol

INTRODUCTION: Electronic prescribing systems can improve the quality and safety of healthcare services, but their implementation is not straightforward and may create unexpected change. However, the added complexity of paediatric prescribing (eg, dose calculations, dilutions, manipulations) may pose additional challenges. This study will aim to (1) understand the complex organisational reality of a paediatric hospital in which a new electronic paediatric prescribing (ePP) system will be introduced; (2) describe ePP-related change, over time, in paediatric hospital ward settings; (3) explore staff perspectives in relation to currently established practices and processes; and (4) assess the impact of ePP on care provision and hospital work from the perspective of paediatricians, paediatric nurses and managers. METHODS AND ANALYSIS: A qualitatively driven mixed-method approach will be adopted, including 3 inter-related substudies. The core component of the study will be qualitative (substudy 1): we will use ethnographic research methods, including non-participant observation in wards and informal conversational interviews with members of staff. In addition, the design will include 2 embedded supplementary components: a qualitative 1 (substudy 2) based on in-depth interviews and/or focus groups with paediatricians, paediatric nurses, paediatric pharmacists/pharmacy technicians and managers; and a quantitative 1 (substudy 3) in which a staff survey will be developed and administered before and after the ePP implementation. Analytic themes will be identified from ethnographic field notes and interview data. Survey data will be analysed using descriptive statistics and baseline and follow-up data compared to establish impact evaluation measures. ETHICS AND DISSEMINATION: A favourable ethical opinion has been obtained from a National Health Service (NHS) Research Ethics Committee (15/SS/0157). NHS research governance approval has been obtained at the relevant hospital site. The results of the study will be disseminated through conferences and peer-reviewed journals, as well as fed back to those involved in clinical practice and policy development at the study site