Structural basis for tuning activity and membrane specificity of bacterial cytolysins

Cholesterol-dependent cytolysins (CDCs) are pore-forming proteins that serve as major virulence factors for pathogenic bacteria. They target eukaryotic cells using different mechanisms, but all require the presence of cholesterol to pierce lipid bilayers. How CDCs use cholesterol to selectively lyse cells is essential for understanding virulence strategies of several pathogenic bacteria, and for repurposing CDCs to kill new cellular targets. Here we address that question by trapping an early state of pore formation for the CDC intermedilysin, bound to the human immune receptor CD59 in a nanodisc model membrane. Our cryo electron microscopy map reveals structural transitions required for oligomerization, which include the lateral movement of a key amphipathic helix. We demonstrate that the charge of this helix is crucial for tuning lytic activity of CDCs. Furthermore, we discover modifications that overcome the requirement of cholesterol for membrane rupture, which may facilitate engineering the target-cell specificity of pore-forming proteins

Mammographic density, lobular involution, and risk of breast cancer

In this review, we propose that age-related changes in mammographic density and breast tissue involution are closely related phenomena, and consider their potential relevance to the aetiology of breast cancer. We propose that the reduction in mammographic density that occurs with increasing age, parity and menopause reflects the involution of breast tissue. We further propose that age-related changes in both mammographic density and breast tissue composition are observable and measurable phenomena that resemble Pike's theoretical construct of ‘breast tissue ageing'. Extensive mammographic density and delayed breast involution are both associated with an increased risk of breast cancer and are consistent with the hypothesis of the Pike model that cumulative exposure of breast tissue to hormones and growth factors that stimulate cell division, as well as the accumulation of genetic damage in breast cells, are major determinants of breast cancer incidence

Providing alternative measures for addressing adverse drug-drug interactions

First Online 30 March 2019Clinical Practice Guidelines (CPGs) are documents used in daily clinical practice that provide advice on how to best diagnose and treat diseases in the form of a list of clinical recommendations. When simultaneously applying multiple CPGs to patients, this can lead to complex multiple drug regimens (polypharmacy) with the potential for harmful combinations of drugs. The need to address these adverse drug events calls forth for systems capable of not only automatically represent the common potential conflicts or interactions that can happen when merging CPGs but also systems capable of providing conflict-free alternatives. This paper presents a solution that represents CPGs as Computer-Interpretable Guidelines (CIGs) and allows the automatic identification of drug conflicts and the provision of alternative measures to resolve these conflicts.This work has been supported by COMPETE: POCI-01-0145-FEDER-0070 43 and FCT – Fundação para a Ciência e Tecnologia within the Project Scope UID/CEC/ 00319/2013. The work of Tiago Oliveira was supported by JSPS KAKENHI Grant Number JP18K18115

Quality of care assessment for people with multimorbidity.

Multimorbidity, the simultaneous presence of multiple health conditions in an individual, is an increasingly common phenomenon globally. The systematic assessment of the quality of care delivered to people with multimorbidity will be key to informing the organization of services for meeting their complex needs. Yet, current assessments tend to focus on single conditions and do not capture the complex processes that are required for providing care for people with multimorbidity. We conducted a scoping review on quality of care and multimorbidity in selected databases in June 2018 and identified 87 documents as eligible for review, predominantly original research and reviews from North America, Europe and Australasia and mostly frequently related to primary care settings. We synthesized data qualitatively in terms of perceived challenges, evidence and proposed metrics. Findings reveal that the association between quality of care and multimorbidity is complex and depends on the conditions involved (quality appears to be higher for those with concordant conditions, and lower in the presence of discordant conditions) and the approach used for measuring quality (quality appears to be higher in people with multimorbidity when measured using condition/drug-specific process or intermediate outcome indicators, and worse when using patient-centred reports of experiences of care). People with discordant multimorbidity may be disadvantaged by current approaches to quality assessment, particularly when they are linked to financial incentives. A better understanding of models of care that best meet the needs of this group is needed for developing appropriate quality assessment frameworks. Capturing patient preferences and values and incorporate patients' voices in the form of patient-reported experiences and outcomes of care will be critical towards the achievement of high-performing health systems that are responsive to the needs of people with multimorbidity

Accurate energy spectrum for double-well potential: periodic basis

We present a variational study of employing the trigonometric basis functions satisfying periodic boundary condition for the accurate calculation of eigenvalues and eigenfunctions of quartic double-well oscillators. Contrary to usual Dirichlet boundary condition, imposing periodic boundary condition on the basis functions results in the existence of an inflection point with vanishing curvature in the graph of the energy versus the domain of the variable. We show that this boundary condition results in a higher accuracy in comparison to Dirichlet boundary condition. This is due to the fact that the periodic basis functions are not necessarily forced to vanish at the boundaries and can properly fit themselves to the exact solutions.Comment: 15 pages, 5 figures, to appear in Molecular Physic

The effectiveness of case management for comorbid diabetes type 2 patients; the CasCo study. Design of a randomized controlled trial

BACKGROUND: More than half of the patients with type 2 diabetes (T2DM) patients are diagnosed with one or more comorbid disorders. They can participate in several single-disease oriented disease management programs, which may lead to fragmented care because these programs are not well prepared for coordinating care between programs. Comorbid patients are therefore at risk for suboptimal treatment, unsafe care, inefficient use of health care services and unnecessary costs. Case management is a possible model to counteract fragmented care for comorbid patients. It includes evidence-based optimal care, but is tailored to the individual patients' preferences.The objective of this study is to examine the effectiveness of a case management program, in addition to a diabetes management program, on the quality of care for comorbid T2DM patients. METHODS/DESIGN: The study is a randomized controlled trial among patients with T2DM and at least one comorbid chronic disease (N=230), who already participate in a diabetes management program. Randomization will take place at the level of the patients in general practices. Trained practice nurses (case managers) will apply a case management program in addition to the diabetes management program. The case management intervention is based on the Guided Care model and includes six elements; assessing health care needs, planning care, create access to other care providers and community resources, monitoring, coordinating care and recording of all relevant information. Patients in the control group will continue their participation in the diabetes management program and receive care-as-usual from their general practitioner and other care providers. DISCUSSION: We expect that the case management program, which includes better structured care based on scientific evidence and adjusted to the patients' needs and priorities, will improve the quality of care coordination from both the patients' and caregivers' perspective and will result in less consumption of health care services. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1847. (aut. ref.

Background risk of breast cancer and the association between physical activity and mammographic density

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The spatial distribution of radiodense breast tissue: a longitudinal study

Introduction Mammographic breast density is one of the strongest known markers of susceptibility to breast cancer. To date research into density has relied on a single measure ( for example, percent density (PD)) summarising the average level of density for the whole breast, with no consideration of how the radiodense tissue may be distributed. This study aims to investigate the spatial distribution of density within the breast using 493 mammographic images from a sample of 165 premenopausal women (similar to 3 medio-lateral oblique views per woman).Methods Each breast image was divided into 48 regions and the PD for the whole breast ( overall PD) and for each one of its regions ( regional PD) was estimated. The spatial autocorrelation ( Moran's I value) of regional PD for each image was calculated to investigate spatial clustering of density, whether the degree of clustering varied between a woman's two breasts and whether it was affected by age and other known density correlates.Results The median Moran's / value for 165 women was 0.31 (interquartile range: 0.26, 0.37), indicating a clustered pattern. High-density areas tended to cluster in the central regions of the breast, regardless of the level of overall PD, but with considerable between-woman variability in regional PD. The degree of clustering was similar between a woman's two breasts (mean within-woman difference in Moran's / values between left and right breasts = 0.00 (95% confidence interval (CI) = -0.01, 0.01); P = 0.76) and did not change with aging (mean within-woman difference in I values between screens taken on average 8 years apart = 0.01 (95% CI = -0.01, 0.02); P = 0.30). Neither parity nor age at first birth affected the level of spatial autocorrelation of density, but increasing body mass index (BMI) was associated with a decrease in the degree of spatial clustering.Conclusions This study is the first to demonstrate that the distribution of radiodense tissue within the breast is spatially autocorrelated, generally with the high-density areas clustering in the central regions of the breast. The degree of clustering was similar within a woman's two breasts and between women, and was little affected by age or reproductive factors although it declined with increasing BMI

Mammographic density does not correlate with Ki-67 expression or cytomorphology in benign breast cells obtained by random periareolar fine needle aspiration from women at high risk for breast cancer

BACKGROUND:Ki-67 expression is a possible risk biomarker and is currently being used as a response biomarker in chemoprevention trials. Mammographic breast density is a risk biomarker and is also being used as a response biomarker. We previously showed that Ki-67 expression is higher in specimens of benign breast cells exhibiting cytologic atypia that are obtained by random periareolar fine needle aspiration (RPFNA). It is not known whether there is a correlation between mammographic density and Ki-67 expression in benign breast ductal cells obtained by RPFNA.METHODS:Included in the study were 344 women at high risk for developing breast cancer (based on personal or family history), seen at The University of Kansas Medical Center high-risk breast clinic, who underwent RPFNA with cytomorphology and Ki-67 assessment plus a mammogram. Mammographic breast density was assessed using the Cumulus program. Categorical variables were analyzed by ?2 test, and continuous variables were analyzed by nonparametric test and linear regression.RESULTS:Forty-seven per cent of women were premenopausal and 53% were postmenopausal. The median age was 48 years, median 5-year Gail Risk was 2.2%, and median Ki-67 was 1.9%. The median mammographic breast density was 37%. Ki-67 expression increased with cytologic abnormality (atypia versus no atypia; P = 0.001) and younger age (=50 years versus >50 years; P = 0.001). Mammographic density was higher in premenopausal women (P = 0.001), those with lower body mass index (P < 0.001), and those with lower 5-year Gail risk (P = 0.001). Mammographic density exhibited no correlation with Ki-67 expression or cytomorphology.CONCLUSION:Given the lack of correlation of mammographic breast density with either cytomorphology or Ki-67 expression in RPFNA specimens, mammographic density and Ki-67 expression should be considered as potentially complementary response biomarkers in breast cancer chemoprevention trials