Immunogenetics in SARS: a case-control study.

Key Messages: 1. Human leukocyte antigen (HLA) genotypes from 102 SARS patients (susceptible) and 108 SARS contacts (resistant) were obtained. 2. Allelic frequencies of the Class I (HLA-A, -B, and -Cw) and Class II (HLA-DR and -DQ) genes from these genetically unrelated subjects were compared. 3. A significantly higher frequency of DRB4*01010101 was found in the SARS-susceptible than SARS-resistant group. In contrast, significantly higher frequencies of HLA-B*1502 and HLADRB3*030101 were found in the SARS-resistant than SARSsusceptible group. However, none of these associations was significant after Bonferroni correction. Further, analysis of 10/36 genetically related families did not reveal any HLA alleles associated with SARS susceptibility or resistance. 4. We could not confirm previous findings of an HLA association with susceptibility or resistance to SARS. The significance of these associations needs to be validated by further independent studies.published_or_final_versio

Development and use of a computer program to detect potentially inappropriate prescribing in older adults residing in Canadian long-term care facilities

BACKGROUND: Inappropriate prescribing has been estimated to be as high as 40% in long-term care. The purpose of this study was to develop a computer program that identifies potentially inappropriate drug prescriptions and to test its reliability. METHODS: Potentially inappropriate prescriptions were identified based on modified McLeod guidelines. A database from one pharmacy servicing long-term care facilities in Ontario was utilized for this cross-sectional study. Prescription information was available for the 356 long-term care residents and included: the date the prescription was filled, the quantity of drug prescribed and the eight-digit drug identification number. The pharmacy database was linked to the computer-based program for targeting potential inappropriate prescriptions. The computer program's reliability was assessed by comparing its results to a manual search conducted by two independent research assistants. RESULTS: There was complete agreement between the computer and manual abstraction for the total number of potentially inappropriate prescriptions detected. In total, 83 potentially inappropriate prescriptions were identified. Fifty-three residents (14.9%) received at least one potentially inappropriate prescription. Of those, twenty (37.7%) received two potential inappropriate prescriptions and eight (15.1%) received 3 or more potential inappropriate prescriptions. The most common potential inappropriate prescriptions were identified as long-term use of non-steroidal anti-inflammatory agents and tricyclic antidepressants with active metabolites. CONCLUSION: A computer program can accurately and automatically detect inappropriate prescribing in residents of long-term care facilities. This tool may be used to identify potentially inappropriate drug combinations and educate health care professionals

BRCA1 positively regulates FOXO3 expression by restricting FOXO3 gene methylation and epigenetic silencing through targeting EZH2 in breast cancer.

BRCA1 mutation or depletion correlates with basal-like phenotype and poor prognosis in breast cancer but the underlying reason remains elusive. RNA and protein analysis of a panel of breast cancer cell lines revealed that BRCA1 deficiency is associated with downregulation of the expression of the pleiotropic tumour suppressor FOXO3. Knockdown of BRCA1 by small interfering RNA (siRNA) resulted in downregulation of FOXO3 expression in the BRCA1-competent MCF-7, whereas expression of BRCA1 restored FOXO3 expression in BRCA1-defective HCC70 and MDA-MB-468 cells, suggesting a role of BRCA1 in the control of FOXO3 expression. Treatment of HCC70 and MDA-MB-468 cells with either the DNA methylation inhibitor 5-aza-2'-deoxycitydine, the N-methyltransferase enhancer of zeste homologue 2 (EZH2) inhibitor GSK126 or EZH2 siRNA induced FOXO3 mRNA and protein expression, but had no effect on the BRCA1-competent MCF-7 cells. Chromatin immunoprecipitation (ChIP) analysis demonstrated that BRCA1, EZH2, DNMT1/3a/b and histone H3 lysine 27 trimethylation (H3K27me3) are recruited to the endogenous FOXO3 promoter, further advocating that these proteins interact to modulate FOXO3 methylation and expression. In addition, ChIP results also revealed that BRCA1 depletion promoted the recruitment of the DNA methyltransferases DNMT1/3a/3b and the enrichment of the EZH2-mediated transcriptional repressive epigenetic marks H3K27me3 on the FOXO3 promoter. Methylated DNA immunoprecipitation assays also confirmed increased CpG methylation of the FOXO3 gene on BRCA1 depletion. Analysis of the global gene methylation profiles of a cohort of 33 familial breast tumours revealed that FOXO3 promoter methylation is significantly associated with BRCA1 mutation. Furthermore, immunohistochemistry further suggested that FOXO3 expression was significantly associated with BRCA1 status in EZH2-positive breast cancer. Consistently, high FOXO3 and EZH2 mRNA levels were significantly associated with good and poor prognosis in breast cancer, respectively. Together, these data suggest that BRCA1 can prevent and reverse FOXO3 suppression via inhibiting EZH2 and, consequently, its ability to recruit the transcriptional repressive H3K27me3 histone marks and the DNA methylases DNMT1/3a/3b, to induce DNA methylation and gene silencing on the FOXO3 promoter

Active wetting of epithelial tissues

Development, regeneration and cancer involve drastic transitions in tissue morphology. In analogy with the behavior of inert fluids, some of these transitions have been interpreted as wetting transitions. The validity and scope of this analogy are unclear, however, because the active cellular forces that drive tissue wetting have been neither measured nor theoretically accounted for. Here we show that the transition between 2D epithelial monolayers and 3D spheroidal aggregates can be understood as an active wetting transition whose physics differs fundamentally from that of passive wetting phenomena. By combining an active polar fluid model with measurements of physical forces as a function of tissue size, contractility, cell-cell and cell-substrate adhesion, and substrate stiffness, we show that the wetting transition results from the competition between traction forces and contractile intercellular stresses. This competition defines a new intrinsic lengthscale that gives rise to a critical size for the wetting transition in tissues, a striking feature that has no counterpart in classical wetting. Finally, we show that active shape fluctuations are dynamically amplified during tissue dewetting. Overall, we conclude that tissue spreading constitutes a prominent example of active wetting --- a novel physical scenario that may explain morphological transitions during tissue morphogenesis and tumor progression

Korean women: breast cancer knowledge, attitudes and behaviors

INTRODUCTION: Clustered within the nomenclature of Asian American are numerous subgroups, each with their own ethnic heritage, cultural, and linguistic characteristics. An understanding of the prevailing health knowledge, attitudes, and screening behaviors of these subgroups is essential for creating population-specific health promotion programs. METHODS: Korean American women (123) completed baseline surveys of breast cancer knowledge, attitudes, and screening behaviors as part of an Asian grocery store-based breast cancer education program evaluation. Follow-up telephone surveys, initiated two weeks later, were completed by 93 women. RESULTS: Low adherence to the American Cancer Society's breast cancer screening guidelines and insufficient breast cancer knowledge were reported. Participants' receptiveness to the grocery store-based breast cancer education program underscores the importance of finding ways to reach Korean women with breast cancer early detection information and repeated cues for screening. The data also suggest that the Asian grocery store-based cancer education program being tested may have been effective in motivating a proportion of the women to schedule a breast cancer screening between the baseline and follow-up surveys. CONCLUSION: The program offers a viable strategy to reach Korean women that addresses the language, cultural, transportation, and time barriers they face in accessing breast cancer early detection information

Early response to antibiotic treatment in European patients hospitalized with complicated skin and soft tissue infections: analysis of the REACH study

Background: The treatment of complicated skin and soft tissue infections (cSSTI) is challenging and many patients do not receive adequate first-line therapy. REACH (REtrospective Study to Assess the Clinical Management of Patients With Moderate-to-Severe cSSTI or Community-Acquired Pneumonia in the Hospital Setting) was a retrospective observational study of cSSTI patients in real-life settings in European hospitals. In this analysis, we review characteristics and outcomes of patients with an early response (<= 72 hours) compared with those without an early response to treatment. We also compare the results according to two differing definitions of early response, one of which (Definition 1) requires resolution of fever within 72 hours, in line with previous US FDA guidelines. Methods: Patients were adults hospitalized with cSSTIs 2010-2011 and requiring treatment with intravenous antibiotics. Clinical management, clinical outcomes and healthcare resource use were assessed using a descriptive analysis approach. Results: The analysis set included 600 patients, of which 363 showed early response with Definition 1 and 417 with Definition 2. Initial treatment modification was frequent, and highest in patients without early response (48.1% with Definition 1). Patients without early response were more likely to have diabetes than those with early response (31.6% vs. 22.9%,respectively) and to suffer from more severe disease (e.g. skin necrosis: 14.8% and 7.7%,respectively), to be infected with difficult-to-treat microorganisms and to have recurrent infections. Furthermore, patients without early response had a higher rate of adverse clinical outcomes (e.g. septic shock) and higher use of healthcare resources. The results obtained with the two definitions for early response were largely similar. Conclusions: This study highlights the significance of early evaluation of patients in hospitals, in potentially preventing prolonged use of inappropriate or ineffective antibacterial therapy

Trends in publications regarding evidence-practice gaps: A literature review

<p>Abstract</p> <p>Background</p> <p>Well-designed trials of strategies to improve adherence to clinical practice guidelines are needed to close persistent evidence-practice gaps. We studied how the number of these trials is changing with time, and to what extent physicians are participating in such trials.</p> <p>Methods</p> <p>This is a literature-based study of trends in evidence-practice gap publications over 10 years and participation of clinicians in intervention trials to narrow evidence-practice gaps. We chose nine evidence-based guidelines and identified relevant publications in the PubMed database from January 1998 to December 2007. We coded these publications by study type (intervention versus non-intervention studies). We further subdivided intervention studies into those for clinicians and those for patients. Data were analyzed to determine if observed trends were statistically significant.</p> <p>Results</p> <p>We identified 1,151 publications that discussed evidence-practice gaps in nine topic areas. There were 169 intervention studies that were designed to improve adherence to well-established clinical guidelines, averaging 1.9 studies per year per topic area. Twenty-eight publications (34%; 95% CI: 24% - 45%) reported interventions intended for clinicians or health systems that met Effective Practice and Organization of Care (EPOC) criteria for adequate design. The median consent rate of physicians asked to participate in these well-designed studies was 60% (95% CI, 25% to 69%).</p> <p>Conclusions</p> <p>We evaluated research publications for nine evidence-practice gaps, and identified small numbers of well-designed intervention trials and low rates of physician participation in these trials.</p

Water quality monitoring records for estimating tap water arsenic and nitrate: a validation study

<p>Abstract</p> <p>Background</p> <p>Tap water may be an important source of exposure to arsenic and nitrate. Obtaining and analyzing samples in the context of large studies of health effects can be expensive. As an alternative, studies might estimate contaminant levels in individual homes by using publicly available water quality monitoring records, either alone or in combination with geographic information systems (GIS).</p> <p>Methods</p> <p>We examined the validity of records-based methods in Washington State, where arsenic and nitrate contamination is prevalent but generally observed at modest levels. Laboratory analysis of samples from 107 homes (median 0.6 μg/L arsenic, median 0.4 mg/L nitrate as nitrogen) served as our "gold standard." Using Spearman's rho we compared these measures to estimates obtained using only the homes' street addresses and recent and/or historical measures from publicly monitored water sources within specified distances (radii) ranging from one half mile to 10 miles.</p> <p>Results</p> <p>Agreement improved as distance decreased, but the proportion of homes for which we could estimate summary measures also decreased. When including all homes, agreement was 0.05-0.24 for arsenic (8 miles), and 0.31-0.33 for nitrate (6 miles). Focusing on the closest source yielded little improvement. Agreement was greatest among homes with private wells. For homes on a water system, agreement improved considerably if we included only sources serving the relevant system (ρ = 0.29 for arsenic, ρ = 0.60 for nitrate).</p> <p>Conclusions</p> <p>Historical water quality databases show some promise for categorizing epidemiologic study participants in terms of relative tap water nitrate levels. Nonetheless, such records-based methods must be used with caution, and their use for arsenic may be limited.</p