Which health-related quality of life score? A comparison of alternative utility measures in patients with Type 2 diabetes in the ADVANCE trial.

BACKGROUND: Diabetes has a high burden of illness both in life years lost and in disability through related co-morbidities. Accurate assessment of the non-mortality burden requires appropriate health-related quality of life and summary utility measures of which there are several contenders. The study aimed to measure the impact of diabetes on various health-related quality of life domains, and compare several summary utility measures. METHODS: In the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) study, 978 Australian patients with Type 2 diabetes completed two health-related quality of life questionnaires at baseline: the EQ-5D and the SF-36v2, from which nine summary utility measures were calculated, and compared. The algorithms were grouped into four classes: (i) based on the EQ-5D; (ii) using fewer items than those in the SF-12 (iii) using the items in the SF-12; and (iv) using all items of the SF-36. RESULTS: Overall health-related quality of life of the subjects was good (mean utility ranged from 0.68 (+/-0.08) to 0.85(+/-0.14) over the nine utility measures) and comparable to patients without diabetes. Summary indices were well correlated with each other (r = 0.76 to 0.99), and showed lower health-related quality of life in patients with major diabetes-related events such as stroke or myocardial infarction. Despite the smaller number of items used in the scoring of the EQ-5D, it generally performed at least as well as SF-36 based methods. However, all utility measures had some limitation such as limited range or ceiling effects. CONCLUSION: The summary utility measures showed good agreement, and showed good discrimination between major and minor health state changes. However, EQ-5D based measures performed as well and are generally simpler to use

Delineation of a unique protein-protein interaction site on the surface of the estrogen receptor

Recent studies have identified a series of estrogen receptor (ER)interacting peptides that recognize sites that are distinct from the classic coregulator recruitment (AF2) region. Here, we report the structural and functional characterization of an ER alpha-specific peptide that binds to the liganded receptor in an AF2-independent manner. The 2-angstrom crystal structure of the ER/peptide complex reveals a binding site that is centered on a shallow depression on the beta-hairpin face of the ligand-binding domain. The peptide binds in an unusual extended conformation and makes multiple contacts with the ligand-binding domain. The location and architecture of the binding site provides an insight into the peptide's ER subtype specificity and ligand interaction preferences. In vivo, an engineered coactivator containing the peptide motif is able to strongly enhance the transcriptional activity of liganded ER alpha, particularly in the presence of 4-hydroxytamoxifen. Furthermore, disruption of this binding surface alters ER's response to the coregulator TIF2. Together, these results indicate that this previously unknown interaction site represents a bona fide control surface involved in regulating receptor activity

Virtual orthopaedic teaching during COVID-19 : Zooming around Scotland

ACKNOWLEDGEMENTS The authors would like to acknowledge the following SCORE collaborators: Peter SE Davies, Ninewells Hospital, Dundee; Matthew Howell, Queen Elizabeth Hospital, Glasgow; Stuart Goudie, Edinburgh Royal Infirmary; Sarah L Gill, Queen Elizabeth Hospital, Glasgow; Arpit Jariwala, Ninewells Hospital, Dundee and George P Ashcroft, University of Aberdeen.Peer reviewedPublisher PD

Crystal structure of monomeric human β-2- microglobulin reveals clues to its amyloidogenic properties

Dissociation of human β-2-microglobulin (β(2)m) from the heavy chain of the class I HLA complex is a critical first step in the formation of amyloid fibrils from this protein. As a consequence of renal failure, the concentration of circulating monomeric β(2)m increases, ultimately leading to deposition of the protein into amyloid fibrils and development of the disorder, dialysis-related amyloidosis. Here we present the crystal structure of a monomeric form of human β(2)m determined at 1.8-Å resolution that reveals remarkable structural changes relative to the HLA-bound protein. These involve the restructuring of a β bulge that separates two short β strands to form a new six-residue β strand at one edge of this β sandwich protein. These structural changes remove key features proposed to have evolved to protect β sheet proteins from aggregation [Richardson, J.&Richardson, D. (2002) Proc. Natl. Acad. Sci. USA 99, 2754–2759] and replaces them with an aggregationcompetent surface. In combination with solution studies using (1)H NMR, we show that the crystal structure presented here represents a rare species in solution that could provide important clues about the mechanism of amyloid formation from the normally highly soluble native protein

COVID-19 Mortality in Patients with a Ward-Based Ceiling of Care

\ua9 2021 by the authors.Objectives: COVID-19 patients thought unlikely to benefit from organ support, thereby having a ward-based ceiling of care (WBCoC), represent a distinct subgroup. There are no associated studies in mortality. We sought to identify clinical risk factors for inpatient COVID-19 mortality. Design and setting: this was a retrospective observational study of patients admitted to Northumbria Healthcare NHS Foundation Trust. Clinical variables were associated with inpatient mortality via logistic regression. Participants: all patients admitted with COVID-19 infection and who had a WBCoC at point of admission were included (n = 114). Main outcome measures: the outcome measure was inpatient death

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

Elevated c-Src protein expression has been shown in breast cancer and <i>in vitro</i> evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan–Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (<i>P</i>=0.047) and lower recurrence rates on tamoxifen (<i>P</i>=0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (<i>P</i><0.05). On subgroup analysis, only ER-positive/progesterone receptor (PgR)-positive tumours were associated with improved survival (<i>P</i>=0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in <i>de novo</i> endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome

Impact of inactivated poliovirus vaccine on mucosal immunity: implications for the polio eradication endgame.

The polio eradication endgame aims to bring transmission of all polioviruses to a halt. To achieve this aim, it is essential to block viral replication in individuals via induction of a robust mucosal immune response. Although it has long been recognized that inactivated poliovirus vaccine (IPV) is incapable of inducing a strong mucosal response on its own, it has recently become clear that IPV may boost immunity in the intestinal mucosa among individuals previously immunized with oral poliovirus vaccine. Indeed, mucosal protection appears to be stronger following a booster dose of IPV than oral poliovirus vaccine, especially in older children. Here, we review the available evidence regarding the impact of IPV on mucosal immunity, and consider the implications of this evidence for the polio eradication endgame. We conclude that the implementation of IPV in both routine and supplementary immunization activities has the potential to play a key role in halting poliovirus transmission, and thereby hasten the eradication of polio

Planned Cesarean or planned vaginal delivery for twins : secondary analysis of randomized controlled trial

ACKNOWLEDGMENTS We thank all the participants in the Twin Birth Study and the staff at the Centre for Mother, Infant, and Child Research for their hard work and dedication. The Twin Birth Study was supported by a grant (63164) from the Canadian Institute of Health Research. P.T. and M.H.Z. were supported by a grant from The Netherlands Organization for Scientific Research (NWO ‐ grant number 401.16.080). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Biomarker Validation of Recent Unprotected Sexual Intercourse in a Prospective Study of Young Women Engaged in Sex Work in Phnom Penh, Cambodia

Summary—A study of female sex workers in Phnom Penh, Cambodia found self-reported condom use to be of questionable validity, particularly among amphetamine-type stimulant (ATS) users and those with multiple partners. Background—Accurate measurement of unprotected sex is essential in HIV prevention research. Since 2001, the 100% Condom Use Program targeting female sex workers (FSW) has been a central element of the Cambodian National HIV/AIDS Strategy. We sought to assess the validity of self-reported condom use using the rapid prostate-specific antigen (PSA) test among Cambodian FSW. Methods—From 2009 to 2010 we enrolled 183 FSW in Phnom Penh in a prospective study of HIV risk behavior. PSA test results from the OneStep ABAcard® were compared to self-reported condom use in the past 48 hours at quarterly follow-up visits. Results—Among women positive for seminal fluid at the first follow-up visit, 42% reported only protected sex or no sex in the detection period. Discordant results were more likely among brothel and street-based FSW vs. entertainment (56% vs. 17%), recent (last 3 months) ATS users (53% vs. 20%), and those with \u3e5 partners in the past month (58% vs. 13%). In multivariable regression models, positive PSA results were associated with recent ATS use (Adjusted Risk Ratio (ARR) = 1.5; 95% confidence interval (CI):1.1 – 2.2), having a non-paying last sex partner (ARR=1.7; CI: 1.2 – 2.5), and sex work venue (ARR=3.0; CI:1.4 – 6.5). Correspondingly, women with a nonpaying last sex partner were more likely to report unprotected sex (ARR=1.5; CI:1.1 – 2.2), but no associations were found with sex work venue or ATS use. Conclusions—Results confirm the questionable validity of self-reported condom use among FSW. The PSA biomarker assay is an important monitoring tool in HIV/STI research including prevention trials