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INTRODUCTION: Elective surgical hubs focusing on high-volume routine surgery using protected facilities and ringfenced resources are key to NHS England's elective recovery strategy. In May 2021, the Getting It Right First Time initiative introduced the high-volume low-complexity programme to coordinate new and existing hubs nationally, and to provide a framework for delivery. This paper presents results from the first national survey to identify their prevalence, location and configuration, the provision of care offered and the contextual setting within healthcare providers in order to provide a strong foundation for future research. METHODS: NHS regional leads were invited to participate in a survey conducted in March 2022 and disseminated by NHS England. RESULTS: A total of 87 elective surgical hubs were identified across 64 acute NHS trusts in England. London, the Midlands and the South East had the greatest concentration of hubs per trust. The contextual setting of hubs within healthcare providers varied widely. Two-fifths (43%) were configured as stand-alone, 34% as integrated and 23% as ringfenced hubs. Half (49%) were established before 2019. Seventy-six per cent catered for patients attending for either day-case or inpatient surgery. The majority (72%) covered multiple specialties, with 80% specialising in trauma and orthopaedic surgery. Two-fifths (43%) provided enhanced care. CONCLUSIONS: Elective surgical hubs are widespread across NHS regions in England. There is wide variation in hub configuration and capacity as well as in the provision of care offered and their contextual setting within healthcare providers, suggesting that the optimal hub model has not been established. Further research into the efficacy of elective hubs is required to aid their potential role in reducing waiting lists and improving quality of care. [ABSTRACT FROM AUTHOR]

Background: NHS England encourages the use of online consultation (OC) systems alongside traditional access methods for patients to contact their general practice online and for practices to manage workflow. Access is a key driver of patients' primary care experience. The use of online technology and patient experience vary by sociodemographic characteristics., Objective: This study aims to assess the association between OC system use and patient experience of primary care in English general practice and how that varies by OC system model and practice sociodemographic characteristics (rurality, deprivation, age, and ethnicity)., Methods: We categorized practices as "low-use" or "high-use" according to the volume of patient-initiated contacts made via the OC system. We considered practices using one of 2 OC systems with distinct designs and implementation models-shorter "free text" input with an embedded single workflow OC system (FT practices) and longer "mixed text" input with variation in implemented workflow OC system (MT practices). We used 2022 General Practice Patient Survey data to capture 4 dimensions of patient experience-overall experience, experience of making an appointment, continuity of care, and use of self-care before making an appointment. We used logistic regression at the practice level to explore the association between OC system use and patient experience, including interaction terms to assess sociodemographic variation., Results: We included 287,194 responses from 2423 MT and 170 FT practices. The proportions of patients reporting positive experiences at MT and FT practices were similar or better than practices nationally, except at high-use MT practices. At high-use MT practices, patients were 19.8% (odds ratio [OR] 0.802, 95% CI 0.782-0.823) less likely to report a good overall experience; 24.5% (OR 0.755, 95% CI 0.738-0.773) less likely to report a good experience of making an appointment; and 18.9% (OR 0.811, 95% CI 0.792-0.83) less likely to see their preferred general practitioner; but 27.8% (OR 1.278, 95% CI 1.249-1.308) more likely to use self-care, compared with low-use MT practices. Opposite trends were seen at FT practices. Sociodemographic inequalities in patient experience were generally lower at high-use than low-use practices; for example, gaps in overall experience between practices with the most and fewest White patients decreased by 2.7 percentage points at MT practices and 6.4 percentage points at FT practices. Trends suggested greater improvements in experience for traditionally underserved groups-patients from urban and deprived areas, younger patients, and non-White patients., Conclusions: An OC system with shorter free text input and an integrated single workflow can enhance patient experience and reduce sociodemographic inequalities. Variation in patient experience between practices with different sociodemographic characteristics and OC systems underscores the importance of tailored design and implementation. Generalizing results across different OC systems is difficult due to variations in how they are integrated into practice workflows and communicated to patients., (©Xiaochen Ge, Paul Chappell, Jean Ledger, Minal Bakhai, Geraldine M Clarke. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 26.07.2024.)

Objectives: Investigate trends in continuity of care with a general practitioner (GP) before and during the COVID-19 pandemic. Identify whether continuity of care is associated with consultation mode, controlling for other patient and practice characteristics., Design: Retrospective cross-sectional and longitudinal observational studies., Setting: Primary care records from 389 general practices participating in Clinical Practice Research Datalink Aurum in England., Participants: In the descriptive analysis, 100 000+ patients were included each month between April 2018 and April 2021. Modelling of the association between continuity of care and consultation mode focused on 153 475 and 125 298 patients in index months of February 2020 (before the pandemic) and February 2021 (during the pandemic) respectively, and 76 281 patients in both index months., Primary and Secondary Outcomes Measures: The primary outcome measure was the Usual Provider of Care index. Secondary outcomes included the Bice-Boxerman index and count of consultations with the most frequently seen GP., Results: Continuity of care was gradually declining before the pandemic but stabilised during it. There were consistent demographic, socioeconomic and regional differences in continuity of care. An average of 23% of consultations were delivered remotely in the year to February 2020 compared with 76% in February 2021. We found little evidence consultation mode was associated with continuity at the patient level, controlling for a range of covariates. In contrast, patient characteristics and practice-level supply and demand were associated with continuity., Conclusions: We set out to examine the association of consultation mode with continuity of care but found that GP supply and patient demand were much more important. To improve continuity for patients, primary care capacity needs to increase. This requires sufficient, long-term investment in clinicians, staff, facilities and digital infrastructure. General practice also needs to transform ways of working to ensure continuity for those that need it, even in a capacity-constrained environment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The COVID-19 pandemic has led to an ongoing increase in the use of remote consultations in general practice in England. Although the evidence is limited, there are concerns that the increase in remote consultations could lead to more antibiotic prescribing., Methods: In this cohort study, we used patient-level primary care data from the Clinical Practice Research Datalink to estimate the association between consultation mode (remote versus face-to-face) and antibiotic prescribing in England for acute respiratory infections (ARI) between April 2021 and March 2022. Eligibility criteria were applied at both practice-level and patient-level. 400 practices in England were sampled at random and then 600,000 patients were randomly sampled from the eligible patients (whose sex was recorded). Consultations for acute respiratory infections were identified. All antibiotic prescriptions were included, with the exception of antituberculosis drugs and antileprotic drugs, as identified through chapter 5.1 of the British National Formulary. The CPRD Aurum data was linked to the COVID-19 ONS infection survey by region. All analyses were done at the individual level. Repeated consultations from the same patient within 7 days were grouped together. We used targeted maximum likelihood estimation, a causal machine learning method with adjustment for infection type and patient-level, clinician-level and practice-level factors., Findings: There were 45,997 ARI consultations (34,555 unique patients) within the study period, of which 28,127 were remote and 17,870 were face-to-face. For children, 48% of consultations were remote and, for adults, 66% were remote. For children, 42% of remote and 43% of face-to-face consultations led to an antibiotic prescription; the equivalent values for adults were 52% and 42%, respectively. After adjustment with TMLE, adults with a remote consultation had 23% (odds ratio [OR] 1.23, 95% CI: 1.18-1.29) higher chance of being prescribed antibiotics than if they had been seen face-to-face. We found no significant association between consultation mode and antibiotic prescribing in children (OR 1.04 95% CI: 0.98-1.11)., Interpretation: The higher rates of antibiotic prescribing in remote consultations for adults are cause for concern. We see no significant difference in antibiotic prescribing between consultation mode for children. These findings should inform antimicrobial stewardship activities for health-care professionals and policy makers. Future research should examine differences in guideline-compliance between remote and face-to-face consultations to understand the factors driving antibiotic prescribing in different consultation modes., Funding: None., Competing Interests: We declare no competing interests., (© 2023 The Author(s).)

Objectives: To explore trends in patient-initiated requests for general practice services and the association between patient characteristics including demographics, preferences for care and clinical needs and modes of patient contact (online vs telephone), and care delivery (face-to-face vs remote) at practices using a modern access model., Design: Retrospective repeated cross-sectional study spanning March 2019 to February 2022., Setting: General practices in England using the askmyGP online consultation system to implement a modern general practice access model using digital and non-digital (multimodal) access pathways and digitally supported triage to manage patient-initiated requests., Participants: 10 435 465 patient-initiated requests from 1 488 865 patients at 154 practices., Results: Most requests were initiated online (72.1% in 2021/2022) rather than by telephone. Online users were likely to be female, younger than 45 years, asking about existing medical problems, had used the system before and frequent attenders (familiar patients). During the pandemic, request rates for face-to-face consultations fell while those for telephone consultations and online messages increased, with telephone consultations being most popular (53.8% in 2021/2022). Video was seldom requested. More than 60% of requests were consistently delivered in the mode requested. Face-to-face consultations were more likely to be used for the youngest and oldest patients, new medical problems, non-frequent attenders (unfamiliar patients) and those who requested a face-to-face consultation. Over the course of the study, request rates for patients aged over 44 years increased, for example, by 15.4% (p<0.01) for patients aged over 74 years. Rates for younger patients decreased by 32.6% (p<0.001) in 2020/2021, compared with 2019/2020, before recovering to prepandemic levels in 2021/2022., Conclusions: Demand patterns shed light on the characteristics of patients making requests for general practice services and the composition of the care backlog with implications for policy and practice. A modern general practice access model can be used effectively to manage patient-initiated demand., Competing Interests: Competing interests: AD and GC declare no competing interests. PC worked as a data analyst for NHS England during the course of this project. JL worked as a freelance consultant to NHS England and academic researcher during the course of this project. JL and MB receive financial support from NHS England for attending meetings., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers., Materials and Methods: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort., Results: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001)., Conclusions: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Background: The COVID-19 pandemic has had a significant impact on primary care service delivery with an increased use of remote consultations. With general practice delivering record numbers of appointments and rising concerns around access, funding, and staffing in the UK National Health Service, we assessed contemporary trends in consultation rate and modes (ie, face-to-face versus remote)., Objective: This paper describes trends in consultation rates in general practice in England for key demographics before and during the COVID-19 pandemic. We explore the use of remote and face-to-face consultations with regard to socioeconomic deprivation to understand the possible effect of changes in consultation modes on health inequalities., Methods: We did a retrospective analysis of 9,429,919 consultations by general practitioners, nurses, or other health care professionals between March 2018 and February 2022 for patients registered at 397 general practices in England. We used routine electronic health records from Clinical Practice Research Datalink Aurum with linkage to national data sets. Negative binomial models were used to predict consultation rates and modes (ie, remote versus face-to-face) by age, sex, and socioeconomic deprivation over time., Results: Overall consultation rates increased by 15% from 4.92 in 2018-2019 to 5.66 in 2021-2022 with some fluctuation during the start of the COVID-19 pandemic. The breakdown into face-to-face and remote consultations shows that the pandemic precipitated a rapid increase in remote consultations across all groups, but the extent varies by age. Consultation rates increased with increasing levels of deprivation. Socioeconomic differences in consultation rates, adjusted for sex and age, halved during the pandemic (from 0.36 to 0.18, indicating more consultations in the most deprived), effectively narrowing relative differences between deprivation quintiles. This trend remains when stratified by sex, but the difference across deprivation quintiles is smaller for men. The most deprived saw a relatively larger increase in remote and decrease in face-to-face consultation rates compared to the least deprived., Conclusions: The substantial increases in consultation rates observed in this study imply an increased pressure on general practice. The narrowing of consultation rates between deprivation quintiles is cause for concern, given ample evidence that health needs are greater in more deprived areas., (©Emma Maria Vestesson, Kaat Lieve An De Corte, Elizabeth Crellin, Jean Ledger, Minal Bakhai, Geraldine M Clarke. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 02.05.2023.)

Objective: To compare the original synthetic control (OSC) method with alternative approaches (Generalized [GSC], Micro [MSC], and Bayesian [BSC] synthetic control methods) and re-evaluate the impact of a significant restructuring of urgent and emergency care in Northeast England, which included the opening of the UK's first purpose-built specialist emergency care hospital., Data Sources: Simulations and data from Secondary Uses Service data, a single comprehensive repository for patient-level health care data in England., Study Design: Hospital use of individuals exposed and unexposed to the restructuring is compared. We estimate the impact using OSC, MSC, BSC, and GSC applied at the general practice level. We contrast the estimation methods' performance in a Monte Carlo simulation study., Data Collection/extraction Methods: Hospital activity data from Secondary Uses Service for patients aged over 18 years registered at a general practice in England from April 2011 to March 2019., Principal Findings: None of the methods dominated all simulation scenarios. GSC was generally preferred. In contrast to an earlier evaluation that used OSC, GSC reported a smaller impact of the opening of the hospital on Accident and Emergency (A&E) department (also known as emergency department or casualty) visits and no evidence for any impact on the proportion of A&E patients seen within 4 h., Conclusions: The simulation study highlights cases where the considered methods may lead to biased estimates in health policy evaluations. GSC was found to be the most reliable method of those considered. Considering more disaggregated data over a longer time span and applying GSC indicates that the specialist emergency care hospitals in Northumbria had less impact on A&E visits and waiting times than suggested by the original evaluation which applied OSC to more aggregated data., (© 2022 The Authors. Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Purpose: MRI-guided transurethral ultrasound ablation (TULSA) uses real-time MR thermometry feedback to target prostate disease. We systematically review the literature to synthesize efficacy, functional, and safety outcomes and assess the influence of planned ablation fraction on outcome. Materials and Methods: PubMed, Embase, and the Cochrane Library were searched from inception to June 2021 following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies reporting at least one efficacy, functional, or safety outcome after a single TULSA treatment were included. The relationship of freedom from salvage treatment and potency preservation with planned ablation volume was modeled. Results: Two hundred twenty-four patients were treated in 10 studies with up to a 5-year follow-up, mainly for primary localized prostate cancer (PCa) plus smaller cohorts with recurrent PCa, and locally advanced PCa (LAPC). The prostate-specific antigen decline from baseline up to 2 years, including focal to whole-gland ablation plans, was 54% to 97%. The rate of salvage treatment after one TULSA treatment for primary PCa was 7% to 17%. Continence and potency preservation were from 92% to 100% and from 75% to 98%. Urinary symptoms were stable in men with good voiding function at baseline, and 85% of men with concurrent PCa and lower urinary tract symptoms met the criteria for improvement. Symptom relief in a small cohort of men with LAPC was observed. Grade III adverse events were incurred by 13/224 men (6%), with no rectal injury/fistula or Grade IV complication. The planned ablation fraction was linearly related to salvage-free survival. The relationship between potency preservation and planned ablation fraction followed a sigmoid curve. Conclusions: As an alternative to conventional treatments, TULSA is safe and effective for prostate tissue ablation in men with primary PCa. There is also evidence that TULSA delivers effective relief of urinary symptoms while treating PCa in a single, low-morbidity procedure. The likelihood of freedom from additional treatment or potency preservation is associated with the planned ablation fraction.

Competing Interests: Competing interests We have read and understood BMJ policy on declaration of interests. All authors work in the Improvements Analytics Unit, a joint project between NHS England and the Health Foundation, which provided support for work reported in references of this report.133760

Background: During the set-up phase of an international study of genetic influences on outcomes from sepsis, we aimed to characterise potential differences in ethics approval processes and outcomes in participating European countries., Methods: Between 2005 and 2007 of the FP6-funded international Genetics Of Sepsis and Septic Shock (GenOSept) project, we asked national coordinators to complete a structured survey of research ethic committee (REC) approval structures and processes in their countries, and linked these data to outcomes. Survey findings were reconfirmed or modified in 2017., Results: Eighteen countries participated in the study, recruiting 2257 patients from 160 ICUs. National practices differed widely in terms of composition of RECs, procedures and duration of the ethics approval process. Eight (44.4%) countries used a single centralised process for approval, seven (38.9%) required approval by an ethics committee in each participating hospital, and three (16.7%) required both. Outcomes of the application process differed widely between countries because of differences in national legislation, and differed within countries because of interpretation of the ethics of conducting research in patients lacking capacity. The RECs in four countries had no lay representation. The median time from submission to final decision was 1.5 (interquartile range 1-7) months; in nine (50%) approval was received within 1 month; six took over 6 months, and in one 24 months; had all countries been able to match the most efficient approvals processes, an additional 74 months of country or institution-level recruitment would have been available. In three countries, rejection of the application by some local RECs resulted in loss of centres; and one country rejected the application outright., Conclusions: The potential benefits of the single application portal offered by the European Clinical Trials Regulation will not be realised without harmonisation of research ethics committee practices as well as national legislation.

Purpose: Linear tumor size (T-size) estimated with conventional histology informs breast cancer management. Previously we demonstrated significant differences in margin and focality estimates using conventional histology versus digital whole-mount serial sections (WMSS). Using WMSS we can measure T-size or volume. Here, we compare WMSS T-size with volume, and with T-size measured conventionally. We also compare the ellipsoid model for calculating tumor volume to direct, WMSS measurement., Methods: Two pathologists contoured regions of invasive carcinoma and measured T-size from both WMSS and (simulated) conventional sections in 55 consecutive lumpectomy specimens. Volume was measured directly from the contours. Measurements were compared using the paired t-test or Spearman's rank-order correlation. A five-point 'border index' was devised and assigned to each case to parametrize tumor shape considering 'compactness' or cellularity. Tumor volumes calculated assuming ellipsoid geometry were compared with direct, WMSS measurements., Results: WMSS reported significantly larger T-size than conventional histology in the majority of cases [61.8%, 34/55; means = (2.34 cm; 1.99 cm), p < 0.001], with a 16.4% (9/55) rate of 'upstaging'. The majority of discordances were due to undersampling. T-size and volume were strongly correlated (r = 0.838, p < 0.001). Significantly lower volume was obtained with WMSS versus ellipsoid modeling [means = (1.18 cm 3 ; 1.45 cm 3 ), p < 0.001]., Conclusions: Significantly larger T-size is measured with WMSS than conventionally, due primarily to undersampling in the latter. Volume and linear size are highly correlated. Diffuse tumors interspersed with normal or non-invasive elements may be sampled less extensively than more localized masses. The ellipsoid model overestimates tumor volume.

Background: Prognostic scores and models of illness severity are useful both clinically and for research. The aim of this study was to develop two prognostic models for the prediction of long-term (6 months) and 28-day mortality of postoperative critically ill patients with faecal peritonitis (FP)., Methods: Patients admitted to intensive care units with faecal peritonitis and recruited to the European GenOSept study were divided into a derivation and a geographical validation subset; patients subsequently recruited to the UK GAinS study were used for temporal validation. Using all 50 clinical and laboratory variables available on day 1 of critical care admission, Cox proportional hazards regression was fitted to select variables for inclusion in two prognostic models, using stepwise selection and nonparametric bootstrapping sampling techniques. Using Area under the receiver operating characteristic curve (AuROC) analysis, the performance of the models was compared to SOFA and APACHE II., Results: Five variables (age, SOFA score, lowest temperature, highest heart rate, haematocrit) were entered into the prognostic models. The discriminatory performance of the 6-month prognostic model yielded an AuROC 0.81 (95% CI 0.76-0.86), 0.73 (95% CI 0.69-0.78) and 0.76 (95% CI 0.69-0.83) for the derivation, geographic and temporal external validation cohorts, respectively. The 28-day prognostic tool yielded an AuROC 0.82 (95% CI 0.77-0.88), 0.75 (95% CI 0.69-0.80) and 0.79 (95% CI 0.71-0.87) for the same cohorts. These AuROCs appeared consistently superior to those obtained with the SOFA and APACHE II scores alone., Conclusions: The two prognostic models developed for 6-month and 28-day mortality prediction in critically ill septic patients with FP, in the postoperative phase, enhanced the day one SOFA score's predictive utility by adding a few key variables: age, lowest recorded temperature, highest recorded heart rate and haematocrit. External validation of their predictive capability in larger cohorts is needed, before introduction of the proposed scores into clinical practice to inform decision making and the design of clinical trials.

The malaria parasite Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genes GYPA and GYPB We find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss of GYPB and gain of two GYPB-A hybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria., (Copyright © 2017, American Association for the Advancement of Science.)

Background: Genome-wide association studies (GWAS) of single nucleotide polymorphisms (SNPs) have been successful in identifying loci contributing genetic effects to a wide range of complex human diseases and quantitative traits. The traditional approach to GWAS analysis is to consider each phenotype separately, despite the fact that many diseases and quantitative traits are correlated with each other, and often measured in the same sample of individuals. Multivariate analyses of correlated phenotypes have been demonstrated, by simulation, to increase power to detect association with SNPs, and thus may enable improved detection of novel loci contributing to diseases and quantitative traits., Results: We have developed the SCOPA software to enable GWAS analysis of multiple correlated phenotypes. The software implements "reverse regression" methodology, which treats the genotype of an individual at a SNP as the outcome and the phenotypes as predictors in a general linear model. SCOPA can be applied to quantitative traits and categorical phenotypes, and can accommodate imputed genotypes under a dosage model. The accompanying META-SCOPA software enables meta-analysis of association summary statistics from SCOPA across GWAS. Application of SCOPA to two GWAS of high-and low-density lipoprotein cholesterol, triglycerides and body mass index, and subsequent meta-analysis with META-SCOPA, highlighted stronger association signals than univariate phenotype analysis at established lipid and obesity loci. The META-SCOPA meta-analysis also revealed a novel signal of association at genome-wide significance for triglycerides mapping to GPC5 (lead SNP rs71427535, p = 1.1x10 -8 ), which has not been reported in previous large-scale GWAS of lipid traits., Conclusions: The SCOPA and META-SCOPA software enable discovery and dissection of multiple phenotype association signals through implementation of a powerful reverse regression approach.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations., Competing Interests: JF: Director of the Wellcome Trust, one of the three founding funders of eLife. The other authors declare that no competing interests exist.

Aims: Technical limitations in conventional pathological evaluation of breast lumpectomy specimens may reduce diagnostic accuracy in the assessment of margin and focality. A novel technique based on whole-mount serial sections enhances sampling while preserving specimen conformation and orientation. The aim of this study was to investigate assessment of focality and margin status by the use of whole-mount serial sections versus simulated conventional sections in lumpectomies., Methods and Results: Two pathologists interpreted whole-mount serial sections and simulated conventional sections for 58 lumpectomy specimens by reporting the closest margin and focality. Measurements were compared by the use of McNemar's chi-squared test. Statistically significant differences were observed in the assignment of both margin positivity (P = 0.014) and multifocality (P = 0.021). A positive margin or multifocal disease was identified by the use of whole-mount serial sections but missed in the simulated conventional assessment in 10.3% and 17.2% of all cases, respectively. There was no case in which a positive margin was detected only in the simulated conventional assessment., Conclusions: The whole-mount technique is more sensitive than conventional assessment for identifying a positive margin or multifocal disease in breast lumpectomy specimens. Undersampling in conventional sections was implicated in almost all cases of discordance. The majority of positive margins or secondary foci identified only in whole-mount serial sections concerned in-situ disease., (© 2015 John Wiley & Sons Ltd.)

In the process of developing a multiplex of 8 common breast cancer biomarkers (Her2/neu, estrogen receptor, progesterone receptor, Ki-67, aldehyde dehydrogenase-1, NaK-ATPase, cytokeratin 8/18, and myosin smooth muscle) on a single formalin-fixed paraffin-embedded slide using a sequential staining, imaging, and dye bleaching technology developed by General Electric Company, membranous Ki-67 staining was observed and colocalized with Her2/neu staining. Using immunohistochemistry as gold standards, we discovered that membranous Ki-67 was an artifact caused by the binding of cyanine 5-conjugated rabbit polyclonal Ki-67 antibody to a secondary cyanine 3-conjugated donkey anti-rabbit antibody which was previously applied and bound to rabbit Her2/neu antibody in our multiplexing experiment. After blocking with rabbit serum, a successful protocol for 8 biomarker multiplexing without cross-reactivity of antibodies from the same species was developed.

Background: Obtaining accurate histopathologic detail for breast lumpectomy specimens is challenging because of sampling and loss of three-dimensional conformational features with conventional processing. The whole-mount (wm) technique is a novel method of serial pathologic sectioning designed to optimize cross-sectional visualization of resected specimens and determination of margin status., Methods: Using a Markov chain cohort simulation cost-effectiveness model, we compared conventional processing with wm technique for breast lumpectomies. Cost-effectiveness was evaluated from the perspective of the Canadian health care system and compared using incremental cost-effectiveness ratios (icers) for cost per quality-adjusted life-year (qaly) over a 10-year time horizon. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the model with willingness-to-pay (wtp) thresholds of $0-$100,000. Costs are reported in adjusted 2014 Canadian dollars, discounted at a rate of 3%., Results: Compared with conventional processing, wm processing is more costly ($19,989 vs. $18,427) but generates 0.03 more qalys over 10 years. The icer is $45,414, indicating that this additional amount is required for each additional qaly obtained. The model was robust to all variance in parameters, with the prevalence of positive margins accounting for most of the model's variability., Conclusions: After a wtp threshold of $45,414, wm processing becomes cost-effective and ultimately generates fewer recurrences and marginally more qalys over time. Excellent baseline outcomes for the current treatment of breast cancer mean that incremental differences in survival are small. However, the overall benefit of the wm technique should be considered in the context of achieving improved accuracy and not just enhancements in clinical effectiveness.

Background: The global prevalence of X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is thought to be a result of selection by malaria, but epidemiological studies have yielded confusing results. We investigated the relationships between G6PD deficiency and both malaria and non-malarial illnesses among children in Kenya., Methods: We did this study in Kilifi County, Kenya, where the G6PD c.202T allele is the only significant cause of G6PD deficiency. We tested the associations between G6PD deficiency and severe and complicated Plasmodium falciparum malaria through a case-control study of 2220 case and 3940 control children. Cases were children aged younger than 14 years, who visited the high dependency ward of Kilifi County Hospital with severe malaria between March 1, 1998, and Feb 28, 2010. Controls were children aged between 3-12 months who were born within the same study area between August 2006, and September 2010. We assessed the association between G6PD deficiency and both uncomplicated malaria and other common diseases of childhood in a cohort study of 752 children aged younger than 10 years. Participants of this study were recruited from a representative sample of households within the Ngerenya and Chonyi areas of Kilifi County between Aug 1, 1998, and July 31, 2001. The primary outcome measure for the case-control study was the odds ratio for hospital admission with severe malaria (computed by logistic regression) while for the cohort study it was the incidence rate ratio for uncomplicated malaria and non-malaria illnesses (computed by Poisson regression), by G6PD deficiency category., Findings: 2863 (73%) children in the control group versus 1643 (74%) in the case group had the G6PD normal genotype, 639 (16%) versus 306 (14%) were girls heterozygous for G6PD c.202T, and 438 (11%) versus 271 (12%) children were either homozygous girls or hemizygous boys. Compared with boys and girls without G6PD deficiency, we found significant protection from severe malaria (odds ratio [OR] 0·82, 95% CI 0·70-0·97; p=0·020) among G6PD c.202T heterozygous girls but no evidence for protection among G6PD c.202T hemizygous boys and homozygous girls (OR 1·18, 0·99-1·40; p=0·056). Median follow-up for the mild disease cohort study was 2·24 years (IQR 2·22-2·85). G6PD c.202T had no effect on other common diseases of childhood in heterozygous girls (incidence rate ratio 0·98, 95% CI 0·86-1·11; p=0·82) or homozygous girls or hemizygous boys (0·93, 0·82-1·04; p=0·25), with the sole exception of a marginally significant increase in the incidence of helminth infections among heterozygous girls., Interpretation: Heterozygous girls might be the driving force for the positive selection of G6PD deficiency alleles. Further studies are needed to definitively establish the mechanisms by which G6PD deficiency confers an advantage against malaria in heterozygous individuals. Such studies could lead to the development of new treatments., Funding: Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health (as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative)., (Copyright © 2015 Uyoga et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Background: Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels., Methods: Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP)4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels., Results: Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2., Conclusion: Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.

Introduction: Patients admitted to intensive care following surgery for faecal peritonitis present particular challenges in terms of clinical management and risk assessment. Collaborating surgical and intensive care teams need shared perspectives on prognosis. We aimed to determine the relationship between dynamic assessment of trends in selected variables and outcomes., Methods: We analysed trends in physiological and laboratory variables during the first week of intensive care unit (ICU) stay in 977 patients at 102 centres across 16 European countries. The primary outcome was 6-month mortality. Secondary endpoints were ICU, hospital and 28-day mortality. For each trend, Cox proportional hazards (PH) regression analyses, adjusted for age and sex, were performed for each endpoint., Results: Trends over the first 7 days of the ICU stay independently associated with 6-month mortality were worsening thrombocytopaenia (mortality: hazard ratio (HR) = 1.02; 95% confidence interval (CI), 1.01 to 1.03; P < 0.001) and renal function (total daily urine output: HR =1.02; 95% CI, 1.01 to 1.03; P < 0.001; Sequential Organ Failure Assessment (SOFA) renal subscore: HR = 0.87; 95% CI, 0.75 to 0.99; P = 0.047), maximum bilirubin level (HR = 0.99; 95% CI, 0.99 to 0.99; P = 0.02) and Glasgow Coma Scale (GCS) SOFA subscore (HR = 0.81; 95% CI, 0.68 to 0.98; P = 0.028). Changes in renal function (total daily urine output and renal component of the SOFA score), GCS component of the SOFA score, total SOFA score and worsening thrombocytopaenia were also independently associated with secondary outcomes (ICU, hospital and 28-day mortality). We detected the same pattern when we analysed trends on days 2, 3 and 5. Dynamic trends in all other measured laboratory and physiological variables, and in radiological findings, changes in respiratory support, renal replacement therapy and inotrope and/or vasopressor requirements failed to be retained as independently associated with outcome in multivariate analysis., Conclusions: Only deterioration in renal function, thrombocytopaenia and SOFA score over the first 2, 3, 5 and 7 days of the ICU stay were consistently associated with mortality at all endpoints. These findings may help to inform clinical decision making in patients with this common cause of critical illness.

Background: Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention., Methods and Findings: The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction  = 1.20×10-4). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction  = 1.50×10-3) and waist circumference (p for interaction  = 7.49×10-9). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score., Conclusions: The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.

Introduction: Community acquired pneumonia (CAP) is the most common infectious reason for admission to the Intensive Care Unit (ICU). The GenOSept study was designed to determine genetic influences on sepsis outcome. Phenotypic data was recorded using a robust clinical database allowing a contemporary analysis of the clinical characteristics, microbiology, outcomes and independent risk factors in patients with severe CAP admitted to ICUs across Europe., Methods: Kaplan-Meier analysis was used to determine mortality rates. A Cox Proportional Hazards (PH) model was used to identify variables independently associated with 28-day and six-month mortality., Results: Data from 1166 patients admitted to 102 centres across 17 countries was extracted. Median age was 64 years, 62% were male. Mortality rate at 28 days was 17%, rising to 27% at six months. Streptococcus pneumoniae was the commonest organism isolated (28% of cases) with no organism identified in 36%. Independent risk factors associated with an increased risk of death at six months included APACHE II score (hazard ratio, HR, 1.03; confidence interval, CI, 1.01-1.05), bilateral pulmonary infiltrates (HR1.44; CI 1.11-1.87) and ventilator support (HR 3.04; CI 1.64-5.62). Haematocrit, pH and urine volume on day one were all associated with a worse outcome., Conclusions: The mortality rate in patients with severe CAP admitted to European ICUs was 27% at six months. Streptococcus pneumoniae was the commonest organism isolated. In many cases the infecting organism was not identified. Ventilator support, the presence of diffuse pulmonary infiltrates, lower haematocrit, urine volume and pH on admission were independent predictors of a worse outcome.