Evaluating mental health decision units in acute care pathways (DECISION): a quasi-experimental, qualitative and health economic evaluation.

Background: People experiencing mental health crises in the community often present to emergency departments and are admitted to a psychiatric hospital. Because of the demands on emergency department and inpatient care, psychiatric decision units have emerged to provide a more suitable environment for assessment and signposting to appropriate care. Objectives: The study aimed to ascertain the structure and activities of psychiatric decision units in England and to provide an evidence base for their effectiveness, costs and benefits, and optimal configuration. Design: This was a mixed-methods study comprising survey, systematic review, interrupted time series, synthetic control study, cohort study, qualitative interview study and health economic evaluation, using a critical interpretive synthesis approach. Setting: The study took place in four mental health National Health Service trusts with psychiatric decision units, and six acute hospital National Health Service trusts where emergency departments referred to psychiatric decision units in each mental health trust. Participants: Participants in the cohort study (n = 2110) were first-time referrals to psychiatric decision units for two 5-month periods from 1 October 2018 and 1 October 2019, respectively. Participants in the qualitative study were first-time referrals to psychiatric decision units recruited within 1 month of discharge (n = 39), members of psychiatric decision unit clinical teams (n = 15) and clinicians referring to psychiatric decision units (n = 19). Outcomes: Primary mental health outcome in the interrupted time series and cohort study was informal psychiatric hospital admission, and in the synthetic control any psychiatric hospital admission; primary emergency department outcome in the interrupted time series and synthetic control was mental health attendance at emergency department. Data for the interrupted time series and cohort study were extracted from electronic patient record in mental health and acute trusts; data for the synthetic control study were obtained through NHS Digital from Hospital Episode Statistics admitted patient care for psychiatric admissions and Hospital Episode Statistics Accident and Emergency for emergency department attendances. The health economic evaluation used data from all studies. Relevant databases were searched for controlled or comparison group studies of hospital-based mental health assessments permitting overnight stays of a maximum of 1 week that measured adult acute psychiatric admissions and/or mental health presentations at emergency department. Selection, data extraction and quality rating of studies were double assessed. Narrative synthesis of included studies was undertaken and meta-analyses were performed where sufficient studies reported outcomes. Results: Psychiatric decision units have the potential to reduce informal psychiatric admissions, mental health presentations and wait times at emergency department. Cost savings are largely marginal and do not offset the cost of units. First-time referrals to psychiatric decision units use more inpatient and community care and less emergency department-based liaison psychiatry in the months following the first visit. Psychiatric decision units work best when configured to reduce either informal psychiatric admissions (longer length of stay, higher staff-to-patient ratio, use of psychosocial interventions), resulting in improved quality of crisis care or demand on the emergency department (higher capacity, shorter length of stay). To function well, psychiatric decision units should be integrated into the crisis care pathway alongside a range of community-based support. Limitations: The availability and quality of data imposed limitations on the reliability of some analyses. Future work: Psychiatric decision units should not be commissioned with an expectation of short-term financial return on investment but, if appropriately configured, they can provide better quality of care for people in crisis who would not benefit from acute admission or reduce pressure on emergency department. Study registration: The systematic review was registered on the International Prospective Register of Systematic Reviews as CRD42019151043. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/49/70) and is published in full in Health and Social Care Delivery Research; Vol. 11, No. 25. See the NIHR Funding and Awards website for further award information.

People who experience mental health crises often go to a hospital emergency department and can be admitted to a psychiatric hospital. Emergency departments and psychiatric wards are not always the best environments for supporting people in a crisis. Emergency departments are overcrowded and waits can be very long; psychiatric wards are also very busy. Psychiatric decision units have been introduced to reduce pressure and improve experiences of crisis care. Psychiatric decision units are short-stay hospital-based units where people can be assessed and signposted to the most appropriate care. This study aimed to evaluate the effect of psychiatric decision units on emergency department visits, psychiatric admissions and the cost of mental health care, and to consider the best way for psychiatric decision units to be structured. We looked at research on similar units internationally and identified all psychiatric decision units in England. We evaluated the impact of psychiatric decision units four mental health NHS trusts on emergency department visits and psychiatric admissions by examining electronic patient records in the 2 years before and after units opened, and by comparing records in areas with and without psychiatric decision units using data from NHS Digital. We compared mental health services used by people in the 9 months before and after their first psychiatric decision unit stay. We interviewed people about their experiences of the psychiatric decision unit and crisis care. We also interviewed staff working on and referring people to psychiatric decision units. There were some reductions in psychiatric admissions, emergency department visits and wait times following opening of psychiatric decision units. The resulting cost savings were small and did not outweigh the costs of running psychiatric decision units. People mostly found units safe, calming and supportive, except where they were discharged too quickly. Psychiatric decision units worked best to reduce psychiatric admissions and improve quality of crisis care where stays were longer and staffing levels higher. Psychiatric decision units had more impact on emergency departments where they were larger and stays were shorter.

Continuity of care and consultation mode in general practice: a cross-sectional and longitudinal study using patient-level and practice-level data from before and during the COVID-19 pandemic in England.

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.

Antibiotic prescribing in remote versus face-to-face consultations for acute respiratory infections in primary care in England: an observational study using target maximum likelihood estimation.

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.

How is primary care access changing? A retrospective, repeated cross-sectional study of patient-initiated demand at general practices in England using a modern access model, 2019-2022.

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.

Consultation Rate and Mode by Deprivation in English General Practice From 2018 to 2022: Population-Based Study.

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.

Service use preceding and following first referral for psychiatric emergency care at a short-stay crisis unit: A cohort study across three cities and one rural area in England.

BACKGROUND: Internationally, hospital-based short-stay crisis units have been introduced to provide a safe space for stabilisation and further assessment for those in psychiatric crisis. The units typically aim to reduce inpatient admissions and psychiatric presentations to emergency departments. AIMS: To assess changes to service use following a service user's first visit to a unit, characterise the population accessing these units and examine equality of access to the units. METHODS: A prospective cohort study design (ISCTRN registered; 53431343) compared service use for the 9 months preceding and following a first visit to a short-stay crisis unit at three cities and one rural area in England. Included individuals first visited a unit in the 6 months between 01/September/2020 and 28/February/2021. RESULTS: The prospective cohort included 1189 individuals aged 36 years on average, significantly younger (by 5-13 years) than the population of local service users (<.001). Seventy percent were White British and most were without a psychiatric diagnosis (55%-82% across sites). The emergency department provided the largest single source of referrals to the unit (42%), followed by the Crisis and Home Treatment Team (20%). The use of most mental health services, including all types of admission and community mental health services was increased post discharge. Social-distancing measures due to the COVID-19 pandemic were in place for slightly over 50% of the follow-up period. Comparison to a pre-COVID cohort of 934 individuals suggested that the pandemic had no effect on the majority of service use variables. CONCLUSIONS: Short-stay crisis units are typically accessed by a young population, including those who previously were unknown to mental health services, who proceed to access a broader range of mental health services following discharge.

A comparison of synthetic control approaches for the evaluation of policy interventions using observational data: Evaluating the impact of redesigning urgent and emergency care in Northumberland.

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.

Short-stay crisis units for mental health patients on crisis care pathways: systematic review and meta-analysis.

BACKGROUND: Internationally, an increasing proportion of emergency department visits are mental health related. Concurrently, psychiatric wards are often occupied above capacity. Healthcare providers have introduced short-stay, hospital-based crisis units offering a therapeutic space for stabilisation, assessment and appropriate referral. Research lags behind roll-out, and a review of the evidence is urgently needed to inform policy and further introduction of similar units. AIMS: This systematic review aims to evaluate the effectiveness of short-stay, hospital-based mental health crisis units. METHOD: We searched EMBASE, Medline, CINAHL and PsycINFO up to March 2021. All designs incorporating a control or comparison group were eligible for inclusion, and all effect estimates with a comparison group were extracted and combined meta-analytically where appropriate. We assessed study risk of bias with Risk of Bias in Non-Randomized Studies - of Interventions and Risk of Bias in Randomized Trials. RESULTS: Data from twelve studies across six countries (Australia, Belgium, Canada, The Netherlands, UK and USA) and 67 505 participants were included. Data indicated that units delivered benefits on many outcomes. Units could reduce psychiatric holds (42% after intervention compared with 49.8% before intervention; difference = 7.8%; P < 0.0001) and increase out-patient follow-up care (χ2 = 37.42, d.f. = 1; P < 0.001). Meta-analysis indicated a significant reduction in length of emergency department stay (by 164.24 min; 95% CI -261.24 to -67.23 min; P < 0.001) and number of in-patient admissions (odds ratio 0.55, 95% CI 0.43-0.68; P < 0.001). CONCLUSIONS: Short-stay mental health crisis units are effective for reducing emergency department wait times and in-patient admissions. Further research should investigate the impact of units on patient experience, and clinical and social outcomes.

The psychiatric decision unit as an emerging model in mental health crisis care: a national survey in England.

Psychiatric decision units have been developed in many countries internationally to address the pressure on inpatient services and dissatisfactory, long waits people in mental health crisis can experience in emergency departments. Research into these units lags behind their development, as they are implemented by healthcare providers to address these problems. This is the first-ever national survey to identify their prevalence, structure, activities, and contextual setting within health services, in order to provide a robust basis for future research. The response rate was high (94%), and six PDUs in England were identified. The results indicated that PDUs open 24/7, accept only voluntary patients, provide recliner chairs for sleeping rather than beds, and limit stays to 12-72 hours. PDUs are predominantly staffed by senior, qualified mental health nurses and healthcare assistants, with psychiatry input. Staff:patient ratios are high (1:2.1 during the day shift). Differences in PDU structure and activities (including referral pathway, length of stay, and staff:patient ratios) were identified, suggesting the optimal configuration for PDUs has not yet been established. Further research into the efficacy of this innovation is needed; PDUs potentially have a role in an integrated crisis care pathway which provides a variety of care options to service users.

Methodological challenges in European ethics approvals for a genetic epidemiology study in critically ill patients: the GenOSept experience.

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.

Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.

BACKGROUND: Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms-many related to the structure or function of red blood cells-and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. METHODS: We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. FINDINGS: Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11-0·20; p=2·61 × 10-58), blood group O (0·74, 0·66-0·82; p=6·26 × 10-8), and -α3·7-thalassaemia (0·83, 0·76-0·90; p=2·06 × 10-6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63-0·92; p=0·001) and FREM3 (0·64, 0·53-0·79; p=3·18 × 10-14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49-0·68; p=3·22 × 10-11), as was homozygosity (0·26, 0·11-0·62; p=0·002). INTERPRETATION: Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. 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.

Derivation and validation of a prognostic model for postoperative risk stratification of critically ill patients with faecal peritonitis.

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.

Resistance to malaria through structural variation of red blood cell invasion receptors.

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.

SCOPA and META-SCOPA: software for the analysis and aggregation of genome-wide association studies of multiple correlated phenotypes.

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.

Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.

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.

Glucose-6-phosphate dehydrogenase deficiency and the risk of malaria and other diseases in children in Kenya: a case-control and a cohort study.

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).

Genetic determinants of anti-malarial acquired immunity in a large multi-centre study.

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.

Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: analysis of the GenOSept cohort.

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.

Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study.

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.