National Health Service Research Research Articles

Influence of combined vitamin D3 supplementation and resistance exercise training on musculoskeletal health in older men and women (EXVITD): protocol for a randomised controlled trial

IntroductionSarcopenia is a progressive loss in muscle mass, strength and function, the adverse consequences of which are severe, affecting quality of life and placing an increasing burden on social and...

Using telemedicine to improve access, cost and quality of secondary care for people in prison in England: a hybrid type 2 implementation effectiveness study

IntroductionPeople in prison tend to experience poorer health, access to healthcare services and health outcomes than the general population. Use of video consultations (telemedicine) has been proven effective at improving...

Proton beam therapy: perspectives on the National Health Service England clinical service and research programme.

The UK has an important role in the evaluation of proton beam therapy (PBT) and takes its place on the world stage with the opening of the first National Health Service (NHS) PBT centre in Manchester in 2018, and the second in London coming in 2020. Systematic evaluation of the role of PBT is a key objective. By September 2019, 108 patients had started treatment, 60 paediatric, 19 teenagers and young adults and 29 adults. Obtaining robust outcome data is vital, if we are to understand the strengths and weaknesses of current treatment approaches. This is important in demonstrating when PBT will provide an advantage and when it will not, and in quantifying the magnitude of benefit.The UK also has an important part to play in translational PBT research, and building a research capability has always been the vision. We are perfectly placed to perform translational pre-clinical biological and physical experiments in the dedicated research room in Manchester. The nature of DNA damage from proton irradiation is considerably different from X-rays and this needs to be more fully explored. A better understanding is needed of the relative biological effectiveness (RBE) of protons, especially at the end of the Bragg peak, and of the effects on tumour and normal tissue of PBT combined with conventional chemotherapy, targeted drugs and immunomodulatory agents. These experiments can be enhanced by deterministic mathematical models of the molecular and cellular processes of DNA damage response. The fashion of ultra-high dose rate FLASH irradiation also needs to be explored.

ActivPAL and ActiGraph Assessed Sedentary Behavior and Cardiometabolic Health Markers.

To establish whether associations between sedentary behavior and cardiometabolic health differ when assessed by thigh-worn and waist-worn accelerometry. Participants were recruited from several areas in the United Kingdom. Sedentary behavior was assessed using the activPAL worn on the thigh and ActiGraph worn on the waist. Average total (TST), prolonged (bouts ≥30 min; PST) and breaks (BST) in sedentary time were calculated. Cardiometabolic health markers included: adiposity (body fat) and surrogate markers of adiposity ((waist circumference, body mass index [BMI]), lipids (total, low density lipoprotein, and high-density lipoprotein [HDL] cholesterol, triglycerides), blood pressure, and glucose (fasting, 2 h and glycated hemoglobin A1c). A clustered cardiometabolic risk score was calculated. Linear regression analysis examined the associations with cardiometabolic health. There were 1457 participants (mean age [± standard deviation], 59.38 ± 11.85 yr; 51.7% male; mean BMI, 30.19 ± 5.59 kg·m) included in the analyses. ActivPAL and ActiGraph sedentary variables were moderately correlated (0.416-0.511, P < 0.01); however, all variables were significantly different from each other (P < 0.05). Consistency was observed across devices in the direction and magnitude of associations of TST and PST with adiposity, surrogate markers of adiposity, HDL, triglycerides, and cardiometabolic risk score and for BST with adiposity, surrogate markers of adiposity, and cardiometabolic risk. Differences across devices were observed in associations of TST and PST with diastolic blood pressure, for TST with 2-h glucose and for BST with HDL. No other associations were observed for any other health marker for either device. Results suggest that associations with cardiometabolic health are largely comparable across the two common assessments of sedentary behavior but some small differences may exist for certain health markers.

Is austerity responsible for the recent change in mortality trends across high-income nations? A protocol for an observational study

IntroductionMortality rates in many high-income countries have changed from their long-term trends since around 2011. This paper sets out a protocol for testing the extent to which economic austerity can...

The Early Impact of COVID-19 on Mental Health and Community Physical Health Services and Their Patients’ Mortality in Cambridgeshire and Peterborough, UK

BACKGROUND: COVID-19 has affected social interaction and healthcare worldwide.METHODS: We examined changes in presentations and referrals to the primary provider of mental health and community health services in Cambridgeshire and Peterborough, UK, plus service activity and deaths. We conducted interrupted time series analyses with respect to the UK “lockdown”. We examined changes in standardized mortality ratio for those with and without severe mental illness (SMI).OUTCOMES: Referrals and presentations to nearly all mental and physical health services dropped at lockdown, with evidence for changes in both supply (service provision) and demand (help-seeking). This was followed by an increase in demand for some services. This pattern was seen for all major forms of presentation to liaison psychiatry services, except for psychosis/mania and eating disorders, for which there was no evidence of change. Inpatient numbers fell, but new detentions under the Mental Health Act were unchanged. Many services shifted from face-to-face to remote contacts. Excess mortality, primarily in the over-70s, lagged slightly behind confirmed numbers of COVID-19 cases. There was a much greater increase in mortality for patients with SMI, which was not explained by ethnicity.INTERPRETATION: COVID-19 has been associated with a system-wide drop in the use of mental health services, with some subsequent return in activity. This may reflect a genuine reduction of need or a lack of help-seeking and pent-up demand. There has been a disproportionate increase in death among those with SMI during the pandemic.FUNDING: UK Medical Research Council and National Institute of Health Research.DECLARATION OF INTERESTS:  Several authors (PBJ, BRU, AM, ETB, ESO, JBD, CFH, FJT, RNC) are CPFT clinicians involved in delivering some of the services discussed here and two (BRU, FJT) are clinical directors and therefore involved in managing them.  PBJ is a scientific advisory board member for Johnson & Johnson and Recordati.  BRU is clinical director of the Windsor Unit at Fulbourn Hospital (CPFT), which delivers clinical trials in dementia/mild cognitive impairment for academic and commercial organisations without personal benefit, and is the clinical lead for dementia for the NIHR Clinical Research Network (CRN) in the East of England. His salary is part-funded by the NIHR CRN. He has been principal investigator on trials for Axovant, Lilly, and EIP Pharma; his institution has benefited from payment for research carried out but he has not personally received any money. His wife is the lead for mental health for Suffolk Clinical Commissioning Group.  AM’s salary is part-funded by the Anna Freud National Centre for Children and Families, a mental health charity.  ETB is a scientific advisory board member for Sosei Hepares, and was a half-time employee of GlaxoSmithKline until May 2019.  RNC consults for Campden Instruments Ltd and receives royalties from Cambridge University Press, Cambridge Enterprise, and Routledge.  SC, SB, EFO, JBD, CFH, FJT, JDA, MPS, and JRL have nothing else to disclose.ETHICS APPROVAL STATEMENT: De-identified data was extracted from CPFT clinical records by CPFT’s Information & Performance team and via the CPFT Research Database (NHS research ethics 17/EE/0442). The study was conducted under UK National Health Service Research Ethics approval (ref. 17/EE/0442).

The feasibility of low-intensity psychological therapy for depression co-occurring with autism in adults: The Autism Depression Trial (ADEPT) - a pilot randomised controlled trial.

Low-intensity cognitive behaviour therapy including behavioural activation is an evidence-based treatment for depression, a condition frequently co-occurring with autism. The feasibility of adapting low-intensity cognitive behaviour therapy for depression to meet the needs of autistic adults via a randomised controlled trial was investigated. The adapted intervention (guided self-help) comprised materials for nine individual sessions with a low-intensity psychological therapist. Autistic adults (n = 70) with depression (Patient Health Questionnaire-9 score ⩾10) recruited from National Health Service adult autism services and research cohorts were randomly allocated to guided self-help or treatment as usual. Outcomes at 10-, 16- and 24-weeks post-randomisation were blind to treatment group. Rates of retention in the study differed by treatment group with more participants attending follow-up in the guided self-help group than treatment as usual. The adapted intervention was well-received, 86% (n = 30/35) of participants attended the pre-defined ‘dose’ of five sessions of treatment and 71% (25/35) attended all treatment sessions. The findings of this pilot randomised controlled trial indicate that low-intensity cognitive behaviour therapy informed by behavioural activation can be successfully adapted to meet the needs of autistic people. Evaluation of the effectiveness of this intervention in a full scale randomised controlled trial is now warranted.

Impact of Sitagliptin on Endometrial Mesenchymal Stem-Like Progenitor Cells: A Randomised, Double-Blind Placebo-Controlled Feasibility Trial

Background: Recurrent pregnancy loss (RPL) is associated with the loss of endometrial mesenchymal stem-like progenitor cells (eMSC). DPP4 inhibitors may increase homing and engraftment of bone marrow-derived cells to sites of tissue injury by preventing inactivation of stromal cell-derived factor-1α, a potent chemoattractant. Aims: To assess the effect of the DPP4 inhibitor sitagliptin on eMSC in women with RPL, to evaluate the impact on endometrial decidualization, and to assess the feasibility of a full-scale clinical trial. Methods: A double-blind, randomised, placebo-controlled feasibility trial on women aged 18 to 42 years with a history of 3 or more consecutive pregnancy losses, regular ovulatory menstrual cycles, and no contraindications to sitagliptin. Thirty-eighty subjects were randomised to either 100 mg sitagliptin daily for 3 consecutive cycles or identical placebo capsules. Computer generated, permuted block randomisation was used to allocate treatment packs. The primary outcome measure was the posttreatment eMSC count, assessed by colony forming unit (CFU) assays, in midluteal biopsies. Secondary outcome measures were change in CFU count before and after placebo or sitagliptin treatment, endometrial thickness, study acceptability, and subsequent pregnancy outcome within 12 months following the study. Tissue samples were subjected to explorative investigations. Findings: CFU counts following sitagliptin were higher compared to placebo when adjusted for baseline CFU counts and age (RR:1.52, 95%CI:1.32-1.75, P<0.01). The CFU count increased 1.68-fold in the sitagliptin group and 1.08-fold in the placebo group. The trial was acceptable and drug compliance high. were no serious adverse events. Explorative investigations showed that sitagliptin inhibits the expression of DIO2, a marker gene of senescent decidual cells. Interpretation: Sitagliptin increases eMSCs and decreases decidual senescence. A large-scale clinical trial evaluating the impact of preconception sitagliptin treatment on pregnancy outcome in RPL is feasible and warranted. Trial Registration: EU Clinical Trials Register no. 2016-001120-54. Funding Statement: The study was sponsored by UHCW NHS Trust and funded by Tommy’s baby charity (registered charity 1060508/ SC039280, Great Britain). R.F. received funding from Juntendo University, Japan. Declaration of Interests: The authors stated: There are no conflicts of interests. Ethics Approval Statement: The SIMPLANT study was approved by the Medicines and Healthcare Regulatory Authority (MHRA), the National Health Service Research Ethics Committee South Central-Hampshire B (16/SC/0229) and Research, Development and Innovation (RD&I) office at University Hospitals Coventry and Warwickshire (UHCW) National Health Service (NHS) Trust.

The Economic Burden of Patients with Eating Disorders to Healthcare Providers: A 27-Year Retrospective Record Linked Electronic Cohort Study

Background: 70 million people worldwide suffer from an eating disorder (ED) and long-term care is often needed. Patients are often young and vulnerable yet ambivalent about recovery. Without specific knowledge of the disease trajectory, patients with ED can evade detection, delaying time to diagnosis and treatment, and influencing long-term outcome and grossly underestimating treatment costs. Aim: The aim of this study was to estimate the healthcare economic burden from 1990 to 2017 of a cohort of patients with a diagnosis of an ED. Methods: The linkage and hosting of data were performed in the Secure Anonymised Information Linkage (SAIL) databank using a retrospective cohort study design. The SAIL databank is a large routine clinical database covering Wales. The data used was from the Patient Episode Database for Wales, Wales Demographics Service and Welsh General Practice datasets between 01/07/1990 and 30/06/2017, which are placed in SAIL by the Welsh National Health Service (NHS) and other data holders. Findings: Between 1990 and 2017, 15,558 individuals had an ED diagnosis. Patients with ED had large costs for inpatient admissions and GP contacts. Interpretation: Routine clinical data can be used effectively to quantify some burden of costs of a mental disorder beyond service use. ED incurred high NHS costs for GP contacts and inpatient admissions. The study included patients across the spectrum of severities, irrespective of whether they are known to specialist services. The scale of costs suggest that suffering from ED is likely to cost the NHS in areas well beyond what specific mental health service provision costs. We suggest that it may be cost-effective to invest in early intervention services that can help patients recover promptly from ED and potentially prevent high long-term costs of treatment and debility. Funding: Health and Care Research Wales (Grant HRA-15-1079). Declaration of Interest: All the authors have no competing interests to declare. Ethical Approval: The study design uses anonymised data and therefore the need for ethical approval and participant consent was waived by the approving IRB (Institutional Review Board), the UK National Health Service Research Ethics Committee. Instead, the SAIL Information Governance Review Panel (IGRP), which contains members from the UK National Health Service Research Ethics Committee, experts in information governance and members of the public, approved the study, IGRP 0487. This study was carried out in Swansea University.

Protocol for a case–control diagnostic accuracy study to develop diagnostic criteria for psoriasis in children (DIPSOC study): a multicentre study recruiting in UK paediatric dermatology clinics

IntroductionDiagnosing psoriasis in children can be challenging. Early and accurate diagnosis is important to ensure patients receive psoriasis specific treatment and monitoring. It is recognised that the physical, psychological, quality...

Study protocol for a randomised controlled trial of carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis (CALIBRE trial)

IntroductionLiver cirrhosis is the fifth largest cause of adult deaths, and a major complication, variceal bleeding is associated with a 1-year mortality of 40%. There is uncertainty on the first-line...

What factors promote or inhibit implementation of a new procedure for screening and treatment of malnutrition in community settings? A prospective process evaluation of the Implementing Nutrition Screening in Community Care for Older People (INSCCOPe) project (UK)

IntroductionMalnutrition remains underdetected, undertreated and often overlooked by those working with older people in primary care in the UK. A new procedure for screening and treatment of malnutrition is currently...

Million Migrants study of healthcare and mortality outcomes in non-EU migrants and refugees to England: Analysis protocol for a linked population-based cohort study of 1.5 million migrants

Background: In 2017, 15.6% of the people living in England were born abroad, yet we have a limited understanding of their use of health services and subsequent health conditions. This linked population-based cohort study aims to describe the hospital-based healthcare and mortality outcomes of 1.5 million non-European Union (EU) migrants and refugees in England. Methods and analysis: We will link four data sources: first, non-EU migrant tuberculosis pre-entry screening data; second, refugee pre-entry health assessment data; third, national hospital episode statistics; and fourth, Office of National Statistics death records. Using this linked dataset, we will then generate a population-based cohort to examine hospital-based events and mortality outcomes in England between Jan 1, 2006, and Dec 31, 2017. We will compare outcomes across three groups in our analyses: 1) non-EU international migrants, 2) refugees, and 3) general population of England. Ethics and dissemination: We will obtain approval to use unconsented patient identifiable data from the Secretary of State for Health through the Confidentiality Advisory Group and the National Health Service Research Ethics Committee. After data linkage, we will destroy identifying data and undertake all analyses using the pseudonymised dataset. The results will provide policy makers and civil society with detailed information about the health needs of non-EU international migrants and refugees in England.

Million Migrants study of healthcare and mortality outcomes in non-EU migrants and refugees to England: Analysis protocol for a linked population-based cohort study of 1.5 million migrants.

Background: In 2017, 15.6% of the people living in England were born abroad, yet we have a limited understanding of their use of health services and subsequent health conditions. This linked population-based cohort study aims to describe the hospital-based healthcare and mortality outcomes of 1.5 million non-European Union (EU) migrants and refugees in England. Methods and analysis: We will link four data sources: first, non-EU migrant tuberculosis pre-entry screening data; second, refugee pre-entry health assessment data; third, national hospital episode statistics; and fourth, Office of National Statistics death records. Using this linked dataset, we will then generate a population-based cohort to examine hospital-based events and mortality outcomes in England between Jan 1, 2006, and Dec 31, 2017. We will compare outcomes across three groups in our analyses: 1) non-EU international migrants, 2) refugees, and 3) general population of England. Ethics and dissemination: We will obtain approval to use unconsented patient identifiable data from the Secretary of State for Health through the Confidentiality Advisory Group and the National Health Service Research Ethics Committee. After data linkage, we will destroy identifying data and undertake all analyses using the pseudonymised dataset. The results will provide policy makers and civil society with detailed information about the health needs of non-EU international migrants and refugees in England.

PP148 A Stakeholder-Informed Strategy For Effective Communication

IntroductionEffective communication is vital for engaging stakeholders in health technology assessment (HTA), as well as the successful dissemination and adoption of HTA research and guidance. As a relatively new organization, Health Technology Wales (HTW) has an ideal opportunity to take an effective, strategic approach to communication and stakeholder engagement from the outset.MethodsHTW commissioned Pagoda Public Relations to develop an informed communications strategy and delivery framework. The strategy used OASIS methodology for public relations planning: Objectives, Audience insight, Strategy, Implementation, and Scoring (evaluation). Initial objectives were developed with input from the HTW team and members of the HTW Assessment Group and Appraisal Panel. Stakeholder insights were collected through an online survey and telephone interviews. These insights were used to inform the communications strategy and framework, outlining key audiences, key messages, communication objectives, methods, tactics, and evaluations.ResultsSeven key objectives were identified, each of which were supported by recommended actions. These were underpinned by the key aims and messages reflecting how we will achieve these objectives. National Health Service boards, government, clinicians, the technology and research sector, patients, and the general public were identified as priority audiences. Various different communication channels and activities were identified, aimed at various audiences. These included the website, social media, traditional media, and exhibitions or workshops, as well as targeted e-mail dissemination of guidance. Evaluation of HTW communications will be aligned with the wider HTW evaluation strategy, and evidence will be recorded through OutNav software (Matter of Focus Ltd).ConclusionsHTW is committed to a strategic, effective approach to communication and engagement. We now have an audience-informed communications strategy and plan that outlines our key objectives, and how to achieve and evaluate these objectives. Successful implementation will raise awareness of and value in profile and outputs of HTW, both in Wales and internationally.

'Text-work' in Research Ethics Review: The significance of documents in and beyond committee meetings

ABSTRACTThis article analyzes how a formal text (the Ethics Review Form) available at National Health Service Research Ethics Committees (NHSRECs) in the United Kingdom was used in meetings. Derived from the work of Dorothy Smith on incorporating texts into institutional ethnography (IE), it proposes the concept of “text work” as a way into understanding more about decision-making in ethics review and describes the extent to which this formal text shaped and influenced review work. The research study used observations of committee meetings, field-notes and interviews to produce an ethnographic mapping of Research Ethics Committees’ (RECs) work. This article draws on one aspect of the research which was the process of isolating a particular, ubiquitous text and analyzing how it worked and was worked on in the meetings. The analysis contributes to contemporary discussion offering an alternative to ongoing debates about idealized ways of conducting ethics review. Finally, some tentative suggestions are made about improving training, based on and starting from the work which reviewers undertake.

Replicable Associations Between Common Mental Distress and Suicide Risk in Young People: Implications for Clinical Practice and Population Suicide Prevention

Background: Recent evidence suggests that multiple symptoms or diagnoses, partucularly when co-ocuring with non-suicidal self-harm, predict suicide risk more strongly than single diagnosis. Method: Suicidal thought (ST) and non-suicidal self-injury (NSSI) were studies in two independent longitudinal UK samples of young people: the Neuroscience in Psychiatry (NSPN) 2400 cohort (n=2403) and the ROOTS cohort (n=1074). Participants, age 14-24 years, were recruited from primary health care registers, schools and colleges, and advertisements to complete quotas in age-sex strata. We calculated a score on a latent construct Common Mental Distress (the summary measure indexing a broad range of symptoms conventionally seen as components of distinct disorders). We examined the relative prevalence of ST and NSSI over the population distribution of mental distress; we used logistic regressions, IRT and ROC analyses to determine associations between suicide risks and mental distress (in continuous and above-the-norm categorical format); and pathway mediation models to examine longitudinal associations. Outcomes: We found a dose-response relationship between levels of mental distress and suicide risk. In both cohorts the majority of all subjects experiencing ST (78% and 76%) and NSSI (66% and 71%) had scores on mental distress no more than two standard deviations above the population mean; higher scores indicated highest risk but were, by definition, infrequent. Mental distress contributed to the longitudinal persistence of ST and NSSI. Interpretation: Universal prevention strategies reducing levels of mental distress in the whole population (in addition to screening) may prevent more suicides than approaches targeting youths with psychiatric disorders. Funding Statement: The ROOTS study was supported by a Wellcome Trust Grant (Grant number 074296) to I.M.G. and P.B.J., the NIHR Collaborations for Leadership in Applied Research and Care (CLAHRC) East of England, and the NIHR Cambridge Biomedical Research Centre. The NSPN study was supported by the Wellcome Trust Strategic Award (095844/Z/11/Z) to I.M.G., E.B., P.B.J., R.D., P.F. The work has been carried out in the Department of Psychiatry, University of Cambridge. Declaration of Interests: E.P., S.N., I.M.G., J.S. and P.B.J. have no competing interests. E.B., P.F. and PBJ are in receipt of National Institute for Health Research (NIHR) Senior Investigator Awards (NF-SI0514-10157, and NF-SI-0514-10117. P.F. was in part supported by the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) North Thames at Barts Health NHS Trust. P.W. has recent/current grant support from NIHR, Cambridgeshire County Council and CLAHRC East of England. P.W. discloses consulting for Lundbeck and Takeda; PBJ discloses consulting for Janssen and Ricordati. E.B. is employed half-time by the University of Cambridge and half-time by GlaxoSmithKline in which he holds stock. Ethics Approval Statement: Written consent from participants age 14 or 15 years was supplemented by written consent from their parent or legal guardian; older participants gave their own written consent. Ethical approval was obtained for Cohort 1 from the National Health Service Research Ethics Service (# 97546) and for Cohort 2 from the Cambridgeshire 2 REC (# 03/302).

Effects of restrictions to Income Support on health of lone mothers in the UK: a natural experiment study

SummaryBackgroundIn the UK, lone parents must seek work as a condition of receiving welfare benefits once their youngest child reaches a certain age. Since 2008, the lower age limit at which these Lone Parent Obligations (LPO) apply has been reduced in steps. We used data from a nationally representative, longitudinal, household panel study to analyse the health effects of increased welfare conditionality under LPO.MethodsFrom the Understanding Society survey, we used data for lone mothers who were newly exposed to LPO when the age cutoff was reduced from 7 to 5 years in 2012 (intervention group 1) and from 10 to 7 years in 2010 (intervention group 2), as well as lone mothers who remained unexposed (control group 1) or continuously exposed (control group 2) at those times. We did difference-in-difference analyses that controlled for differences in the fixed characteristics of participants in the intervention and control groups to estimate the effect of exposure to conditionality on the health of lone mothers. Our primary outcome was the difference in change over time between the intervention and control groups in scores on the Mental Component Summary (MCS) of the 12-item Short-Form Health Survey (SF-12).FindingsThe mental health of lone mothers declined in the intervention groups compared with the control groups. For intervention group 1, scores on the MCS decreased by 1·39 (95% CI −1·29 to 4·08) compared with control group 1 and by 2·29 (0·00 to 4·57) compared with control group 2. For intervention group 2, MCS scores decreased by 2·45 (−0·57 to 5·48) compared with control group 1 and by 1·28 (−1·45 to 4·00) compared with control group 2. When pooling the two intervention groups, scores on the MCS decreased by 2·13 (0·10 to 4·17) compared with control group 1 and 2·21 (0·30 to 4·13) compared with control group 2.InterpretationStringent conditions for receiving welfare benefits are increasingly common in high-income countries. Our results suggest that requiring lone parents with school-age children toseek work as a condition of receiving welfare benefits adversely affects their mental health.FundingUK Medical Research Council, Scottish Government Chief Scientist Office, and National Health Service Research Scotland.

Frailty and pre-frailty in middle-aged and older adults and its association with multimorbidity and mortality: a prospective analysis of 493 737 UK Biobank participants

SummaryBackgroundFrailty is associated with older age and multimorbidity (two or more long-term conditions); however, little is known about its prevalence or effects on mortality in younger populations. This paper aims to examine the association between frailty, multimorbidity, specific long-term conditions, and mortality in a middle-aged and older aged population.MethodsData were sourced from the UK Biobank. Frailty phenotype was based on five criteria (weight loss, exhaustion, grip strength, low physical activity, slow walking pace). Participants were deemed frail if they met at least three criteria, pre-frail if they fulfilled one or two criteria, and not frail if no criteria were met. Sociodemographic characteristics and long-term conditions were examined. The outcome was all-cause mortality, which was measured at a median of 7 years follow-up. Multinomial logistic regression compared sociodemographic characteristics and long-term conditions of frail or pre-frail participants with non-frail participants. Cox proportional hazards models examined associations between frailty or pre-frailty and mortality. Results were stratified by age group (37–45, 45–55, 55–65, 65–73 years) and sex, and were adjusted for multimorbidity count, socioeconomic status, body-mass index, smoking status, and alcohol use.Findings493 737 participants aged 37–73 years were included in the study, of whom 16 538 (3%) were considered frail, 185 360 (38%) pre-frail, and 291 839 (59%) not frail. Frailty was significantly associated with multimorbidity (prevalence 18% [4435/25 338] in those with four or more long-term conditions; odds ratio [OR] 27·1, 95% CI 25·3–29·1) socioeconomic deprivation, smoking, obesity, and infrequent alcohol consumption. The top five long-term conditions associated with frailty were multiple sclerosis (OR 15·3; 99·75% CI 12·8–18·2); chronic fatigue syndrome (12·9; 11·1–15·0); chronic obstructive pulmonary disease (5·6; 5·2–6·1); connective tissue disease (5·4; 5·0–5·8); and diabetes (5·0; 4·7–5·2). Pre-frailty and frailty were significantly associated with mortality for all age strata in men and women (except in women aged 37–45 years) after adjustment for confounders.InterpretationEfforts to identify, manage, and prevent frailty should include middle-aged individuals with multimorbidity, in whom frailty is significantly associated with mortality, even after adjustment for number of long-term conditions, sociodemographics, and lifestyle. Research, clinical guidelines, and health-care services must shift focus from single conditions to the requirements of increasingly complex patient populations.FundingCSO Catalyst Grant and National Health Service Research for Scotland Career Research Fellowship.

Anti-protein immunoglobulin M responses to pneumococcus are not associated with aging

BackgroundThe incidence of community-acquired pneumonia and lower respiratory tract infection rises considerably in later life. Immunoglobulin M (IgM) antibody levels to pneumococcal capsular polysaccharide are known to decrease with age; however, whether levels of IgM antibody to pneumococcal proteins are subject to the same decline has not yet been investigated.MethodsThis study measured serum levels and binding capacity of IgM antibody specific to the pneumococcal surface protein A (PspA) and an unencapsulated pneumococcal strain in serum isolated from hospital patients aged < 60 and ≥ 60, with and without lower respiratory tract infection. A group of young healthy volunteers was used as a comparator to represent adults at very low risk of pneumococcal pneumonia. IgM serum antibody levels were measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry was performed to assess IgM binding capacity. Linear regression and one-way analysis of variance (ANOVA) tests were used to analyse the results.ResultsLevels and binding capacity of IgM antibody to PspA and the unencapsulated pneumococcal strain were unchanged with age.ConclusionsThese findings suggest that protein-based pneumococcal vaccines may provide protective immunity in the elderly.Trial registrationThe LRTI trial (LRTI and control groups) was approved by the National Health Service Research Ethics Committee in October 2013 (12/NW/0713). Recruitment opened in January 2013 and was completed in July 2013. Healthy volunteer samples were taken from the EHPC dose-ranging and reproducibility trial, approved by the same Research Ethics Committee in October 2011 (11/NW/0592). Recruitment for this study ran from October 2011 until December 2012. LRTI trial: (NCT01861184), EHPC dose-ranging and reproducibility trial: (ISRCTN85403723).