NIHR Cambridge Biomedical Research Centre Research Articles

Improving transparency of longitudinal health research: glossary, infographic and accessible study summaries

BackgroundLongitudinal studies collect information repeatedly about the same group of people, allowing for analyses of changes over time. They are vital in mental health research, as elsewhere. As longitudinal studies rely on the participation of patients and the public, their methods, purposes and results must be transparent and accessible. IntroductionMany UK longitudinal research studies with mental health data are indexed via the Catalogue of Mental Health Measures (‘Catalogue’), and organisations including DATAMIND provide broader information about mental health data research. However, the information on such platforms is primarily researcher-oriented, creating a barrier to its transparency and accessibility. Barriers can be alleviated by providing clear definitions of specialist terms, a transparent overview of longitudinal mental health research, and ‘bite-sized’ summaries of the Catalogue studies. MethodsThis project was co-designed and co-created by patient/public representatives from the DATAMIND Super Research Advisory Group (SRAG) and researchers. UK Health Data Research Alliance transparency standards were followed across the delivery of three outputs. (1) To provide clear definitions of specialist terms, SRAG members and researchers collected terms commonly used longitudinal research and researchers clarified definitions. Definitions were revised by SRAG members and terms were added to an existing data science glossary. (2) To create a transparent overview of longitudinal mental health research, the patient/public involvement (PPI) lead and SRAG co-applicant proposed content for an infographic about longitudinal research. The design was discussed with a graphic designer who created the infographic, and involved the PPI lead for the UK Longitudinal Linkage Collaboration. This was then revised iteratively for clarity, accessibility and diversity. (3) To generate accessible summaries of the Catalogue studies, psychology undergraduate students drafted summaries for an initial six studies, which were reviewed via a workshop led by the SRAG. Following revisions to the content and style, summaries were created for all 55+ studies on the Catalogue. Unfamiliar terms encountered during the process were also added to the glossary. ResultsThree new resources were created. (1) We developed a glossary of terms commonly used in longitudinal studies and research, to be incorporated into the DATAMIND glossary (https://datamind.org.uk/glossary/). (2) We created an infographic ‘storyboard’ to show how researchers, patients and the public can work together in the creation and curation of longitudinal research. The infographic illustrates the intertwined relationships between patients and the public, providing a transparent representation of challenges such as sharing studies, data access, patient benefit, and the importance and impact of public involvement. It illustrates many ways to find out about longitudinal research. (3) Accessible and transparent short summaries were created for all longitudinal studies in the Catalogue (https://www.cataloguementalhealth.ac.uk/). These provide clear and concise overviews, enough to capture the essence of each study and inform researchers and the public quickly and easily. ConclusionsCo-production supports the transparency of longitudinal research, and ensures resources designed and produced for the public have public input. Two generic information resources and one specific resource are presented. AcknowledgementsProject funded by HDR UK (HDRUK2023.0465). DATAMIND is funded by the Medical Research Council (MR/W014386/1). All research at the Department of Psychiatry in the University of Cambridge is supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312) and the NIHR Applied Research Collaboration East of England; the views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Cardiovascular morbidity and mortality in patients in Wales, UK with resistance to thyroid hormone β (RTHβ): a linked-record cohort study

Individuals with resistance to thyroid hormone owing to mutations in the thyroid hormone receptor β gene (RTHβ) exhibit impaired tissue sensitivity to thyroid hormones, but retain sensitivity in cardiac tissue. Long-term health and survival outcomes in this rare disorder have not been evaluated. We investigated all-cause mortality and cardiovascular event risk in a cohort of patients with RTHβ, followed-up in UK endocrine clinics. In a retrospective cohort design, we linked genetically confirmed patients with RTHβ and age-matched and sex-matched population controls to outcomes in datasets within the Welsh Secure Anonymised Information Linkage (SAIL) Databank. Kaplan-Meier and Cox regression models analysed associations of RTHβ with all-cause mortality and cardiovascular events. We identified 61 patients with a genetic diagnosis of RTHβ between Jan 1, 1997, and Dec 31, 2019, and matched them with 2750 controls. Compared with controls, patients exhibited increased risks for all-cause mortality (hazard ratio [HR] 2·84, 95% CI 1·59-5·08), atrial fibrillation (10·56, 4·72-23·63), heart failure (HR 6·35, 95% CI 2·26-17·86), and major adverse cardiovascular events (MACE), comprising cardiovascular death, acute myocardial infarction, heart failure, or strokes (HR 3·49, 95% CI 2·04-5·99). The median age of first occurrence of any adverse event was 11 years earlier in patients (56 years, 95% CI 44-65) compared with controls (67 years, 65-70). Cubic spline analyses showed positive associations between FT4 concentrations at diagnosis and mortality or MACE, with FT4 concentration of 30 pmol/L or greater conferring increased risk. Compared with no intervention, treatment with antithyroid drugs, surgery or radioiodine gland ablation, or thyroxine did not control thyroid hormone excess. We have documented reduced survival and increased cardiovascular morbidity in a cohort of patients with RTHβ for the first time. These outcomes might be driven by lifelong cardiac exposure to thyroid hormone excess; and effective therapies, targeting hormone resistant pathways, could potentially curtail this risk. Royal College of Physicians, Wellcome Trust Investigator Award, and NIHR Cambridge Biomedical Research Centre.

Novel Approach for Assessing Postinfarct Myocardial Injury and Inflammation Using Hybrid Somatostatin Receptor Positron Emission Tomography/Magnetic Resonance Imaging.

Novel Approach for Assessing Postinfarct Myocardial Injury and Inflammation Using Hybrid Somatostatin Receptor Positron Emission Tomography/Magnetic Resonance Imaging.

Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD).

Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD).

Evidence of previous SARS-CoV-2 infection in seronegative patients with long COVID.

SummaryBackgroundThere is currently no consensus on the diagnosis, definition, symptoms, or duration of COVID-19 illness. The diagnostic complexity of Long COVID is compounded in many patients who were or might have been infected with SARS-CoV-2 but not tested during the acute illness and/or are SARS-CoV-2 antibody negative.MethodsGiven the diagnostic conundrum of Long COVID, we set out to investigate SARS-CoV-2-specific T cell responses in patients with confirmed SARS-CoV-2 infection and/or Long COVID from a cohort of mostly non-hospitalised patients.FindingsWe discovered that IL-2 release (but not IFN-γ release) from T cells in response to SARS-CoV-2 peptides is both sensitive (75% +/−13%) and specific (88%+/−7%) for previous SARS-CoV-2 infection >6 months after a positive PCR test. We identified that 42–53% of patients with Long COVID, but without detectable SARS-CoV-2 antibodies, nonetheless have detectable SARS-CoV-2 specific T cell responses.InterpretationOur study reveals evidence (detectable T cell mediated IL-2 release) of previous SARS-CoV-2 infection in seronegative patients with Long COVID.FundingThis work was funded by the Addenbrooke's Charitable Trust (900276 to NS), NIHR award (G112259 to NS) and supported by the NIHR Cambridge Biomedical Research Centre. NJM is supported by the MRC (TSF MR/T032413/1) and NHSBT (WPA15-02). PJL is supported by the Wellcome Trust (PRF 210688/Z/18/Z, 084957/Z/08/Z), a Medical Research Council research grant MR/V011561/1 and the United Kingdom Research and a Innovation COVID Immunology Consortium grant (MR/V028448/1).

Computational pathology aids derivation of microRNA biomarker signals from Cytosponge samples.

SummaryBackgroundNon-endoscopic cell collection devices combined with biomarkers can detect Barrett's intestinal metaplasia and early oesophageal cancer. However, assays performed on multi-cellular samples lose information about the cell source of the biomarker signal. This cross-sectional study examines whether a bespoke artificial intelligence-based computational pathology tool could ascertain the cellular origin of microRNA biomarkers, to inform interpretation of the disease pathology, and confirm biomarker validity.MethodsThe microRNA expression profiles of 110 targets were assessed with a custom multiplexed panel in a cohort of 117 individuals with reflux that took a Cytosponge test. A computational pathology tool quantified the amount of columnar epithelium present in pathology slides, and results were correlated with microRNA signals. An independent cohort of 139 Cytosponges, each from an individual patient, was used to validate the findings via qPCR.FindingsSeventeen microRNAs are upregulated in BE compared to healthy squamous epithelia, of which 13 remain upregulated in dysplasia. A pathway enrichment analysis confirmed association to neoplastic and cell cycle regulation processes. Ten microRNAs positively correlated with columnar epithelium content, with miRNA-192–5p and -194–5p accurately detecting the presence of gastric cells (AUC 0.97 and 0.95). In contrast, miR-196a-5p is confirmed as a specific BE marker.InterpretationComputational pathology tools aid accurate cellular attribution of molecular signals. This innovative design with multiplex microRNA coupled with artificial intelligence has led to discovery of a quality control metric suitable for large scale application of the Cytosponge. Similar approaches could aid optimal interpretation of biomarkers for clinical use.FundingFunded by the NIHR Cambridge Biomedical Research Centre, the Medical Research Council, the Rosetrees and Stoneygate Trusts, and CRUK core grants.

Efficacy of FFP3 respirators for prevention of SARS-CoV-2 infection in healthcare workers.

Respiratory protective equipment recommended in the UK for healthcare workers (HCWs) caring for patients with COVID-19 comprises a fluid-resistant surgical mask (FRSM), except in the context of aerosol generating procedures (AGPs). We previously demonstrated frequent pauci- and asymptomatic severe acute respiratory syndrome coronavirus 2 infection HCWs during the first wave of the COVID-19 pandemic in the UK, using a comprehensive PCR-based HCW screening programme (Rivett et al., 2020; Jones et al., 2020). Here, we use observational data and mathematical modelling to analyse infection rates amongst HCWs working on 'red' (coronavirus disease 2019, COVID-19) and 'green' (non-COVID-19) wards during the second wave of the pandemic, before and after the substitution of filtering face piece 3 (FFP3) respirators for FRSMs. Whilst using FRSMs, HCWs working on red wards faced an approximately 31-fold (and at least fivefold) increased risk of direct, ward-based infection. Conversely, after changing to FFP3 respirators, this risk was significantly reduced (52-100% protection). FFP3 respirators may therefore provide more effective protection than FRSMs for HCWs caring for patients with COVID-19, whether or not AGPs are undertaken. Wellcome Trust, Medical Research Council, Addenbrooke's Charitable Trust, NIHR Cambridge Biomedical Research Centre, NHS Blood and Transfusion, UKRI.

The Origins of the Protein Spread in Parkinson's Disease.

The Origins of the Protein Spread in Parkinson's Disease.

National Trends in Coronary Artery Disease Imagingassociations with Health Care Outcomes and Costs

Background: We sought to determine the impact of temporal trends and the 2016 updated National Institute for Health and Care Excellence chest pain guidelines (CG95) on imaging investigations and outcomes for coronary artery disease. Methods: Investigations for coronary artery disease from 2012-2018 were extracted from the English national database of imaging procedures and linked to national hospital admission and mortality registries. Growth rates were calculated, adjusted for population size, and linked with trends in cardiovascular hospital admissions and mortality compared across tertiles of imaging growth. The impact of CG95 was assessed using an interrupted time-series analysis. Findings: From 2012-2018, 1,909,314 investigations for coronary artery disease were performed, with an annualised per capita growth rate of 4·8%. At a national level, CG95 was associated with a rise in coronary computed tomography angiography (CTA) (exp(β) 1·10 [95% confidence interval 1·03 to 1·18], p=0·006), with no change in myocardial perfusion imaging and a potential modest fall in invasive coronary angiography (exp(β) 0·997 [0·993 to 1·00], p=0·06). At a regional level, greater CTA growth was associated with reduced hospitalisations for myocardial infarction (-0·7 [-0·8 to 1·7] admissions/100,000 population/year) whereas lower growth was associated with increased hospitalisations for myocardial infarction (1·8 [0·9 to 2·7] admissions/100,000 population/year). Cardiovascular and coronary artery disease deaths fell by -2·95 [-3·11 to -2·72] and -1·66 [-1·79 to -1·51] deaths/100,000/year respectively (p<0·0001 for both). Coronary artery disease deaths fell more in regions with the highest CTA growth compared to those with the lowest growth (-3·29 [-3·60 to -2·95] versus -2·32 [-2·82 to -2·10] deaths/100,000/year). Interpretation: Imaging investigations for coronary artery disease are increasing, with the greatest growth seen in coronary CTA following CG95. Greater regional increases in coronary CTA were associated with fewer hospitalisations for myocardial infarction and a more rapid fall in coronary artery disease mortality. Funding: JRWM is supported by the NIHR Cambridge Biomedical Research Centre. JHFR is part-supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, HEFCE, the EPSRC and the Wellcome Trust. DEN is supported by the British Heart Foundation (CH/09/002, RG/16/10/32375, RE/18/5/34216) and is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). MCW (FS/ICRF/20/26002) is supported by the British Heart Foundation. Declaration of Interest: JRWM, MCW, GR and DEN were investigators in the SCOT-HEART trial.

B Cell Receptor Repertoire Kinetics after SARS-CoV-2 Infection and Vaccination

B cells play a central role in the immune response to both SARS-CoV-2 infection and vaccination, but the development of the B cell receptor (BCR) repertoire in both contexts has not been defined nor compared. We analysed serial samples from 171 SARS-CoV-2-infected individuals with a range of disease severities together with 63 vaccine recipients, and found marked differences in the global BCR repertoire after natural infection compared to vaccination. Following infection, the proportion of BCRs bearing IgG1/3 and IgA1 isotypes increased, somatic hypermutation (SHM) was markedly decreased and, in patients with severe disease, expansion of IgM and IgA clones was observed. In contrast, after vaccination the proportion of BCRs bearing IgD/M isotypes increased, SHM was unchanged and expansion of IgG clones was prominent. Infection generated a broad distribution of SARS-CoV-2-specific clones predicted to target the spike protein whilst vaccination produced a more focused response mainly targeting the spike’s receptor-binding domain. These findings offer insights into how different immune exposure to SARS-CoV-2 impacts upon BCR repertoire development, potentially informing vaccine strategies.Funding: We are grateful to CVC Capital Partners, the Evelyn Trust (20/75), Addenbrooke's Charitable Trust, Cambridge University Hospitals (12/20A), the NIHR Cambridge Biomedical Research Centre, and the UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC) for their financial support. Further support: K.G.C.S.: Wellcome Investigator Award (200871/Z/16/Z); C.H.: Wellcome COVID-19 Rapid Response DCF and the Fondation Botnar; N.M.: MRC (CSF MR/P008801/1), NHSBT (WPA15-02), and Addenbrooke's Charitable Trust, (grant ref. to 900239 NJM); I.G.G.: Wellcome Senior Fellowship and Wellcome grant (Ref: 207498/Z/17/Z); N.M. was funded by the MRC (CSF MR/P008801/1), NHSBT (WPA15-02) and Addenbrooke’s Charitable Trust (grant ref. to 900239 NJM); RKG is supported by a Wellcome Trust Senior Fellowship in Clinical Science (WT108082AIA). Z.K.T. and M.R.C. are supported by a Medical Research Council Human Cell Atlas Research Grant (MR/S035842/1). M.R.C is supported by an NIHR Research Professorship (RP-2017-08-ST2- 002). P.K. is the recipient of a Jacquot Research Entry Scholarship of the Royal Australasian College of Physicians Foundation. W.M.R. is funded by the Wellcome Trust (216382/Z/19/Z). We would like to thank the NIHR Cambridge Clinical Research Facility outreach team for enrolment of patients; the NIHR Cambridge Biomedical Research Centre Cell Phenotyping Hub and the CRUK Cambridge Institute flow cytometry core facility for flow and mass cytometry; and the Cambridge NIHR BRC Stratified Medicine Core Laboratory NGS Hub (supported by an MRC Clinical Infrastructure Award) for BCR sequencing. Declaration of Interests: The authors declare they have no competing interests.Ethics Approval Statement: Ethical approval was obtained from the East of England – Cambridge Central Research Ethics Committee (“NIHR BioResource” REC ref 17/EE/0025, and “Genetic variation AND Altered Leucocyte Function in health and disease - GANDALF” REC ref 08/H0308/176). All participants provided informed consent.

Development and Validation of a Dynamic 48-Hour In-Hospital Mortality Risk Stratification for COVID-19 in a UK Teaching Hospital: A Retrospective Cohort Study

Background: While numerous point-of-admission disease severity models for COVID-19 have been proposed, disease stratification that accounts for changes in a patient’s condition while in hospital is urgently needed to facilitate patient management and resource allocation.Methods: We developed a prognostic model for 48-hour in-hospital mortality using 473 consecutive patients with COVID-19 presenting to a UK hospital between March 1 and September 12, 2020; and temporally validated using data on 405 patients presenting between September 13, 2020 and January 3, 2021.The primary outcome was all-cause in-hospital mortality. We additionally considered the competing risks of discharge from hospital and transfer to a tertiary Intensive Care Unit for extracorporeal membrane oxygenation. We adopted a landmarking approach to dynamic prediction that accounts for competing risks and informative missingness, and selected predictors using penalised regression. The model estimates, at any point during a hospital visit, the probability of in-hospital mortality during the next 48 hours.Results: Our final model includes age, Clinical Frailty Scale score, heart rate, respiratory rate, SpO2/FiO2 ratio, white cell count, presence of acidosis (pH Interpretation: Our model uniquely incorporates both static risk factors (e.g. age) and evolving clinical and laboratory data, to provide a dynamic risk prediction model that adapts to both sudden and gradual changes in an individual patient’s clinical condition. External validation outside the study hospital will be required before adoption.Funding: NIHR Cambridge Biomedical Research Centre, UKRI Medical Research CouncilDeclaration of Interest: None to declare. Ethical Approval: The study was approved by a UK Health Research Authority ethics committee (20/WM/0125). Patient consent was waived because the de-identified data presented here were collected during routine clinical practice; there was no requirement for informed consent.

The Utility of P53 Immunohistochemistry in the Diagnosis of Barrett's Esophagus with Indefinite for Dysplasia

Background: Barrett's esophagus with indefinite for dysplasia (BE-IND) is a subjective diagnosis with a low interobserver agreement (IOA) among pathologists and uncertain clinical implications. This study aimed to assess the utility of p53 immunohistochemistry (p53-IHC) in assessing BE-IND specimens. Methods: Archive endoscopic biopsies with a BE-IND diagnosis from two academic centers were analyzed. Firstly, hematoxylin and eosin-stained slides (H&E) were reviewed by four expert GI pathologists allocated into two groups (A and B). After a wash-out period of at least eight weeks, H&E slides were re-assessed side-to-side with p53-IHC available. We compared the rate of changed diagnosis and the IOA for all BE grades before and after p53-IHC. Findings: We included 216 BE-IND specimens from 185 patients, of which 44.0% and 32.9% were confirmed after H&E slide revision by Groups A and B, respectively. Over half of the cases were downgraded to a non-dysplastic BE (NDBE), while 5.6% of cases in Group A and 7.4% in Group B were upgraded to dysplasia. The IOA for NDBE, BE-IND, low-grade dysplasia (LGD), and high-grade dysplasia (HGD)/intramucosal cancer (IMC) was 0.31, 0.21, -0.03, and -0.02, respectively. Use of p53-IHC led to a >40% reduction in BE-IND diagnoses (P<.001), and increased IOA for all BE grades (κ=0.46 [NDBE], 0.26 [BE-IND], 0.49 [LGD], 0.35 [HGD/IMC]). An aberrant p53-IHC pattern significantly increased the likelihood of reclassifying BE-IND to definite dysplasia (odds ratio 44.3, 95%CI:18.8-113.0). Interpretation: P53-IHC reduces the rate of BE-IND diagnoses and improves the IOA among pathologists when reporting BE with equivocal epithelial changes. Funding: This study received infrastructure support from the NIHR Cambridge Biomedical Research Centre. Declaration of Interest: None to declare. Ethical Approval: An ethics committee approval for this study was granted at both institutions (Cambridge University: 7 LREC01/149; Mayo Clinic: 9-000514).

Early Immune Pathology and Persistent Dysregulation Characterise Severe COVID-19

In a study of 207 SARS-CoV2-infected individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust immune response, without systemic inflammation, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed adaptive responses and systemic inflammation already evident at around symptom onset. Such early evidence of inflammation suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune cell defects, if persistent, may contribute to “long COVID”.Funding: We are grateful for the generous support of CVC Capital Partners, the Evelyn Trust (20/75), UKRI COVID Immunology Consortium, Addenbrooke’s Charitable Trust (12/20A) and the NIHR Cambridge Biomedical Research Centre for their financial support. K.G.C.S. is the recipient of a Wellcome Investigator Award (200871/Z/16/Z); M.P.W. is the recipient of Wellcome Senior Clinical Research Fellowship (108070/Z/15/Z); C.H. was funded by a Wellcome COVID-19 Rapid Response DCF and the Fondation Botnar; N.M. was funded by the MRC (CSF MR/P008801/1) and NHSBT (WPA15-02); I.G.G. is a Wellcome Senior Fellow and was supported by funding from the Wellcome (Ref: 207498/Z/17/Z).Conflict of Interest: The authors declare they have no competing interests.

A Prospective Study of Risk Factors Associated with Seroprevalence of SARS-CoV-2 Antibodies in Healthcare Workers at a Large UK Teaching Hospital

Background: The COVID-19 pandemic continues to grow at an unprecedented rate. Healthcare workers (HCWs) are at higher risk of SARS-CoV-2 infection than the general population but risk factors for HCW infection are not well described.Methods: We conducted a prospective sero-epidemiological study of HCWs at a UK teaching hospital using a SARS-CoV-2 immunoassay. Risk factors for seropositivity were analysed using multivariate logistic regression.Findings: 410/5,698 (7·2%) staff tested positive for SARS-CoV-2 antibodies. Seroprevalence was higher in those working in designated COVID-19 areas compared with other areas (9·47% versus 6·16%) Healthcare assistants (aOR 2·06 [95%CI 1·14-3·71]; p =0·016) and domestic and portering staff (aOR 3·45 [95% CI 1·07-11·42]; p =0·039) had significantly higher seroprevalence than other staff groups after adjusting for age, sex, ethnicity and COVID-19 working location. Staff working in acute medicine and medical sub-specialities were also at higher risk (aOR 2·07 [95% CI 1·31-3·25]; p Interpretation: Risk of SARS-CoV-2 infection amongst HCWs is heterogeneous and influenced by COVID-19 working location, role, age and ethnicity. Increased risk amongst BAME staff cannot be accounted for solely by occupational factors.Funding: Wellcome Trust, Addenbrookes Charitable Trust, National Institute for Health Research, Academy of Medical Sciences, the Health Foundation and the NIHR Cambridge Biomedical Research Centre.Declaration of Interests: None to declare.Ethics Approval Statement: Ethical approval for this study was granted by the East of England – Cambridge Central Research Ethics Committee (IRAS ID: 220277).

Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices.

BackgroundPAIS exhibits a complex spectrum of phenotypes and pubertal outcomes. The paucity of reliable prognostic indicators can confound management decisions including sex-of-rearing. We assessed whether external masculinisation score (EMS) at birth or functional assays correlates with pubertal outcome in PAIS patients and whether the EMS is helpful in sex assignment.MethodsWe collected pubertal outcome data for 27 male-assigned PAIS patients, all with confirmed androgen receptor (AR) mutations, including two previously uncharacterized variants (I899F; Y916C). Patients were grouped as follows; EMS at birth <5 and ≥ 5 (EMS in normal males is 12; median EMS in PAIS is 4·7) and pubertal outcomes compared.FindingsOnly 6/9 patients (67%) with EMS <5 underwent spontaneous onset of puberty, versus all 18 patients with EMS ≥5 (p = .03). Only 1/6 patients (17%) with EMS <5 developed adult genitalia reaching Tanner stage 4 or 5, versus 11/13 (85%) with EMS ≥5 (p = 0·01). There was no significant difference between the two groups of patients in being prescribed androgen replacement, who reached adult testicular volume ≥ 15 ml, pubic hair Tanner stage 4 or 5, above average adult height, had gynaecomastia, and mastectomy. No correlation was observed between EMS and in vitro AR function.InterpretationIn PAIS with AR mutation, birth EMS is a simple predictor of spontaneous pubertal onset and satisfactory adult genitalia. This provides useful information when discussing the likely options for management at puberty.FundEuropean Commission Framework 7 Programme, NIHR Cambridge Biomedical Research Centre, BBSRC DTP.

Targeting Aged Astrocytes May Be a New Therapeutic Strategy in Parkinson's Disease.

CHWG holds a MRC Clinician Scientist fellowship, and receives grants from the Rosetrees Trust, the Evelyn Trust and Addenbrooke’s Charitable Trust. She is also supported by the NIHR Cambridge Biomedical Research Centre. KMS holds a fellowship from the Wellcome Trust and her work is also supported by the NIHR Cambridge Biomedical Research Centre

Efficiency and safety of varying the frequency of whole blood donation: randomised trial of 45,000 donors

EDA received research funding from the UK Medical Research Council, British Heart Foundation, National Institute for Health Research, and NHSBT during the conduct of the study. SGT received grants from the UK Medical Research Council, British Heart Foundation, National Institute for Health Research, and NHSBT during the conduct of the study. SK received grants from the UK Medical Research Council, British Heart Foundation, National Institute for Health Research, and NHSBT during the conduct of the study. JD has received research funding from the UK Medical Research Council, British Heart Foundation, National Institute for Health Research, NHSBT, European Commission, European Research Council, Merck Sharpe & Dohme UK, Biogen, Novartis, Pfizer, Merck, and Wellcome Trust during the conduct of the study. All other members of the writing committee declare no competing interests. The trial was funded by NHSBT and the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). The trial’s coordinating centre at the Department of Public Health and Primary Care at the University of Cambridge, Cambridge, UK, has received core support from the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), and the NIHR Cambridge Biomedical Research Centre. Investigators at the University of Oxford, Oxford, UK, have been supported by the Research and Development Programme of NHSBT, the NHSBT Howard Ostin Trust Fund, and the NIHR Oxford Biomedical Research Centre through the programme grant NIHR-RP-PG-0310-1004.

Defining PD subtypes — a step toward personalized management?

The work of the authors is supported by the NIHR Cambridge Biomedical Research Centre and the Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute.

Apathy and impulsivity in frontotemporal lobar degeneration syndromes.

Apathy and impulsivity are common and disabling consequences of frontotemporal lobar degeneration. They cause substantial carer distress, but their aetiology remains elusive. There are critical limitations to previous studies in this area including (i) the assessment of either apathy or impulsivity alone, despite their frequent co-existence; (ii) the assessment of behavioural changes within single diagnostic groups; and (iii) the use of limited sets of tasks or questions that relate to just one aspect of these multifactorial constructs. We proposed an alternative, dimensional approach that spans behavioural and language variants of frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. This accommodates the commonalities of apathy and impulsivity across disorders and reveals their cognitive and anatomical bases. The ability to measure the components of apathy and impulsivity and their associated neural correlates across diagnostic groups would provide better novel targets for pharmacological manipulations, and facilitate new treatment strategies and strengthen translational models. We therefore sought to determine the neurocognitive components of apathy and impulsivity in frontotemporal lobar degeneration syndromes. The frequency and characteristics of apathy and impulsivity were determined by neuropsychological and behavioural assessments in 149 patients and 50 controls from the PIck's disease and Progressive supranuclear palsy Prevalence and INcidence study (PiPPIN). We derived dimensions of apathy and impulsivity using principal component analysis and employed these in volumetric analyses of grey and white matter in a subset of 70 patients (progressive supranuclear palsy, n = 22; corticobasal syndrome, n = 13; behavioural variant, n = 14; primary progressive aphasias, n = 21) and 27 control subjects. Apathy and impulsivity were present across diagnostic groups, despite being criteria for behavioural variant frontotemporal dementia alone. Measures of apathy and impulsivity frequently loaded onto the same components reflecting their overlapping relationship. However, measures from objective tasks, patient-rated questionnaires and carer-rated questionnaires loaded onto separate components and revealed distinct neurobiology. Corticospinal tracts correlated with patients' self-ratings. In contrast, carer ratings correlated with atrophy in established networks for goal-directed behaviour, social cognition, motor control and vegetative functions, including frontostriatal circuits, orbital and temporal polar cortex, and the brainstem. Components reflecting response inhibition deficits correlated with focal frontal cortical atrophy. The dimensional approach to complex behavioural changes arising from frontotemporal lobar degeneration provides new insights into apathy and impulsivity, and the need for a joint therapeutic strategy against them. The separation of objective tests from subjective questionnaires, and patient from carer ratings, has important implications for clinical trial design.awx101media15448041163001.

Cortical and Striatal Reward Processing in Parkinson's Disease Psychosis.

Psychotic symptoms frequently occur in Parkinson’s disease (PD), but their pathophysiology is poorly understood. According to the National Institute of Health RDoc programme, the pathophysiological basis of neuropsychiatric symptoms may be better understood in terms of dysfunction of underlying domains of neurocognition in a trans-diagnostic fashion. Abnormal cortico-striatal reward processing has been proposed as a key domain contributing to the pathogenesis of psychotic symptoms in schizophrenia. This theory has received empirical support in the study of schizophrenia spectrum disorders and preclinical models of psychosis, but has not been tested in the psychosis associated with PD. We, therefore, investigated brain responses associated with reward expectation and prediction error signaling during reinforcement learning in PD-associated psychosis. An instrumental learning task with monetary gains and losses was conducted during an fMRI study in PD patients with (n = 12), or without (n = 17), a history of psychotic symptoms, along with a sample of healthy controls (n = 24). We conducted region of interest analyses in the ventral striatum (VS), ventromedial prefrontal and posterior cingulate cortices, and whole-brain analyses. There was reduced activation in PD patients with a history of psychosis, compared to those without, in the posterior cingulate cortex and the VS during reward anticipation (p < 0.05 small volume corrected). The results suggest that cortical and striatal abnormalities in reward processing, a putative pathophysiological mechanism of psychosis in schizophrenia, may also contribute to the pathogenesis of psychotic symptoms in PD. The finding of posterior cingulate dysfunction is in keeping with prior results highlighting cortical dysfunction in the pathogenesis of PD psychosis.