Negative variance components and intercept-slope correlations greater than one in magnitude: How do such "non-regular" random intercept and slope models arise, and what should be done when they do?

Statistical models with random intercepts and slopes (RIAS models) are commonly used to analyze longitudinal data. Fitting such models sometimes results in negative estimates of variance components or estimates on parameter space boundaries. This can be an unlucky chance occurrence, but can also occur because certain marginal distributions are mathematically identical to those from RIAS models with negative intercept and/or slope variance components and/or intercept-slope correlations greater than one in magnitude. We term such parameters "pseudo-variances" and "pseudo-correlations," and the models "non-regular." We use eigenvalue theory to explore how and when such non-regular RIAS models arise, showing: (i) A small number of measurements, short follow-up, and large residual variance increase the parameter space for which data (with a positive semidefinite marginal variance-covariance matrix) are compatible with non-regular RIAS models. (ii) Non-regular RIAS models can arise from model misspecification, when non-linearity in fixed effects is ignored or when random effects are omitted. (iii) A non-regular RIAS model can sometimes be interpreted as a regular linear mixed model with one or more additional random effects, which may not be identifiable from the data. (iv) Particular parameterizations of non-regular RIAS models have no generality for all possible numbers of measurements over time. Because of this lack of generality, we conclude that non-regular RIAS models can only be regarded as plausible data-generating mechanisms in some situations. Nevertheless, fitting a non-regular RIAS model can be acceptable, allowing unbiased inference on fixed effects where commonly recommended alternatives such as dropping the random slope result in bias.

Statistical analysis plan for a cluster randomised trial in Madhya Pradesh, India: community health promotion and medical provision and impact on neonates (CHAMPION2).

BACKGROUND: Neonatal mortality in India has fallen steadily and was estimated to be 24 per 1000 live births in the year 2017. However, neonatal mortality remains high in rural parts of the country. The Community Health Promotion and Medical Provision and Impact On Neonates (CHAMPION2) trial investigates the effect of a complex health intervention on neonatal mortality in the Satna District of Madhya Pradesh. METHODS/DESIGN: The CHAMPION2 trial forms one part of a cluster-randomised controlled trial with villages (clusters) randomised to receive either a health (CHAMPION2) or education (STRIPES2) intervention. Villages receiving the health intervention are controls for the education intervention and vice versa. The primary outcome is neonatal mortality. The effect of the active intervention on the primary outcome (compared to usual care) will be expressed as a risk ratio, estimated using a generalised estimating equation approach with robust standard errors that take account of clustering at village level. Secondary outcomes include maternal mortality, stillbirths, perinatal deaths, causes of death, health care and knowledge, hospital admissions of enrolled women during pregnancy or in the immediate post-natal care period or of their babies (during the neonatal period), maternal blood transfusions, and the cost effectiveness of the intervention. A total of 196 villages have been randomised and over 34,000 women have been recruited in CHAMPION2. DISCUSSION: This update to the published trial protocol gives a detailed plan for the statistical analysis of the CHAMPION2 trial. TRIAL REGISTRATION: Registry of India: CTRI/2019/05/019296. Registered on 23 May 2019. https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MzExOTg=&Enc=&userName=champion2.

Predicting progression to Alzheimer's disease dementia using cognitive measures.

OBJECTIVES: It is important to determine if cognitive measures identified as being prognostic in dementia research cohorts also have utility in memory clinics. We aimed to identify measures with the greatest power to predict future Alzheimer's disease (AD) dementia in a clinical setting where expensive biomarkers are not widely available. METHODS: This study utilized routine Memory Clinic data collected over 18 years. From 2214 patients assessed in the clinic, we selected 328 patients with an initial diagnosis of subjective cognitive decline or mild cognitive impairment. We compared two types of statistical model for the prediction of AD dementia. The first model included baseline cognitive test scores only, while the second model also included change scores between baseline and the first follow-up. RESULTS: Baseline scores on tests of global cognitive function (Mini-mental state examination and Cambridge Cognitive Examination-Revised), verbal episodic memory and psychomotor speed were the best predictors of conversion to AD dementia. The inclusion of cognitive change scores over 1 year of follow-up improved predictive accuracy versus baseline scores alone. CONCLUSIONS: We found that the best cognitive predictors of AD dementia in a clinical setting were similar to those previously identified using research cohorts. Taking change in cognitive function into account enabled the onset of AD dementia to be predicted with greater accuracy.

How important is the linearity assumption in a sample size calculation for a randomised controlled trial where treatment is anticipated to affect a rate of change?

BACKGROUND: For certain conditions, treatments aim to lessen deterioration over time. A trial outcome could be change in a continuous measure, analysed using a random slopes model with a different slope in each treatment group. A sample size for a trial with a particular schedule of visits (e.g. annually for three years) can be obtained using a two-stage process. First, relevant (co-) variances are estimated from a pre-existing dataset e.g. an observational study conducted in a similar setting. Second, standard formulae are used to calculate sample size. However, the random slopes model assumes linear trajectories with any difference in group means increasing proportionally to follow-up time. The impact of these assumptions failing is unclear. METHODS: We used simulation to assess the impact of a non-linear trajectory and/or non-proportional treatment effect on the proposed trial's power. We used four trajectories, both linear and non-linear, and simulated observational studies to calculate sample sizes. Trials of this size were then simulated, with treatment effects proportional or non-proportional to time. RESULTS: For a proportional treatment effect and a trial visit schedule matching the observational study, powers are close to nominal even for non-linear trajectories. However, if the schedule does not match the observational study, powers can be above or below nominal levels, with the extent of this depending on parameters such as the residual error variance. For a non-proportional treatment effect, using a random slopes model can lead to powers far from nominal levels. CONCLUSIONS: If trajectories are suspected to be non-linear, observational data used to inform power calculations should have the same visit schedule as the proposed trial where possible. Additionally, if the treatment effect is expected to be non-proportional, the random slopes model should not be used. A model allowing trajectories to vary freely over time could be used instead, either as a second line analysis method (bearing in mind that power will be lost) or when powering the trial.

Development and usability testing of an electronic patient-reported outcome (ePRO) solution for patients with inflammatory diseases in an Advanced Therapy Medicinal Product (ATMP) basket trial.

BACKGROUND: Electronic patient-reported outcome (ePRO) systems are increasingly used in clinical trials to provide evidence of efficacy and tolerability of treatment from the patient perspective. The aim of this study is twofold: (1) to describe how we developed an electronic platform for patients to report their symptoms, and (2) to develop and undertake usability testing of an ePRO solution for use in a study of cell therapy seeking to provide early evidence of efficacy and tolerability of treatment and test the feasibility of the system for use in later phase studies. METHODS: An ePRO system was designed to be used in a single arm, multi-centre, phase II basket trial investigating the safety and activity of the use of ORBCEL-C™ in the treatment of patients with inflammatory conditions. ORBCEL-C™ is an enriched Mesenchymal Stromal Cells product isolated from human umbilical cord tissue using CD362+ cell selection. Usability testing sessions were conducted using cognitive interviews and the 'Think Aloud' method with patient advisory group members and Research Nurses to assess the usability of the system. RESULTS: Nine patient partners and seven research nurses took part in one usability testing session. Measures of fatigue and health-related quality of life, the PRO-CTCAE™ and FACT-GP5 global tolerability question were included in the ePRO system. Alert notifications to the clinical team were triggered by PRO-CTCAE™ and FACT-GP5 scores. Patient participants liked the simplicity and responsiveness of the patient-facing app. Two patients were unable to complete the testing session, due to technical issues. Research Nurses suggested minor modifications to improve functionality and the layout of the clinician dashboard and the training materials. CONCLUSION: By testing the effectiveness, efficiency, and satisfaction of our novel ePRO system (PROmicsR), we learnt that most people with an inflammatory condition found it easy to report their symptoms using an app on their own device. Their experiences using the PROmicsR ePRO system within a trial environment will be further explored in our upcoming feasibility testing. Research nurses were also positive and found the clinical dashboard easy-to-use. Using ePROs in early phase trials is important in order to provide evidence of therapeutic responses and tolerability, increase the evidence based, and inform methodology development. TRIAL REGISTRATION: ISRCTN, ISRCTN80103507. Registered 01 April 2022, https://www.isrctn.com/ISRCTN80103507.

More and more patients tell clinicians how they feel by completing questionnaires electronically. Therefore, it is important to assess how easy it is for patients to do this. In this study, we describe how we developed an electronic platform for patients to report their symptoms and how we tested the usability of this platform with patient partners and research nurses. Once the electronic platform was developed, quality of life and symptoms questionnaires were programmed onto it. Alerts were sent to the clinical team if specific scores were obtained on the symptoms questionnaires. Although two patient partners were not able to finish the testing session because of technical issues, the ones who completed the session liked its simplicity and responsiveness. The research nurses also liked the system and only suggested minor modifications. Following this testing, we refined the electronic platform to test it further in a larger study which investigates the safety and use of a drug. We hope that thanks to this electronic platform, we will obtain useful information on the safety and efficacy of treatment.

Statistical analysis plan for a cluster randomised trial in Madhya Pradesh, India: support to rural India's public education system and impact on numeracy and literacy scores (STRIPES2).

BACKGROUND: India has made steady progress in improving rates of primary school enrolment but levels of learning achievement remain low. The Support To Rural India's Public Education System (STRIPES) trial provided evidence that an after-school para-teacher intervention improved numeracy and literacy levels in Telangana, India. The STRIPES2 trial investigates whether such an intervention will have a similar effect on the literacy and numeracy of primary school age children in the Satna District of Madhya Pradesh, India. METHODS/DESIGN: The STRIPES2 trial forms one part of a cluster-randomised controlled trial with villages (clusters) randomised to receive either a health (CHAMPION2) or education (STRIPES2) intervention. Building on the design of the earlier CHAMPION/STRIPES trial, villages receiving the health intervention are controls for the education intervention and vice versa. The primary outcome is a combined literacy and numeracy score. Secondary outcomes include separate scores for literacy and numeracy; caregivers' engagement with child's learning; expenditure on education; enrolment in school; caregiver's report of school attendance and the cost effectiveness of the intervention. Over 7000 primary school age children have been recruited and randomised in STRIPES2. DISCUSSION: This update to the published trial protocol gives a detailed plan for the statistical analysis of the STRIPES 2 trial. TRIAL REGISTRATION: Registry of India: CTRI/2019/05/019296. Registered on 23 May 2019. http://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=31198&EncHid=&modid=&compid=%27,%2731198det%27.

Selective Thumb Carpometacarpal Joint Denervation Versus Trapeziectomy and Ligament Reconstruction With Tendon Interposition for Painful Arthritis: A Prospective Study With 2 Years of Follow-Up.

PURPOSE: Thumb carpometacarpal (CMC) joint denervation is a relatively novel method for the management of osteoarthritis-associated pain by selective transection of articular nerve branches of the CMC joint. This study compared functional/patient-reported outcomes after CMC denervation with those after trapeziectomy and ligament reconstruction with tendon interposition (T + LRTI) over a 2-year follow-up period. We hypothesized that the outcomes of denervation and T + LRTI would be similar over the course of the study and at the final 2-year follow-up. METHODS: Adults with Eaton stage 2-4 disease, no evidence of CMC subluxation, and no history of thumb injury/surgery were included. Pain scores, brief Michigan Hand Questionnaire (bMHQ), Kapandji score, 2-point discrimination, and grip/key/3-point pinch strength were measured at 3-, 6-, 12-, and 24-months after surgery. On average, T + LRTI patients underwent 7 weeks of splinting, with release to full activity at 3 months; denervation patients were placed in a soft postoperative dressing for 2 weeks, with release to full activity as tolerated at 3 weeks. RESULTS: Thirty-three denervation and 20 T + LRTI patients were included. Preoperative characteristics were similar between both groups. Two denervation patients underwent secondary T + LRTI during the study period; one denervation patient underwent fat grafting to the CMC joint at an outside institution. Data prior to secondary surgeries were included in the analysis. The average tourniquet times (minutes) for denervation and T + LRTI were 43.5 ± 11.8 and 82.7 ± 14.2 minutes, respectively. For denervation and T + LRTI, the postoperative bMHQ scores were significantly higher than those at baseline at all time points. No significant differences were found between both groups for bMHQ, sensation, or strength measures. CONCLUSIONS: Carpometacarpal denervation is well tolerated, with shorter tourniquet times and faster return to full activity than T + LRTI. For the study cohort, the conversion rate to T + LRTI at 2 years was 9%. Both procedures demonstrated durable improvement in bMHQ compared with the preoperative state with similar long-term outcomes over 2 years of follow-up. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Considerations for patient and public involvement and engagement in health research.

Patient and public involvement and engagement (PPIE) can provide valuable insights into the experiences of those living with and affected by a disease or health condition. Inclusive collaboration between patients, the public and researchers can lead to productive relationships, ensuring that health research addresses patient needs. Guidelines are available to support effective PPIE; however, evaluation of the impact of PPIE strategies in health research is limited. In this Review, we evaluate the impact of PPIE in the 'Therapies for Long COVID in non-hospitalised individuals' (TLC) Study, using a combination of group discussions and interviews with patient partners and researchers. We identify areas of good practice and reflect on areas for improvement. Using these insights and the results of a survey, we synthesize two checklists of considerations for PPIE, and we propose that research teams use these checklists to optimize the impact of PPIE for both patients and researchers in future studies.

Effects of the visual environment on object localization in posterior cortical atrophy and typical Alzheimer's disease.

Introduction: Visual processing deficits in Alzheimer's disease are associated with diminished functional independence. While environmental adaptations have been proposed to promote independence, recent guidance gives limited consideration to such deficits and offers conflicting recommendations for people with dementia. We evaluated the effects of clutter and color contrasts on performances of everyday actions in posterior cortical atrophy and memory-led typical Alzheimer's disease. Methods: 15 patients with posterior cortical atrophy, 11 with typical Alzheimer's disease and 16 healthy controls were asked to pick up a visible target object as part of two pilot repeated-measures investigations from a standing or seated position. Participants picked up the target within a controlled real-world setting under varying environmental conditions: with/without clutter, with/without color contrast cue and far/near target position. Task completion time was recorded using a target-mounted inertial measurement unit. Results: Across both experiments, difficulties locating a target object were apparent through patient groups taking an estimated 50-90% longer to pick up targets relative to controls. There was no evidence of effects of color contrast when locating objects from standing/seated positions and of any other environmental conditions from a standing position on completion time in any participant group. Locating objects, surrounded by five distractors rather than none, from a seated position was associated with a disproportionately greater effect on completion times in the posterior cortical atrophy group relative to the control or typical Alzheimer's disease groups. Smaller, not statistically significant but directionally consistent, ratios of relative effects were seen for two distractors compared with none. Discussion: Findings are consistent with inefficient object localization in posterior cortical atrophy relative to typical Alzheimer's disease and control groups, particularly with targets presented within reaching distance among visual clutter. Findings may carry implications for considering the adverse effects of visual clutter in developing and implementing environmental modifications to promote functional independence in Alzheimer's disease.

Depression and anxiety during the year before death from cancer.

OBJECTIVE: Previous studies of depression and anxiety during the year before death have reported different findings. We therefore aimed to study depression and anxiety in patients who had died from cancer and had previously attended cancer clinics. METHODS: We analysed routine data on 4869 deceased patients who had completed the Hospital Anxiety and Depression Scale (HADS) as part of their routine cancer care. The HADS data were linked with demographic, cancer and mortality data from national registries. We used data from all HADS completed in the last year of life to investigate the relationships between mean depression (HADS-D) and anxiety (HADS-A) scores and the percentages of high scores (≥11 on each subscale) and time to death (Analysis 1). This analysis used multivariable linear regression with cubic splines and robust standard errors to allow for multiple HADS from the same patients. We also investigated within-patient changes in scores (Analysis 2) in a subset of patients who had completed more than one HADS. RESULTS: In Analysis 1, modelled mean HADS-D scores increased by around 2.5 and the percentage of high HADS-D scores increased from 13% at six months before death to 30% at one month before death. Changes in HADS-A were smaller and occurred later. In Analysis 2, similar patterns were observed in individual patients' HADS scores. CONCLUSION: Depression should be looked for and treated in patients with cancer and a prognosis of six months or less, in order to maximise the quality of patients' remaining life.

Development and validation of the symptom burden questionnaire for long covid (SBQ-LC): Rasch analysis.

OBJECTIVE: To describe the development and validation of a novel patient reported outcome measure for symptom burden from long covid, the symptom burden questionnaire for long covid (SBQ-LC). DESIGN: Multiphase, prospective mixed methods study. SETTING: Remote data collection and social media channels in the United Kingdom, 14 April to 1 August 2021. PARTICIPANTS: 13 adults (aged ≥18 years) with self-reported long covid and 10 clinicians evaluated content validity. 274 adults with long covid field tested the draft questionnaire. MAIN OUTCOME MEASURES: Published systematic reviews informed development of SBQ-LC's conceptual framework and initial item pool. Thematic analysis of transcripts from cognitive debriefing interviews and online clinician surveys established content validity. Consensus discussions with the patient and public involvement group of the Therapies for Long COVID in non-hospitalised individuals: From symptoms, patient reported outcomes and immunology to targeted therapies (TLC Study) confirmed face validity. Rasch analysis of field test data guided item and scale refinement and provided initial evidence of the SBQ-LC's measurement properties. RESULTS: SBQ-LC (version 1.0) is a modular instrument measuring patient reported outcomes and is composed of 17 independent scales with promising psychometric properties. Respondents rate their symptom burden during the past seven days using a dichotomous response or 4 point rating scale. Each scale provides coverage of a different symptom domain and returns a summed raw score that can be transformed to a linear (0-100) score. Higher scores represent higher symptom burden. After rating scale refinement and item reduction, all scales satisfied the Rasch model requirements for unidimensionality (principal component analysis of residuals: first residual contrast values <2.00 eigenvalue units) and item fit (outfit mean square values within 0.5 -1.5 logits). Rating scale categories were ordered with acceptable category fit statistics (outfit mean square values <2.0 logits). 14 item pairs had evidence of local dependency (residual correlation values >0.4). Across the 17 scales, person reliability ranged from 0.34 to 0.87, person separation ranged from 0.71 to 2.56, item separation ranged from 1.34 to 13.86, and internal consistency reliability (Cronbach's alpha) ranged from 0.56 to 0.91. CONCLUSIONS: SBQ-LC (version 1.0) is a comprehensive patient reported outcome instrument developed using modern psychometric methods. It measures symptoms of long covid important to people with lived experience of the condition and may be used to evaluate the impact of interventions and inform best practice in clinical management.

Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis: From the MS-STAT Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Improved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS. METHODS: The MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity. RESULTS: A total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables. DISCUSSION: We found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS. TRIAL REGISTRATION INFORMATION: MS-STAT: NCT00647348. CLASSIFICATION OF EVIDENCE: This study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.

Suicidal Thoughts in Patients With Cancer and Comorbid Major Depression: Findings From a Depression Screening Program.

BACKGROUND: Major depression is found in around ten percent of patients attending cancer clinics. One of the symptoms of major depression, defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM), is "thoughts of death or suicide." To implement depression screening programs for patients with cancer, we need to know the prevalence not only of this broadly defined symptom but also of more specific suicidal thoughts, as only the latter clearly indicates the need for specialist psychiatric assessment and management of suicide risk. METHODS: We analyzed data from a routine 2-stage depression screening program that operated in 3 UK cancer centers, linked with demographic and clinical data obtained from a national cancer registry. We included data on 2217 patients with common cancers and comorbid, interview-diagnosed, major depression. We determined the percentage of patients with (a) the DSM-IV symptom "thoughts of death or suicide" and (b) suicidal thoughts, defined as an affirmative response to the question "have you had thoughts of ending your life?" We investigated the associations of patients' demographic and clinical characteristics with each of these using logistic regression models. RESULTS: We found that 641 of 2217 (29%) of patients had the DSM symptom "thoughts of death or suicide" and 207 of 2217 (9%) had suicidal thoughts. Of the demographic and clinical characteristics that we studied, none had statistically significant associations with having the DSM symptom. Only younger age and primary cancer were associated with having suicidal thoughts. CONCLUSIONS: We found that almost one-third of patients with cancer and comorbid major depression have the DSM symptom "thoughts of death or suicide." However, only a third of the patients with this symptom report suicidal thoughts. These findings suggest that around one in ten patients found by a screening program to have major depression will have suicidal thoughts requiring a psychiatric assessment. The staffing of depression screening programs should be designed with these data in mind.

Feasibility of a new electronic patient-reported outcome (ePRO) system for an advanced therapy clinical trial in immune-mediated inflammatory disease (PROmics): protocol for a qualitative feasibility study.

INTRODUCTION: The use of electronic patient-reported outcome (ePRO) systems to capture PRO data in clinical trials is increasing; however, their feasibility, acceptability and utility in clinical trials of advanced therapy medicinal products (ATMPs) are not yet well understood. This protocol describes a qualitative study that aims to evaluate the feasibility and acceptability of ePRO data capture using a trial-specific ePRO system (the PROmics system) within an advanced therapy trial involving patients with immune-mediated inflammatory disease (rheumatoid arthritis, lupus, primary sclerosing cholangitis (PSC) and Crohn's disease). METHODS AND ANALYSIS: This protocol for a remote, qualitative, interview-based feasibility study is embedded within the POLARISE trial, a single-arm, phase II, multisite ATMP basket trial in the UK. 10-15 patients enrolled in the POLARISE trial and 10-15 research team members at the trial sites will be recruited. Participants will take part in semistructured interviews which will be transcribed verbatim and analysed thematically according to the framework method. Data collection and analysis will occur concurrently and iteratively. Researcher triangulation will be used to achieve a consensus-based analysis, enhancing rigour and trustworthiness. ETHICS AND DISSEMINATION: This study was approved by the London-West London and GTAC Research Ethics Committee (Ref: 21/LO/0475). Informed consent will be obtained from all participants prior to data collection. The study findings will be published in peer-review journals and disseminated via conference presentations and other media. Our patient and public involvement and engagement group and ATMP stakeholder networks will be consulted to maximise dissemination and impact. TRIAL REGISTRATION NUMBER: ISRCTN80103507.

The prevalence of anxiety in general hospital inpatients: A systematic review and meta-analysis.

OBJECTIVE: To determine the prevalence of anxiety in general hospital inpatients by conducting a systematic review and meta-analysis of all relevant published studies. METHOD: We searched Ovid Medline, Ovid Embase and Ovid PsycINFO from inception to December 2020. We included studies of the prevalence of anxiety symptoms of clinically significant severity (using cut-off scores on rating scales) and of the prevalence of anxiety disorders (using diagnostic interviews) in general hospital inpatients. Two independent reviewers assessed articles and extracted data. The review is registered with PROSPERO, number CRD42020189722. RESULTS: We included 32 studies. Pooled prevalence estimates in random-effects meta-analyses were: anxiety symptoms 28% (95% CI 19% to 38%, 95% prediction interval 5% to 72%), any anxiety disorder 8% (95% CI 5% to 12%, 95% prediction interval 2% to 33%), panic disorder 3% (95% CI 2% to 4%, 95% prediction interval 1% to 8%), generalized anxiety disorder 5% (95% CI 3% to 8%, 95% prediction interval 1% to 23%). There was high heterogeneity in prevalence, little of which was explained in exploratory analyses of a limited number of potential determinants. CONCLUSION: Anxiety symptoms of clinically significant severity affect more than one in four inpatients and anxiety disorders affect nearly one in ten.

'Do not attempt cardiopulmonary resuscitation' (DNACPR)-difficulty in discussions with older medical inpatients and their families: a survey of hospital doctors.

OBJECTIVES: To determine, for doctors looking after older medical inpatients: (1) how difficult they find discussions about 'do not attempt cardiopulmonary resuscitation' (DNACPR); (2) whether difficulty is associated with doctors' personal and professional characteristics; (3) how frequently DNACPR discussions are made more difficult by practical issues and by doctors' uncertainties. METHODS: Survey of hospital doctors working on the acute medical wards of a UK NHS teaching hospital. RESULTS: 171/200 (86%) of eligible doctors participated. 165 had experience of DNACPR discussions with older inpatients and/or their families and were included in our analysis. 'Difficulty' (defined as finding discussions 'fairly difficult' or 'difficult') was experienced by 52/165 (32%) for discussions with patients and 60/165 (36%) for discussions with families. Doctors with specific training in DNACPR discussions were less likely to have difficulty in discussions with patients. Older, more experienced doctors were less likely to have difficulty in discussions with families. Lack of time and place, and uncertainty about prognosis were the most frequently reported causes of difficulty. CONCLUSIONS: Many doctors have difficulty in DNACPR discussions. Training needs to include managing discussions with families, as well as with patients, and doctors need time and space to deliver this important part of their job.

Laughter as a paradigm of socio-emotional signal processing in dementia.

Laughter is a fundamental communicative signal in our relations with other people and is used to convey a diverse repertoire of social and emotional information. It is therefore potentially a useful probe of impaired socio-emotional signal processing in neurodegenerative diseases. Here we investigated the cognitive and affective processing of laughter in forty-seven patients representing all major syndromes of frontotemporal dementia, a disease spectrum characterised by severe socio-emotional dysfunction (twenty-two with behavioural variant frontotemporal dementia, twelve with semantic variant primary progressive aphasia, thirteen with nonfluent-agrammatic variant primary progressive aphasia), in relation to fifteen patients with typical amnestic Alzheimer's disease and twenty healthy age-matched individuals. We assessed cognitive labelling (identification) and valence rating (affective evaluation) of samples of spontaneous (mirthful and hostile) and volitional (posed) laughter versus two auditory control conditions (a synthetic laughter-like stimulus and spoken numbers). Neuroanatomical associations of laughter processing were assessed using voxel-based morphometry of patients' brain MR images. While all dementia syndromes were associated with impaired identification of laughter subtypes relative to healthy controls, this was significantly more severe overall in frontotemporal dementia than in Alzheimer's disease and particularly in the behavioural and semantic variants, which also showed abnormal affective evaluation of laughter. Over the patient cohort, laughter identification accuracy was correlated with measures of daily-life socio-emotional functioning. Certain striking syndromic signatures emerged, including enhanced liking for hostile laughter in behavioural variant frontotemporal dementia, impaired processing of synthetic laughter in the nonfluent-agrammatic variant (consistent with a generic complex auditory perceptual deficit) and enhanced liking for numbers ('numerophilia') in the semantic variant. Across the patient cohort, overall laughter identification accuracy correlated with regional grey matter in a core network encompassing inferior frontal and cingulo-insular cortices; and more specific correlates of laughter identification accuracy were delineated in cortical regions mediating affective disambiguation (identification of hostile and posed laughter in orbitofrontal cortex) and authenticity (social intent) decoding (identification of mirthful and posed laughter in anteromedial prefrontal cortex) (all p < .05 after correction for multiple voxel-wise comparisons over the whole brain). These findings reveal a rich diversity of cognitive and affective laughter phenotypes in canonical dementia syndromes and suggest that laughter is an informative probe of neural mechanisms underpinning socio-emotional dysfunction in neurodegenerative disease.

Major Depression and Survival in People With Cancer.

OBJECTIVE: The question of whether depression is associated with worse survival in people with cancer remains unanswered because of methodological criticism of the published research on the topic. We aimed to study the association in a large methodologically robust study. METHODS: We analyzed data on 20,582 patients with breast, colorectal, gynecological, lung, and prostate cancers who had attended cancer outpatient clinics in Scotland, United Kingdom. Patients had completed two-stage screening for major depression as part of their cancer care. These data on depression status were linked to demographic, cancer, and subsequent mortality data from national databases. We estimated the association of major depression with survival for each cancer using Cox regression. We adjusted for potential confounders and interactions between potentially time-varying confounders and the interval between cancer diagnosis and depression screening, and used multiple imputation for missing depression and confounder data. We pooled the cancer-specific results using fixed-effects meta-analysis. RESULTS: Major depression was associated with worse survival for all cancers, with similar adjusted hazard ratios (HRs): breast cancer (HR = 1.42, 95% confidence interval [CI] = 1.15-1.75), colorectal cancer (HR = 1.47, 95% CI = 1.11-1.94), gynecological cancer (HR = 1.36, 95% CI = 1.08-1.71), lung cancer (HR = 1.39, 95% CI = 1.24-1.56), and prostate cancer (HR = 1.76, 95% CI = 1.08-2.85). The pooled HR was 1.41 (95% CI = 1.29-1.54, p < .001, I2 = 0%). These findings were not materially different when we only considered the deaths (90%) that were attributed to cancer. CONCLUSIONS: Major depression is associated with worse survival in patients with common cancers. The mechanisms of this association and the clinical implications require further study.