Changes in immunoglobulin levels during clozapine treatment in schizophrenia.

BACKGROUND AND HYPOTHESIS: Use of clozapine in treatment-resistant schizophrenia is often limited due to risk of adverse effects. Cross-sectional associations between clozapine treatment and low immunoglobulin levels have been reported, however prospective studies are required to establish temporal relationships. We tested the hypothesis that reductions in immunoglobulin levels would occur over the first 6 months following initiation of clozapine treatment. Relationships between immunoglobulin levels and symptom severity over the course of clozapine treatment were also explored. DESIGN: This prospective observational study measured immunoglobulin (Ig) levels (A, M and G) in 56 patients with treatment-resistant schizophrenia at 6-, 12- and 24-weeks following initiation with clozapine. Clinical symptoms were also measured at 12 weeks using the positive and negative syndrome scale (PANSS). RESULTS: IgA, IgG and IgM all decreased during clozapine treatment. For IgA and IgG the reduction was significant at 24 weeks (IgA: ß = -32.66, 95% CI = -62.38, -2.93, p = 0.03; IgG: ß = -63.96, 95% CI = -118.00, -9.31, p = 0.02). For IgM the reduction was significant at 12 and 24 weeks (12 weeks: ß = -23.48, 95% CI = -39.56, -7.42, p = 0.004; 24 weeks: ß = -33.12, 95 %CI = -50.30, -15.94, p = <0.001). Reductions in IgA and IgG during clozapine treatment were correlated with reductions in PANSS-total over 12 weeks (n = 32, IgA r = 0.59, p = 0.005; IgG r = 0.48, p = 0.03). CONCLUSIONS: The observed reductions in immunoglobulin levels over six months of clozapine treatment add further evidence linking clozapine to secondary antibody deficiency. Associations between Ig reduction and symptom improvement may however indicate that immune mechanisms contribute to both desirable and undesirable effects of clozapine.

Associations between peripheral inflammation and clinical phenotypes of bipolar depression in a lower-middle income country.

OBJECTIVE: There has been increased interest in repurposing anti-inflammatories for the treatment of bipolar depression. Evidence from high-income countries suggests that these agents may work best for specific depressive symptoms in a subset of patients with biochemical evidence of inflammation but data from lower-middle income countries (LMICs) is scarce. This secondary analysis explored the relationship between pretreatment inflammatory markers and specific depressive symptoms, clinical measures, and demographic variables in participants with bipolar depression in Pakistan. METHODS: The current study is a cross-sectional secondary analysis of a randomized controlled trial of two anti-inflammatory medications (minocycline and celecoxib) for bipolar depression (n = 266). A series of logistic and linear regression models were completed to assess the relationship between C-reactive protein (CRP) (CRP > or < 3 mg/L and log10CRP) and clinical and demographic features of interest and symptoms of depression. Baseline clinical trial data was used to extract clinical and demographic features and symptoms of depression were assessed using the 24-item Hamilton Depression Rating Scale. RESULTS: The prevalence of low-grade inflammation (CRP > 3 mg/L) in the sample was 70.9%. After adjusting for baseline body mass index, socioeconomic status, age, gender, symptoms related to anhedonia, fatigue, and motor retardation were most associated with low-grade inflammation. CONCLUSIONS: Bipolar disorder (BD) patients from LMICs may experience higher rates of peripheral inflammation than have been reported in Western populations with BD. Future trials of repurposed anti-inflammatory agents that enrich for participants with these symptom profiles may inform the development of personalized treatment for bipolar depression in LMICs.

Moderators of treatment effect in a randomised controlled trial of single- and multi-family therapy for anorexia nervosa in adolescents and emerging adults.

INTRODUCTION: Multi-family therapy for anorexia nervosa (MFT-AN) is a novel, group-based intervention that intensifies single-family therapy for anorexia nervosa (FT-AN), with the aim of improving outcomes. The current study explored treatment moderators in a randomised controlled trial (N = 167) of FT-AN and MFT-AN for young people (adolescents/emerging adults aged 13-20 years) with anorexia nervosa. METHODS: Data were analysed using multiple linear regression. Six hypothesised baseline participant and parent factors were tested as possible moderators of treatment effect on end-of-treatment and follow-up percentage of median Body Mass Index (%mBMI); age, eating disorder symptom severity, perceived family conflict (young person and parent ratings) and parent-rated experiences of caregiving (positive and negative). RESULTS: Greater parent-rated positive caregiving experiences moderated treatment outcomes at follow-up (ß = -0.47, 95%CI: -0.91, -0.03, p = 0.04), but not end-of-treatment. Participants who had fewer parent-rated positive caregiving experiences at baseline had higher weight at follow-up if they had MFT-AN compared to FT-AN. No other hypothesised baseline factors moderated treatment outcome (p's > 0.05). DISCUSSION: The current study suggests MFT-AN may be indicated for families who present with fewer positive caregiving experiences to treatment. The MFT-AN group context may help to promote mentalisation and hope for these families, which may be harder to achieve in single-family treatment. Future research is needed to empirically evaluate how and why MFT-AN supports this group more. TRIAL REGISTRATION: ISRCTN registry: ISRCTN11275465, registered 29 January 2007.

Increased suicide attempt risk in people with epilepsy in the presence of concurrent psychogenic nonepileptic seizures.

OBJECTIVES: To test the hypothesis that people with concurrent diagnosis of epilepsy and psychogenic nonepileptic seizures (PNES) are at increased risk of attempting suicide as compared to people with epilepsy or PNES alone. To report on suicide rates. METHODS: Retrospective cohort study from the UK largest tertiary mental health care provider, with linked nationwide admission and mortality data from the Hospital Episode Statistics and Office for National Statistics. Participants were 2460 people with a primary or secondary diagnosis of epilepsy, PNES or concurrent epilepsy and PNES attending between 1 January 2007 and 18 June 2021. The primary outcome was a first hospital admission for suicide attempt (International Classification of Diseases, version 10 X60-X84). RESULTS: 9% of participants had at least one suicide attempt-related hospital admission. For people with concurrent diagnosis of epilepsy and PNES, the odds for suicide attempt-related admissions were 2.52 times the odds of people with epilepsy alone (OR 0.40; 95% CI 0.21 to 0.79; p=0.01). Odds were comparable between people with concurrent diagnosis and people with PNES alone (OR 0.75; 95% CI 0.41 to 1.48; p=0.40). Post hoc analyses revealed that the odds of people with PNES alone were 1.93 times the odds of people with epilepsy alone (OR 0.52; 95% CI 0.38 to 0.70; p<0.001). CONCLUSIONS: People with concurrent diagnosis of epilepsy and PNES or PNES alone have significantly increased odds of hospitalisation due to suicide attempt as compared to people with epilepsy alone (152% and 93% increase, respectively). These findings have direct implications for the clinical management of suicide risk in people with epilepsy.

Targeting binge eating in bulimia nervosa and binge eating disorder using inhibitory control training and implementation intentions: a feasibility trial.

BACKGROUND: This trial examined the feasibility, acceptability, and effect sizes of clinical outcomes of an intervention that combines inhibitory control training (ICT) and implementation intentions (if-then planning) to target binge eating and eating disorder psychopathology. METHODS: Seventy-eight adult participants with bulimia nervosa or binge eating disorder were randomly allocated to receive food-specific, or general, ICT and if-then planning for 4 weeks. RESULTS: Recruitment and retention rates at 4 weeks (97.5% and 79.5%, respectively) met the pre-set cut-offs. The pre-set adherence to the intervention was met for the ICT sessions (84.6%), but not for if-then planning (53.4%). Binge eating frequency and eating disorder psychopathology decreased in both intervention groups at post-intervention (4 weeks) and follow-up (8 weeks), with moderate to large effect sizes. There was a tendency for greater reductions in binge eating frequency and eating disorders psychopathology (i.e. larger effect sizes) in the food-specific intervention group. Across both groups, ICT and if-then planning were associated with small-to-moderate reductions in high energy-dense food valuation (post-intervention), food approach (post-intervention and follow-up), anxiety (follow-up), and depression (follow-up). Participants indicated that both interventions were acceptable. CONCLUSIONS: The study findings reveal that combined ICT and if-then planning is associated with reductions in binge eating frequency and eating disorder psychopathology and that the feasibility of ICT is promising, while improvements to if-then planning condition may be needed.

App-based food-specific inhibitory control training as an adjunct to treatment as usual in binge-type eating disorders: A feasibility trial.

Current treatments for binge eating disorder (BED) and bulimia nervosa (BN) only show moderate efficacy, warranting the need for novel interventions. Impairments in food-related inhibitory control contribute to BED/BN and could be targeted by food-specific inhibitory control training (ICT). The aim of this study was to establish the feasibility and acceptability of augmenting treatment for individuals with BN/BED with an ICT app (FoodT), which targets motor inhibition to food stimuli using a go/no-go paradigm. Eighty patients with BED/BN receiving psychological and/or pharmacological treatment were randomly allocated to a treatment-as-usual group (TAU; n = 40) or TAU augmented with the 5-min FoodT app daily (n = 40) for 4 weeks. This mixed-methods study assessed feasibility outcomes, effect sizes of clinical change, and acceptability using self-report measures. Pre-registered cut-offs for recruitment, retention, and adherence were met, with 100% of the targeted sample size (n = 80) recruited within 12 months, 85% of participants retained at 4 weeks, and 80% of the FoodT + TAU group completing ≤8 sessions. The reduction in binge eating did not differ between groups. However, moderate reductions in secondary outcomes (eating disorder psychopathology: SES = -0.57, 95% CI [-1.12, -0.03]; valuation of high energy-dense foods: SES = -0.61, 95% CI [-0.87, -0.05]) were found in the FoodT group compared to TAU. Furthermore, small greater reductions in food addiction (SES = -0.46, 95% CI [-1.14, 0.22]) and lack of premeditation (SES = -0.42, 95% CI [-0.77, -0.07]) were found in the FoodT group when compared to TAU. The focus groups revealed acceptability of FoodT. Participants discussed personal barriers (e.g. distractions) and suggested changes to the app (e.g. adding a meditation exercise). Augmenting treatment for BED/BN with a food-specific ICT app is feasible, acceptable, and may reduce clinical symptomatology with high reach and wide dissemination.

Remember as we empathize. Do brain mechanisms engaged in autobiographical memory retrieval causally affect empathy awareness? A combined TMS and EEG registered report.

Social interactions are partly driven by our ability to empathize-the capacity to share and understand others' inner states. While a growing body of evidence suggests a link between past experiences and empathy, to what degree empathy is dependent on our own previous experiences (autobiographical memories, AMs) is still unclear. Whereas neuroimaging studies have shown wide overlapping brain networks underpinning AM and empathic processes, studies on clinical populations with memory loss have not always shown empathy is impaired. The current transcranial magnetic stimulation (TMS) and electroencephalography study will seek to shed light on this neuropsychological puzzle by testing whether self-perceived empathy is causally linked to AM retrieval. Cortical activity, together with self-rating of empathy, will be recorded for scenarios that echo personal experiences while a brain region critical for AM retrieval will be transiently inhibited using TMS before task performance.

Cognitive remediation therapy for patients with bipolar disorder: A randomised proof-of-concept trial.

OBJECTIVES: Cognitive remediation therapy (CRT) may benefit people with bipolar disorder type I and II for whom cognitive impairment is a major contributor to disability. Extensive research has demonstrated CRT to improve cognition and psychosocial functioning in people with different diagnoses, but randomised trials of evidenced therapy programmes are lacking for bipolar disorders. The Cognitive Remediation in Bipolar (CRiB) study aimed to determine whether an established CRT programme is feasible and acceptable for people with bipolar disorders. METHODS: This proof-of-concept, single-blind randomised trial recruited participants aged 18-65 with bipolar disorder, not currently experiencing an episode. They were 1:1 block randomised to treatment-as-usual (TAU) with or without individual CRT for 12 weeks. The partly computerised CRT programme ("CIRCuiTS") was therapist-led and is evidence-based from trials in those with psychotic illnesses. Data were collected and analysed by investigators blinded to group allocation. The main outcomes (week 13 and 25) examined participant retention, intervention feasibility and putative effects of CRT on cognitive and psychosocial functioning via intention-to-treat analyses. TRIAL REGISTRATION: ISRCTN ID32290525. RESULTS: Sixty participants were recruited (02/2016-06/2018) and randomised to CRT (n = 29) or TAU (n = 31). Trial withdrawals were equivalent (CRT n = 2/29; TAU n = 5/31). CRT satisfaction indicated high acceptability. Intention-to-treat analyses (N = 60) demonstrated greater improvements for CRT- than TAU-randomised participants: at both week 13 and 25, CIRCuiTS participants showed larger improvements in the following domains (week 25 effect sizes reported here): IQ (SES = 0.71, 95% CI [0.29,1.13]), working memory (SES = 0.70, 95% CI [0.31,1.10]), executive function (SES = 0.93, 95% CI [0.33,1.54]), psychosocial functioning (SES = 0.49, 95% CI [0.18,0.80]) and goal attainment (SES = 2.02, 95% CI [0.89,3.14]). No serious adverse events were reported. CONCLUSIONS: CRT is feasible for individuals with bipolar disorders and may enhance cognition and functioning. The reported effect sizes from this proof-of-concept trial encourage further investigation in a definitive trial.

A preliminary investigation of a novel method to manipulate penis length to measure female sexual satisfaction: a single-case experimental design.

OBJECTIVES: To investigate a novel methodology and explore whether artificially reducing the depth of penetration during intercourse matters to women. STUDY DESIGN AND METHODS: A study with a single-case experimental design ('n of 1'), in which a heterosexual couple act as their own control and the study is then replicated in subsequent couples, was conducted. Thirty-five couples were assessed for eligibility to participate. Twenty-nine couples without any sexual problems were randomized and 12 submitted sufficient data to analyse. As a proxy for reducing penis length, we artificially reduced the depth of penetration by using different sizes of silicone rings around the base of the man's erect penis. The main outcome measures were provided by the female partner on a scale of 0-100 and comprised: degree of (i) overall sexual pleasure; (ii) sexual pleasure from intercourse alone; and (iii) emotional connection to the male partner. The female partner was also asked before the experiment began to rate the degree of positive or negative change that would be personally meaningful for her. RESULTS: On average, reducing the depth of penetration led to a statistically significant 18% reduction of overall sexual pleasure with an average 15% reduction in length of the penis. The longer the erect penis, the less likely the rings were to have an impact on sexual pleasure. There was a range of individual responses, however, with a minority of women reporting that reducing the depth of penetration was more pleasurable on some occasions. CONCLUSIONS: Size may matter in women in a healthy stable relationship when there is penile shortening. Because of the small number of couples and the inclusion of men with an apparently long penis, our results are preliminary, and we welcome replication in a larger sample with a more diverse range of penile lengths. Our results should not be misinterpreted as meaning that increasing penile length will increase sexual pleasure in women.

Resting-state EEG for the diagnosis of idiopathic epilepsy and psychogenic nonepileptic seizures: A systematic review.

Quantitative markers extracted from resting-state electroencephalogram (EEG) reveal subtle neurophysiological dynamics which may provide useful information to support the diagnosis of seizure disorders. We performed a systematic review to summarize evidence on markers extracted from interictal, visually normal resting-state EEG in adults with idiopathic epilepsy or psychogenic nonepileptic seizures (PNES). Studies were selected from 5 databases and evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. 26 studies were identified, 19 focusing on people with epilepsy, 6 on people with PNES, and one comparing epilepsy and PNES directly. Results suggest that oscillations along the theta frequency (4-8 Hz) may have a relevant role in idiopathic epilepsy, whereas in PNES there was no evident trend. However, studies were subject to a number of methodological limitations potentially introducing bias. There was often a lack of appropriate reporting and high heterogeneity. Results were not appropriate for quantitative synthesis. We identify and discuss the challenges that must be addressed for valid resting-state EEG markers of epilepsy and PNES to be developed.

Duration of untreated eating disorder and relationship to outcomes: A systematic review of the literature.

OBJECTIVE: This systematic review assesses the average duration of untreated eating disorder (DUED) in help-seeking populations at the time of first eating disorder (ED) treatment and investigates the relationship between DUED and symptom severity/clinical outcomes. METHOD: PRISMA guidelines were followed throughout. Selected studies provided information on either: (i) length of DUED, (ii) components of DUED, (iii) cross-sectional associations between DUED and symptom severity, (iv) associations between DUED and clinical outcomes, or (v) experimental manipulation of DUED. Study quality was assessed. RESULTS: Fourteen studies from seven countries were included. Across studies, average DUED weighted by sample size was 29.9 months for anorexia nervosa, 53.0 months for bulimia nervosa and 67.4 months for binge eating disorder. A younger age at time of first treatment was indicative of shorter DUED. Retrospective studies suggest that a shorter DUED may be related to a greater likelihood of remission. Manipulation of DUED by shortening service-related delays may improve clinical outcomes. CONCLUSIONS: Data on length of DUED provide a benchmark for early intervention in EDs. Preliminary evidence suggests DUED may be a modifiable factor influencing outcomes in EDs. To accurately determine the role of DUED, definition and measurement must be uniformly operationalised. Highlights This systematic review is the first to examine duration of untreated eating disorder (DUED) across different eating disorders. Definitions and measurement of DUED and its components vary considerably between studies. Across different eating disorders average DUED weighted by sample size ranges from approximately two and a half years (for anorexia nervosa) to nearly 6 years (for binge eating disorder). DUED appears to be related to age such that younger patients have shorter DUED.

Task-sharing interventions for patients with anorexia nervosa or their carers: a systematic evaluation of the literature and meta-analysis of outcomes.

The eating disorder clinical and scientific community advocates for the use of a shared approach to healthcare that actively involves patients and carers. A systematic review of the literature on guided self-help or self-help in anorexia nervosa (targeting either the individual affected by the illness or their carers) and meta-analyses of studies using randomised controlled designs for the evaluation of the outcomes: (1) drop-out from end-of-treatment assessment, (2) body mass index (BMI), (3) anxiety, (4) depression and (5) quality of life, were undertaken. Guided self-help was directed to patients in 15 studies and to carers in seven studies. The interventions were based on a variety of theoretical models, used different formats (books and digital materials), and were delivered by individuals with a range of experiences and expertise (e.g. individuals with lived experience of the illness, graduate students, or clinically trained professionals). Guided self-help was associated with significantly lower drop-out from the completion of end-of-treatment assessments compared to a control condition. There was an improvement in carers' wellbeing from skill-sharing interventions. Guided self-help may facilitate patients' treatment engagement and also improve carers' wellbeing.

Stimulating thought: a functional MRI study of transcranial direct current stimulation in schizophrenia.

Individuals with schizophrenia typically suffer a range of cognitive deficits, including prominent deficits in working memory and executive function. These difficulties are strongly predictive of functional outcomes, but there is a paucity of effective therapeutic interventions targeting these deficits. Transcranial direct current stimulation is a novel neuromodulatory technique with emerging evidence of potential pro-cognitive effects; however, there is limited understanding of its mechanism. This was a double-blind randomized sham controlled pilot study of transcranial direct current stimulation on a working memory (n-back) and executive function (Stroop) task in 28 individuals with schizophrenia using functional magnetic resonance imaging. Study participants received 30 min of real or sham transcranial direct current stimulation applied to the left frontal cortex. The 'real' and 'sham' groups did not differ in online working memory task performance, but the transcranial direct current stimulation group demonstrated significant improvement in performance at 24 h post-transcranial direct current stimulation. Transcranial direct current stimulation was associated with increased activation in the medial frontal cortex beneath the anode; showing a positive correlation with consolidated working memory performance 24 h post-stimulation. There was reduced activation in the left cerebellum in the transcranial direct current stimulation group, with no change in the middle frontal gyrus or parietal cortices. Improved performance on the executive function task was associated with reduced activity in the anterior cingulate cortex. Transcranial direct current stimulation modulated functional activation in local task-related regions, and in more distal nodes in the network. Transcranial direct current stimulation offers a potential novel approach to altering frontal cortical activity and exerting pro-cognitive effects in schizophrenia.

A pilot evaluation of a novel First Episode and Rapid Early Intervention service for Eating Disorders (FREED).

This pilot study assesses the impact of FREED (First Episode Rapid Early Intervention for Eating Disorders [ED]), a novel transdiagnostic service for emerging adults with recent ED onset, on clinical outcomes. Data were collected from 56 patients and 19 carers for 12 months following enrolment. FREED patients showed significant improvements in ED and other symptoms across time. Carers also showed psychological improvements. For FREED anorexia nervosa (AN) patients, body mass index (BMI) at initial clinical assessment was similar to that of comparable patients (audit cohort) seen in our service before (16.4 vs 16.1 kg/m2 ). By start of treatment, because of their shorter wait, FREED-AN had gained weight whereas audit patients had lost (16.7 vs 15.8 kg/m2 ). This difference continued throughout treatment, and at 12 months, nearly 60% FREED-AN patients returned to a BMI of 18.5 or greater. FREED shows promise as a service model for emerging adults with EDs.

Identifying disordered eating behaviours in adolescents: how do parent and adolescent reports differ by sex and age?

This study investigated the prevalence of disordered eating cognitions and behaviours across mid-adolescence in a large European sample, and explored the extent to which prevalence ratings were affected by informant (parent/adolescent), or the sex or age of the adolescent. The Development and Well-Being Assessment was completed by parent-adolescent dyads at age 14 (n = 2225) and again at age 16 (n = 1607) to explore the prevalence of 7 eating disorder symptoms (binge eating, purging, fear of weight gain, distress over shape/weight, avoidance of fattening foods, food restriction, and exercise for weight loss). Informant agreement was assessed using kappa coefficients. Generalised estimating equations were performed to explore the impact of age, sex and informant on symptom prevalence. Slight to fair agreement was observed between parent and adolescent reports (kappa estimates between 0.045 and 0.318); however, this was largely driven by agreement on the absence of behaviours. Disordered eating behaviours were more consistently endorsed amongst girls compared to boys (odds ratios: 2.96-5.90) and by adolescents compared to their parents (odds ratios: 2.71-9.05). Our data are consistent with previous findings in epidemiological studies. The findings suggest that sex-related differences in the prevalence of disordered eating behaviour are established by mid-adolescence. The greater prevalence rates obtained from adolescent compared to parent reports may be due to the secretive nature of the behaviours and/or lack of awareness by parents. If adolescent reports are overlooked, the disordered behaviour may have a greater opportunity to become more entrenched.

A Pilot, Multicentre Pragmatic Randomised Trial to Explore the Impact of Carer Skills Training on Carer and Patient Behaviours: Testing the Cognitive Interpersonal Model in Adolescent Anorexia Nervosa.

AIM: The aim of the study is to establish the acceptability, feasibility and approximate size of the effect of adding a carer intervention [Experienced Caregivers Helping Others (ECHO)] to treatment as usual (TAU) for adolescents with anorexia nervosa. METHODS: The study is a pilot randomised trial comparing TAU (n = 50) alone or TAU plus ECHO with (n = 50) or without (n = 49) telephone guidance. Effect sizes (ESs) were regression coefficients standardised by baseline standard deviations of measure. RESULTS: Although engagement with ECHO was poor (only 36% of carers in the ECHO group read over 50% of the book), there were markers of intervention fidelity, in that caregivers in the ECHO group showed a moderate increase in carer skills (ES = 0.4) at 12 months and a reduction in accommodating and enabling behaviour at 6 months (ES = 0.17). In terms of efficacy, in the ECHO group, carers spent less time care giving (ES = 0.40, p = 0.04) at 1 year, and patients had a minor advantage in body mass index (ES = 0.17), fewer admissions, decreased peer problems (ES = -0.36) and more pro-social behaviours (ES = 0.53). The addition of telephone guidance to ECHO produced little additional benefit. CONCLUSIONS: The provision of self-management materials for carers to standard treatment for adolescent anorexia nervosa shows benefits for both carers and patients. This could be integrated as a form of early intervention in primary care. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial.

BACKGROUND: Post-stroke pneumonia is associated with increased mortality and poor functional outcomes. This study assessed the effectiveness of antibiotic prophylaxis for reducing pneumonia in patients with dysphagia after acute stroke. METHODS: We did a prospective, multicentre, cluster-randomised, open-label controlled trial with masked endpoint assessment of patients older than 18 years with dysphagia after new stroke recruited from 48 stroke units in the UK, accredited and included in the UK National Stroke Audit. We excluded patients with contraindications to antibiotics, pre-existing dysphagia, or known infections, or who were not expected to survive beyond 14 days. We randomly assigned the units (1:1) by computer to give either prophylactic antibiotics for 7 days plus standard stroke unit care or standard stroke unit care only to patients clustered in the units within 48 h of stroke onset. We did the randomisation with minimisation to stratify for number of admissions and access to specialist care. Patient and staff who did the assessments and analyses were masked to stroke unit allocation. The primary outcome was post-stroke pneumonia in the first 14 days, assessed with both a criteria-based, hierarchical algorithm and by physician diagnosis in the intention-to-treat population. Safety was also analysed by intention to treat. This trial is closed to new participants and is registered with isrctn.com, number ISRCTN37118456. FINDINGS: Between April 21, 2008, and May 17, 2014, we randomly assigned 48 stroke units (and 1224 patients clustered within the units) to the two treatment groups: 24 to antibiotics and 24 to standard care alone (control). 11 units and seven patients withdrew after randomisation before 14 days, leaving 1217 patients in 37 units for the intention-to-treat analysis (615 patients in the antibiotics group, 602 in control). Prophylactic antibiotics did not affect the incidence of algorithm-defined post-stroke pneumonia (71 [13%] of 564 patients in antibiotics group vs 52 [10%] of 524 in control group; marginal adjusted odds ratio [OR] 1·21 [95% CI 0·71-2·08], p=0·489, intraclass correlation coefficient [ICC] 0·06 [95% CI 0·02-0·17]. Algorithm-defined post-stroke pneumonia could not be established in 129 (10%) patients because of missing data. Additionally, we noted no differences in physician-diagnosed post-stroke pneumonia between groups (101 [16%] of 615 patients vs 91 [15%] of 602, adjusted OR 1·01 [95% CI 0·61-1·68], p=0·957, ICC 0·08 [95% CI 0·03-0·21]). The most common adverse events were infections unrelated to post-stroke pneumonia (mainly urinary tract infections), which were less frequent in the antibiotics group (22 [4%] of 615 vs 45 [7%] of 602; OR 0·55 [0·32-0·92], p=0·02). Diarrhoea positive for Clostridium difficile occurred in two patients (<1%) in the antibiotics group and four (<1%) in the control group, and meticillin-resistant Staphylococcus aureus colonisation occurred in 11 patients (2%) in the antibiotics group and 14 (2%) in the control group. INTERPRETATION: Antibiotic prophylaxis cannot be recommended for prevention of post-stroke pneumonia in patients with dysphagia after stroke managed in stroke units. FUNDING: UK National Institute for Health Research.

Higher cough flow is associated with lower risk of pneumonia in acute stroke.

UNLABELLED: There is little available evidence to demonstrate how cough strength mediates the risk of aspiration-related pneumonia in acute stroke. Our secondary analysis of trial data indicates that risk of pneumonia reduces with increasing peak cough flow (PCF) of voluntary cough (OR 0.994 for each 1 L/min increase in PCF, 95% CI 0.988 to 1.0, p=0.035); and to a lesser degree with increasing PCF of reflex cough (OR 0.998 for each 1 L/min increase in PCF, 95% CI 0.992 to 1.004, p=0.475). These data serve hypothesis generation. Further studies are needed to confirm these findings and validate their clinical utility. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN40298220 (post-results).

Comparison of the diagnostic utility of physician-diagnosed with algorithm-defined stroke-associated pneumonia.

OBJECTIVE: Diagnosing stroke-associated pneumonia (SAP) is challenging and may result in inappropriate antibiotic use or confound research outcomes. This study evaluates the diagnostic accuracy of algorithm-defined versus physician-diagnosed SAP in 1088 patients who had dysphagic acute stroke from 37 UK stroke units between 21 April 2008 and 17 May 2014. METHODS: SAP in the first 14 days was diagnosed by a criteria-based algorithm applied to blinded patient data and independently by treating physicians. Patients in whom diagnoses differed were reassigned following blinded adjudication of individual patient records. The sensitivity, specificity, positive predictive value (PPV) and diagnostic OR of algorithmic and physician diagnosis of SAP were assessed using adjudicated SAP as the reference standard. Agreement was assessed using the κ statistic. RESULTS: Physicians diagnosed SAP in 176/1088 (16%) and the algorithm in 123/1088 (11.3%) patients. Diagnosis agreed in 885/1088 (81.3%) patients (κ 0.22 (95% CI 0.14 to 0.29)). On a blinded review, 129/1088 (11.8%) patients were adjudicated as patients with SAP. The algorithm and the physicians had high specificity (97% (95% CI 96% to 98%) and 90% (95% CI 88% to 92%), respectively) but only moderate sensitivity (72% (95% CI 64% to 80%) and 65% (95% CI 56% to 73%), respectively) in diagnosing SAP. The algorithm showed better PPV (76% (95% CI 67% to 83%) vs 48% (95% CI 40% to 55%)), diagnostic OR (80 (95% CI 42 to 136) vs 18 (95% CI 12 to 27)) and agreement (κ 0.70 (95% CI 0.63 to 0.78) vs 0.48 (95% CI 0.41 to 0.54)) than physician diagnosis with adjudicated SAP. CONCLUSIONS: Algorithm-based approaches can standardise SAP diagnosis for clinical practice and research. TRIAL REGISTRATION NUMBER: ISRCTN37118456; Post-results.

A pragmatic randomised multi-centre trial of multifamily and single family therapy for adolescent anorexia nervosa.

BACKGROUND: Considerable progress has been made in recent years in developing effective treatments for child and adolescent anorexia nervosa, with a general consensus in the field that eating disorders focussed family therapy (often referred to as Maudsley Family Therapy or Family Based Treatment) currently offers the most promising outcomes. Nevertheless, a significant number do not respond well and additional treatment developments are needed to improve outcomes. Multifamily therapy is a promising treatment that has attracted considerable interest and we report the results of the first randomised controlled trial of multifamily therapy for adolescent anorexia nervosa. METHODS: The study was a pragmatic multicentre randomised controlled superiority trial comparing two outpatient eating disorder focussed family interventions - multifamily therapy (MFT-AN) and single family therapy (FT-AN). A total of 169 adolescents with a DSM-IV diagnosis of anorexia nervosa or eating disorder not otherwise specified (restricting type) were randomised to the two treatments using computer generated blocks of random sizes to ensure balanced numbers in the trial arms. Independent assessors, blind to the allocation, completed evaluations at baseline, 3 months, 12 months (end of treatment) and 18 months. RESULTS: Both treatment groups showed clinically significant improvements with just under 60% achieving a good or intermediate outcome (on the Morgan-Russell scales) at the end of treatment in the FT-AN group and more than 75% in the MFT-AN group - a statistically significant benefit in favour of the multifamily intervention (OR = 2.55 95%; CI 1.17, 5.52; p = 0.019). At follow-up (18 months post baseline) there was relatively little change compared to end of treatment although the difference in primary outcome between the treatments was no longer statistically significant. Clinically significant gains in weight were accompanied by improvements in mood and eating disorder psychopathology. Approximately half the patients in FT-AN and nearly 60% of those in MFT-AN had started menstruating. CONCLUSIONS: This study confirms previous research findings demonstrating the effectiveness of eating disorder focused family therapy and highlights the additional benefits of bringing together groups of families that maximises the use of family resources and mutual support leading to improved outcomes. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11275465 ; Registered 29 January 2007 (retrospectively registered).