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Objective: To carry out a systematic review of recently published large-scale observational studies assessing the effects of red blood cell transfusion (RBCT) on mortality, with particular emphasis on the statistical methods used to adjust for confounding. Given the limited number of randomised trials of the efficacy of RBCT, clinicians often use evidence from observational studies. However, confounding factors, for example, individuals receiving blood generally being sicker than those who do not, make their interpretation challenging. Design: Systematic review. Information sources: We searched MEDLINE and EMBASE for studies published from 1 January 2006 to 31 December 2010. Eligibility criteria for included studies: We included prospective cohort, case-control studies or retrospective analyses of databases or disease registers where the effect of risk factors for mortality or survival was examined. Studies must have included more than 1000 participants receiving RBCT for any cause. We assessed the effects of RBCT versus no RBCT and different volumes and age of RBCT. Results: -32 studies were included in the review; 23 assessed the effects of RBCT versus no RBCT; 5 assessed different volumes and 4 older versus newer RBCT. There was a considerable variability in the patient populations, study designs and level of statistical adjustment. Overall, most studies showed a higher rate of mortality when comparing patients who received RBCT with those who did not, even when these rates were adjusted for confounding; the majority of these increases were statistically significant. The same pattern was observed in studies where protection from bias was likely to be greater, such as prospective studies. Conclusions: Recent observational studies do show a consistently adverse effect of RBCT on mortality. Whether this is a true effect remains uncertain as it is possible that even the best conducted adjustments cannot completely eliminate the impact of confounding.
\n \n\n \n \nObjectives The aim of this study was to test the effectiveness of Provent, an expiratory nasal resistance valve, to prevent the recurrence of OSA following CPAP withdrawal. Design Randomised, partially blinded, parallel, placebo-controlled trial. Setting Outpatient sleep clinics in the UK (Oxford) and Switzerland (Zurich). Participants 67 patients with OSA receiving CPAP were randomised to one of three groups for 2 weeks: continuing CPAP, Provent or placebo Provent. Main outcome measures Primary outcomes included for Provent versus placebo Provent, OSA severity (oxygen desaturation index (ODI), apnoea-hypopnoea index (AHI)) and Epworth Sleepiness Scale (ESS) score. Secondary outcomes for Provent versus placebo Provent included ODI from ambulatory pulse oximetry and blood pressure (BP). For CPAP versus Provent, or CPAP versus placebo Provent, secondary outcomes included ODI/AHI, ESS and BP. Results 63 patients were included in the per protocol analysis. OSA recurred in the Provent (ODI 35.8, SD 17.4) and placebo Provent (ODI 28.2, SD 18.3) groups, and there was no significant difference in ODI, AHI and ESS between Provent and placebo Provent at 2 weeks (mean difference ODI -1.0, 95% CI -10.0 to +12.0, p=0.85; AHI +3.2, 95% CI -7.7 to +14.1, p=0.52; and ESS -1.4, 95% CI -4.1 to +1.4, p=0.33). ODI from ambulatory pulse-oximetry and BP at 2 weeks were not different in the Provent versus placebo Provent groups. ODI, AHI and BP, but not ESS, were significantly higher in the Provent and placebo Provent groups compared with CPAP. Conclusions Provent cannot be recommended as an alternative short-term therapy for patients with moderate to severe OSA already on CPAP.
\n \n\n \n \nObjective: To assess persistence of immunity to hepatitis B (HBV) in primary school children vaccinated following perinatal exposure. Design: Serological survey. Setting: Five UK sites (Berkshire East, Birmingham, Buckinghamshire, Milton Keynes and Oxfordshire). Participants: Children from 3 years 4 months to 10 years of age (mean age 6.2 years), vaccinated against HBV from birth following perinatal exposure. Interventions: A single booster dose of the paediatric formulation of a recombinant HBV vaccine. Main outcome measures: Titres of antibody against hepatitis B Surface Antigen (anti-HBs) measured immediately before and 21-35 days after the HBV vaccine booster. Results: Prebooster anti-HBs titres were >10 mIU/ml in 84.6% of children (n=26; 95% CI 65.1 to 95.6%). All children (n=25, 95% CI 86.3 to 100%) had titres >100 mIU/ml after the booster. Conclusions: This study of antibody persistence among UK children born to hepatitis B infected women, immunised with a 3-dose infant schedule with a toddler booster suggests sustained immunity through early childhood. These data should prompt further studies to address the need for a preschool booster. Trial registration: Eudract Number 2008-004785-98.
\n \n\n \n \n\u00a9 The Author 2014. Background. Protection against Haemophilus influenzae type b (Hib), a rapidly invading encapsulated bacteria, is dependent on maintenance of an adequate level of serum antibody through early childhood. In many countries, Hib vaccine booster doses have been implemented after infant immunization to sustain immunity. We investigated the long-term persistence of antibody and immunological memory in primary-school children following infant (with or without booster) Hib vaccination. Methods. Anti-polyribosylribitol phosphate (PRP) immunoglobulin G (IgG) concentration and the frequency of circulating Hib-specific memory B cells were measured before a booster of a Hib-serogroup C meningococcal (MenC) conjugate vaccine and again 1 week, 1 month, and 1 year after the booster in 250 healthy children aged 6-12 years in an open-label phase 4 clinical study. Results. Six to 12 years following infant priming with 3 doses of Hib conjugate vaccine, anti-PRP IgG geometric mean concentrations were 3.11 \u03bcg/mL and 0.71 \u03bcg/mL and proportions with anti-PRP IgG \u22651.0 \u03bcg/mL were 79% and 43% in children who had or had not, respectively, received a fourth Hib conjugate vaccine dose (mean age, 3.9 years). Higher baseline and post-Hib-MenC booster responses (anti-PRP IgG and memory B cells) were found in younger children and in those who had received a fourth Hib dose. Conclusions. Sustained Hib conjugate vaccine-induced immunity in children is dependent on time since infant priming and receipt of a booster. Understanding the relationship between humoral and cellular immunity following immunization with conjugate vaccines may direct vaccine design and boosting strategies to sustain individual and population immunity against encapsulated bacteria in early childhood.
\n \n\n \n \nOBJECTIVES: To examine the reporting characteristics and methodological details of randomised trials indexed in PubMed in 2000 and 2006 and assess whether the quality of reporting has improved after publication of the Consolidated Standards of Reporting Trials (CONSORT) Statement in 2001. DESIGN: Comparison of two cross sectional investigations. Study sample All primary reports of randomised trials indexed in PubMed in December 2000 (n=519) and December 2006 (n=616), including parallel group, crossover, cluster, factorial, and split body study designs. MAIN OUTCOME MEASURES: The proportion of general and methodological items reported, stratified by year and study design. Risk ratios with 95% confidence intervals were calculated to represent changes in reporting between 2000 and 2006. RESULTS: The majority of trials were two arm (379/519 (73%) in 2000 v 468/616 (76%) in 2006) parallel group studies (383/519 (74%) v 477/616 (78%)) published in specialty journals (482/519 (93%) v 555/616 (90%)). In both 2000 and 2006, a median of 80 participants were recruited per trial for parallel group trials. The proportion of articles that reported drug trials decreased between 2000 and 2006 (from 393/519 (76%) to 356/616 (58%)), whereas the proportion of surgery trials increased (51/519 (10%) v 128/616 (21%)). There was an increase between 2000 and 2006 in the proportion of trial reports that included details of the primary outcome (risk ratio (RR) 1.18, 95% CI 1.04 to 1.33), sample size calculation (RR 1.66, 95% CI 1.40 to 1.95), and the methods of random sequence generation (RR 1.62, 95% CI 1.32 to 1.97) and allocation concealment (RR 1.40, 95% CI 1.11 to 1.76). There was no difference in the proportion of trials that provided specific details on who was blinded (RR 0.91, 95% CI 0.75 to 1.10). CONCLUSIONS: Reporting of several important aspects of trial methods improved between 2000 and 2006; however, the quality of reporting remains well below an acceptable level. Without complete and transparent reporting of how a trial was designed and conducted, it is difficult for readers to assess its conduct and validity.
\n \n\n \n \nBackground. Typhoid fever is a major global health problem, the control of which is hindered by lack of a suitable animal model in which to study Salmonella Typhi infection. Until 1974, a human challenge model advanced understanding of typhoid and was used in vaccine development. We set out to establish a new human challenge model and ascertain the S. Typhi (Quailes strain) inoculum required for an attack rate of 60%-75% in typhoid-naive volunteers when ingested with sodium bicarbonate solution.Methods. Groups of healthy consenting adults ingested escalating dose levels of S. Typhi and were closely monitored in an outpatient setting for 2 weeks. Antibiotic treatment was initiated if typhoid diagnosis occurred (temperature \u226538\u00b0C sustained \u226512 hours or bacteremia) or at day 14 in those remaining untreated.Results. Two dose levels (103 or 104 colony-forming units) were required to achieve the primary objective, resulting in attack rates of 55% (11/20) or 65% (13/20), respectively. Challenge was well tolerated; 4 of 40 participants fulfilled prespecified criteria for severe infection. Most diagnoses (87.5%) were confirmed by blood culture, and asymptomatic bacteremia and stool shedding of S. Typhi was also observed. Participants who developed typhoid infection demonstrated serological responses to flagellin and lipopolysaccharide antigens by day 14; however, no anti-Vi antibody responses were detected.Conclusions. Human challenge with a small inoculum of virulent S. Typhi administered in bicarbonate solution can be performed safely using an ambulant-model design to advance understanding of host-pathogen interactions and immunity. This model should expedite development of diagnostics, vaccines, and therapeutics for typhoid control. \u00a9 The Author 2014.
\n \n\n \n \nAn approach is described for monitoring urine samples using a portable system based on chromatic techniques and for predicting urinary tract infection (UTI) from the results. The system uses a webcam-computer combination with the screen of a computer visual display unit as a tuneable illumination source. It is shown that the system can operate in a robust manner under ambient lighting conditions and with potential for use as a point of care test in primary care. The present approach combines information on urine liquid concentration and turbidity. Its performance in an exploratory study is compared with microbiological culture of 200 urine samples, of which 79 had bacterial growth >105 colony forming unit/millilitre (cfu ml-1) indicative of UTI. It is shown that both sensitivity and negative predictive value of 0.92 could be achieved. \u00a9 2014 Institute of Physics and Engineering in Medicine.
\n \n\n \n \nBackground: Pneumococcal disease is a significant cause of morbidity and mortality in young children in Nepal, and currently available pneumococcal conjugate vaccines offer moderate coverage of invasive disease isolates. Methods: A prevalence study of children aged 1.5 to 24 months in urban and rural Nepal was conducted. In the urban group, nasopharyngeal swabs (NPS) were transported using silica desiccant packages (SDP) with delayed processing (2 weeks), or skim-milk-tryptone-glucose-glycerin (STGG) with immediate processing (within 8 hours). Pneumococcal nasopharyngeal carriage prevalence, serogroup/type distribution and isolate genotypes (as defined by multilocus sequence typing) were determined. Results: 1101 children were enrolled into the study: 574 in the urban group and 527 in the rural group. Overall carriage prevalence based on culture from specimens transported and stored in STGG was 58.7% (337/574), compared to 40.9% (235/574) in SDP. There was concordance of detection of pneumococcus in 67% of samples. Using the SDP method, pneumococcal carriage prevalence was higher in the rural population (69.2%; 364/526) compared to the urban population (40.9%; 235/574). Serogroup/type distribution varied with geographical location. Over half of the genotypes identified in both the urban and rural pneumococcal populations were novel. Conclusion: The combination of delayed culture and transport using SDP underestimates the prevalence of pneumococcal carriage; however, in remote areas, this method could still provide a useful estimate of carriage prevalence and serogroup/type distribution. Vaccine impact is unpredictable in a setting with novel genotypes and limited serotype coverage as described here. Consequently, continued surveillance of pneumococcal isolates from carriage and disease in Nepali children following the planned introduction of pneumococcal conjugate vaccines introduction will be essential. \u00a9 2014 Hanieh et al.
\n \n\n \n \nObjective: To investigate the relationship between the prevalence of smoking in the population and incidence of invasive meningococcal disease (IMD) among children under 5 years of age. Design: Retrospective, longitudinal, observational study. Poisson regression controlled for confounding factors. Setting: Norway, Sweden, Denmark and the Netherlands between 1975 and 2009. Population: Total population of approximately 35 million people in these four countries. Data sources: Data were collected from the Ministries of Health, National Statistics Bureaus and other relevant national institutes. Results: In Norway, there was a significant positive relationship between the annual prevalence of daily smokers among individuals aged 25-49 years and the incidence of IMD in children under 5 years of age, unadjusted (RR=1.04-1.06, 95% CI 1.02 to 1.07, p<0.001) and after adjustment for time of year (quarter), incidence of influenza-like illness and household crowding (RR=1.05-1.07, 95% CI 1.03 to 1.09, p<0.001). Depending on age group, the risk of IMD increased by 5.2-6.9% per 1% increase in smoking prevalence among individuals aged 25-49 years in adjusted analyses. Using limited datasets from the three other countries, unadjusted analysis showed positive associations between IMD in children related to older smokers in Sweden and the Netherlands and negative associations related to younger smokers in Sweden. However, there were no demonstrable associations between incidence of IMD and prevalence of smoking, after adjustment for the same confounding variables. Conclusions: The reduced incidence of IMD in Norway between 1975 and 2009 may partly be explained by the reduced prevalence of smoking during this period. High-quality surveillance data are required to confirm this in other countries. Strong efforts to reduce smoking in the whole population including targeted campaigns to reduce smoking among adults may have a role to play in the prevention of IMD in children.
\n \n\n \n \nMeningococcal conjugate vaccines are today successfully deployed in universal programs for children and adolescents in different geographic regions to control meningitis and septicemia. However, in adults, the advantages of these conjugates over the older polysaccharide vaccines are less clear. In this randomized clinical trial, we demonstrated that both conjugate and polysaccharide quadrivalent meningococcal vaccines elicit protective antibody responses in adults aged 18 to 70. (This study has been registered at www.clinicaltrials.gov under registration no. NCT00901940.). Copyright \u00a9 2014, American Society for Microbiology. All Rights Reserved.
\n \n\n \n \n\u00a9 The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. OBJECTIVES: The Arterial Revascularization Trial (ART) is a randomized comparison of bilateral internal mammary artery (BIMA) versus single internal mammary artery (SIMA) grafting in coronary artery bypass graft (CABG) surgery and is one of the largest randomized trials of surgery ever conducted. ART is also one of the largest studies of contemporary CABG with a high proportion of off-pump surgeries (41%). The objective of this post hoc analysis was to evaluate the surgical process and 1-year outcomes for surgery performed on-pump compared with off-pump. METHODS: ART randomized 3102 patients with multivessel coronary artery disease (CAD) to SIMA or BIMA grafts to determine if BIMA grafts have an additional survival advantage at 10 years. The 1-year interim analysis showed an overall very low mortality and major morbidity rate irrespective of whether the procedure was with an SIMA or BIMA. The surgical process and 1-year outcomes were analysed according to whether surgery was performed on-pump or off-pump. RESULTS: Baseline variables were not statistically significantly different between on- and off-pump surgery within each treatment group after taking account of the effects of clustering by individual surgeons. At both 30 days and 1 year, there was a low incidence of death (1.2%, 2.3%), stroke (1.1%, 1.7%), myocardial infarction (MI) (1.4%, 1.9%), repeat revascularization (0.5%, 1.5%) and wound reconstruction (1.2%). A similar average number of grafts were performed with on- and off-pump surgery (median = 3), but the duration of surgery was 20-30 min and ventilation time ~2 h shorter with off-pump surgery. Blood loss and platelet transfusions were lower in the off-pump group, with no difference in the need for balloon pump or renal support. Sternal wound reconstruction was similar with off-pump surgery in the SIMA group (0.5 vs 0.6%) and lower with off-pump surgery in the BIMA group (1.4 vs 2.2%). Repeat revascularization was marginally higher in off-pump patients at 30 days (0.8 vs 0.3%) and at 1 year (1.7 vs 1.3%). CONCLUSIONS: The outcomes of contemporary CABG are excellent with low mortality, stroke, myocardial infarction and need for wound reconstruction and repeat revascularization whether performed on-pump or off-pump. CLINICAL TRIAL REGISTRATION: Controlled-trials.com (ISRCTN46552265).
\n \n\n \n \n\u00a9 2014 AMDA - The Society for Post-Acute and Long-Term Care Medicine. Background: Neuropsychiatric symptoms in Alzheimer disease (AD) cause significant distress and present a complex clinical challenge for treatment. Pharmacological treatment options are limited to antipsychotics, which carry extensive safety issues. There is emerging evidence to support the potential benefits of memantine, currently licensed for moderate to severe AD, in the prophylaxis of neuropsychiatric symptoms. Methods: The MAIN-AD study is a double-blind randomized placebo-controlled withdrawal trial comparing memantine with antipsychotics for the treatment of neuropsychiatric symptoms over 24weeks. A total of 199 people with probable AD living in care homes already receiving an antipsychotic were randomized to receive either memantine or to continue an antipsychotic. The primary outcomes were function (Bristol Activities of Daily Living Scale [BADLS]) and agitation (Cohen-Mansfield Agitation Inventory [CMAI]). Secondary outcomes were Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), and mortality. Results: There was no significant difference between groups on the BADLS or CMAI. At 24weeks, there was a nonsignificant adjusted difference in favor of memantine on the BADLS of 0.23 (95% CI -1.80-2.27; P=.82) and in favor of antipsychotic on the CMAI of 0.09 (95% CI -0.35-8.53; P=.07). Although there were no significant differences in total NPI, there were 5.01 (95% CI -1.68-11.70; P=.05) and 3.63 (95% CI -1.40-8.67; P=.16) point advantages favoring antipsychotics at weeks 12 and 24, respectively. In addition, in an exploratory analysis, individuals allocated to antipsychotics were significantly less likely to experience relapse of neuropsychiatric symptoms at all time points. The group receiving memantine had a nonsignificant 1.3-point advantage on the MMSE at 24weeks. Discussion: This study indicates no benefits for memantine in the long-term treatment and prophylaxis of clinically significant neuropsychiatric symptoms. The results did indicate some benefits for antipsychotic medications in reducing the relapse of neuropsychiatric symptoms, but this must be balanced against increased mortality risk.
\n \n\n \n \n\u00a9 2015 Springer-Verlag Berlin Heidelberg Currently available point-of-care (POC) diagnostic tests for managing urinary tract infections (UTIs) in general practice are limited by poor performance characteristics, and laboratory culture generally provides results only after a few days. This laboratory evaluation compared the analytic performance of the POC UK Flexicult\u2122 (Statens Serum Institut) (SSI) urinary kit for quantification, identification and antibiotic susceptibility testing and routine UK National Health Service (NHS) urine processing to an advanced urine culture method. Two hundred urine samples routinely submitted to the Public Health Wales Microbiology Laboratory were divided and: (1) analysed by routine NHS microbiological tests as per local laboratory standard operating procedures, (2) inoculated onto the UK Flexicult\u2122 SSI urinary kit and (3) spiral plated onto Colorex Orientation UTI medium (E&O Laboratories Ltd). The results were evaluated between the NHS and Flexicult\u2122 methods, and discordant results were compared to the spiral plating method. The UK Flexicult\u2122 SSI urinary kit was compared to routine NHS culture for identification of a pure or predominant uropathogen at \u226510<sup>5</sup> cfu/mL, with a positive discordancy rate of 13.5 % and a negative discordancy rate of 3 %. The sensitivity and specificity were 86.7 % [95 % confidence interval (CI) 73.8\u201393.7] and 82.6 % (95 % CI 75.8\u201387.7), respectively. The UK Flexicult\u2122 SSI urinary kit was comparable to routine NHS urine processing in identifying microbiologically positive UTIs in this laboratory evaluation. However, the number of false-positive samples could lead to over-prescribing of antibiotics in clinical practice. The Flexicult\u2122 SSI kit could be useful as a POC test for UTIs in primary care but further pragmatic evaluations are necessary.
\n \n\n \n \n\u00a9 2015 AMDA - The Society for Post-Acute and Long-Term Care Medicine. Background: Neuropsychiatric symptoms in Alzheimer disease (AD) cause significant distress and present a complex clinical challenge for treatment. Pharmacological treatment options are limited to antipsychotics, which carry extensive safety issues. There is emerging evidence to support the potential benefits of memantine, currently licensed for moderate to severe AD, in the prophylaxis of neuropsychiatric symptoms. Methods: The MAIN-AD study is a double-blind randomized placebo-controlled withdrawal trial comparing memantine with antipsychotics for the treatment of neuropsychiatric symptoms over 24weeks. A total of 199 people with probable AD living in care homes already receiving an antipsychotic were randomized to receive either memantine or to continue an antipsychotic. The primary outcomes were function (Bristol Activities of Daily Living Scale [BADLS]) and agitation (Cohen-Mansfield Agitation Inventory [CMAI]). Secondary outcomes were Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), and mortality. Results: There was no significant difference between groups on the BADLS or CMAI. At 24weeks, there was a nonsignificant adjusted difference in favor of memantine on the BADLS of 0.23 (95% CI -1.80-2.27; P=.82) and in favor of antipsychotic on the CMAI of 0.09 (95% CI -0.35-8.53; P=.07). Although there were no significant differences in total NPI, there were 5.01 (95% CI -1.68-11.70; P=.05) and 3.63 (95% CI -1.40-8.67; P=.16) point advantages favoring antipsychotics at weeks 12 and 24, respectively. In addition, in an exploratory analysis, individuals allocated to antipsychotics were significantly less likely to experience relapse of neuropsychiatric symptoms at all time points. The group receiving memantine had a nonsignificant 1.3-point advantage on the MMSE at 24weeks. Discussion: This study indicates no benefits for memantine in the long-term treatment and prophylaxis of clinically significant neuropsychiatric symptoms. The results did indicate some benefits for antipsychotic medications in reducing the relapse of neuropsychiatric symptoms, but this must be balanced against increased mortality risk.
\n \n\n \n \n\u00a9 2015 Freeman et al. Open Access article distributed under the terms of CC BY. Background: Sleep disturbance occurs in most patients with delusions or hallucinations and should be treated as a clinical problem in its own right. However, cognitive behavioural therapy (CBT)-the best evidence-based treatment for insomnia-has not been tested in this patient population. We aimed to pilot procedures for a randomised trial testing CBT for sleep problems in patients with current psychotic experiences, and to provide a preliminary assessment of potential benefit. Methods: We did this prospective, assessor-blind, randomised controlled pilot trial (Better Sleep Trial [BEST]) at two mental health centres in the UK. Patients (aged 18-65 years) with persistent distressing delusions or hallucinations in the context of insomnia and a schizophrenia spectrum diagnosis were randomly assigned (1:1), via a web-based randomisation system with minimisation to balance for sex, insomnia severity, and psychotic experiences, to receive either eight sessions of CBT plus standard care (medication and contact with the local clinical team) or standard care alone. Research assessors were masked to group allocation. Assessment of outcome was done at weeks 0, 12 (post-treatment), and 24 (follow-up). The primary efficacy outcomes were insomnia assessed by the Insomnia Severity Index (ISI) and delusions and hallucinations assessed by the Psychotic Symptoms Rating Scale (PSYRATS) at week 12. We did analysis by intention to treat, with an aim to provide confidence interval estimation of treatment effects. This study is registered with ISRCTN, number 33695128. Findings: Between Dec 14, 2012, and May 22, 2013, and Nov 7, 2013, and Aug 26, 2014, we randomly assigned 50 patients to receive CBT plus standard care (n=24) or standard care alone (n=26). The last assessments were completed on Feb 10, 2015. 48 (96%) patients provided follow-up data. 23 (96%) patients offered CBT took up the intervention. Compared with standard care, CBT led to reductions in insomnia in the large effect size range at week 12 (adjusted mean difference 6.1, 95% CI 3.0-9.2, effect size d=1.9). By week 12, nine (41%) of 22 patients receiving CBT and one (4%) of 25 patients receiving standard care alone no longer had insomnia, with ISI scores lower than the cutoff for insomnia. The treatment effect estimation for CBT covered a range from reducing but also increasing delusions (adjusted mean difference 0.3, 95% CI -2.0 to 2.6) and hallucinations (-1.9, -6.5 to 2.7). Three patients, all in the CBT group, had five adverse events, although none were regarded as related to study treatment. Interpretation: Our findings show that CBT for insomnia might be highly effective for improving sleep in patients with persistent delusions or hallucinations. A larger, suitably powered phase 3 study is now needed to provide a precise estimate of the effects of CBT for sleep problems, both on sleep and psychotic experiences. Funding: Research for Patient Benefit Programme, National Institute for Health Research.
\n \n\n \n \n\u00a9 2016 Geddes et al. Background: Depressive symptoms are a major cause of disability in bipolar disorder and there are few safe and effective treatments. The combination of lamotrigine plus quetiapine potentially offers improved outcomes for people with bipolar depression. We aimed to determine if combination therapy with quetiapine plus lamotrigine leads to greater improvement in depressive symptoms over 12 weeks than quetiapine monotherapy plus lamotrigine placebo. Methods: In this double-blind, randomised, placebo-controlled, parallel group, 2 ;\u00d7 2 factorial trial (CEQUEL), patients with DSM-IV bipolar disorder I or II, who were aged 16 years or older, and required new treatment for a depressive episode, were enrolled from 27 sites in the UK. Patients were randomly assigned (1:1) by an adaptive minimisation algorithm to lamotrigine or placebo and to folic acid or placebo. Participants and investigators were masked to the treatment groups. The primary outcome was improvement in depressive symptoms at 12 weeks with the Quick Inventory of Depressive Symptomatology-self report version 16 (QIDS-SR16). Analysis was by modified intention-to-treat. This trial is registered with EUdraCT, number 2007-004513-33. Findings: Between Oct 21, 2008, and April 27, 2012, 202 participants were randomly assigned; 101 to lamotrigine and 101 to placebo. The mean difference in QIDS-SR16 total score between the group receiving lamotrigine versus the placebo group at 12 weeks was -1\u00b773 ([95% CI -3\u00b757 to 0\u00b711]; p=0\u00b7066) and at 52 weeks was -2\u00b769 ([-4\u00b789 to -0\u00b749]; p=0\u00b7017). Folic acid was not superior to placebo. There was a significant interaction (p=0\u00b7028), with folic acid reducing the effectiveness of lamotrigine at 12 weeks. The mean difference on QIDS-SR16 was -4\u00b714 ([95% CI -6\u00b790 to -1\u00b737]; p=0\u00b7004) for patients receiving lamotrigine without folic acid compared with 0\u00b712 ([-2\u00b758 to 2\u00b782]; p=0\u00b7931) for those receiving lamotrigine and folic acid. Interpretation: Addition of lamotrigine to quetiapine treatment improved outcomes. Folic acid seems to nullify the effect of lamotrigine. CEQUEL should encourage clinicians and patients to consider lamotrigine for bipolar depression, but also to be aware that concurrent folic acid might reduce its effectiveness. Funding: Medical Research Council.
\n \n\n \n \nBackground: The World Health Organisation estimates that by 2030 there will be approximately 350 million people with type 2 diabetes. Associated with renal complications, heart disease, stroke and peripheral vascular disease, early identification of patients with undiagnosed type 2 diabetes or those at an increased risk of developing type 2 diabetes is an important challenge. We sought to systematically review and critically assess the conduct and reporting of methods used to develop risk prediction models for predicting the risk of having undiagnosed (prevalent) or future risk of developing (incident) type 2 diabetes in adults.Methods: We conducted a systematic search of PubMed and EMBASE databases to identify studies published before May 2011 that describe the development of models combining two or more variables to predict the risk of prevalent or incident type 2 diabetes. We extracted key information that describes aspects of developing a prediction model including study design, sample size and number of events, outcome definition, risk predictor selection and coding, missing data, model-building strategies and aspects of performance.Results: Thirty-nine studies comprising 43 risk prediction models were included. Seventeen studies (44%) reported the development of models to predict incident type 2 diabetes, whilst 15 studies (38%) described the derivation of models to predict prevalent type 2 diabetes. In nine studies (23%), the number of events per variable was less than ten, whilst in fourteen studies there was insufficient information reported for this measure to be calculated. The number of candidate risk predictors ranged from four to sixty-four, and in seven studies it was unclear how many risk predictors were considered. A method, not recommended to select risk predictors for inclusion in the multivariate model, using statistical significance from univariate screening was carried out in eight studies (21%), whilst the selection procedure was unclear in ten studies (26%). Twenty-one risk prediction models (49%) were developed by categorising all continuous risk predictors. The treatment and handling of missing data were not reported in 16 studies (41%).Conclusions: We found widespread use of poor methods that could jeopardise model development, including univariate pre-screening of variables, categorisation of continuous risk predictors and poor handling of missing data. The use of poor methods affects the reliability of the prediction model and ultimately compromises the accuracy of the probability estimates of having undiagnosed type 2 diabetes or the predicted risk of developing type 2 diabetes. In addition, many studies were characterised by a generally poor level of reporting, with many key details to objectively judge the usefulness of the models often omitted. \u00a9 2011 Collins et al; licensee BioMed Central Ltd.
\n \n\n \n \nBackground: Reporting of the flow of participants through each stage of a randomized trial is essential to assess the generalisability and validity of its results. We assessed the type and completeness of information reported in CONSORT (Consolidated Standards of Reporting Trials) flow diagrams published in current reports of randomized trials.Methods: A cross sectional review of all primary reports of randomized trials which included a CONSORT flow diagram indexed in PubMed core clinical journals (2009). We assessed the proportion of parallel group trial publications reporting specific items recommended by CONSORT for inclusion in a flow diagram.Results: Of 469 primary reports of randomized trials, 263 (56%) included a CONSORT flow diagram of which 89% (237/263) were published in a CONSORT endorsing journal. Reports published in CONSORT endorsing journals were more likely to include a flow diagram (62%; 237/380 versus 29%; 26/89). Ninety percent (236/263) of reports which included a flow diagram had a parallel group design, of which 49% (116/236) evaluated drug interventions, 58% (137/236) were multicentre, and 79% (187/236) compared two study groups, with a median sample size of 213 participants. Eighty-one percent (191/236) reported the overall number of participants assessed for eligibility, 71% (168/236) the number excluded prior to randomization and 98% (231/236) the overall number randomized. Reasons for exclusion prior to randomization were more poorly reported. Ninety-four percent (223/236) reported the number of participants allocated to each arm of the trial. However, only 40% (95/236) reported the number who actually received the allocated intervention, 67% (158/236) the number lost to follow up in each arm of the trial, 61% (145/236) whether participants discontinued the intervention during the trial and 54% (128/236) the number included in the main analysis.Conclusions: Over half of published reports of randomized trials included a diagram showing the flow of participants through the trial. However, information was often missing from published flow diagrams, even in articles published in CONSORT endorsing journals. If important information is not reported it can be difficult and sometimes impossible to know if the conclusions of that trial are justified by the data presented. \u00a9 2011 Hopewell et al; licensee BioMed Central Ltd.
\n \n\n \n \n\u00a9 2019 The Author(s). Background: Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care. Methods: We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2-4 consecutive days no later than 7 days from baseline. It will continue 4-5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2-3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response. Discussion: The SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies. Trial registration: ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017.
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