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© 2020 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society. BACKGROUND/OBJECTIVES: Randomized controlled trials are used to inform clinical guidelines on the management of hypertension in older adults, but it is unclear to what extent these trials represent the general population attending routine clinical practice. This study aimed to define the proportion and characteristics of patients eligible for hypertension trials conducted in older people. DESIGN: Cross-sectional study. SETTING: A total of 24 general practices in England. PARTICIPANTS: Anonymized electronic health record data from all individuals aged 80 and older. MEASUREMENTS: Descriptive statistics were used to define the proportion and characteristics of patients eligible for two previous medication intensification trials (HYVET, SPRINT) and one medication reduction trial (OPTiMISE). A logistic regression model was constructed to estimate predictors of eligibility for each trial. RESULTS: Of 15,376 patients identified, 268 (1.7%; 95% confidence interval [CI] = 1.5–2.0%), 5,290 (34.4%; 95%CI = 33.7–35.2%), and 3,940 (25.6%; 95%CI = 24.9–26.3%) were eligible for the HYVET, SPRINT, and OPTiMISE trials, respectively. Between 5.6% and 30.7% of exclusions from each trial were due to eligibility criteria excluding those with high or uncontrolled blood pressure. Frailty (odds ratio [OR] =.44; 95%CI =.36–.54 [OPTiMISE]), cardiovascular polypharmacy (OR =.61; 95%CI =.55–.68 [SPRINT]) and multimorbidity (OR =.72; 95%CI =.64–.82 [SPRINT]) were associated with a lower likelihood of being eligible for one or more of the trials. CONCLUSION: A possible unintended consequence of blood pressure criteria used by trials attempting to answer different primary questions is that for many older patients, no trial evidence exists to inform treatment decisions in routine practice. Caution should be exercised when applying results from existing trials to patients with frailty or multimorbidity.

BACKGROUND Many people are accessing digital self-help for mental health problems, often with little evidence of effectiveness. Social anxiety is one of the most common sources of mental distress in the population, and many people with symptoms do not seek help for what represents a significant public health problem. OBJECTIVE This study aimed to evaluate the effectiveness of a self-guided cognitive behavioral internet intervention for people with social anxiety symptoms in the general population. METHODS We conducted a two-group randomized controlled trial in England between May 11, 2016, and June 27, 2018. Adults with social anxiety symptoms who were not receiving treatment for social anxiety were recruited using online advertisements. All participants had unrestricted access to usual care and were randomized in a 1:1 ratio to either a Web-based unguided self-help intervention based on cognitive behavioral principles or a waiting list control group. All outcomes were collected through self-report online questionnaires. The primary outcome was the change in 17-item Social Phobia Inventory (SPIN-17) score from baseline to 6 weeks using a linear mixed-effect model that used data from all time points (6 weeks, 3 months, 6 months, and 12 months). RESULTS A total of 2122 participants were randomized, and 6 were excluded from analyses because they were ineligible. Of the 2116 eligible randomized participants (mean age 37 years; 80.24%, 1698/2116 women), 70.13% (1484/2116) had follow-up data available for analysis, and 56.95% (1205/2116) had data on the primary outcome, although attrition was higher in the intervention arm. At 6 weeks, the mean (95% CI) adjusted difference in change in SPIN-17 score in the intervention group compared with control was −1.94 (−3.13 to −0.75; P=.001), a standardized mean difference effect size of 0.2. The improvement was maintained at 12 months. Given the high dropout rate, sensitivity analyses explored missing data assumptions, with results that were consistent with those of the primary analysis. The economic evaluation demonstrated cost-effectiveness with a small health status benefit and a reduction in health service utilization. CONCLUSIONS For people with social anxiety symptoms who are not receiving other forms of help, this study suggests that the use of an online self-help tool based on cognitive behavioral principles can provide a small improvement in social anxiety symptoms compared with no intervention, although dropout rates were high. CLINICALTRIAL ClinicalTrials.gov NCT02451878; https://clinicaltrials.gov/ct2/show/NCT02451878

Background and Purpose— Oral anticoagulants (OAC) substantially reduce risk of stroke in atrial fibrillation, but uptake is suboptimal. Electronic health records enable automated identification of people at risk but not receiving treatment. We investigated the effectiveness of a software tool (AURAS-AF [Automated Risk Assessment for Stroke in Atrial Fibrillation]) designed to identify such individuals during routine care through a cluster-randomized trial. Methods— Screen reminders appeared each time the electronic health records of an eligible patient was accessed until a decision had been taken over OAC treatment. Where OAC was not started, clinicians were prompted to indicate a reason. Control practices continued usual care. The primary outcome was the proportion of eligible individuals receiving OAC at 6 months. Secondary outcomes included rates of cardiovascular events and reports of adverse effects of the software on clinical decision-making. Results— Forty-seven practices were randomized. The mean proportion–prescribed OAC at 6 months was 66.3% (SD=9.3) in the intervention arm and 63.9% (9.5) in the control arm (adjusted difference 1.21% [95% confidence interval −0.72 to 3.13]). Incidence of recorded transient ischemic attack was higher in the intervention practices (median 10.0 versus 2.3 per 1000 patients with atrial fibrillation; P =0.027), but at 12 months, we found a lower incidence of both all cause stroke ( P =0.06) and hemorrhage ( P =0.054). No adverse effects of the software were reported. Conclusions— No significant change in OAC prescribing occurred. A greater rate of diagnosis of transient ischemic attack (possibly because of improved detection or overdiagnosis) was associated with a reduction (of borderline significance) in stroke and hemorrhage over 12 months. Clinical Trial Registration— URL: http://www.isrctn.com . Unique Identifier: ISRCTN55722437.

Summary Background Closure of an abdominal stoma, a common elective operation, is associated with frequent complications; one of the commonest and impactful is incisional hernia formation. We aimed to investigate whether biological mesh (collagen tissue matrix) can safely reduce the incidence of incisional hernias at the stoma closure site. Methods In this randomised controlled trial (ROCSS) done in 37 hospitals across three European countries (35 UK, one Denmark, one Netherlands), patients aged 18 years or older undergoing elective ileostomy or colostomy closure were randomly assigned using a computer-based algorithm in a 1:1 ratio to either biological mesh reinforcement or closure with sutures alone (control). Training in the novel technique was standardised across hospitals. Patients and outcome assessors were masked to treatment allocation. The primary outcome measure was occurrence of clinically detectable hernia 2 years after randomisation (intention to treat). A sample size of 790 patients was required to identify a 40% reduction (25% to 15%), with 90% power (15% drop-out rate). This study is registered with ClinicalTrials.gov, NCT02238964. Findings Between Nov 28, 2012, and Nov 11, 2015, of 1286 screened patients, 790 were randomly assigned. 394 (50%) patients were randomly assigned to mesh closure and 396 (50%) to standard closure. In the mesh group, 373 (95%) of 394 patients successfully received mesh and in the control group, three patients received mesh. The clinically detectable hernia rate, the primary outcome, at 2 years was 12% (39 of 323) in the mesh group and 20% (64 of 327) in the control group (adjusted relative risk [RR] 0·62, 95% CI 0·43–0·90; p=0·012). In 455 patients for whom 1 year postoperative CT scans were available, there was a lower radiologically defined hernia rate in mesh versus control groups (20 [9%] of 229 vs 47 [21%] of 226, adjusted RR 0·42, 95% CI 0·26–0·69; p

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. Electronic supplementary material The online version of this article (10.1186/s13063-019-3336-1) contains supplementary material, which is available to authorized users.

Background Severe asthma exacerbations are costly to patients and the NHS, and occur frequently in severely allergic patients. Objective To ascertain whether or not nocturnal temperature-controlled laminar airflow (TLA) device usage over 12 months can reduce severe exacerbations and improve asthma control and quality of life compared with a placebo device, while being cost-effective and acceptable to adults with severe allergic asthma. Design A pragmatic, multicentre, randomised, double-blind, placebo-controlled, parallel-group, superiority trial with qualitative interviews. The trial included an internal pilot with qualitative focus groups. Setting Fourteen hospitals in the UK that manage patients with severe asthma. Participants Adults (16–75 years) with severe, poorly controlled, exacerbation-prone asthma despite high-intensity treatment, and who are sensitised to a perennial indoor aeroallergen. Intervention Nocturnal, home-based TLA treatment using an Airsonett® (Airsonett AB, Ängelholm, Sweden) device. The comparator was a placebo device that was identical to the active device except that it did not deliver the laminar airflow. Participants were allocated 1 : 1 to TLA therapy or placebo, minimised by site, origin of case, baseline severe exacerbation frequency, maintenance oral corticosteroid use and pre-bronchodilator forced expiratory volume in 1 second. Main outcome measures Primary outcome – frequency of severe asthma exacerbations occurring within the 12-month follow-up period, defined as worsening of asthma requiring systemic corticosteroids [≥ 30 mg of prednisolone or equivalent daily (or ≥ 50% increase in dose if on maintenance dose of ≥ 30 mg of prednisolone)] for ≥ 3 days. Secondary outcomes – changes in asthma control, lung function, asthma-specific and global quality of life for participants, adherence to the intervention, device acceptability, health-care resource use and cost-effectiveness. Results Between May 2014 and January 2016, 489 patients consented to participate in the trial, of whom 249 failed screening and 240 were randomised (n = 119 in the treatment group and n = 121 in the placebo group); all were analysed. In total, 202 participants (84%) reported use of the device for 9–12 months. Qualitative analyses showed high levels of acceptability. The mean [standard deviation (SD)] rate of severe exacerbations did not differ between groups [active 1.39 (1.57), placebo 1.48 (2.03); risk ratio 0.92, 95% CI 0.66 to 1.27; p = 0.616]. There were no significant differences in secondary outcomes for lung function, except for a reduction in mean daily peak expiratory flow [mean (SD) difference 14.7 l/minute (7.35 l/minute), 95% CI 0.32 to 29.1 l/minute; p = 0.045) for those in the active device group. There were no differences in asthma control or airway inflammation and no serious harms related to the device. No significant difference between the groups in quality-adjusted life-years gained over 1 year was observed. In addition, there was no difference in generic or disease-specific health-related quality of life overall, although statistically significant higher quality of life at month 6 was observed. Increases in quality of life were not sufficient to offset the annual costs associated with use of the TLA device. Limitations Missing outcome data could have resulted in an underestimation of exacerbations and rendered the study inconclusive. Conclusions Within the limits of the data, no consistent benefits of the active device were demonstrated, and the differences observed were not sufficient to make the device cost-effective. The types of patients who may benefit from the TLA device, and the reasons for large reductions in exacerbation frequency in severe asthma trials, which also incorporate other methods of recording exacerbations, need to be explored. Trial registration Current Controlled Trials ISRCTN46346208. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 29. See the NIHR Journals Library website for further project information.

Background The Brief Intervention for Weight Loss Trial enrolled 1882 consecutively attending primary care patients who were obese and participants were randomised to physicians opportunistically endorsing, offering, and facilitating a referral to a weight loss programme (support) or recommending weight loss (advice). After one year, the support group lost 1.4 kg more (95%CI 0.9 to 2.0): 2.4 kg versus 1.0 kg. We use a cohort simulation to predict effects on disease incidence, quality of life, and healthcare costs over 20 years. Methods Randomly sampling from the trial population, we created a virtual cohort of 20 million adults and assigned baseline morbidity. We applied the weight loss observed in the trial and assumed weight regain over four years. Using epidemiological data, we assigned the incidence of 12 weight-related diseases depending on baseline disease status, age, gender, body mass index. From a healthcare perspective, we calculated the quality adjusted life years (QALYs) accruing and calculated the incremental difference between trial arms in costs expended in delivering the intervention and healthcare costs accruing. We discounted future costs and benefits at 1.5% over 20 years. Results Compared with advice, the support intervention reduced the cumulative incidence of weight-related disease by 722/100,000 people, 0.33% of all weight-related disease. The incremental cost of support over advice was £2.01million/100,000. However, the support intervention reduced health service costs by £5.86 million/100,000 leading to a net saving of £3.85 million/100,000. The support intervention produced 992 QALYs/100,000 people relative to advice. Conclusions A brief intervention in which physicians opportunistically endorse, offer, and facilitate a referral to a behavioural weight management service to patients with a BMI of at least 30 kg/m2 reduces healthcare costs and improves health more than advising weight loss.

Summary Background Nepalese infants receive ten-valent pneumococcal conjugate vaccine (PCV10) with a 1 month interval between priming doses for programmatic reasons. We aimed to investigate whether immune responses to PCV10 serotypes were non-inferior if the second priming dose of PCV10 was delivered at a 1 month interval as opposed to a 2 month interval. Methods We did an open-label, randomised, parallel group trial in healthy Nepalese infants aged 40–60 days at Patan Hospital, Kathmandu, Nepal. Children were eligible for inclusion if they were healthy, were born at more than or equal to 37 weeks' gestation, were residing in Kathmandu, and had not had any previous vaccinations other than BCG, and oral polio vaccine. Participants were randomly assigned (1:1) by means of a computer-generated list with randomly varying permuted block sizes accessed through a validated web-based interface, to receive PCV10 either at 6 weeks and 10 weeks of age (6 + 10 group) or at 6 weeks and 14 weeks of age (6 + 14 group), with both groups receiving a booster at 9 months of age. Laboratory staff, masked to study intervention, analysed serum samples for antibodies against PCV10 serotypes by ELISA. The primary outcome was to determine whether the 6 + 10 schedule was non-inferior to the 6 + 14 schedule at 9 months of age, on the basis of the proportion of infants with serotype-specific IgG greater than or equal to 0·35 μg/mL. Non-inferiority was established with a 10% margin, and the primary endpoint was measured in a modified intention-to-treat population, which included only participants who successfully had a blood sample collected. This trial is registered at ClinicalTrials.gov , number NCT02385513 . Findings Between Aug 21, 2015, and April 4, 2016, 304 Nepalese children were randomly assigned to either the 6 + 10 group (n=152) or the 6 + 14 group (n=152). At 9 months of age, the 6 + 10 schedule was non-inferior for serotype 5 (79 [55·2%] of 143 vs 78 [53·4%] of 146, difference 1·82% [95% CI −9·6 to 13·25], p=0·021), serotype 9V (66 [46·1%] of 143 vs 55 [37·6%] of 146, difference 8·48% [−2·84 to 19·8], p=0·001), serotype 14 (110 [77·4%] of 142 vs 110 [74·8%] of 147, difference 2·63% [−7·27 to 12·54], p=0·006), and serotype 19F (135 [95%] of 142 vs 146 [100%] of 146, difference −4·92% [−9·86 to 0], p=0·022). At the same timepoint, non-inferiority was not shown for serotype 1 (36 [25·1%] of 143 vs 42 [28·5%] of 147, difference −3·39% [95% CI −13·56 to 6·77], p=0·102), serotype 4 (70 [48·9%] of 143 vs 87 [59·1%] of 147, difference −10·23% [−21·64 to 1·18], p=0·516), serotype 6B (96 [67·1%] of 143 vs 114 [77·5%] of 147, difference −10·41% [−20·65 to −0·18], p=0·532), serotype 7F (99 [69·2%] of 143 vs 109 [74·1%] of 147, difference −4·91% [−15·26 to 5·42], p=0·168), serotype 18C (89 [62·2%] of 143 vs 114 [77·5%] of 147, difference −15·31% [−25·78 to −4·83], p=0·840), and serotype 23F (37 [25·8%] of 143 vs 41 [27·8%] of 147, difference −2·01% [−12·19 to 8·16], p=0·062). After the booster dose, at 10 months of age, there were no significant differences in immunogenicity (proportion of children with antibody greater than or equal to 0.35 μg/mL) for any of the ten serotypes, when comparing the two schedules. Serious adverse events occurred in 32 participants, 11 (7%) of 152 in the 6 + 10 group and 21 (14%) of 152 in the 6 + 14 group. Interpretation The 6 week, 14 week, and 9 month schedule should be implemented where possible. However, post-booster responses, which are thought to drive herd immunity, were similar in the two schedules. Therefore, the 6 week, 10 week, and 9 month schedule is an alternative that can be used when logistically necessary, and is expected to provide herd protection. Funding Gavi, the Vaccine Alliance.

Summary Background The effectiveness of the COVID-19 vaccination programme depends on mass participation: the greater the number of people vaccinated, the less risk to the population. Concise, persuasive messaging is crucial, particularly given substantial levels of vaccine hesitancy in the UK. Our aim was to test which types of written information about COVID-19 vaccination, in addition to a statement of efficacy and safety, might increase vaccine acceptance. Methods For this single-blind, parallel-group, randomised controlled trial, we aimed to recruit 15 000 adults in the UK, who were quota sampled to be representative. Participants were randomly assigned equally across ten information conditions stratified by level of vaccine acceptance (willing, doubtful, or strongly hesitant). The control information condition comprised the safety and effectiveness statement taken from the UK National Health Service website; the remaining conditions addressed collective benefit, personal benefit, seriousness of the pandemic, and safety concerns. After online provision of vaccination information, participants completed the Oxford COVID-19 Vaccine Hesitancy Scale (outcome measure; score range 7–35) and the Oxford Vaccine Confidence and Complacency Scale (mediation measure). The primary outcome was willingness to be vaccinated. Participants were analysed in the groups they were allocated. p values were adjusted for multiple comparisons. The study was registered with ISRCTN, ISRCTN37254291. Findings From Jan 19 to Feb 5, 2021, 15 014 adults were recruited. Vaccine hesitancy had reduced from 26·9% the previous year to 16·9%, so recruitment was extended to Feb 18 to recruit 3841 additional vaccine-hesitant adults. 12 463 (66·1%) participants were classified as willing, 2932 (15·6%) as doubtful, and 3460 (18·4%) as strongly hesitant (ie, report that they will avoid being vaccinated for as long as possible or will never get vaccinated). Information conditions did not alter COVID-19 vaccine hesitancy in those willing or doubtful (adjusted p values >0·70). In those strongly hesitant, COVID-19 vaccine hesitancy was reduced, in comparison to the control condition, by personal benefit information (mean difference –1·49, 95% CI –2·16 to –0·82; adjusted p=0·0015), directly addressing safety concerns about speed of development (−0·91, –1·58 to –0·23; adjusted p=0·0261), and a combination of all information (−0·86, –1·53 to –0·18; adjusted p=0·0313). In those strongly hesitant, provision of personal benefit information reduced hesitancy to a greater extent than provision of information on the collective benefit of not personally getting ill (−0·97, 95% CI –1·64 to –0·30; adjusted p=0·0165) or the collective benefit of not transmitting the virus (−1·01, –1·68 to –0·35; adjusted p=0·0150). Ethnicity and gender were found to moderate information condition outcomes. Interpretation In the approximately 10% of the population who are strongly hesitant about COVID-19 vaccines, provision of information on personal benefit reduces hesitancy to a greater extent than information on collective benefits. Where perception of risk from vaccines is most salient, decision making becomes centred on the personal. As such, messaging that stresses the counterbalancing personal benefits is likely to prove most effective. The messaging from this study could be used in public health communications. Going forwards, the study highlights the need for future health campaigns to engage with the public on the terrain that is most salient to them. Funding National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and NIHR Oxford Health Biomedical Research Centre.

Aim Hernia formation occurs at closed stoma sites in up to 30% of patients. The Reinforcement of Closure of Stoma Site (ROCSS) randomized controlled trial is evaluating whether placement of biological mesh during stoma closure safely reduces hernia rates compared with closure without mesh, without increasing surgical or wound complications. This paper aims to report recruitment, deliverability and safety from the internal feasibility study. Method A multicentre, patient and assessor blinded, randomized controlled trial, delivered through surgical trainee research networks. A 90-patient internal feasibility study assessed recruitment, randomization, deliverability and early (30 day) safety of the novel surgical technique (ClinicalTrials.gov registration number NCT02238964). Results The feasibility study recruited 90 patients from the 104 considered for entry (45 to mesh, 45 to no mesh). Seven of eight participating centres randomized patients within 30 days of opening. Overall, 41% of stomas were created for malignant disease and 73% were ileostomies. No mesh-specific complications occurred. Thirty-one postoperative adverse events were experienced by 31 patients, including surgical site infection (9%) and postoperative ileus (6%). One mesh was removed for re-access to the abdominal cavity, for reasons unrelated to the mesh. Independent review by the Data Monitoring and Ethics Committee of adverse event data by treatment allocation found no safety concerns. Conclusion Multicentre randomization to this trial of biological mesh is feasible, with no early safety concerns. Progression to the full Phase III trial has continued. ROCSS shows that trainee research networks can efficiently develop and deliver complex interventional surgical trials.

Long term follow-up of vaccine trials is essential to establish the duration of protection. In the context of worldwide concern about rising pertussis incidence, estimates of antibody persistence after vaccination, which do not account for the rise in antibody due to natural boosting or infection, may overestimate the degree of protection afforded by pertussis vaccines.This was a 5year follow up study of a randomised controlled trial of diphtheria, tetanus, pertussis and polio booster vaccines in UK children aged 3.5-5years. Antibody persistence was measured at 1month, 1, 3, and 5years after vaccination and the kinetics of antibody decline were modelled longitudinally. Estimates of predicted antibody persistence 9years after the pre-school booster were derived from model parameters.Antibody levels 9years after vaccination were predicted to be above accepted thresholds for protection for diphtheria, tetanus and polio. Antibody responses to pertussis toxoid were undetectable in 49% of children at the 5year follow up visit, and responses were predicted to be undetectable in 69% (95% CI 45-88%) of children by the time of their teenage booster at 13-14years of age.There is no defined correlate of protection for pertussis. However, the large proportion of participants in this study with undetectable pertussis antibody levels at both measured and predicted timepoints suggests sub-optimal immunity in adolescence. Adding pertussis to the teenage booster for UK children as is done in other countries, would enhance immunity in adolescence.

Background— We assessed the effect of automated treatment adherence support delivered via mobile phone short message system (SMS) text messages on blood pressure. Methods and Results— In this pragmatic, single-blind, 3-arm, randomized trial (SMS-Text Adherence Support [StAR]) undertaken in South Africa, patients treated for high blood pressure were randomly allocated in a 1:1:1 ratio to information only, interactive SMS text messaging, or usual care. The primary outcome was change in systolic blood pressure at 12 months from baseline measured with a validated oscillometric device. All trial staff were masked to treatment allocation. Analyses were intention to treat. Between June 26, 2012, and November 23, 2012, 1372 participants were randomized to receive information-only SMS text messages (n=457), interactive SMS text messages (n=458), or usual care (n=457). Primary outcome data were available for 1256 participants (92%). At 12 months, the mean adjusted change in systolic blood pressure compared with usual care was −2.2 mm Hg (95% confidence interval, −4.4 to −0.04) with information-only SMS and −1.6 mm Hg (95% confidence interval, −3.7 to 0.6) with interactive SMS. Odds ratios for the proportion of participants with a blood pressure Conclusions— In this randomized trial of an automated adherence support program delivered by SMS text message in a general outpatient population of adults with high blood pressure, we found a small reduction in systolic blood pressure control compared with usual care at 12 months. There was no evidence that an interactive intervention increased this effect. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02019823. South African National Clinical Trials Register, number SANCTR DOH-27-1212-386; Pan Africa Trial Register, number PACTR201411000724141.

Importance Deprescribing of antihypertensive medications is recommended for some older patients with polypharmacy and multimorbidity when the benefits of continued treatment may not outweigh the harms. Objective This study aimed to establish whether antihypertensive medication reduction is possible without significant changes in systolic blood pressure control or adverse events during 12-week follow-up. Design, Setting, and Participants The Optimising Treatment for Mild Systolic Hypertension in the Elderly (OPTIMISE) study was a randomized, unblinded, noninferiority trial conducted in 69 primary care sites in England. Participants, whose primary care physician considered them appropriate for medication reduction, were aged 80 years and older, had systolic blood pressure lower than 150 mm Hg, and were receiving at least 2 antihypertensive medications were included. Participants enrolled between April 2017 and September 2018 and underwent follow-up until January 2019. Interventions Participants were randomized (1:1 ratio) to a strategy of antihypertensive medication reduction (removal of 1 drug [intervention], n = 282) or usual care (control, n = 287), in which no medication changes were mandated. Main Outcomes and Measures The primary outcome was systolic blood pressure lower than 150 mm Hg at 12-week follow-up. The prespecified noninferiority margin was a relative risk (RR) of 0.90. Secondary outcomes included the proportion of participants maintaining medication reduction and differences in blood pressure, frailty, quality of life, adverse effects, and serious adverse events. Results Among 569 patients randomized (mean age, 84.8 years; 276 [48.5%] women; median of 2 antihypertensive medications prescribed at baseline), 534 (93.8%) completed the trial. Overall, 229 (86.4%) patients in the intervention group and 236 (87.7%) patients in the control group had a systolic blood pressure lower than 150 mm Hg at 12 weeks (adjusted RR, 0.98 [97.5% 1-sided CI, 0.92 to ∞]). Of 7 prespecified secondary end points, 5 showed no significant difference. Medication reduction was sustained in 187 (66.3%) participants at 12 weeks. Mean change in systolic blood pressure was 3.4 mm Hg (95% CI, 1.1 to 5.8 mm Hg) higher in the intervention group compared with the control group. Twelve (4.3%) participants in the intervention group and 7 (2.4%) in the control group reported at least 1 serious adverse event (adjusted RR, 1.72 [95% CI, 0.7 to 4.3]). Conclusions and Relevance Among older patients treated with multiple antihypertensive medications, a strategy of medication reduction, compared with usual care, was noninferior with regard to systolic blood pressure control at 12 weeks. The findings suggest antihypertensive medication reduction in some older patients with hypertension is not associated with substantial change in blood pressure control, although further research is needed to understand long-term clinical outcomes. Trial Registration EudraCT Identifier:2016-004236-38; ISRCTN identifier:97503221

IntroductionRecent evidence suggests that larger blood pressure reductions and multiple antihypertensive drugs may be harmful in older people, particularly frail individuals with polypharmacy and multimorbidity. However, there is a lack of evidence to support deprescribing of antihypertensives, which limits the practice of medication reduction in routine clinical care. The aim of this trial is to examine whether antihypertensive medication reduction is possible in older patients without significant changes in blood pressure control at follow-up.Methods and analysisThis trial will use a primary care-based, open-label, randomised controlled trial design. A total of 540 participants will be recruited, aged ≥80 years, with systolic blood pressure Ethics and disseminationThe protocol, informed consent form, participant information sheet and all other participant facing material have been approved by the Research Ethics Committee (South Central—Oxford A; ref 16/SC/0628), Medicines and Healthcare products Regulatory Agency (ref 21584/0371/001–0001), host institution(s) and Health Research Authority. All research outputs will be published in peer-reviewed journals and presented at national and international conferences.Trial registration numberEudraCT 2016-004236-38;ISRCTN97503221; Pre-results.

IntroductionType 2 diabetes is common, affecting over 400 million people worldwide. Risk of serious complications can be reduced through use of effective treatments and active self-management. However, people are often concerned about starting new medicines and face difficulties in taking them regularly. Use of brief messages to provide education and support self-management, delivered through mobile phone-based text messages, can be an effective tool for some long-term conditions. We have developed messages aiming to support patients’ self-management of type 2 diabetes in the use of medications and other aspects of self-management, underpinned by theory and evidence. The aim of this trial is to determine the feasibility of a large-scale clinical trial to test the effectiveness and cost-effectiveness of the intervention, compared with usual care.Methods and analysisThe feasibility trial will be a multicentre individually randomised, controlled trial in primary care recruiting adults (≥35 years) with type 2 diabetes in England. Consenting participants will be randomised to receive short text messages three times a week with messages designed to produce change in medication adherence or non-health-related messages for 6 months. The aims are to test recruitment methods, retention to the study, the feasibility of data collection and the mobile phone and web-based processes of a proposed definitive trial and to refine the text messaging intervention. The primary outcome is the rate of recruitment to randomisation of participants to the trial. Data, including patient reported measures, will be collected online at baseline and the end of the 6-month follow-up period. With 200 participants (100 in each group), this trial is powered to estimate 80% follow-up within 95% CIs of 73.8% to 85.3%. The analysis will follow a prespecified plan.Ethics and disseminationEthics approval was obtained from the West of Scotland Research Ethics Committee 05. The results will be disseminated through conference presentations, peer-reviewed journals and will be published on the trial website: www.summit-d.org (SuMMiT-D (SUpport through Mobile Messaging and digital health Technology for Diabetes)).Trial registration numberISRCTN13404264.

BACKGROUND: The capsular group B meningococcal vaccine (4CMenB) is recommended for children with complement deficiencies, asplenia, and splenic dysfunction; however, data on the immunogenicity of 4CMenB in these “at-risk” children are missing. METHODS: Participants aged 2 to 17 years in Italy, Spain, Poland, the United Kingdom, and Russia with complement deficiencies, asplenia, or splenic dysfunction received 2 doses of 4CMenB 2 months apart, as did healthy children in the control group. Exogenous and endogenous human complement serum bactericidal activity (SBA) was determined at baseline and 1 month after the second immunization against 4 test strains: H44/76 (assessing vaccine antigen factor H binding protein), 5/99 (Neisserial adhesion A), NZ98/254 (Porin A), and M10713 (Neisserial heparin binding antigen). RESULTS: Of 239 participants (mean age 10.3 years, 45% female), 40 children were complement deficient (9 eculizumab therapy, 4 terminal-chain deficiencies, 27 “other”), 112 children had asplenia or splenic dysfunction (8 congenital asplenia, 8 functional asplenia, 96 splenectomy), and 87 children were in the control group. After immunization, the proportions of complement-deficient participants with exogenous complement SBA titers ≥1:5 were 87% (H44/76), 95% (5/99), 68% (NZ98/254), and 73% (M10713), compared with 97%, 100%, 86%, and 94%, respectively, for asplenic children and 98%, 99%, 83%, and 99% for children in the control group. When testing with endogenous complement, strain-specific bactericidal activity was evident in only 1 eculizumab-treated participant and 1 terminal chain complement-deficient participant. CONCLUSIONS: 4CMenB administration is similarly immunogenic in healthy children and those with asplenia or splenic dysfunction. The significance of the trend to lower responses of SBA titers in complement-deficient children (especially those with terminal chain complement deficiency or those on eculizumab therapy) must be determined by ongoing surveillance for vaccine failures.

IntroductionInfluenza and influenza-like illness (ILI) create considerable burden on healthcare resources each winter. Children with pre-existing conditions such as asthma, diabetes mellitus and cerebral palsy are among those at greatest risk of clinical deterioration from influenza/ILI. The Antibiotics for at Risk CHildren with InfluEnza (ARCHIE) trial aims to determine whether early oral treatment with the antibiotic co-amoxiclav reduces the likelihood of reconsultation due to clinical deterioration in these ‘at risk’ children.Methods and analysisThe ARCHIE trial is a double-blind, parallel, randomised, placebo-controlled trial. ‘At risk’ children aged 6 months to 12 years inclusive who present within the first 5 days of an ILI episode will be randomised to receive a 5-day course of oral co-amoxiclav 400/57 twice daily or placebo. Randomisation will use a non-deterministic minimisation algorithm to balance age and seasonal influenza vaccination status.To detect respiratory virus infections, a nasal swab will be obtained from each participant before commencing study medication. To identify carriage of potential bacterial respiratory pathogens, we will also obtain a throat swab where possible.The primary outcome is reconsultation in any healthcare setting due to clinical deterioration within 28 days of randomisation. We will analyse this outcome using log-binomial regression model adjusted for region, age and seasonal influenza vaccination status.Secondary outcomes include duration of fever, duration of symptoms and adverse events. Continuous outcomes will be compared using regression analysis (or equivalent non-parametric method for non-normal data) adjusting for minimisation variables. Binary outcomes will be compared using χ2/Fisher’s exact test and log-binomial regression.EthicsThe ARCHIE trial has been reviewed and approved by the North West-Liverpool East Research Ethics Committee, Health Research Authority and Medicines and Healthcare Products Regulatory Agency. Our findings will be published in peer-reviewed journals and disseminated via our study website (www.archiestudy.com) and links with relevant charities.Trial registration numbersISRCTN70714783; Pre-results.

BACKGROUND: Studies evaluating titration of antihypertensive medication using self-monitoring give contradictory findings and the precise place of telemonitoring over self-monitoring alone is unclear. The TASMINH4 trial aimed to assess the efficacy of self-monitored blood pressure, with or without telemonitoring, for antihypertensive titration in primary care, compared with usual care.METHODS: This study was a parallel randomised controlled trial done in 142 general practices in the UK, and included hypertensive patients older than 35 years, with blood pressure higher than 140/90 mm Hg, who were willing to self-monitor their blood pressure. Patients were randomly assigned (1:1:1) to self-monitoring blood pressure (self-montoring group), to self-monitoring blood pressure with telemonitoring (telemonitoring group), or to usual care (clinic blood pressure; usual care group). Randomisation was by a secure web-based system. Neither participants nor investigators were masked to group assignment. The primary outcome was clinic measured systolic blood pressure at 12 months from randomisation. Primary analysis was of available cases. The trial is registered with ISRCTN, number ISRCTN 83571366.FINDINGS: 1182 participants were randomly assigned to the self-monitoring group (n=395), the telemonitoring group (n=393), or the usual care group (n=394), of whom 1003 (85%) were included in the primary analysis. After 12 months, systolic blood pressure was lower in both intervention groups compared with usual care (self-monitoring, 137·0 [SD 16·7] mm Hg and telemonitoring, 136·0 [16·1] mm Hg vs usual care, 140·4 [16·5]; adjusted mean differences vs usual care: self-monitoring alone, -3·5 mm Hg [95% CI -5·8 to -1·2]; telemonitoring, -4·7 mm Hg [-7·0 to -2·4]). No difference between the self-monitoring and telemonitoring groups was recorded (adjusted mean difference -1·2 mm Hg [95% CI -3·5 to 1·2]). Results were similar in sensitivity analyses including multiple imputation. Adverse events were similar between all three groups.INTERPRETATION: Self-monitoring, with or without telemonitoring, when used by general practitioners to titrate antihypertensive medication in individuals with poorly controlled blood pressure, leads to significantly lower blood pressure than titration guided by clinic readings. With most general practitioners and many patients using self-monitoring, it could become the cornerstone of hypertension management in primary care.FUNDING: National Institute for Health Research via Programme Grant for Applied Health Research (RP-PG-1209-10051), Professorship to RJM (NIHR-RP-R2-12-015), Oxford Collaboration for Leadership in Applied Health Research and Care, and Omron Healthcare UK.

This serological follow up study assessed the kinetics of antibody response in children who previously participated in a single centre, open-label, randomised controlled trial of low-dose compared to standard-dose diphtheria booster preschool vaccinations in the United Kingdom (UK). Children had previously been randomised to receive one of three combination vaccines: either a combined adsorbed tetanus, low-dose diphtheria, 5-component acellular pertussis and inactivated polio vaccine (IPV) (Tdap-IPV, Repevax(®); Sanofi Pasteur MSD); a combined adsorbed tetanus, low-dose diphtheria and 5-component acellular pertussis vaccine (Tdap, Covaxis(®); Sanofi Pasteur MSD) given concomitantly with oral polio vaccine (OPV); or a combined adsorbed standard-dose diphtheria, tetanus, 2-component acellular pertussis and IPV (DTap-IPV, Tetravac(®); Sanofi Pasteur MSD). Blood samples for the follow-up study were taken at 1, 3 and 5 years after participation in the original trial (median, 5.07 years of age at year 1), and antibody persistence to each vaccine antigen measured against defined serological thresholds of protection. All participants had evidence of immunity to diphtheria with antitoxin concentrations greater than 0.01IU/mL five years after booster vaccination and 75%, 67% and 79% of children who received Tdap-IPV, Tdap+OPV and DTap-IPV, respectively, had protective antitoxin levels greater than 0.1IU/mL. Long lasting protective immune responses to tetanus and polio antigens were also observed in all groups, though polio responses were lower in the sera of those who received OPV. Low-dose diphtheria vaccines provided comparable protection to the standard-dose vaccine and are suitable for use for pre-school booster vaccination.

BackgroundCognitive–behavioural therapy (CBT) for childhood anxiety disorders is associated with modest outcomes in the context of parental anxiety disorder.ObjectivesThis study evaluated whether or not the outcome of CBT for children with anxiety disorders in the context of maternal anxiety disorders is improved by the addition of (i) treatment of maternal anxiety disorders, or (ii) treatment focused on maternal responses. The incremental cost-effectiveness of the additional treatments was also evaluated.DesignParticipants were randomised to receive (i) child cognitive–behavioural therapy (CCBT); (ii) CCBT with CBT to target maternal anxiety disorders [CCBT + maternal cognitive–behavioural therapy (MCBT)]; or (iii) CCBT with an intervention to target mother–child interactions (MCIs) (CCBT + MCI).SettingA NHS university clinic in Berkshire, UK.ParticipantsTwo hundred and eleven children with a primary anxiety disorder, whose mothers also had an anxiety disorder.InterventionsAll families received eight sessions of individual CCBT. Mothers in the CCBT + MCBT arm also received eight sessions of CBT targeting their own anxiety disorders. Mothers in the MCI arm received 10 sessions targeting maternal parenting cognitions and behaviours. Non-specific interventions were delivered to balance groups for therapist contact.Main outcome measuresPrimary clinical outcomes were the child’s primary anxiety disorder status and degree of improvement at the end of treatment. Follow-up assessments were conducted at 6 and 12 months. Outcomes in the economic analyses were identified and measured using estimated quality-adjusted life-years (QALYs). QALYS were combined with treatment, health and social care costs and presented within an incremental cost–utility analysis framework with associated uncertainty.ResultsMCBT was associated with significant short-term improvement in maternal anxiety; however, after children had received CCBT, group differences were no longer apparent. CCBT + MCI was associated with a reduction in maternal overinvolvement and more confident expectations of the child. However, neither CCBT + MCBT nor CCBT + MCI conferred a significant post-treatment benefit over CCBT in terms of child anxiety disorder diagnoses [adjusted risk ratio (RR) 1.18, 95% confidence interval (CI) 0.87 to 1.62,p = 0.29; adjusted RR CCBT + MCI vs. control: adjusted RR 1.22, 95% CI 0.90 to 1.67,p = 0.20, respectively] or global improvement ratings (adjusted RR 1.25, 95% CI 1.00 to 1.59,p = 0.05; adjusted RR 1.20, 95% CI 0.95 to 1.53,p = 0.13). CCBT + MCI outperformed CCBT on some secondary outcome measures. Furthermore, primary economic analyses suggested that, at commonly accepted thresholds of cost-effectiveness, the probability that CCBT + MCI will be cost-effective in comparison with CCBT (plus non-specific interventions) is about 75%.ConclusionsGood outcomes were achieved for children and their mothers across treatment conditions. There was no evidence of a benefit to child outcome of supplementing CCBT with either intervention focusing on maternal anxiety disorder or maternal cognitions and behaviours. However, supplementing CCBT with treatment that targeted maternal cognitions and behaviours represented a cost-effective use of resources, although the high percentage of missing data on some economic variables is a shortcoming. Future work should consider whether or not effects of the adjunct interventions are enhanced in particular contexts. The economic findings highlight the utility of considering the use of a broad range of services when evaluating interventions with this client group.Trial registrationCurrent Controlled Trials ISRCTN19762288.FundingThis trial was funded by the Medical Research Council (MRC) and Berkshire Healthcare Foundation Trust and managed by the National Institute for Health Research (NIHR) on behalf of the MRC–NIHR partnership (09/800/17) and will be published in full inHealth Technology Assessment; Vol. 19, No. 38.

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 24 weeks. 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 24 weeks, 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 24 weeks. 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.

BACKGROUND: The multicomponent serogroup B meningococcal (4CMenB) vaccine induces antibodies against indicator strains of serogroup B meningococcus under various schedules. We investigated the persistence of antibodies in 5-year-old children 18-20 months after their last dose (at about 3.5 years of age). METHODS: We assessed 5-year-old children who received the 4CMenB vaccine or a recombinant protein vaccine in a previous randomized trial. We also recruited 50 vaccine-naive 5-year-olds and administered 2 doses of 4CMenB to each child. We measured serum bactericidal antibody titres against 4 indicator strains of serogroup B meningococcus matched to each individual vaccine component and against 4 mismatched strains. RESULTS: Of those who received the 4CMenB vaccine at 2, 4, 6, 12 and 40 months (n = 16), the percentage with protective antibody titres (≥ 1:4) at 60 months ranged from 44% to 88% against matched strains and from 13% to 81% against mismatched strains. Loss of protective titres was also observed for those who received the 4CMenB vaccine at 12, 40 and 42 months (n = 5) (80%-100% against matched strains, 60%-100% against mismatched strains) or at 40 and 42 months (n = 29) (31%-100% against matched strains, 41%-81% against mismatched strains). Administering the 4CMenB vaccine to 5-year-old children yielded protective titres against matched strains in 92%-100% and against mismatched strains in 59%-100%. The majority of these children reported injection-site pain (40/50 [80%] after dose 1, 39/46 [85%] after dose 2) and erythema (47/50 [94%] and 40/46 [87%], respectively); rates of fever were low (5/50 [10%] and 2/46 [4%], respectively). INTERPRETATION: Waning of immunity by 5 years of age occurred after receipt of the 4CMenB vaccine in infancy, even with an additional booster at 40 months. The 4CMenB vaccine is immunogenic and was fairly well tolerated by 5-year-old children, although injection-site pain was noteworthy. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01027351.

Background There is concern that existing models of acute hospital care will become unworkable as the health service admits an increasing number of frail older people with complex health needs, and that there is inadequate evidence to guide the planning of acute hospital level services. We aim to evaluate whether geriatrician-led admission avoidance to hospital at home is an effective alternative to hospital admission. Methods/Design We are conducting a multi-site randomised open trial of geriatrician-led admission avoidance hospital at home, compared with admission to hospital. We are recruiting older people with markers of frailty or prior dependence who have been referred to admission avoidance hospital at home for an acute medical event. This includes patients presenting with delirium, functional decline, dependence, falls, immobility or a background of dementia presenting with physical disease. Participants are randomised using a computerised random number generator to geriatrician-led admission avoidance hospital at home or a control group of inpatient admission in a 2:1 ratio in favour of the intervention. The primary endpoint ‘living at home’ (the inverse of death or living in a residential care setting) is measured at 6 months follow-up, and we also collect data on this outcome at 12 months. Secondary outcomes include the incidence of delirium, mortality, new long-term residential care, cognitive impairment, activities of daily living, quality of life and quality-adjusted survival, length of stay, readmission or transfer to hospital. We will conduct a parallel economic evaluation, and a process evaluation that includes an interview study to explore the experiences of patients and carers. Discussion Health systems around the world are examining how to provide acute hospital-level care to older adults in greater numbers with a fixed or shrinking hospital resource. This trial is the first large multi-site randomised trial of geriatrician-led admission avoidance hospital at home, and will provide evidence on alternative models of healthcare for older people who require hospital admission. Trial registration ISRCTN60477865: Registered on 10 March 2014. Trial Sponsor: University of Oxford. Version 3.1, 14/06/2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2214-y) contains supplementary material, which is available to authorized users.

BACKGROUND: We conducted a randomized controlled trial of a digital health system supporting clinical care through monitoring and self-management support in community-based patients with moderate to very severe chronic obstructive pulmonary disease (COPD).OBJECTIVE: The aim of this study was to determine the efficacy of a fully automated Internet-linked, tablet computer-based system of monitoring and self-management support (EDGE' sElf-management anD support proGrammE) in improving quality of life and clinical outcomes.METHODS: We compared daily use of EDGE with usual care for 12 months. The primary outcome was COPD-specific health status measured with the St George's Respiratory Questionnaire for COPD (SGRQ-C).RESULTS: A total of 166 patients were randomized (110 EDGE, 56 usual care). All patients were included in an intention to treat analysis. The estimated difference in SGRQ-C at 12 months (EDGE-usual care) was -1.7 with a 95% CI of -6.6 to 3.2 (P=.49). The relative risk of hospital admission for EDGE was 0.83 (0.56-1.24, P=.37) compared with usual care. Generic health status (EQ-5D, EuroQol 5-Dimension Questionnaire) between the groups differed significantly with better health status for the EDGE group (0.076, 95% CI 0.008-0.14, P=.03). The median number of visits to general practitioners for EDGE versus usual care were 4 versus 5.5 (P=.06) and to practice nurses were 1.5 versus 2.5 (P=.03), respectively.CONCLUSIONS: The EDGE clinical trial does not provide evidence for an effect on COPD-specific health status in comparison with usual care, despite uptake of the intervention. However, there appears to be an overall benefit in generic health status; and the effect sizes for improved depression score, reductions in hospital admissions, and general practice visits warrants further evaluation and could make an important contribution to supporting people with COPD.TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 40367841; http://www.isrctn.com/ISRCTN40367841 (Archived by WebCite at http://www.webcitation.org/6pmfIJ9KK).

Meningococcal 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 atwww.clinicaltrials.govunder registration no. NCT00901940.)

BACKGROUND: The internet is frequently used to share experiences of health and illness, but this phenomenon has not been harnessed as an intervention to achieve health behaviour change. The aim of this study was to determine the feasibility of a randomised trial assessing the effects of a novel, experience-based website as a smoking cessation intervention. The secondary aim was to measure the potential impact on smoking behaviour of both the intervention and a comparator website. METHODS: A feasibility randomised controlled single-blind trial assessed a novel, experience-based website containing personal accounts of quitting smoking as a cessation intervention, and a comparator website providing factual information. Feasibility measures including recruitment, and usage of the interventions were recorded, and the following participant-reported outcomes were also measured: Smoking Abstinence Self-Efficacy Questionnaire, the single-item Motivation to Stop Scale, self-reported abstinence, quit attempts and health status outcomes. Eligible smokers from two English regions were entered into the trial and given access to their allocated website for two weeks. RESULTS: Eighty-seven smokers were randomised, 65 completed follow-up (75 %). Median usage was 15 min for the intervention, and 5 min for the comparator (range 0.5-213 min). Median logins for both sites was 2 (range 1-20). All participant-reported outcomes were similar between groups. CONCLUSIONS: It was technically feasible to deliver a novel intervention harnessing the online sharing of personal experiences as a tool for smoking cessation, but recruitment was slow and actual use was relatively low, with attrition from the trial. Future work needs to maximize engagement and to understand how best to assess the value of such interventions in everyday use, rather than as an isolated 'dose of information'. TRIAL REGISTRATION: ISRCTN29549695 DOI 10.1186/ISRCTN29549695 . Registered 17/05/2013.

Objective To determine the feasibility of a randomised control trial (RCT) assessing the effects of an experience-based website as a resource for the self-management of chronic asthma. Design and setting Feasibility, single-blind RCT in 2 regions of England. Randomisation used computer-generated random number sequence in a 1:1 ratio, after baseline data collection, to website access for 2 weeks. Participants Adults (age ≥18 years) with clinically diagnosed asthma as coded in their primary care electronic record, prescribed inhaled corticosteroids for at least 3 months in the previous year were recruited from 9 general practices. Intervention The EXPERT asthma intervention is an interactive PC/laptop/tablet/smartphone compatible website designed with extensive input from adults with asthma. It provides experience-based information and aims to support subjective perception of self-efficacy, self-management and improve health status. Outcome measures Primary outcomes were consent/recruitment, website usage and completion of outcome measures. Secondary outcomes included Partners in Health (PIH) questionnaire, the Chronic Disease Self-Efficacy Scale (CDSES), the SF36 and the E-Health Impact Questionnaire (eHIQ). Participant blinding postrandomisation was not possible. The analysis was blind to allocation. Results Recruitment target exceeded. 148 participants randomised (73 intervention group). Age range 19-84 years; 59% female. 121/148 (84%; 62 intervention group) followed up. Median number of logins was 2 (IQR 2-3, range 1-48). Minimal differences of change from baseline between groups; both showed improvement in health state or management of their condition with no significant differences between arms. No adverse events. Conclusions Recruitment and retention confirmed feasibility. The trends towards improved outcomes suggest that further research on digital interventions based on exposure to others’ personal experiences may be of value in the self-management of chronic asthma.

Haemophilus influenzae type b (Hib) is a major cause of invasive bacterial infection in children that can be prevented by a vaccine, but there is still uncertainty about its relative importance in Asia. This study investigated the age-specific prevalence of Hib carriage and its molecular epidemiology in carriage and disease in Nepal. Oropharyngeal swabs were collected from children in Kathmandu, Nepal, from 3 different settings: a hospital outpatient department (OPD), schools, and children's homes. Hib was isolated using Hib antiserum agar plates, and serotyping was performed with latex agglutination. Hib isolates from children with invasive disease were obtained during active microbiological surveillance at Patan Hospital, Kathmandu, Nepal. Genotyping of disease and carriage isolates was undertaken using multilocus sequence typing (MLST). Swabs were taken from 2,195 children, including 1,311 children at an OPD, 647 children attending schools, and 237 children in homes. Overall, Hib was identified in 5.0% (110/2,195; 95% confidence interval [95% CI], 3.9% to 6.4%). MLST was performed on 108 Hib isolates from children carrying Hib isolates and 15 isolates from children with invasive disease. Thirty-one sequence types (STs) were identified, and 20 of these were novel STs. The most common ST isolates were sequence type 6 (ST6) and the novel ST722. There was marked heterogeneity among the STs from children with disease and children carrying Hib. STs identified from invasive infections were those commonly identified in carriage. This study provides evidence of Hib carriage among children in urban Nepal with genetically diverse strains prior to introduction of universal vaccination. The Hib carriage rate in Nepal was similar to the rates observed in other populations with documented high disease rates prior to vaccination, supporting implementation of Hib vaccine in Nepal in 2009.

BackgroundThere have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.Methods and findingsDesignRandomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.SettingOxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.ParticipantsPatients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.InterventionsContinue neuroleptic treatment for 12 mo or switch to an identical placebo.Outcome measuresPrimary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).Results165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) -0.4 (95% confidence interval [CI] -6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) -2.4 (95% CI -8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI >/= 15 benefited on neuropsychiatric symptoms from continuing treatment.ConclusionsFor most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.Trial registrationCochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).

OBJECTIVE: Dizziness is a symptom of acute mountain sickness (AMS). This study tested whether immediate fall in systolic blood pressure (BP) on standing was more severe at altitude and whether this was associated with symptoms of dizziness. METHODS: Eighty-five lowlanders flew into La Paz, Bolivia (3650 m), and after 4 to 5 days of acclimatization ascended in 90 minutes to the Chacaltaya Laboratory (5200 m) by road. Blood pressure was measured on 5 occasions, 3 times at 5200 m and twice at sea level, before and after the expedition using a mercury sphygmomanometer. Both a supine and an erect (within 15 seconds of standing) BP measurement were recorded. Participants recorded whether they felt dizzy on standing. A mixed-effect model was used to test for a difference in the change in BP for time and altitude. RESULTS: The immediate fall in systolic BP observed on standing was significantly greater (P < .001) on all 3 altitude study days (18.2, 23.4, and 20.7 mm Hg) than at sea level (12.2 and 12.4 mm Hg). There was no significant difference in the change in diastolic BP or change in mean arterial BP between sea level and altitude. CONCLUSIONS: The immediate drop in systolic BP observed on standing was greater at altitude. However, mean arterial pressure was maintained, and we found no association between the degree of immediate fall in BP and dizziness or AMS.

Background— Beating heart coronary artery bypass grafting (CABG) improves early postoperative cardiac function in patients with normal ventricular function, but its effect in patients with impaired function is uncertain. We compared a novel hybrid technique of on-pump beating heart CABG (ONBEAT) with conventional on-pump CABG (ONSTOP) in patients with impaired ventricular function. Methods and Results— In a single-center randomized trial, 50 patients with impaired ventricular function were randomly assigned to ONBEAT or ONSTOP. Patients underwent cardiac magnetic resonance imaging for function and delayed hyperenhancement early and later after surgery. Serial assessment of biochemical markers was also undertaken. Preoperative characteristics were well matched; cardiac index was 2.85±0.53 (ONBEAT) and 2.62±0.59 L · min −1 · m −2 (ONSTOP). Early after surgery, there was a trend toward a greater reduction in end-systolic volume index in ONSTOP patients versus ONBEAT (−9±8 versus −4±11 mL · m −2 ; P =0.06). The changes were sustained and significant at 6 months (−14±18 versus −2±19 mL · m −2 ; P =0.04). Furthermore, the incidence of new hyperenhancement at 6 days was higher in ONBEAT patients ( P =0.05), with 6 of 17 (35%) sustaining 8.2±5.2 g of new hyperenhancement each versus 2 of 23 (9%) in the ONSTOP group, each with 9.8±9.0 g ( P =0.86). Finally, median area under the curve for troponin was higher in ONBEAT at 461 (interquartile range, 226 to 1141) μg/L versus 160 (interquartile range, 98 to 357) μg/L for ONSTOP ( P =0.002). Conclusions— The incidence of new irreversible myocardial injury was significantly higher in ONBEAT than in ONSTOP patients. Furthermore, at 6 months, only ONSTOP patients demonstrated an improvement in ventricular geometry. The most likely mechanism is inadequate coronary perfusion to distal myocardial territories in patients with severe proximal coronary disease.

Objective To determine the persistence of bactericidal antibody titres following immunisation with serogroup C meningococcal glycoconjugate vaccine at age 6-15 years in order to examine changes in persistence of antibodies with age. Design Observational study. Setting Secondary and tertiary educational institutions in the United Kingdom. Participants Healthy adolescents aged 11-20 years previously immunised between 6 and 15 years of age with one of the three serogroup C meningococcal vaccines. Intervention Serum obtained by venepuncture. Main outcome measures Percentage of participants with (rabbit complement) serum bactericidal antibody titres of at least 1:8; geometric mean titres of serogroup C meningococcal serum bactericidal antibody. Results Five years after immunisation, 84.1% (95% confidence interval 81.6% to 86.3%) of 987 participants had a bactericidal antibody titre of at least 1:8. Geometric mean titres of bactericidal antibody were significantly lower in 11-13 year olds (147, 95% confidence interval 115 to 188) than in 14-16 year olds (300, 237 to 380) and 17-20 year olds (360, 252 to 515) (P

OBJECTIVES: 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. TRIALREGNO: NCT01332175.

Background: A 2-, 4-, and 12-month schedule of a novel 13-valent-pneumococcal conjugate vaccine (PCV13), containing serotype 1, 3, 4, 5, 6A, 6B 7F, 9V, 14, 18C, 19A, 19F, and 23F polysaccharides individually conjugated to CRM197 was evaluated in a randomized, double-blind, controlled infant study. Methods: Two hundred eighty-six healthy infants received PCV13 or the 7-valent-pneumococcal conjugate vaccine (PCV7) at 2, 4, and 12 months of age, alongside a serogroup C meningococcal (MenC) vaccine (2 and 4 months of age), DTaP-IPV-Hib (2, 3, and 4 months), and a Hib-MenC vaccine (12 months). Specific antibody responses were assessed at age 5, 12, and 13 months. Results: At 13 months of age, >97% of PCV13 recipients had pneumococcal serotype-specific serum IgG concentrations ?0.35 ?g/mL for each vaccine serotype except serotype 3 (88.2%), and at least 93% of PCV13 recipients had OPA titers ?1:8 for each serotype. At 5 months, 110/114 (96.5%) of PCV13 recipients and 100/102 (98.0%) of PCV7 recipients had serum anti-PRP (Hib) IgG concentration ?0.15 ?g/mL (difference, 1.5%; CI, ?7.1%–3.7%), while 119/120 (99.2%) and 117/118 (99.2%), respectively, had MenC serum bactericidal assay titers of ?1:8. All PCV13 recipients and 110/113 (97.3%) of PCV7 recipients had IgG concentrations against fimbrial agglutinogens of ?2.2 EU/mL; IgG concentrations for the remaining pertussis antigens were ?5 EU/mL for all participants. Local reactions and systemic events were similar in the PCV13 and PCV7 groups. Conclusions: A 2-, 4-, and 12-month course of PCV13 was immunogenic for all 13 vaccine serotypes and was well tolerated.

In Hong Kong, bacterial pathogens, the majority of them Salmonellae, cause approximately one-third of paediatric admissions for diarrhoea. This study retrospectively reviewed inpatient gastro-enteritis management, with particular focus on antibiotic use. Antibiotics are generally recommended for Salmonella gastro-enteritis in infants under 3 months of age but not for older infants and children unless they are so toxic that bacteraemia is suspected. Three groups of children admitted with acute gastro-enteritis were randomly identified from a computerised discharge database. Based on pathological reports held in the case records department, the final groups for analysis were Salmonella (n = 86), rotavirus (n = 55) and non-specified (n = 126). Epi Info version 6 (CDC, Atlanta) was used for data entry and analysis. Compared with a combined rotavirus/non-specified group, the Salmonella group were significantly more likely to have blood (OR 6.1, 95% CI 3.2-11.7, p < 0.0001) and mucus (OR 4.8, 95% CI 2.6-8.9, p < 0.0001) in the stool, fever during admission (OR 3.6, 95% CI 1.6-8.4, p = 0.001), more stools per day (median 6.2 vs 4.2, p < 0.0001), a longer stay in hospital (median 3.4 vs 2 days, p < 0.0001) and to be younger (median 7.1 vs 14.6 mths, p < 0.0001). The Salmonella group were more likely to have been given antibiotics (38% vs 15%, OR 3.6, 95% CI 1.9-6.9, p < 0.0001) but age did not influence the likelihood that antibiotics would be given.

Background: The multicomponent serogroup B meningococcal (4CMenB) vaccine was recently licensed for use in Europe. There are currently no data on the persistence of bactericidal antibodies induced by use of this vaccine in infants. Our objective was to evaluate serogroup B–specific bactericidal antibodies in children aged 40–44 months previously vaccinated at 2, 4, 6 and 12 months of age. Methods: Participants given 4 doses of 4CMenB as infants received a fifth dose of the vaccine at 40–44 months of age. Age-matched participants who were MenB vaccine–naive received 4CMenB and formed the control group. We evaluated human complement serum bactericidal activity (hSBA) titres at baseline and 1 month after each dose of 4CMenB. Results: Before a booster dose at enrolment, 41%–76% of 17 participants previously vaccinated with 4CMenB in infancy had hSBA titres of 4 or greater against 4 reference strains. Before vaccination in the control group (n = 40) these proportions were similar for strains 44/76-SL (63%) and M10713 (68%) but low for strains NZ98/254 (0%) and 5/99 (3%). A booster dose in the 4CMenB-primed participants generated greater increases in hSBA titres than in controls. Interpretation: As has been observed with other meningococcal vaccines, bactericidal antibodies waned after vaccination with 4CMenB administered according to an approved infant vaccination schedule of 2, 4, 6 and 12 months of age, but there was an anamnestic response to a booster dose at 40–44 months of age. If 4CMenB were introduced into routine vaccination schedules, assessment of the need for a booster dose would require data on the impact of these declining titres on vaccine effectiveness. ClinicalTrials.gov, no. NCT01027351

Background The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. Methods Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. Findings All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. Conclusions This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. Trial Registration Controlled-Trials.com ISRCTN 30087513, Author Summary All human deaths from rabies result from failure to give adequate prophylaxis. After a rabid animal bite, immediate wound cleaning, rabies vaccine and immunoglobulin injections effectively prevent fatal infection. Immunoglobulin is very rarely available in developing countries, where prevention relies on efficacious vaccine. WHO approved vaccines are prohibitively expensive, but 2 economical regimens (injecting small amounts of vaccine intradermally, into the skin, at 2 or 8 sites on the first day of the course) have been used for many years in a few places. Practical or perceived difficulties have restricted widespread uptake of economical methods. These could largely be overcome by introducing a new, simpler regimen, involving 4 site injections on the first day. We vaccinated volunteers to compare the antibody levels induced by the 4-site intradermal regimen with those induced by the current 2-site and 8-site regimens and the “gold standard” intramuscular regimen favoured internationally. All the economical intradermal regimens were at least as immunogenic as the intramuscular method. The results provide sufficient evidence that the 4-site regimen meets the criteria necessary for its recommendation for use wherever the cost of vaccine is prohibitive and especially where 2 or more patients are treated on the same day.

Objective: To study the immunogenicity and reactogenicity of a combined Haemophilus influenzae type b and Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine (Hib-MenC-TT), when administered as a booster dose in combination with a measles, mumps and rubella vaccine (MMR). Design: A phase 3 open randomised controlled trial. Setting: One centre in Oxford, UK and nine centres in Poland Subjects: 12-15 month old healthy children Interventions: In the primary stage of the study 500 healthy, 6-12 week old infants were randomised in a 3:1 ratio to receive Hib-MenC-TT + DTPa-IPV or MenC-CRM197 vaccine + DTPa-IPV-Hib. In the booster stage 476 of participants, 190 in the UK and 286 in Poland, were vaccinated with Hib-MenC-TT and MMR. Main outcome measures: The proportion of children with protective serum antibody levels against MenC and Hib, 6 weeks following a Hib-MenC-TT booster dose. Results: The co-primary objectives were met: the Hib-MenC-TT booster dose induced protective antibody titres in children who were vaccinated with a combination of Hib-MenC-TT + DTPa-IPV or MenC-CRM197 + DTPa-IPV-Hib at 2, 3 and 4 months of age. 94.8% (LL 95%CI 92.4) of participants had rSBA-MenC ≥1:128 and 100% (LL 95%CI 99.2) achieved anti-PRP concentrations ≥1.0μg/ml. The percentage of toddlers with a post boost rSBA-MenC of 1:128 was significantly higher after priming with Hib-MenC-TT (97.7%) than after MenC-CRM197 (86%) (difference: 11.7%; 95%CI 6.2 to 19.4). Conclusion: The waning antibody titres against Hib and MenC following primary immunisation can be boosted to protective levels by administering a dose of the Hib-MenC-TT vaccine at 12-15 months of age, supporting the recent introduction of this vaccine in the UK immunisation schedule to sustain protection of children against Hib and MenC disease. Trial registration: Clinical trials.gov, NCT00258700. Study ID: 103974.

Study Design. A review of the surgical costs and results in a group of patients randomly allocated to surgery as part of a large prospective randomized trial of patients with chronic back pain. Objective. To report the observational data from the surgical arm of a randomized trial comparing surgery with intensive rehabilitation for chronic low back pain. Clinical and economic data are reported. Summary of Background Data. Surgery for chronic low back pain is a well established but unproven intervention. The most cost-effective technique for spinal stabilization is still not established. Methods. One hundred six patients with chronic low back pain were randomized to the surgical group of a randomized trial comparing spinal fusion of the lumbar with a 3 week intensive rehabilitation program. The primary outcomes were the Oswestry Disability Index (ODI) and the Shuttle Walking Test measured at baseline and 2 years postrandomization. Patients were stratified by preoperative diagnosis, smoking habit, and litigation. Complications were assessed and costs analyzed. Results. Of the 176 surgical patients, 56 underwent postern-lateral fusion, 57 underwent interbody fusion, and 24 underwent flexible stabilization of the spine. The mean ODI for all patients in the surgical arm of the trial improved from a baseline of 46.5 (SD 14.6) to 34.2 (SD 21) at 2 years. Health care costs were higher ( 3109 difference) for more complex procedures, and nearly 6 times as many early complications occurred with the more complex procedures. Smoking and unemployment were associated with worse results whereas litigation did not adversely affect the outcome. Conclusion. These observational changes in the ODI after surgery are similar to those reported from other studies of spinal fusion. More complex surgery is more expensive with more complications than postern-lateral fusion.

Background: In a previous study, 60 infants receiving an investigational serogroup B meningococcal vaccine containing recombinant meningococcal proteins alone (rMenB) or combined with an outer membrane vesicle from Neisseria meningitidis (4CMenB) at 6, 8 and 12 months of age produced serum bactericidal antibodies (SBAs) against meningococcal strains expressing vaccine antigens. We studied persistence of this response and the response to a booster dose of vaccine. Methods: In this extension study, SBA titers were evaluated before and after a booster dose of rMenB or 4CMenB at 40 months of age. MenB vaccine naïve age-matched children served as a control group. Results: Before the booster doses, the proportions of 4CMenB recipients with SBA titers ≥1:4 were 36% (n = 14, 95% confidence interval: 13-65%) for strain 44/76-SL, 100% (77-100%) for 5/99, 14% (2-43%) for NZ98/254 and 79% (49-95%) for M10713. These percentages were 14% to 29% for rMenB recipients (n = 14), except for 5/99 (93%, 66-100%). For controls (n = 40), these proportions were ≤3% for all strains except M10713 (53%, 36-68%). One month after the boosters, ≥93% of 4CMenB recipients had SBA titers ≥1:4 for all 4 strains. For controls receiving their first dose of 4CMenB, 23% (11-39%) had SBA titers ≥1:4 for NZ98/254, compared with 62% to 87% for the remaining strains. Conclusions: Bactericidal antibodies wane after infant immunization with rMenB or 4CMenB, but there is an anamnestic response to a booster dose. Booster doses of 4CMenB may be required to maintain immune protection through childhood and adolescence. Copyright © 2013 by Lippincott Williams and Wilkins.

The induction of persistent protective levels of pathogen-specific antibody is an important goal of immunization against childhood infections. However, antibody persistence is poor after immunization in infancy versus later in life. Serogroup C meningococci (MenC) are an important cause of bacteraemia and meningitis in children. The use of protein-polysaccharide conjugate vaccines against MenC has been associated with a significant decline in the incidence of invasive disease. However, vaccine effectiveness is negligible by more than 1 year after a three-dose priming series in infancy and corresponds to a rapid decline in antibody following an initial immune response. The cellular mechanisms underlying the generation of persistent antibody in this age group are unclear. An essential prelude to larger studies of peripheral blood B cells is an understanding of B-cell kinetics following immunization. We measured MenC- and diphtheria-specific plasma and memory B-cell kinetics in infants receiving a CRM(197) (cross-reactive material; mutant diphtheria toxoid)-conjugated MenC vaccine at 2, 3 and 4 months of age. Plasma cell responses were more delayed after the first dose when compared with the rapid appearance of plasma cells after the third dose. Memory B cells were detectable at all time-points following the third dose as opposed to the low frequency seen following a first dose. This study provides data on B-cell kinetics following a primary schedule of immunization in young infants upon which to base further studies of the underlying cellular mechanism of humoral immunity.

Background: During seasonal influenza epidemics, 5-15% of the population are affected with an illness having a nontrivial mortality, morbidity and economic burden. Inactivated influenza vaccines are routinely used to prevent influenza infection, primarily by inducing humoral immunity. In addition, trivalent-inactivated influenza vaccines have previously been shown to boost influenza-specific T-cell responses in a small percentage of adults. We investigate here the influenza-specific T-cell response, in children, 1 year after pandemic H1N1 vaccination and the ability to boost the T-cell response with trivalent-inactivated influenza immunization. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from children previously vaccinated with pandemic H1N1 vaccine, pre-and postseasonal 2010-2011 trivalent influenza vaccine (TIV) vaccination. Samples were analyzed by interferon-gamma enzyme-linked immunosorbent spot for reactogenicity toward internal influenza antigens (nucleoprotein, matrix protein 1 and nonstructural protein 1). Results: Basal ex vivo T-cell responses to nucleoprotein, matrix protein 1 and nonstructural protein 1 measured by interferon-gamma enzyme-linked immunosorbent spot assay were significantly higher in those children who had previously received an AS0 3B-adjuvanted split virion pandemic vaccine 12 months earlier rather than a nonadjuvanted whole virion vaccine. Boosting of these responses, 21 days after 2010/2011 seasonal TIV vaccination was observed regardless of age or prior pandemic vaccination regime, although boosting was greater in those groups with the lowest initial response. Conclusions: We show here that children previously vaccinated with the 2009 pandemic H1N1 vaccine have measurable T-cell responses 1 year after vaccination. The magnitudes of these responses are dependent on both age of vaccine and type of pandemic H1N1 vaccine used. After 2010/2011 seasonal TIV vaccination, these T-cell responses undergo a small but significant boost. © 2012 Lippincott Williams and Wilkins.

Organophosphorus (OP) insecticide self-poisoning is responsible for about one-quarter of global suicides. Treatment focuses on the fact that OP compounds inhibit acetylcholinesterase (AChE); however, AChE-reactivating drugs do not benefit poisoned humans. We therefore studied the role of solvent coformulants in OP toxicity in a novel minipig model of agricultural OP poisoning. Gottingen minipigs were orally poisoned with clinically relevant doses of agricultural emulsifiable concentrate (EC) dimethoate, dimethoate active ingredient (AI) alone, or solvents. Cardiorespiratory physiology and neuromuscular (NMJ) function, blood AChE activity, and arterial lactate concentration were monitored for 12 h to assess poisoning severity. Poisoning with agricultural dimethoate EC40, but not saline, caused respiratory arrest within 30 min, severe distributive shock and NMJ dysfunction, that was similar to human poisoning. Mean arterial lactate rose to 15.6 [SD 2.8] mM in poisoned pigs compared to 1.4 [0.4] in controls. Moderate toxicity resulted from poisoning with dimethoate AI alone, or the major solvent cyclohexanone. Combining dimethoate with cyclohexanone reproduced severe poisoning characteristic of agricultural dimethoate EC poisoning. A formulation without cyclohexanone showed less mammalian toxicity. These results indicate that solvents play a crucial role in dimethoate toxicity. Regulatory assessment of pesticide toxicity should include solvents as well as the AIs which currently dominate the assessment. Reformulation of OP insecticides to ensure that the agricultural product has lower mammalian toxicity could result in fewer deaths after suicidal ingestion and rapidly reduce global suicide rates.

BACKGROUND: Haemophilus influenzae type b (Hib) carriage and disease studies in Nepali children suggest a significant burden of infection. Hib conjugate vaccines (HibCV) do not have uniform immunogenicity between populations. We determined the immunogenicity of HibCV in Nepali infants, before its introduction into the routine immunization schedule. METHODS: Ninety infants recruited at Patan Hospital, Kathmandu, received 3 doses of the HibCV with routine immunizations (diphtheria, tetanus, whole cell pertussis-hepatitis B vaccine + oral polio vaccine) at 6, 10 and 14 weeks of age, and a HibCV booster at 52 weeks. Anti-polyribosylribitol phosphate (PRP) concentrations were measured at 18, 52 and 56 weeks, and the antibody persistence at 52 weeks was compared with antibody values in unimmunized controls (n = 30). RESULTS: After 3 doses of primary immunizations, at 18 weeks of age (n = 74), all infants had anti-PRP concentrations above the accepted thresholds for short- and long-term protection (0.15 and 1.0 µg/mL, respectively). At 1 year of age, before administration of the booster of HibCV, the anti-PRP geometric mean antibody concentration was 2.76 µg/mL (confidence interval: 1.88-4.07) in sera from the immunized children compared with 0.11 µg/mL (95% confidence interval: 0.08-0.17) in the nonimmunized control group (n = 30). Twenty-seven percent (20/74) of participants, however, had anti-PRP concentrations

Summary 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 × 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 −1·73 ([95% CI −3·57 to 0·11]; p=0·066) and at 52 weeks was −2·69 ([–4·89 to −0·49]; p=0·017). Folic acid was not superior to placebo. There was a significant interaction (p=0·028), with folic acid reducing the effectiveness of lamotrigine at 12 weeks. The mean difference on QIDS-SR16 was −4·14 ([95% CI −6·90 to −1·37]; p=0·004) for patients receiving lamotrigine without folic acid compared with 0·12 ([–2·58 to 2·82]; p=0·931) 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.

BACKGROUND: The widely used 23-valent plain polysaccharide vaccine (23vP) has limited effectiveness, produces short-lived immune responses, and induces attenuated antibody production after subsequent challenge with pneumococcal vaccines. Our goal was to examine whether priming with the 7-valent pneumococcal conjugate vaccine (PCV7) could enhance the immunogenicity of 23vP for the PCV7 serotypes and to investigate whether 23vP induced hyporesponsiveness could be overcome using PCV7. METHODS: We conducted an open-label randomized study that compared 3 vaccine schedules, each of which consisted of 2 doses of PCV7 and 1 dose of 23vP (23vP-PCV7-PCV7, PCV7-23vP-PCV7, PCV7-PCV7-23vP) administered over a 1-year period in a cohort of 348 adults 50-70 years of age. All vaccines were administered intramuscularly and were given 6 months apart. Blood samples were obtained prior to and 1 month after each vaccination. RESULTS: 23vP administered after priming with 2 doses of PCV7 produced significantly higher antibody concentrations for 3 of the 7 PCV7 serotypes, compared with vaccination with a single dose of 23vP; however, the same immunogenicity could be achieved with a single dose of PCV7. Prior vaccination with 23vP attenuated the antibody response to subsequent PCV7, which was not restored by additional doses of PCV7. CONCLUSION: In adults, vaccination schedules combining PCV7 and 23vP do not provide improved immunogenicity over the use of a single dose of 23vP for most of the serotypes contained in PCV7.

Background: Studies of glycoconjugate vaccines have traditionally used an immune challenge with a plain polysaccharide vaccine to demonstrate immunologic memory. Plain polysaccharide vaccines are poorly immunogenic in children and can induce subsequent immunologic hyporesponsiveness. We therefore assessed the use of glycoconjugate vaccines as an alternative method of demonstrating immunologic memory. Methods: Children immunized with hepatitis B vaccine or serogroup C meningococcal glycoconjugate vaccine (MenCC) at age 2, 3, 4 months received a plain polysaccharide meningococcal serogroup A/C vaccine (MenACP) or MenCC at age 12 months. A post hoc analysis of serum bactericidal activity responses to MenCC assessed whether this differed in MenCC primed and MenCC naive infants. Results: MenCC primed children displayed higher geometric mean serum bactericidal titers than MenCC naive children following MenACP (1518 compared with 30; P = 0.003). A similar difference was seen after a dose of MenCC to toddlers (MenCC primed: 8663, MenCC naive: 710; P < 0.001). The latter comparison became a borderline significance after adjusting for higher pretoddler immunization serum bactericidal geometric mean titers in the MenCC primed group (P = 0.068). Conclusions: Administration of glycoconjugate vaccines provides an important alternative method of demonstrating immunologic memory, avoiding the use of plain polysaccharide vaccines that are potentially deleterious in children. This has implications for the design of all future clinical trials of glycoconjugate vaccines. © 2009 by Lippincott Williams & Wilkins.

Background: Despite the excellent immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines, breakthrough cases of Hib disease still affect a small proportion of vaccinated children in the United Kingdom. We performed a retrospective study to compare the avidity of antibody directed against the Hib polysaccharide capsule (PRP) in children who experienced Hib vaccine failure in the United Kingdom among 3 historical cohorts and with age-matched healthy control subjects. Methods: Serum samples from vaccinated children with invasive Hib disease were collected beginning in 1992 as part of enhanced surveillance for Hib disease following vaccine introduction. A total of 251 children who experienced Hib vaccine failure were identified from 3 historical cohorts (1992-1995, 1996-1999, and 2000-2003). The anti-PRP antibody concentration and avidity from healthy age-matched control subjects was obtained for the 3 contemporary time points (1995, 1999, and 2002). Serum anti-PRP antibody concentration was measured in each of the samples using a standard Hib ELISA, and antibody avidity was determined using thiocyanate elution. Results. Within the first 60 days after disease onset, there was no change in the anti-PRP antibody avidity, and there was no statistically significant difference in the geometric mean Hib antibody avidity over the 3 study periods. However, the children who experienced Hib vaccine failure had significantly lower Hib antibody avidity than did healthy control subjects, despite a marked antibody response following infection. Conclusions. Children who experience Hib disease despite vaccination appear to have a defect in immunological priming, leading to a qualitative difference in Hib-specific memory B cells. Low anti-PRP antibody avidity decreases the functional activity of anti-PRP antibody in the sera of these children experiencing vaccine failure, leading to disease susceptibility.

BACKGROUND and AIMS: In patients with stones in their bile ducts and gallbladders, cholecystectomy is generally recommended after endoscopic sphincterotomy and clearance of bile duct stones. However, only approximately 10% of patients with gallbladders left in situ will return with further biliary complications. Expectant management is alternately advocated. In this study, we compared the treatment strategies of laparoscopic cholecystectomy and gallbladders left in situ. METHODS: We randomized patients (>60 years of age) after endoscopic sphincterotomy and clearance of their bile duct stones to receive early laparoscopic cholecystectomy or expectant management. The primary outcome was further biliary complications. Other outcome measures included adverse events after cholecystectomy and late deaths from all causes. RESULTS: One hundred seventy-eight patients entered into the trial (89 in each group); 82 of 89 patients who were randomized to receive laparoscopic cholecystectomy underwent the procedure. Conversion to open surgery was needed in 16 of 82 patients (20%). Postoperative complications occurred in 8 patients (9%). Analysis was by intention to treat. With a median follow-up of approximately 5 years, 6 patients (7%) in the cholecystectomy group returned with further biliary events (cholangitis, n = 5; biliary pain, n = 1). Among those with gallbladders in situ, 21 (24%) returned with further biliary events (cholangitis, n = 13; acute cholecystitis, n = 5; biliary pain, n = 2; and jaundice, n = 1; log rank, P = .001). Late deaths were similar between groups (cholecystectomy, n = 19; gallbladder in situ, n = 11; P = .12). CONCLUSIONS: In the Chinese, cholecystectomy after endoscopic treatment of bile duct stones reduces recurrent biliary events and should be recommended.