Contingent screening for down syndrome is an efficient alternative to non-disclosure sequential screening

Objective To present a first and second trimester Down syndrome screening strategy, whereby second-trimester marker determination is contingent on the first-trimester results. Unlike non-disclosure sequential screening (the Integrated test), which requires all women to have markers in both trimesters, this allows a large proportion of the women to complete screening in the first trimester. Methods Two first-trimester risk cut-offs defined three types of results: positive and referred for early diagnosis; negative with screening complete; and intermediate, needing second-trimester markers. Multivariate Gaussian modelling with Monte Carlo simulation was used to estimate the false-positive rate for a fixed 85% detection rate. The false-positive rate was evaluated for various early detection rates and early test completion rates. Model parameters were taken from the SURUSS trial. Results Completion of screening in the first trimester for 75% of women resulted in a 30% early detection rate and a 55% second trimester detected rate (net 85%) with a false-positive rate only 0.1% above that achievable by the Integrated test. The screen-positive rate was 0.1% in the first trimester and 4.7% for those continuing to be tested in the second trimester. If the early detection rate were to be increased to 45% or the early completion rate were to be increased to 80%, there would be a further 0.1% increase in the false-positive rate. Conclusion Contingent screening can achieve results comparable with the Integrated test but with earlier completion of screening for most women. Both strategies need to be evaluated in large-scale prospective studies particularly in relation to psychological impact and practicability.

Physiotherapy for Sleep Disturbance in People With Chronic Low Back Pain:Results of a Feasibility Randomized Controlled Trial

Objective: To determine the feasibility of a randomized controlled trial investigating the effectiveness of physiotherapy for sleep disturbance in chronic low back pain (CLBP) (=12wks). Design: Randomized controlled trial with evaluations at baseline, 3 months, and 6 months. Setting: Outpatient physiotherapy department in an academic teaching hospital. Participants: Participants with CLBP were randomly assigned to a walking program (n=20; mean age ± SD, 46.4±13.8y), supervised exercise class (n=20; mean age ± SD, 41.3±11.9y), or usual physiotherapy (n=20; mean age ± SD, 47.1±14.3y). The 3-month evaluation was completed by 44 participants (73%), and 42 (70%) participants completed the 6-month evaluation. Interventions: Participants received a physiotherapy-delivered 8-week walking program, an 8-week group supervised exercise class (1 class/wk), or 1-to-1 usual physiotherapy (advice, manual therapy, and exercise). Main Outcome Measures: Sleep was assessed by the self-reported Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Pittsburgh Sleep Diary, and objective actigraphy. Results: Groups were comparable at baseline. Most (95%, n=57) of the participants had sleep disturbance. The acceptability of actigraphy was excellent at baseline (58 of 60 participants), but dropped at 3 months (26 of 44 participants). There were improvements on the PSQI and ISI in all groups at 3 and 6 months, with predominantly medium effect sizes (Cohen d=0.2-0.5). Conclusions: The high prevalence of sleep disturbance indicated the feasibility of good recruitment in future trials. The PSQI would be a suitable screening tool and outcome measure alongside an objective nonobtrusive sleep outcome measure. The effectiveness of physiotherapy for sleep disturbance in CLBP warrants investigation in a fully powered randomized controlled trial. © 2013 American Congress of Rehabilitation Medicine.

Use of the child health utility and strengths and difficulties outcome measures in economic evaluations of school-based interventions: data from a cluster-randomised controlled trial in Northern Ireland

Background There is growing evidence linking early social and emotional wellbeing to later academic performance and various health outcomes including mental health. An economic evaluation was designed alongside the Roots of Empathy cluster-randomised trial evaluation, which is a school-based intervention for improving pupils’ social and emotional wellbeing. Exploration of the relevance of the Strengths and Diffi culties Questionnaire (SDQ) and Child Health Utility 9D (CHU9D) in school-based health economic evaluations is warranted. The SDQ is a behavioural screening questionnaire for 4–17-year-old children, consisting of a total diffi culties score, and also prosocial behaviour,
which aims to identify positive aspects of behaviour. The CHU9D is a generic preference-based health-related quality of life instrument for 7–17-year-old children.

Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry:A randomised controlled trial

Background: Ivacaftor has shown a clinical benefit in patients with cystic fibrosis who have the G551D-CFTR mutation and reduced lung function. Lung clearance index (LCI) using multiple-breath washout might be an alternative to and more sensitive method than forced expiratory volume in 1 s (FEV₁) to assess treatment response in the growing number of children and young adults with cystic fibrosis who have normal spirometry. The aim of the study was to assess the treatment effects of ivacaftor on LCI in patients with cystic fibrosis, a G551D-CFTR mutation, and an FEV₁ >90% predicted. Methods: This phase 2, multicentre, placebo-controlled, double-blind 2×2 crossover study of ivacaftor treatment was conducted in patients with cystic fibrosis, at least one G551D-CFTR allele, and an FEV₁ >90% predicted. Patients also had to have an LCI higher than 7·4 at screening, age of 6 years or older, and a weight higher than or equal to 15 kg. Eligible patients were randomly allocated to receive one of two treatment sequences (placebo first followed by ivacaftor 150 mg twice daily [sequence 1] or ivacaftor 150 mg twice daily first followed by placebo [sequence 2]) of 28 days' treatment in each period, with a 28-day washout between the two treatment periods. Randomisation (ratio 1:1) was done with block sizes of 4, and all site personnel including the investigator, the study monitor, and the Vertex study team were masked to treatment assignment. The primary outcome measure was change from baseline in LCI. The study is registered at ClinicalTrials.gov, NCT01262352. Findings: Between February and November, 2011, 21 patients were enrolled, of which 11 were assigned to the sequence 1 group, and 10 to the sequence 2 group. 20 of these patients received treatment and 17 completed the trial (eight in sequence 1 group and 9 in sequence 2 group). Treatment with ivacaftor led to significant improvements compared with placebo in LCI (difference between groups in the average of mean changes from baseline at days 15 and 29 was -2·16 [95% CI -2·88 to -1·44]; p<0·0001). Adverse events experienced by study participants were similar between treatment groups; at least one adverse event was reported by 15 (79%) of 19 patients who received placebo and 13 (72%) of 18 patients who received ivacaftor. No deaths occurred during study period. Interpretation: In patients with cystic fibrosis aged 6 years or older who have at least one G551D-CFTR allele, ivacaftor led to improvements in LCI. LCI might be a more sensitive alternative to FEV₁ in detecting response to intervention in these patients with mild lung disease. Funding: Vertex Pharmaceuticals Incorporated. © 2013 Elsevier Ltd.

How individual participant data meta-analyses have influenced trial design, conduct, and analysis

OBJECTIVES: To demonstrate how individual participant data (IPD) meta-analyses have impacted directly on the design and conduct of trials and highlight other advantages IPD might offer.

STUDY DESIGN AND SETTING: Potential examples of the impact of IPD meta-analyses on trials were identified at an international workshop, attended by individuals with experience in the conduct of IPD meta-analyses and knowledge of trials in their respective clinical areas. Experts in the field who did not attend were asked to provide any further examples. We then examined relevant trial protocols, publications, and Web sites to verify the impacts of the IPD meta-analyses. A subgroup of workshop attendees sought further examples and identified other aspects of trial design and conduct that may inform IPD meta-analyses.

RESULTS: We identified 52 examples of IPD meta-analyses thought to have had a direct impact on the design or conduct of trials. After screening relevant trial protocols and publications, we identified 28 instances where IPD meta-analyses had clearly impacted on trials. They have influenced the selection of comparators and participants, sample size calculations, analysis and interpretation of subsequent trials, and the conduct and analysis of ongoing trials, sometimes in ways that would not possible with systematic reviews of aggregate data. We identified additional potential ways that IPD meta-analyses could be used to influence trials.

CONCLUSIONS: IPD meta-analysis could be better used to inform the design, conduct, analysis, and interpretation of trials.

Safety of Spectacles for Children's Vision: A Cluster-Randomized Controlled Trial.

Purpose: To study safety of children’s glasses in rural China, where fear that glasses harm vision is an important barrier for families and policy-makers. Design: Exploratory analysis from a cluster-randomized, investigator-masked, controlled trial.Methods: Among primary schools (n=252) in western China, children were randomized by school to one of three interventions: free glasses provided in class, vouchers for free glasses at a local facility or glasses prescriptions only (Control group). The main outcome of this analysis is uncorrected visual acuity after 8 months, adjusted for baseline acuity.Results: Among 19,934 children randomly selected for screening, 5852 myopic (spherical equivalent refractive error <= -0.5 D) eyes of 3001 children (14.7%, mean age 10.5 years) had VA <= 6/12 without glasses correctable to > 6/12 with glasses, and were eligible. Among these, 1903 (32.5%), 1798 (30.7%), and 2151 (36.8%) were randomized to Control, Voucher and Free Glasses respectively. Intention-to-treat analyses were performed on all 1831 (96.2%), 1699 (94.5%), and 2007 (93.3%) eyes of children with follow-up in Control, Voucher and Free Glasses groups. Final visual acuity for eyes of children in the treatment groups (Free Glasses and Voucher) was significantly better than for Control children, adjusting only for baseline visual acuity (difference of 0.023 logMAR units [0.23 vision chart lines, 95% CI: 0.03, 0.43]) or for other baseline factors as well (0.025 logMAR units [0.25 lines, 95% CI 0.04, 0.45]). Conclusion: We found no evidence that spectacles promote decline in uncorrected vision with aging among children.

A randomized, controlled trial of an intervention promoting cataract surgery acceptance in Rural China:The Guangzhou uptake of surgery trial (GUSTO)

PURPOSE. To evaluate an educational intervention promoting acceptance of cataract surgery in rural China using a randomized controlled design. METHODS. Patients aged 50 years or older with presenting visual acuity (PVA) less than 6/18 in one or both eyes due to cataract were recruited from 26 screening sessions (13 intervention, 13 control) conducted by five rural hospitals in Guangdong, China. At intervention sessions, subjects were shown a 5- minute informational video, and counseled about cataract, surgery, and surgical cost. During screening, all subjects answered questionnaires on knowledge and attitudes about cataract, their finances, and transportation, and were referred for definitive examination if eligible. Study outcomes were acceptance of surgery (principal outcome) and hospital followup. RESULTS. Subjects in the intervention group were younger than controls (P = 0.01), but the groups did not otherwise differ. Among 212 intervention patients and 222 controls, no differences in knowledge and attitude regarding cataract were found. Surgery was accepted by 31.1% of intervention patients and 34.2% of controls (P > 0.50). Predictors of acceptance included younger age, worse logMAR PVA, knowing that cataract can be treated surgically only, greater anticipated loss in income from hospitalization, and greater house floor space per person. Membership in the intervention group was not associated with accepting surgery (odds ratio [OR]=1.11, 95% confidence interval [CI] 0.67-1.84) or hospital follow-up (OR= 1.03, 95% CI = 0.63-1.67). CONCLUSIONS. Educational interventions that successfully impart the knowledge that cataract can be only treated surgically may be more effective in increasing uptake in this setting. © 2012 The Association for Research in Vision and Ophthalmology, Inc.

Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine in HIV-infected adults on combination antiretroviral therapy: a phase I/II, randomized trial.

OBJECTIVE: Tuberculosis (TB) is highly prevalent among HIV-infected people, including those receiving combination antiretroviral therapy (cART), necessitating a well tolerated and efficacious TB vaccine for these populations. We evaluated the safety and immunogenicity of the candidate TB vaccine M72/AS01 in adults with well controlled HIV infection on cART. DESIGN: A randomized, observer-blind, controlled trial (NCT00707967). METHODS: HIV-infected adults on cART in Switzerland were randomized 3 : 1 : 1 to receive two doses, 1 month apart, of M72/AS01, AS01 or 0.9% physiological saline (N = 22, N = 8 and N = 7, respectively) and were followed up to 6 months postdose 2 (D210). Individuals with CD4⁺ cell counts below 200 cells/μl were excluded. Adverse events (AEs) including HIV-specific and laboratory safety parameters were recorded. Cell-mediated (ICS) and humoral (ELISA) responses were evaluated before vaccination, 1 month after each dose (D30, D60) and D210. RESULTS: Thirty-seven individuals [interquartile range (IQR) CD4⁺ cell counts at screening: 438-872 cells/μl; undetectable HIV-1 viremia] were enrolled; 73% of individuals reported previous BCG vaccination, 97.3% tested negative for the QuantiFERON-TB assay. For M72/AS01 recipients, no vaccine-related serious AEs or cART-regimen adjustments were recorded, and there were no clinically relevant effects on laboratory safety parameters, HIV-1 viral loads or CD4⁺ cell counts. M72/AS01 was immunogenic, inducing persistent and polyfunctional M72-specific CD4⁺ T-cell responses [medians 0.70% (IQR 0.37-1.07) at D60] and 0.42% (0.24-0.61) at D210, predominantly CD40L⁺IL-2⁺TNF-α⁺, CD40L⁺IL-2⁺ and CD40L⁺IL-2⁺TNF-α⁺IFN-γ⁺]. All M72/AS01 vaccines were seropositive for anti-M72 IgG after second vaccination until study end. CONCLUSION: M72/AS01 was clinically well tolerated and immunogenic in this population, supporting further clinical evaluation in HIV-infected individuals in TB-endemic settings.

Outcome and Experience from the Swiss Mammography Screening Pilot Programmes

BACKGROUND:The Swiss breast cancer screening pilot programme was conducted in 3 districts of theFrench-speaking canton of Vaud (ca. 300,000 resident women) between October 1993 and January 1999.Women aged 50 to 69 were invited by mail every 2 years for a free of charge screening mammography (doubleview, multiple reading). This first ever-organised cancer screening programme in Switzerland showed thefeasibility and acceptability of this kind of public health intervention in the liberal Swiss healthcare system, whichwas the main objective of the pilot programme. This mammographic screening programme was extended to thewhole canton in 1999, and contributed to the implementation of similar programmes in 2 neighbouring cantons. OBJECTIVE:To appraise the use, the quality and the effectiveness of the Swiss screening pilot programme. METHODS:About 15,000 women (aged 50-69) were enrolled. Logistic regression analyses were performedseparately to identify determinants of initial and subsequent attendance. Standard indicators of quality,effectiveness and impact of the programme were assessed and compared with European recommendations. Tothis intent, linkage with data from the Vaud Cancer Registry was performed. RESULTS:About half the target population was screened at least once during the pilot trial. Participation washigher among Swiss than foreigners, among widowed or married women than among single, divorced or separatedones. Attendance also increased with age and decreasing distance between residence and the dedicatedscreening centre. Apart from Swiss citizenship, socio-demographic factors were not associated with reattendance.Intensity of prior recruitment, outcome of previous screening test (positive vs. negative) and indicators of women'shealth behaviour (time of last mammography prior to initial screen, smoking status) were the main determinants ofreattendance. Programme performance and quality indicators were, overall, in line with European Guidelines. Theywere overall more favourable among 60-69 than 50-59 year-olds and improved over time. CONCLUSION:The objectives of the pilot programme were met. Even if participation should increase in order toreach European standards, performance indicators overall met quality requirements. Ways to improve screeninguse, quality and effectiveness were devised and taken into account for the generalisation of the programme.

HIV-1 vaccines and adaptive trial designs.

Developing a vaccine against the human immunodeficiency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.

Preoperative nutritional screening by the specialist instead of the nutritional risk score might prevent excess nutrition: a multivariate analysis of nutritional risk factors.

BACKGROUND: The aim of the current study was to assess whether widely used nutritional parameters are correlated with the nutritional risk score (NRS-2002) to identify postoperative morbidity and to evaluate the role of nutritionists in nutritional assessment. METHODS: A randomized trial on preoperative nutritional interventions (NCT00512213) provided the study cohort of 152 patients at nutritional risk (NRS-2002 ≥3) with a comprehensive phenotyping including diverse nutritional parameters (n=17), elaborated by nutritional specialists, and potential demographic and surgical (n=5) confounders. Risk factors for overall, severe (Dindo-Clavien 3-5) and infectious complications were identified by univariate analysis; parameters with P<0.20 were then entered in a multiple logistic regression model. RESULTS: Final analysis included 140 patients with complete datasets. Of these, 61 patients (43.6%) were overweight, and 72 patients (51.4%) experienced at least one complication of any degree of severity. Univariate analysis identified a correlation between few (≤3) active co-morbidities (OR=4.94; 95% CI: 1.47-16.56, p=0.01) and overall complications. Patients screened as being malnourished by nutritional specialists presented less overall complications compared to the not malnourished (OR=0.47; 95% CI: 0.22-0.97, p=0.043). Severe postoperative complications occurred more often in patients with low lean body mass (OR=1.06; 95% CI: 1-1.12, p=0.028). Few (≤3) active co-morbidities (OR=8.8; 95% CI: 1.12-68.99, p=0.008) were related with postoperative infections. Patients screened as being malnourished by nutritional specialists presented less infectious complications (OR=0.28; 95% CI: 0.1-0.78), p=0.014) as compared to the not malnourished. Multivariate analysis identified few co-morbidities (OR=6.33; 95% CI: 1.75-22.84, p=0.005), low weight loss (OR=1.08; 95% CI: 1.02-1.14, p=0.006) and low hemoglobin concentration (OR=2.84; 95% CI: 1.22-6.59, p=0.021) as independent risk factors for overall postoperative complications. Compliance with nutritional supplements (OR=0.37; 95% CI: 0.14-0.97, p=0.041) and supplementation of malnourished patients as assessed by nutritional specialists (OR=0.24; 95% CI: 0.08-0.69, p=0.009) were independently associated with decreased infectious complications. CONCLUSIONS: Nutritional support based upon NRS-2002 screening might result in overnutrition, with potentially deleterious clinical consequences. We emphasize the importance of detailed assessment of the nutritional status by a dedicated specialist before deciding on early nutritional intervention for patients with an initial NRS-2002 score of ≥3.

Phase-I clinical trial on the effect of palatal brushing on denture stomatitis

Introduction: La stomatite prothétique est une condition inflammatoire chronique de la muqueuse buccale recouverte par une prothèse. Cette maladie est considérée comme la lésion buccale la plus fréquente chez les porteurs de prothèses amovibles. Des études récentes sur l'étiologie de la stomatite prothétique suggèrent que des traitements basés sur la réduction de l'inflammation seraient efficaces dans le traitement de cette maladie. Objectifs: Évaluer l'efficacité du brossage du palais dans le traitement de la stomatite prothétique. Méthodes: Quarante-huit participants (âge moyen : 66,0 ± 11,2 ans) avec un diagnostic de stomatite prothétique, ont été sélectionnés à partir d’un examen préalable de 143 individus, afin de participer à cet essai clinique de phase I à deux centres, réalisé selon un devis de type pré-test/post-test à un seul groupe. L'intervention a consisté en un brossage du palais avec une brosse manuelle après chaque repas et avant le coucher. Des examens cliniques et microbiologiques ont été effectués avant le traitement, et à 1 mois et 3 mois de suivi. Des données supplémentaires ont été obtenues par l'utilisation d'un questionnaire validé. Les résultats primaires et secondaires étaient, respectivement, la rémission de stomatite prothétique et la diminution du nombre de colonies de Candida. Des tests statistiques descriptifs et non paramétriques ont été menés pour analyser les données. Résultats: À 3 mois de suivi, 10,4 % des participants ont été guéris et 70,8 % ont eu une amélioration clinique de la stomatite prothétique grâce au brossage du palais. Une réduction statistiquement significative de la surface et de l’intensité de l’inflammation après 3 mois de brossage du palais a été démontrée (p < 0,0001). L’ampleur de l’effet a varié d’un effet modéré à important (0,34 à 0,54) selon la classification utilisée pour le diagnostique de la stomatite prothétique. De plus, le nombre de colonies de Candida, recueillies par sonication des prothèses et par échantillonnage du palais, a diminué de manière statistiquement significative après 3 mois de brossage (p ≤ 0,05). Conclusion: Les résultats de cette étude suggèrent que le brossage du palais est efficace comme traitement de la stomatite prothétique.

Primary Prevention and Screening Strategies for Colorectal Cancer: Which Strategy Should Take?

Objective: To explore and define the utility of different strategies for primary prevention (ASA, diet, physical activity) and strategies of screening test (FOBT, sigmoidoscopy, colonoscopy, etc.) for colorectal cancer. Data source: Databases consulted were MEDLINE (1966 to 2006), DARE (1980 to 2006), Cochrane Central Register of Controlled Trials, Cochrane Collaboration’s Registry of Clinical Trials, Cochrane Database of Systematic Reviews and LILACS. Study selection: Studies such clinical trial, cohort and case-control studies of the effectiveness of tests for screening and primary prevention adenoma and colorectal cancer were identified by two reviewers. Data Extraction: The extraction of data and its evaluation is done in most of the process so paired. Limitations: Not strictly complies with the methodology of a systematic review and therefore reproducibility is questionable, the conclusions of this study should be extrapolated with caution. Conclusions: The major strategy of screening on the effectiveness of early detection of premalignant lesions or cancer is colonoscopy every 5 years, however it is necessary to evaluate this measure cost-effectiveness studies. For primary prevention, aspirin and cyclooxygenase-2 inhibitors reduce the incidence of colorectal adenomas. Aspirin can reduce colorectal cancer incidence. However, these medications may be associated with a significant risk of cardiovascular events and gastrointestinal bleeding. The balance between risks and benefits must be evaluated in future studies.

Using historical lesion volume data in the design of a new phase II clinical trial in acute stroke

Background and Purpose-Clinical research into the treatment of acute stroke is complicated, is costly, and has often been unsuccessful. Developments in imaging technology based on computed tomography and magnetic resonance imaging scans offer opportunities for screening experimental therapies during phase II testing so as to deliver only the most promising interventions to phase III. We discuss the design and the appropriate sample size for phase II studies in stroke based on lesion volume. Methods-Determination of the relation between analyses of lesion volumes and of neurologic outcomes is illustrated using data from placebo trial patients from the Virtual International Stroke Trials Archive. The size of an effect on lesion volume that would lead to a clinically relevant treatment effect in terms of a measure, such as modified Rankin score (mRS), is found. The sample size to detect that magnitude of effect on lesion volume is then calculated. Simulation is used to evaluate different criteria for proceeding from phase II to phase III. Results-The odds ratios for mRS correspond roughly to the square root of odds ratios for lesion volume, implying that for equivalent power specifications, sample sizes based on lesion volumes should be about one fourth of those based on mRS. Relaxation of power requirements, appropriate for phase II, lead to further sample size reductions. For example, a phase III trial comparing a novel treatment with placebo with a total sample size of 1518 patients might be motivated from a phase II trial of 126 patients comparing the same 2 treatment arms. Discussion-Definitive phase III trials in stroke should aim to demonstrate significant effects of treatment on clinical outcomes. However, more direct outcomes such as lesion volume can be useful in phase II for determining whether such phase III trials should be undertaken in the first place. (Stroke. 2009;40:1347-1352.)