Standardized Protocol Items Recommendations for Observational Studies (SPIROS) for Observational Study Protocol Reporting Guidelines: Protocol for a Delphi Study.

BACKGROUND: Approximately 90% of currently published clinical and public health research is in the form of observational studies. Having a detailed and registered study protocol prior to data collection is important in any empirical study. Without this, there is no reliable way to assess the occurrence of publication bias, outcome reporting bias, and other protocol deviations. However, there is currently no solid guidance available on the information that a protocol for an observational study should contain. OBJECTIVE: The aim of this study is to formulate the Standardized Protocol Items Recommendations for Observational Studies (SPIROS) reporting guidelines, which focus on 3 main study designs of analytical epidemiology: cohort, case-control, and cross-sectional studies. METHODS: A scoping review of published protocol papers of observational studies in epidemiology will identify candidate items for the SPIROS reporting guidelines. The list of items will be extended with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist items and recommendations from the SPIROS steering committee. This long list serves as the basis for a 2-round Delphi survey among experts to obtain consensus on which items to include. Each candidate item from the long list will be rated on a 5-point Likert scale to assess relevance for inclusion in the SPIROS reporting guidelines. Following the Delphi survey, an expert-driven consensus workshop will be convened to finalize the reporting guidelines. RESULTS: A scoping review of published observational study protocols has been completed, with 59 candidate items identified for inclusion into the Delphi survey, itself launched in early 2020. CONCLUSIONS: This project aims to improve the timeliness, completeness, and clarity of study protocols of observational studies in analytical epidemiology by producing expert-based recommendations of items to be addressed. These reporting guidelines will facilitate and encourage researchers to prepare and register study protocols of sufficient quality prior to data collection in order to improve the transparency, reproducibility, and quality of observational studies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/17864.

TIDieR-Placebo: A guide and checklist for reporting placebo and sham controls.

BACKGROUND: Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions. METHODS AND FINDINGS: We developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator. CONCLUSIONS: We encourage TIDieR-Placebo to be used alongside TIDieR to assist the reporting of placebo or sham components and the trials in which they are used.

Affecting patients with work-related problems by educational training of their GPs: a cost-effectiveness study.

BACKGROUND: Assessing the cost effectiveness of training aimed at increasing general practitioners' (GP) work awareness and patients' work-related self-efficacy and quality of life. METHODS: A cluster randomized controlled trial in twenty-six GP practices in the southeast of the Netherlands with 32 participating GPs. GPs working in an intervention group practice received training and GPs working in a control group practice delivered usual care. The training intervention consisted of lectures and workshops aimed at increasing GPs' work awareness and more proactive counseling for patients with work-related problems (WRP). Subjects were working age patients with paid work for at least 12 h per week, who visited one of the participating GPs during the study period. As outcome measures we used the Return to Work Self Efficacy scale to assess patients' work-related self-efficacy and the Euroquol to assess quality of life. We also measured health care costs and productivity costs. With a 4-item questionnaire we asked patients to assess their GPs' work awareness. Data were collected at baseline, after 6 and 12 months. RESULTS: Data of 280 patients could be analyzed. The patient related outcomes did not improve after GP training. The change in GP work awareness and the overall mean cost difference (of €770) in favor of the intervention group were not significant. CONCLUSIONS: The training intervention presented in this paper was not cost-effective. Training which is further personalized and targeted at high risk groups with respect to WRP, is more likely to be cost effective.

[Influenza vaccination in the elderly: is a trial on mortality ethically acceptable?] / Effect influenzavaccinatie op sterfte onder ouderen.

The effectiveness of influenza vaccination in the elderly has long been a topic of debate, fueled by the absence of direct evidence on its effect on mortality. It is argued that new placebo-controlled trials should be undertaken to resolve this uncertainty. However, such trials may be ethically questionable. We provide an overview of the ethical challenges of an influenza vaccine efficacy trial designed to evaluate mortality in the elderly. An important condition in the justification of a trial is the existence of genuine uncertainty regarding the answer to a research question. Therefore an extensive analysis of the existing levels of knowledge is needed to support the conclusion that an effect of vaccination on mortality is uncertain. Even if a so-called 'clinical equipoise' status applies, denying a control group vaccination would be problematic because vaccination is considered 'competent care' and withholding vaccination could substantially increase patients' risk for influenza and its complications. Given the high burden of disease and proven benefits of vaccination, the importance of a trial is unlikely to outweigh the risk patients are exposed to. While a placebo-controlled trial in vaccine refusers may be considered, such a trial is unlikely to meet methodological standards regarding trial size and generalizability. We conclude that a new trial is unlikely to provide a direct answer, let alone change current policy. At the same time, given the lack of consensus on this topic, we invite researchers considering vaccine efficacy trials on mortality to address the ethical challenges as discussed.

Economic evaluation of multidisciplinary rehabilitation treatment versus cognitive behavioural therapy for patients with chronic fatigue syndrome: A randomized controlled trial.

BACKGROUND: A multi-centre RCT has shown that multidisciplinary rehabilitation treatment (MRT) is more effective in reducing fatigue over the long-term in comparison with cognitive behavioural therapy (CBT) for patients with chronic fatigue syndrome (CFS), but evidence on its cost-effectiveness is lacking. AIM: To compare the cost-effectiveness of MRT versus CBT for patients with CFS from a societal perspective. METHODS: A multi-centre randomized controlled trial comparing MRT with CBT was conducted among 122 patients with CFS diagnosed using the 1994 criteria of the Centers for Disease Control and Prevention and aged between 18 and 60 years. The societal costs (healthcare costs, patient and family costs, and costs for loss of productivity), fatigue severity, quality of life, quality-adjusted life-year (QALY), and cost-effectiveness ratios (ICERs) were measured over a follow-up period of one year. The main outcome of the cost-effectiveness analysis was fatigue measured by the Checklist Individual Strength (CIS). The main outcome of the cost-utility analysis was the QALY based on the EuroQol-5D-3L utilities. Sensitivity analyses were performed, and uncertainty was calculated using the cost-effectiveness acceptability curves and cost-effectiveness planes. RESULTS: The data of 109 patients (57 MRT and 52 CBT) were analyzed. MRT was significantly more effective in reducing fatigue at 52 weeks. The mean difference in QALY between the treatments was not significant (0.09, 95% CI: -0.02 to 0.19). The total societal costs were significantly higher for patients allocated to MRT (a difference of €5,389, 95% CI: 2,488 to 8,091). MRT has a high probability of being the most cost effective, using fatigue as the primary outcome. The ICER is €856 per unit of the CIS fatigue subscale. The results of the cost-utility analysis, using the QALY, indicate that the CBT had a higher likelihood of being more cost-effective. CONCLUSIONS: The probability of being more cost-effective is higher for MRT when using fatigue as primary outcome variable. Using QALY as the primary outcome, CBT has the highest probability of being more cost-effective. TRIAL REGISTRATION: ISRCTN77567702.

Pilot study to test the feasibility of a trial design and complex intervention on PRIoritising MUltimedication in Multimorbidity in general practices (PRIMUMpilot).

OBJECTIVE: To improve medication appropriateness and adherence in elderly patients with multimorbidity, we developed a complex intervention involving general practitioners (GPs) and their healthcare assistants (HCA). In accordance with the Medical Research Council guidance on developing and evaluating complex interventions, we prepared for the main study by testing the feasibility of the intervention and study design in a cluster randomised pilot study. SETTING: 20 general practices in Hesse, Germany. PARTICIPANTS: 100 cognitively intact patients ≥65 years with ≥3 chronic conditions, ≥5 chronic prescriptions and capable of participating in telephone interviews; 94 patients completed the study. INTERVENTION: The HCA conducted a checklist-based interview with patients on medication-related problems and reconciled their medications. Assisted by a computerised decision-support system (CDSS), the GPs discussed medication intake with patients and adjusted their medication regimens. The control group continued with usual care. OUTCOME MEASURES: Feasibility of the intervention and required time were assessed for GPs, HCAs and patients using mixed methods (questionnaires, interviews and case vignettes after completion of the study). The feasibility of the study was assessed concerning success of achieving recruitment targets, balancing cluster sizes and minimising drop-out rates. Exploratory outcomes included the medication appropriateness index (MAI), quality of life, functional status and adherence-related measures. MAI was evaluated blinded to group assignment, and intra-rater/inter-rater reliability was assessed for a subsample of prescriptions. RESULTS: 10 practices were randomised and analysed per group. GPs/HCAs were satisfied with the interventions despite the time required (35/45 min/patient). In case vignettes, GPs/HCAs needed help using the CDSS. The study made no patients feel uneasy. Intra-rater/inter-rater reliability for MAI was excellent. Inclusion criteria were challenging and potentially inadequate, and should therefore be adjusted. Outcome measures on pain, functionality and self-reported adherence were unfeasible due to frequent missing values, an incorrect manual or potentially invalid results. CONCLUSIONS: Intervention and trial design were feasible. The pilot study revealed important limitations that influenced the design and conduct of the main study, thus highlighting the value of piloting complex interventions. TRIAL REGISTRATION NUMBER: ISRCTN99691973; Results.

Implementing cardiometabolic health checks in general practice: a qualitative process evaluation.

BACKGROUND: A stepwise screening approach for the detection and management of cardiometabolic disease is proposed in various primary care guidelines. The aim of this study was to explore the implementation of a cardiometabolic health check as perceived by the involved caregivers and patients. METHODS: Qualitative process evaluation of the implementation of a cardiometabolic screening programme in a multidisciplinary primary healthcare centre in Eindhoven, the Netherlands, in which 1270 patients had participated. We explored the caregivers' experiences though focus group discussions and collected patients' experiences through a written questionnaire containing two open-ended questions. We analyzed our data using a thematic content analysis based on grounded theory principles. RESULTS: Five general practitioners, three practice nurses and five medical receptionists participated in the focus groups. Additionally we collected experiences of 657 (52% of 1270) participating patients through an open-ended questionnaire.GPs were enthusiastic about offering a health check and preferred systematic screening over case-finding, both in terms of yield and workload. The level of patient participation was high and most participants were enthusiastic about the health check being offered by their GP. Despite their enthusiasm, the GPs realized that they lacked experience in the design and implementation of a structured, large-scale prevention programme. This resulted in suboptimal instruction of the involved practice nurses and medical receptionists. The recruitment strategy was unnecessarily aggressive. There were shortcomings in communicating the outcomes of the health check to the patients and there was no predefined follow-up programme. Based on our findings we developed a checklist that can be used by designers of similar health checks. CONCLUSIONS: A number of fundamental issues may arise when GPs organize a systematic screening programme in their practice. These issues are related to the preparation of the involved staff, the importance of integration with everyday clinical practice, the approach of healthy patients and the provision of adequate follow-up programmes. The identified challenges and recommendations can be taken into account during future screening programmes.

Chronic Diseases among Older Cancer Survivors.

Objective. To compare the occurrence of pre-existing and subsequent comorbidity among older cancer patients (≥60 years) with older non-cancer patients. Material and Methods. Each cancer patient (n = 3835, mean age 72) was matched with four non-cancer patients in terms of age, sex, and practice. The occurrence of chronic diseases was assessed cross-sectionally (lifetime prevalence at time of diagnosis) and longitudinally (incidence after diagnosis) for all cancer patients and for breast, prostate, and colorectal cancer patients separately. Cancer and non-cancer patients were compared using logistic and Cox regression analysis. Results. The occurrence of the most common pre-existing and incident chronic diseases was largely similar in cancer and non-cancer patients, except for pre-existing COPD (OR 1.21, 95% CI 1.06-1.37) and subsequent venous thrombosis in the first two years after cancer diagnosis (HR 4.20, 95% CI 2.74-6.44), which were significantly more frequent (P < 0.01) among older cancer compared to non-cancer patients. Conclusion. The frequency of multimorbidity in older cancer patients is high. However, apart from COPD and venous thrombosis, the incidence of chronic diseases in older cancer patients is similar compared to non-cancer patients of the same age, sex, and practice.

Cognitive behavioural therapy versus multidisciplinary rehabilitation treatment for patients with chronic fatigue syndrome: study protocol for a randomised controlled trial (FatiGo).

BACKGROUND: Patients with chronic fatigue syndrome experience extreme fatigue, which often leads to substantial limitations of occupational, educational, social and personal activities. Currently, there is no consensus regarding the treatment. Patients try many different therapies to overcome their fatigue. Although there is no consensus, cognitive behavioural therapy is seen as one of the most effective treatments. Little is known about multidisciplinary rehabilitation treatment, a combination of cognitive behavioural therapy with principles of mindfulness, gradual increase of activities, body awareness therapy and pacing. The difference in effectiveness and cost-effectiveness between multidisciplinary rehabilitation treatment and cognitive behavioural therapy is as yet unknown. The FatiGo (Fatigue-Go) trial aims to compare the effects of both treatment approaches in outpatient rehabilitation on fatigue severity and quality of life in patients with chronic fatigue syndrome. METHODS: One hundred twenty patients who meet the criteria of chronic fatigue syndrome, fulfil the inclusion criteria and sign the informed consent form will be recruited. Both treatments take 6 months to complete. The outcome will be assessed at 6 and 12 months after the start of treatment. Two weeks after the start of treatment, expectancy and credibility will be measured, and patients will be asked to write down their personal goals and score their current performance on these goals on a visual analogue scale. At 6 and 14 weeks after the start of treatment, the primary outcome and three potential mediators-self-efficacy, causal attributions and present-centred attention-awareness-will be measured. Primary outcomes are fatigue severity and quality of life. Secondary outcomes are physical activity, psychological symptoms, self-efficacy, causal attributions, impact of disease on emotional and physical functioning, present-centred attention-awareness, life satisfaction, patient personal goals, self-rated improvement and economic costs. The primary analysis will be based on intention to treat, and longitudinal analysis of covariance will be used to compare treatments. DISCUSSION: The results of the trial will provide information on the effects of cognitive behavioural therapy and multidisciplinary rehabilitation treatment at 6 and 12 months follow-up, mediators of the outcome, cost-effectiveness, cost-utility, and the influence of treatment expectancy and credibility on the effectiveness of both treatments in patients with chronic fatigue syndrome. TRIAL REGISTRATION: Current Controlled Trials ISRCTN77567702.

Serotonin receptor 3A polymorphism c.-42C > T is associated with severe dyspepsia.

BACKGROUND: The association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT) modulates visceral sensitivity by its action on 5-HT3 receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT3 receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT), which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity. METHODS: Data from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial) were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR). Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe). Sum score ≥20 was defined severe dyspepsia. RESULTS: HTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20). This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39) and patients homozygous for the long (L) variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94). Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90). CONCLUSIONS: The HTR3A c.-42T allele is associated with severe dyspeptic symptoms. The stronger association among patients carrying the 5-HTTLPR L allele suggests an additive effect of the two polymorphisms. These results support the hypothesis that diminished 5-HT3 mediated antinociception predisposes to increased visceral sensitivity of the gastrointestinal tract. Moreover, the HTR3A c.-42C > T and 5-HTTLPR polymorphisms likely represent predisposing genetic variants in common to psychiatric morbidity and dyspepsia.