Alternative endpoints to overall survival (OS) are frequently used to assess treatment efficacy in randomized controlled trials (RCT). Their properties in terms of surrogate outcomes for OS need to be assessed. We evaluated the surrogate properties of progression-free survival (PFS), time-to-progression (TTP) and time-to-treatment failure (TTF) in advanced soft tissue sarcomas (STS).N = 2846) were included in the analysis. Individual-level associations were moderate . Trial-level associations were ranked as low for the three endpoints as per the IQWiG criterion.A total of 21 trials originally met the selection criteria and 14 RCTs . Phase II/III RCTs evaluating therapies for adults with advanced STS were eligible. We estimated the individual- and the trial-level associations between then candidate surrogates and OS. Statistical methods included weighted linear regression and the two-stage model introduced by Buyse and Burzykowski. The strength of the trial-level association was ranked according to the German Institute for Quality and Efficiency in Health Care (IQWiG) guidelines.Our results do not support strong surrogate properties of PFS, TTP and TTF for OS in advanced STS. The choice of the primary endpoint is a key step when designing a randomized controlled trial (RCT). In oncology, the most commonly used endpoint to assess the efficacy of a new treatment in RCTs is overall survival (OS) which is easily measurable, objectively defined as the time from randomization to death and validated by health regulatory authorities . Alternaet al.  AND “randomized controlled trial” [Text Word] AND trial [Text Word]. We limited our research to trials published before April the 7th, 2016. We also searched for trials on We gathered IPD from all eligible trials. We assessed the surrogate properties of PFS, TTP and TTF evaluated at six and twelve months for 18-month OS. Outcomes were defined following the international DATECAN guidelines . When noSpearman) calculated from the copula parameter.The individual-level surrogacy was assessed following a copula-based approach . The ind2WLR) of a linear regression model weighted by the trial size. The second method follows the two-stage model (2SM) adapted to time-to-event endpoints introduced by Burzykowski et al. ) using Cox proportional hazard models. We assessed the association between the treatment effects using the coefficient of determination . All analyses were performed using SAS software v9.3 following Burzykowski et al. .2 ≥ 0.72), low association (higher limit of the 95% CI of R2 ≤ 0.49) or medium association (neither low nor high), meaning that the validity of the surrogate remains unclear.The strength of the trial-level association was ranked according to the Institute for Quality and Efficiency in Health Care (IQWiG) guidelines : high asTo control for trials’ heterogeneity, we performed two subgroup analyses. Firstly, we retained only trials focusing on first line treatment that included doxorubicin- or ifosfamide-based therapies in the control arm. In the second analysis, we included only patients with leiomyosarcomas.Even though we highlighted moderate individual-level associations between the surrogate candidates and OS, our meta-analysis did not lead to significant evidence to validate PFS, TTP or TTF as surrogate markers for OS when assessing systemic treatment in advanced STS. PFS, TTP and TTF can be used as primary endpoints in phase II trials or as futility endpoints in phase III trials. However, OS should remain the primary endpoint in phase III trials until sufficient proof of surrogacy is provided. To achieve that goal, improvement in the conduct of sarcoma trials, particularly regarding the selection of histological subtypes, is necessary.Not applicable.The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.


To investigate (1) the feasibility of scanning the optic nerve (ON) and central retina with hand-held optical coherence tomography (HH-OCT) without sedation or anaesthesia in primary congenital glaucoma (PCG), (2) the characteristics of ON changes in comparison with adult primary open-angle glaucoma (POAG) in comparison with matched controls, (3) the sensitivity and specificity of ON parameters for diagnosis, and (4) changes of foveal morphology.HH-OCT  was used to investigate ON and foveal morphology of 20 children with PCG (mean age 4.64±2.79) and 10 adult patients with POAG (mean age 66.8±6.94), and compared with age-matched, gender-matched and ethnicity-matched healthy controls without sedation or anaesthesia.HH-OCT yielded useful data in 20 out of 24 young children with PCG. Patients with PCG had significantly deeper cup changes than patients with POAG . ON changes in PCG are characterised by significant increase in cup depth (165%), increased cup diameter (159%) and reduction in rim area (36.4%) as compared with controls with high sensitivity  and specificity . Patients with PCG have a significantly smaller width of the macula pit (p<0.001) with non-detectable external limiting membrane.HH-OCT has the potential to be a useful tool in glaucoma management for young children. We have demonstrated the use of HH-OCT in confirming a diagnosis of glaucoma within the studied cohort and found changes in disc morphology which characterise differently in PCG from POAG. Optical coherence tomography (OCT) is widely used in older patients with glaucoma in whom normative ranges have been established and patterns of disease are well described.Using hand-held OCT (HH-OCT) in a younger group of patients (mean age=4.64 years), our novel findings in primary congenital glaucoma were a particularly increased cup depth (vs primary open-angle glaucoma), a reduction of the macula pit width and a non-detectable external limiting membrane.HH-OCT in children with glaucoma confirmed many similar findings to those in adults .We identify particular threshold parameters to optimise recognition of glaucomatous nerve changes within the studied population.Sensitivity and specificity of optic nerve changes for a clinical diagnosis of glaucoma suggest that HH-OCT has the potential to be a useful tool to detect disease in young children and is optimised by using the threshold values which this work suggests.This is groundwork for a larger prospective study powered to evaluate childhood glaucoma diagnosis and disease control.Glaucoma is an important cause of preventable visual loss in childhood.5Assessment of children with glaucoma is challenging because of limited co-operation, media opacity and examination equipment designed for adults rather than paediatric use. While in adults optical coherence tomography (OCT) imaging is standard for assessing glaucoma, infants and young children have not benefited from this technology as they cannot co-operate with standard table-mounted devices. To date, limited literature about the use of OCT in PCG is available.Retinal nerve fibre layer (RNFL), ganglion cell layer (GCL) thinning and enlarged cup with smaller rim areas/volumes of the optic nerve (ON) were found in a cohort of children of an average age of 10.1±3.6 years after glaucoma surgery on OCT.9The aim of this study was to investigate in PCG (1) the feasibility of scanning the ON and central retina with hand-held OCT (HH-OCT) without sedation or anaesthesia; (2) the characteristics of ON changes in comparison with adult open-angle glaucoma (POAG), and for both groups, comparison with matched controls; (3) the sensitivity and specificity of ON parameters for diagnosis; and (4) changes of the size and shape of the foveal pit and individual retinal layers.In this observational cross-sectional study, we investigated 20 patients with PCG , and 20 age-matched, gender-matched and ethnicity-matched healthy controls .http://www.worldglaucoma.org/consensus-9/) criteria were used for PCG diagnosis. Inclusion criteria for the study were two or more of the following (in the absence of other ocular or systemic causes): elevated intraocular pressure (IOP), ON cupping, corneal changes of glaucoma, increasing axial length or myopia. Only clinically confirmed PCG was included. Secondary glaucomas were excluded including all in which structural abnormalities of the anterior segment were found . Those children for whom cooperation or media opacity prevented adequate image acquisition were excluded. Healthy children were recruited from Leicester nurseries and schools and matched by age, gender, ethnicity and clinical/scanning protocol.All patients were imaged between November 2015 and November 2016. Twenty-four patients were recruited from paediatric glaucoma clinics at Birmingham Children’s Hospital and University Hospitals of Leicester, UK. All eligible sequential patients were included as part of this study. PCG was confirmed based on the presence of clinical features documented in the clinical record (reference test). The ninth Consensus Report of the World Glaucoma Association (https://wga.one/wga/consensus-10/) . POAG cases were recruited from glaucoma clinics at Leicester Royal Infirmary during 12 months from November 2015. POAG controls were recruited from hospital staff and the general public and were matched for age, gender, ethnicity and refractive error.To compare ON changes with POAG, we included data from 10 patients with POAG . Demographic characteristics and clinical data of participants are shown in HH-OCT was performed without anaesthesia or sedation in outpatient clinics by research orthoptists without knowledge of the specific clinical details and diagnosis of the patients. A hand-held SD-OCT device  840 nm wavelength, 2.6 mm theoretic axial resolution was used. ON and macula imaging was carried out using 12 mm wide by 8 mm high scans with 80 horizontal B-scans composed of 600 A-scans and a 1.67 s acquisition time. To ensure central ON and fovea position of the B-scan, position was verified on the en-face view.http://rsbweb.nih.gov/ij/; accessed 3 March 2016) by SS. Cup and disc measurements are derived as shown in Masked optic nerve head analysis was performed on one B-scan through the centre of the ON cup using a custom-written ImageJ macro . This addresses the problems of calibration errors of lateral distance measures caused by changing axial lengths in the developing eye and in eyes with severe refractive error present in children with glaucoma.Segmentation of the foveal region masked to PCG or control was performed using ImageJ and included the RNFL, and inner nuclear (INL) and outer plexiform (OPL) layers.10SPSS software V.16.0 was used. ON head and macular parameters were normally distributed. Separate linear mixed models were generated for each of the OCT parameters to allow inclusion of repeated measures data  and non-repeated measures data  in the same statistical models. In each model, the OCT parameter was the outcome variable, participant-anonymised ID was included as a random factor; group and eye were included as fixed factors; and age as a covariate. Bonferroni correction was used to correct for the multiple comparisons. To compare glaucoma between children and adults, each ON parameter was expressed as percentage of the mean control value.Sensitivity and specificity of ON parameters for PCG detection were calculated using fixed thresholds for each ON parameter that demonstrated statistically significant difference.Correlations between ON and macular parameters, IOP and horizontal corneal diameter were calculated using Pearson’s correlation. P value ≤0.05 was considered statistically significant.Four patients were excluded from analysis; in two children, the affected eye could not be assessed due to low scan quality secondary to corneal oedema, and two children did not co-operate  than patients with POAG (117% from adult controls) (p=0.014) .Differences in disc diameters were not significant for PCG and adult glaucoma  and negative predictive values (NPVs) for OCT detection of clinically diagnosed PCG . SensitiOn visual inspection  bottom, Analysis of individual retinal layers of the central horizontal B-scan did not reveal any significant changes except the thickening in the INL pericentrally in the temporal retina in the PCG group as compared with controls .The foveal width in the PCG group was smaller  than in controls.This study represents the largest cohort of atients with PCG that have been imaged using HH-OCT to date. OCT was successful in 83.3% eyes of the patients with PCG without sedation or anaesthesia.In our study, children with PCG had significantly deeper cups than patients with POAG underlining the importance of measuring cup depth in addition to CDR. Changes of collagen fibril diameter and increased elasticity of the lamina cribosa early in life have been found in animal experiments.Standard ON assessment of adult patients with glaucoma includes the measurement of the average RNFL thickness of the peripapillary area on OCT. In our study, we have found significantly thinner RNFL in PCG in the nasal segment only using one single horizontal B-scan. It is likely that volumetric peripapillary RNFL thickness analysis involving all quadrants around the ON is more sensitive for assessment of ON damage in PCG and POAG. RNFL thinning starts with the inferior and superior segments and then involves nasal and temporal parts in adults.CDR measured by OCT in adult patients with glaucoma was found to be larger as compared with clinical assessment.Cup depth, cup diameter, CDR and rim width/area show useful sensitivity (74.1%–88.9%) and specificity (70.0%–85.0%) parameters for PCG detection. The thresholds of 600 µm, 2.5°, 0.5 and 2.8/400 µm, respectively, found in our study could be selected for screening children suspected of glaucoma with OCT. Cup depth was the most specific parameter (85%). Moreover, it is one of the easiest parameters to analyse as it can be measured using callipers available on the HH-OCT machine without the need of segmentation.It is important to recognise the limitations of our analysis of HH-OCT as a diagnostic tool. We used HH-OCT to identify childhood glaucoma in a specific clinical cohort with disease which differs from non-selected screening; this cohort has moderate to severe surgical PCG and differs from a non-targeted screening population in prevalence and severity of disease. The parameters we describe  apply to this cohort. We chose to study PCG (vs controls) because here, early-onset disease allowed us to characterise ON morphology at younger ages and the aggressive nature of the disease gives a higher prevalence of those structural changes. This allows the study to establish feasibility and characterise the differences between the groups. The diagnostic accuracy of HH-OCT or any diagnostic test is contextual,diagnostic tool in childhood glaucomas will likely be greatest in non-PCG glaucomas which can present relatively insidiously, such as distinguishing GCFCs (glaucoma following cataract surgery/aphakic glaucoma) from ocular hypertension in this group.The clinical presentation of PCG differs from POAG in that the disease is usually symptomatic and the diagnosis is more often obvious to practitioners familiar with the condition, so the need for a tool for screening is less. We foresee that the primary use of HH-OCT in PCG is for disease monitoring. This study into the diagnostic use of HH-OCT informs which ON head parameters are most likely to yield useful disease monitoring information in these children and to prioritise those parameters in imaging algorithms: cup depth is promising with highest specificity and PPV of the ON parameters studied . We would advocate a longitudinal cohort study to evaluate HH-OCT disease monitoring of PCG and suggest that those ON parameters presented here might inform such work. The use of HH-OCT as a et al.In a recent study, outer retinal layer changes and isolated INL cysts were found in a heterogeneous group of patients with paediatric glaucoma as well as non-glaucomatous optic atrophy.We found significant reduction of the foveal pit width. It is reported in the literature that patients with POAG have progressive retinal thinning which is related to GCL loss.The number of patients was relatively small and ON and foveal analyses were based only on single horizontal B-scan images rather than volumetric analysis to allow fast scans in children with poor co-operation. Consequently, the described changes do not represent all the structural abnormalities in patients with PCG that could be captured by volumetric analysis. Vertical scans are probably more likely to detect early changes, as is seen in POAG.In conclusion, our study shows that HH-OCT in children with PCG is feasible in a large percentage of children without sedation or anaesthesia. ON changes in children showed increased CDR, similar to POAG; however, excavation of the cup was deeper in children.HH-OCT has the potential to be a useful tool for detecting glaucoma in young children. These findings form the groundwork for an expanded prospective study powered to evaluate HH-OCT for both disease monitoring in PCG and disease detection in non-PCG cohorts.


Data audits are often evaluated soon after completion, even though the identification of systematic issues may lead to additional data quality improvements in the future. In this study, we assess the impact of the entire data audit process on subsequent statistical analyses.We conducted on-site audits of datasets from nine international HIV care sites. Error rates were quantified for key demographic and clinical variables among a subset of records randomly selected for auditing. Based on audit results, some sites were tasked with targeted validation of high-error-rate variables resulting in a post-audit dataset. We estimated the times from antiretroviral therapy initiation until death and first AIDS-defining event using the pre-audit data, the audit data, and the post-audit data.n = 250) across all audited variables was 17.1%. The estimated probability of mortality and an AIDS-defining event over time was higher in the audited data relative to the pre-audit data. Among patients represented in both the post-audit and pre-audit cohorts , AIDS and mortality estimates also were higher in the post-audit data.The overall discrepancy rate between pre-audit and audit data (Though some changes may have occurred independently, our findings suggest that improved data quality following the audit may impact epidemiological inferences. Source document verification (SDV) is a strategy for research data quality assessment. Typically, SDV involves the partial (or complete) comparison of research study data against original source documents, such as study case report forms, patient clinical charts, laboratory reports, or electronic health records. This practice of data auditing allows investigators to verify data are entered according to study definitions, identify systematic issues with research data collection, and calibrate their confidence for making inferences based on study findings.Concerns regarding data quality are magnified for studies using routinely collected observational data from international cohorts. Given that many HIV observational datasets were originally created for clinical or administrative purposes, data are susceptible to errors with respect to completeness and correctness . StudiesBecause SDV is resource-intensive – locating the original source documents, travel by external auditors to local sites, comparing source documents to the current research dataset, and recording discrepancies – it is becoming increasingly important to justify its expense. Many data audits assess data quality according to whether the error rate is above or below an arbitrary threshold . HoweverThe analysis of observational HIV data allows for a robust evaluation of the antiretroviral treatment [ART] experience over time. For example, we have pooled data from multiple HIV clinical care sites to better understand outcomes of key populations  is a consortium of clinics from seven Latin American countries that collects and shares HIV care data. CCASAnet has been described elsewhere ; additioIn 2013–14, on-site audits of submitted data were conducted through a joint effort between data auditors from the CCASAnet Data Coordinating Center at Vanderbilt University (CDCC-VU) and investigators at nine participating sites. For each site, approximately 30 patient records were randomly selected to be audited. Source documents available at the sites included paper-based patient charts from the HIV clinic, general hospital charts, laboratory result forms (both paper and electronic), and electronic medical record systems.An audit team from the CDCC-VU, consisting of at least one clinician and one informatician, traveled to each of the nine sites. The audit team had a paper audit form, prepared by the CDCC-VU data manager, displaying all submitted research data for each patient record selected. Over the course of 2–3 days, the data audit team compared values in the research database with the source documents. Additionally, the authors reviewed all available source documents to check whether values or entire visits that were present in the source documents were missing from the research database. Each entry was labeled with an audit code (A1-A5) adapted from standardized audit codes : value mIn response to the audit, each site received scans of the audit forms and a report describing errors found and general recommendations. Site-specific advice included (but was not limited to) re-abstraction of ART regimens from older records, entry of missed visit or lab data that was available in the paper chart, more timely record updates for research data submissions, and more thorough collection of clinical events data.pre-audit dataset. Approximately two years after the audit (October 2016), the CDCC-VU again archived the most recent submission from each site and aggregated records for all patients to generate a post-audit dataset. This time frame encompassed 1–2 scheduled data submission cycles for each site, thereby allowing enough time for audit recommendations potentially to be incorporated in the new dataset. We note one key modification to the post-audit dataset: any data points after the site-specific pre-audit freeze date were removed from the post-audit dataset so that pre- and post- audit datasets covered the same time period. However, patient records not present in the pre-audit dataset but present in the post-audit dataset were included if the patient was enrolled prior to the pre-audit freeze date. Lastly, an audited dataset was generated for the subset of records that were audited. This dataset contained patient records according to the source document verification findings. The connection between all three datasets is shown visually in Fig. As part of routine CCASAnet collaboration, each site regularly submitted to the CDCC-VU a dataset containing records for all past and present enrolled patients. Prior to the audit, the most recent submission from each site was archived. These site-specific datasets were aggregated to generate a primary variables. We also generated 14 additional variables that were relevant for our statistical analyses. These derived variables were typically calculated using one or more of the primary variables . A complete list of variables considered for this study is included in Additional file The three datasets each contained 21 variables (as defined and standardized in the CCASAnet data transfer protocol) that were routinely submitted by CCASAnet sites. Two variables (CDC and WHO stage at enrollment) were collected in the pre-audit and audited datasets, but were replaced with two different variables  in the post-audit dataset; the remaining 19 were included in all three datasets. We refer to these variables as We defined a data discrepancy as an instance where recorded values were different or a value was missing in one of the two datasets. When comparing the audited dataset with the pre-audit dataset, we also counted instances where a value could not be verified as a discrepancy. We calculated discrepancy (error) rates for both the originally collected and derived variables used in analyses between (1) the pre-audit and audited datasets in the subset of records that were audited, and (2) the entire pre-audit and post-audit datasets.To assess the impact of errors identified during a data audit on a typical statistical analysis, we replicated the same statistical analyses in all datasets. Patients were excluded if they were not adults (< 18 years) or never initiated ART. Two countries had multiple sites (Argentina and Honduras); for this analysis, we combined sites within a country into a single site. We estimated the overall and country-specific (when data were available) cumulative incidences for both the time from ART initiation to death and the time from ART initiation to first AIDS-defining event. A multivariable Cox regression model was fit to estimate cause-specific hazard ratios (HRs) for predictors of death and AIDS after ART initiation. All models were adjusted for the following covariates: age, sex, probable route of HIV infection, clinical history of AIDS, CD4 cell count, initial ART regimen, and calendar year. All Cox models were stratified by site to allow the underlying hazard to differ for each site  and usedGiven that some patient records were included in only one dataset, we performed a sensitivity analyses that repeated the above-described analyses using only patient records that were available in both the pre-audit and post-audit dataset.http://www.R-project.org); corresponding code is available at http://biostat.mc.vanderbilt.edu/ArchivedAnalyses. Institutional review board approval was obtained from each site and the CDCC-VU.All analyses were performed using R Statistical Software  of the selected records during the audit visits. The remaining 66 records were not audited, mainly due to insufficient time during the audit visits or unavailable source documents . The number of audited records varied by site, ranging from 12 to 31 ; the remaining were due to discrepant data entries  and data that could not be verified . Among variables typically collected at enrollment, error rates were low for sex  and birth date , and high for probable mode of infection . Only 5% (7/138) of patients had a discordant death status, yet approximately 25% (6/24) of all audited death dates had a discrepancy. Date variables had higher discrepancy rates, including 31% (133/431) for ART regimen end dates and 49% (120/243) for clinical event dates. Error rates for all audited variables are included in Additional file The pre-audit dataset for these 250 patients contained 19,289 values across 21 variables; 14,489 (75%) were audited due to time constraints and incomplete source documents. Overall, the discrepancy rate across all audited variables was 17.1% (n = 233), discrepancy rates for derived variables ranged from 3 to 36%  and follow-up time .Of the 250 audited patients, 228 (91%) originally met inclusion criteria for analyses (adult patients who initiated ART) in the pre-audit dataset and 232 (93%) in the audited dataset; 227 (91%) met inclusion criteria in both datasets. Of the five patients excluded from the pre-audit dataset only, four had discrepancies in ART data and one was missing follow-up data. For the single patient excluded in the audited dataset only, a revised birthdate revealed the patient was under 18 at ART initiation. For records present in at least one dataset  previously included in the pre-audit dataset were not present in the updated dataset; duplicate records or instances where the original paper forms could not be located were removed.The full pre-audit database included 19,331 adult patients. The post-audit dataset, which incorporated sites’ data revisions in response to the audit findings, contained 22,146 eligible adult patients from the same time period  The post-audit revisions produced a dataset with 18,999 patients from the pre-audit dataset plus 3147 newly added patients. Some patients  of the discrepancies between the two datasets was due to missing values in the pre-audit dataset that were subsequently included in the post-audit dataset. Missing values in the post-audit dataset  that existed in the pre-audit dataset explained 11% of discrepancies and conflicting values  accounted for the remaining 6%. The variables with the highest proportion of discrepancies were prior history of AIDS at enrollment , the date of diagnosis of a clinical endpoint , and the date of clinic visit   were identical in both datasets. The plurality (n = 2480) for sex to 52% (n = 9265) for time from ART initiation to death or censoring  were in both the pre-audit and post-audit analysis cohorts and the remaining 2450 (14%) were discordant. Discrepancy rates for derived variables among the 17,703 patients that met inclusion criteria for at least one dataset ranged from 14%  than the pre-audit  dataset. The estimated percentage of patients who died by three years was 6.9%  in the pre-audit dataset and 8.7%  in the post-audit dataset. Using patient data from the five regions where clinical event data was available, estimated probabilities of an AIDS-defining event  than the pre-audit dataset (n = 7422). The estimated percentage of patients with AIDS at three years was 18.6%  in the pre-audit dataset and 20.5%  in the post-audit dataset. Changes in mortality rates . Differences in the hazards of death  were identical. The variables with the highest proportion of entries with discrepancies were similar to the full dataset comparison: the date of diagnosis of a clinical endpoint (51%), prior history of AIDS at enrollment (52%) and the date of clinic visit (60%). Among this cohort of 18,999 patients, 15,441 patients met inclusion criteria for at least one analysis dataset. Discrepancy rates for derived variables ranged from 2% for sex to 23% for clinical AIDS status at baseline. Most variables had a lower relative frequency of discrepancies in the post-audit dataset compared to the error rates from the audited subset of records alone. The key exception was occurrence of an AIDS-defining event at baseline (23% vs. 12%). While the estimated percentage of patients with an AIDS-defining event at three years was still higher in the post-audit dataset (20.9% vs. 18.6%), mortality estimates over time were similar using the pre-audit and post-audit datasets.This study demonstrated that results and corresponding inferences can be affected by improvements in data quality following data audits. Source data verification in our multi-region observational HIV cohort revealed substantial errors in the recording of certain variables, in particular clinical events. Recommendations by audit teams led to re-entry of some variables at some sites. Subsequent analyses of revised, post-audit datasets yielded results consistent with audit findings. In particular, rates of AIDS-defining events after ART initiation were substantially higher in audit data than in pre-audit data, and ensuing analyses using post-audit data similarly estimated rates of an AIDS-defining event to be much higher than those observed pre-audit. These results suggest that the quality of clinical events data improved as a result of the audit.There are many possible reasons for data errors, ranging from isolated errors such as typographical mistakes and misread values due to illegible handwriting to systematic issues such as misinterpreted variable definitions, miscoded value sets, or mistakes in assembling databases. For example, high error rates in dates of CD4 and viral load measurements discovered during an audit at one site uncovered a systematic error in how data entry personnel had been trained to enter this data into the study database. As a result of the audit, investigators at that site were made aware of the issue and were able to fix existing errors and prevent future invalid entries. For a multi-site consortium, early identification and rapid resolution of systematic issues can have a profound impact on data quality.A previous CCASAnet audit was conducted in 2008–2009. However, this was the first time that the clinical endpoints data were audited. Error rates for these variables tended to be higher than those for variables that had been previously audited. Clinical endpoint entries may be particularly prone to error and improper extraction by data capture personnel who lack the necessary clinical background to identify diagnoses from paper charts. However, the high error rates in clinical endpoints variables may also be indirect evidence that the audit process worked: variables that have been previously audited could be less likely to be error-prone in the next wave of audits because major errors have been identified and causes recognized and fixed.Our findings suggest that variable modification  rates for most variables were higher in the audit database than in the post-audit database. This is not surprising: variables with low audit-determined error rates would remain largely unchanged in post-audit databases. However, it does serve as a reminder that when conducted on a random subset of records, data audits mostly improve data quality among all patients for specific variables with systematic issues and to a lesser extent the remaining variables among the audited patients. In ongoing work, we are considering statistical methods that can use audit data to predict errors for unaudited patients and thus improve analyses using error-prone data .Discrepancy rates tended to be lower for derived variables than for primary variables. Given that derived variables are typically composed of two or more primary variables, we had anticipated that they would be more error-prone. A closer review reveals that a large number of discrepancies in the primary variables were due to missingness. For variables that were routinely collected at each visit, a missing entry was often inconsequential when generating analysis variables as derived variables were often calculated using windows that include multiple visits. This reaffirms that the impact of questionable data on study findings is difficult to assess by only using error rates , 9.While source data verification is frequently used to monitor data quality in a clinical setting, there is little consensus on best practices for implementing and assessing such audits. A recent review of 15 published studies regarding SDV found a wide range of approaches with no standard method of evaluation . Our finOur study has limitations. Most notably, our study design did not allow us to differentiate between improvements in data quality due to the audit process and natural improvements in data over time. We recognize that some changes  may have occurred independently from the audit process. In addition, there is no gold standard, and some audit data may not reflect the patient’s reality.The SDV process can improve data quality, which can in turn have an impact on epidemiological inferences, especially for variables like the CCASAnet clinical endpoints data that had not been audited previously. We encourage the implementation of data audits for observational studies that rely on the extraction of study data from source documents.Additional file 1: Table S1. Complete list of study variables with descriptions. Table S2. Overview of audit frequency by site. Figure S1. Summary of reported audit findings for all audited variables. Table S3. Auditing results for each variable entry. Figure S2. Adjusted hazard ratios of mortality (a) and AIDS-defining event (b) for patients in the pre-audit and audited datasets. Figure S3. Estimated cumulative incidence of death by site for patients in the pre-audit and post-audit datasets. Solid lines denote the estimated incidence and dotted lines denote the corresponding 95% confidence intervals. Figure S4. Estimated cumulative incidence of an AIDS-defining event by site for patients in the pre-audit and post-audit datasets. Solid lines denote the estimated incidence and dotted lines denote the corresponding 95% confidence intervals. Figure S5. Association between patient characteristics at baseline and hazard of death by site using pre-audit and post-audit data. The dots denote the estimated incidence and the lines denote the corresponding 95% confidence intervals. Figure S6. Association between patient characteristics at baseline and hazard of an AIDS-defining event by site using pre-audit and post-audit data. The dots denote the estimated incidence and the lines denote the corresponding 95% confidence intervals.


The calcitonin gene-related peptide (CGRP)-receptor component protein (RCP) is a 17-kDa intracellular peripheral membrane protein required for signal transduction at CGRP receptors. To determine the role of RCP in CGRP-mediated signal transduction, RCP was depleted from NIH3T3 cells using antisense strategy. Loss of RCP protein correlated with loss of cAMP production by CGRP in the antisense cells. In contrast, loss of RCP had no effect on CGRP-mediated binding; therefore RCP is not acting as a chaperone for the CGRP receptor. Instead, RCP is a novel signal transduction molecule that couples the CGRP receptor to the cellular signal transduction machinery. RCP thus represents a prototype for a new class of signal transduction proteins that are required for regulation of G protein-coupled receptors.


The research objectives of the 5-year and 10-year assessments in the Finnish degenerative meniscal lesion study (FIDELITY) are twofold: (1) to assess the long-term efficacy of arthroscopic partial meniscectomy (APM) in adults (age 35 to 65 years) with a degenerative meniscus tear and (2) to determine the respective effects of APM and degenerative meniscus tear on the development of radiographic and clinical knee osteoarthritis (OA).FIDELITY is an ongoing multi-center, randomized, participant and outcome assessor blinded, placebo-surgery-controlled trial in 146 patients. This statistical analysis plan (SAP) article describes the overall principles for analysis of long-term outcomes (5-year and 10-year follow up), including how participants will be included in each analysis, the primary and secondary outcomes and their respective analyses, adjustments for covariates, and the presentation of the results. In addition, we will present the planned sensitivity and subgroup analyses.To assess the long-term efficacy of APM on knee symptoms and function we are carrying out a long-term (5-year and 10-year) follow up of our placebo-surgery-controlled FIDELITY trial according to statistical principles outlined in detail in this document. As our second primary objective, whether APM (resection of torn meniscus tear) accelerates or delays the development of knee osteoarthritis in patients with an arthroscopically verified degenerative tear of the medial meniscus, a pre-registered follow-up is also carried out.NCT00549172 . Registered on 25 October 2007 (NCT00549172). ClinicalTrials.gov, NCT01052233 . Registered on 20 January 2010.ClinicalTrials.gov,  The Finnish degenerative meniscal lesion study (FIDELITY) is a trial to assess the efficacy of arthroscopic partial meniscectomy (APM) in patients with a degenerative meniscus tear. The primary outcome assessment point of the trial was at 1 year post surgery. The original study protocol , 3 and aTo safeguard against the imminent risk of outcome reporting bias, selective reporting, and data-driven interpretation of results, this statistical analysis plan  for the 5-year and 10-year follow up is published as an update to the previously published protocol .By the end of the 21st century, APM had become the most common orthopedic procedure with well over half a million such surgeries performed annually in the USA alone , 8, mostHowever, there is mounting evidence to suggest that APM is associated with increased risk of accelerated progression of knee osteoarthritis (OA) and earlier need for “corrective” surgery  or total knee replacement (TKR)) in middle-aged to older patients , 15. It What is the long-term efficacy of APM (versus placebo surgery) on functional outcome and knee symptoms in patients with an arthroscopically verified degenerative tear of the medial meniscus?Does APM either accelerate or delay the development/progression of radiographic and clinical knee OA in these patients?The following two research questions capture the primary objectives of these 5-year and 10-year follow-up investigations:FIDELITY is a multicenter, randomized, participant and outcome assessor blinded, placebo-surgery-controlled trial. This study is carried out at five orthopedic clinics of Tampere University Hospital Hatanpää, Kuopio University Hospital, Helsinki Central Hospital (Jorvi), Turku University Hospital, and the Central Finland Central Hospital in Jyväskylä, all in Finland. The study group at each center consists of a main investigator (an orthopedic surgeon experienced in knee arthroscopy) who took care of the recruitment of the patients and all surgical procedures, a study nurse, an orthopedic surgeon for possible postoperative problems and another for scheduled follow-up examinations, the latter two both blinded to the treatment allocation. Patients were enrolled between 2007 and 2012 and all follow-up assessments were carried out between October 2013 and January 2017. The study was approved by the Pirkanmaa Hospital District’s committee of ethics (no. R06157). The two research questions were registered as separate studies in the ClinicalTrials database . The study process shown in Fig. Box 1 Inclusion and exclusion criteria used in the FIDELITY trialInclusion criteriaAge: 35–65 years of agePersistent (> 3 months) pain on the medial joint line of the kneePain provoked by palpation or compression of the joint line or a positive McMurray signMRI showing signals characteristic of medial meniscus injuryDegenerative injury to the medial meniscus confirmed at arthroscopyExclusion criteriaTrauma-induced onset of symptomsLocked knee Previous surgical procedure on the affected kneeClinical osteoarthritis (OA) of the knee (American College of Rheumatology criteria)Radiological OA of the knee (Kellgren-Lawrence grade > 1) at clinical site readingsAcute (within the previous year) fracture of the affected extremityDecreased range of motion of the kneeInstability of the kneeMRI assessment shows pathology other than degenerative knee disease requiring treatment other than arthroscopic partial meniscectomy (APM)Arthroscopic examination reveals pathologic change other than a degenerative injury to the medial meniscus requiring intervention other than APMMRI magnetic resonance imaging, OA osteoarthritisTo assess the efficacy of APM (versus placebo surgery) on the functional outcome and knee symptoms in patients with an arthroscopically verified degenerative tear of the medial meniscus, we will be using the same three patient-relevant outcomes (PROMs) that were used as our primary outcomes in the previous, 1-year and 2-year follow-up publications of this data .Western Ontario Meniscal Evaluation Tool (WOMET) score, a disease-specific instrument for assessing quality of life that was developed and validated for patients with meniscal pathologic conditions , 18Lysholm knee score, the most commonly used outcome instrument for various knee conditions , 20 and Knee pain after exercise, assessed on an 11-point scale ranging from 0 (no pain) to 10 (extreme pain)The primary outcomes are:The secondary outcome is the frequency of unblinding in the two study groups: patients with inadequate relief of symptoms underwent unblinding of the treatment-group allocation.These outcomes and the justification for these have previously been elaborated in detail –4.To assess whether APM either accelerates or delays the development/progression of radiographic and clinical knee OA in these patients, we will use radiographs and established clinical criteria to assess the progression of knee OA at the 5-year and 10-year time point after the index surgeries as follows.An increase of one grade or more in the Kellgren-Lawrence (KL) knee OA grading (dichotomous outcome: yes or no)The KL scale is a semi-quantitative instrument  to assess the severity of radiographic tibiofemoral knee OA . PatientDevelopment/progression of radiographic OARadiographic progression based on the sum of marginal tibiofemoral osteophyte grades and tibiofemoral joint space narrowing (JSN) grades ) atlas The primary outcomes are:The OARSI atlas is a semi-quantitative instrument  with focus to assess the severity of JSN and osteophytes, respectively, in knee OA .Knee OA according to the American College of Rheumatology Clinical Criteria The secondary outcome:2.More sensitive than a one full grade (above) but may potentially capture “too many” patients as progressed in the two treatment arms, in particular at the 10-year follow upDevelopment/progression of radiographic OA by a grade increase of 0.5 or more in the Kellgren-Lawrence (KL) knee OA grading (dichotomous outcome: yes or no)3.Quantitative analysis of the joint-space width based on radiographs4.Time-to-event analysis 5.Magnetic resonance imaging (MRI)-based progression by semi-quantitative scoring (MOAKS) 6.MRI-based progression of knee degeneration by quantitative assessment of change in OA features 7.Lower extremity alignment : change from baseline to 5 years8.Patient satisfaction and self-rated improvement9.Patients’ return to normal activities10.The presence of mechanical symptoms 11.Clinical knee examination12.Serious adverse events13.Frequency of repeat APM, and the number of osteotomies and knee arthroplasties14.Possible derivates from the above noted outcomesAuxiliary outcomes:For all radiographic outcomes, two experienced musculoskeletal radiologist , unaware of the treatment allocation and clinical data, will grade the baseline, and the 5- and 10-year radiographs of the operated (index) knee of all participants. After readings by both readers, a consensus will be sought. All the analyses of secondary outcomes are supportive, exploratory, and/or hypothesis-generating.For the assessment of the efficacy of APM (NCT00549172), we will use the same PROMs used in the previous publications depicting the 1-year  follow-uAs for the evaluation of the development/progression of knee OA (NCT01052233), the 5-year follow up is the first time point one can reasonably expect any OA-related changes to take place or to be quantifiable. Having said that, the outcome measures we originally registered in the ClinicalTrials.gov database  clinical criteria) are quite insensitive to change, so we have decided to add the sum of OARSI atlas osteophyte grades and JSN grades as an additional primary outcome of radiographic progression of OA.All the analyses will be performed according to the intention to treat (ITT) principle or, if impossible, using the full analysis set . In sensMixed model linear regression will be used to analyze continuous outcomes related to objective 1 (efficacy of APM). In this model the patient will be included as the random effect and time point , treatment arm (APM or placebo) and their interaction, and randomization stratification factors, i.e., age (35–50 years or 51–65 years), sex, absence or presence of minor degenerative changes on a radiograph (KL grade 0 or 1), and study center, will be included as fixed effects. The model will be adjusted for baseline values of the respective outcome variable.not adjust for site in the logistic regression analysis due to the small number of participants in some centers and anticipated sparse data. Sensitivity will be analyzed including the study site as a covariate. We will use a linear regression model adjusted for randomization stratification variables and the baseline value of the outcome to analyze continuous outcomes related to objective 2. Serious adverse events will also be reported.Logistic regression will be used to analyze the binary outcomes. The model will be adjusted for the baseline randomization stratification factors (age (35–50 years or 51–65 years), sex, and absence or presence of minor degenerative changes on a radiograph (KL grade 0 or 1). The method of standardization will be used to obtain the adjusted risk ratio and the adjusted risk difference from the logistic regression model . AlthougWe note that we originally powered the study to detect a minimal clinically important difference in the efficacy (patient-reported) outcomes - the Lysholm and WOMET scores  and in the score for knee pain after exercise (difference of at least 2.0 points) - between the APM and placebo-surgery groups. The original sample size calculation for the FIDELITY trial - which was geared at assessing the (short-term) efficacy of APM on pain and function - yielded a sample size of 70 patients per group. At the moment, having completed the 5-year follow up, we know that we have 96% adherence to follow up . Based on this, we anticipate the loss to follow up to be no more than 5 additional patients per group at the end of the follow-up period (at 10 years), thus leaving approximately 63–67 patients per group for the final analyses. These values provide us with 80% power, based on a two-sided type 1 error rate of 5%, to detect a 20% unit difference in the proportion of knee OA between APM and placebo-surgery. However, we consider it important to report estimates of the difference with a measure of uncertainty , even if smaller differences cannot be declared as statistically significant in a conventional way. This is due to two reasons: (1) even a statistically non-significant difference can potentially exclude a clinically relevant difference in one direction ; (2) even if the results of this particular study are inconclusive, they can inform any future meta-analysis, as we can expect the estimate to be unbiased due to the stringent design of the study.blinded data interpretation [Given the widely acknowledged importance of adequate blinding of all stakeholders in eliminating potential bias from the findings of RCTs , we haveretation . In brieretation –4, they The study was approved by the Pirkanmaa Hospital District committee of ethics no. R06157). Our application contained a specific, 6-point ethical analysis focusing on the methodological rationale for use of placebo surgery, risk-benefit assessment, and informed consent  to treat persistent knee pain in middle-aged and older patients is one of the most common orthopedic surgical procedures in use, despite mounting evidence of no or only marginal benefits on patient-relevant outcomes. A degenerative meniscal tear has been reported to be an independent risk factor for progression of cartilage damage and the subsequent development of knee OA. However, the respective roles and individual contributions of meniscal tear and APM in the progression of OA remain unclear. Current evidence, primarily based on observational data and unblinded randomized controlled trials, suggest that APM increases the risk of development of knee OA, but the studies are hampered by confounding by indication or high rates of crossover and loss to follow up.Our multicenter, randomized, placebo-surgery-controlled FIDELITY trial that involves patients with an arthroscopically verified degenerative medial meniscus tear provides an exceptionally rigorous design to address the aforementioned questions, namely whether arthroscopic partial meniscectomy is associated with an increased risk of progression of radiographic knee OA and whether APM has any beneficial effect on knee pain or function or other symptoms.Additional file 1: SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*.


D-dimer levels measured during and after vitamin K antagonist withdrawal may be used in clinical practice to assess the individual risk of recurrent venous thromboembolism. Currently, direct oral anticoagulants (DOACs) are frequently used in venous thromboembolism treatment; however, their pharmacokinetics and pharmacodynamics characteristics are completely different than vitamin K antagonists. The present study aimed at comparing the results of D-dimer levels during and after anticoagulation withdrawal in patients with venous thromboembolism treated with DOACs or warfarin.D-dimer levels were measured in 527 patients (“cases”) during DOACs treatment (T0) and after 15 (T15), 30 (T30), 60 (T60) and 90 (T90) days after their discontinuation and in 527 patients (“controls”) enrolled in the DULCIS study , matched for sex, age (+/-3 y), type of D-dimer assay and site of venous thromboembolism. Both cases and controls received anticoagulant treatment after a first venous thromboembolism event that was unprovoked or associated with weak risk factors.The rate of positive D-dimer results was significantly higher in cases than in controls at T0  and at T30 , as well as at the other time-points, though not statistically significant.D-dimer levels during and after stopping an anticoagulant treatment for a venous thromboembolism episode differ between patients treated with a DOAC than in those treated with warfarin. Specifically designed prospective studies are warranted to reassess the use of D-dimer as predictor of the risk of recurrent venous thromboembolism in patients treated with DOACs. Venous thromboembolism (VTE), that includes deep vein thrombosis (DVT) and/or pulmonary embolism (PE), is a frequent, severe, acute disease. After the first episode, VTE has a risk to recur that increases sharply after anticoagulation is stopped, especially in patients with unprovoked events. Anticoagulant therapy is absolutely necessary to treat the acute phase of the disease, to avoid early complications, and it is also indicated in the long term to avoid recurrences. Clinical studies have shown that three months of initial treatment reduce the risk of recurrence over a shorter period of anticoagulation . HoweverThe present study aimed at assessing the results of D-dimer levels during and after anticoagulation is stopped in VTE patients treated with DOACs, in comparison with the D-dimer changes recorded in patients treated with warfarin who were included in the DULCIS study, in which serial D-dimer measurements were used to decide on management of anticoagulant therapy duration in patients after unprovoked VTE events .The present is a retrospective, case-control study, focusing on D-dimer level changes during and after anticoagulant treatment was stopped in patients who received either DOACs or warfarin for VTE therapy. The present study does not address the predictive value for VTE recurrence of D-dimer testing. The “cases” were VTE patients treated with DOACs who were evaluated to manage the duration of anticoagulant treatment (see below). The “controls” were matched patients selected among the patients included in the DULCIS study who were treated with warfarin . Both caTo realize this study, we asked some Italian centers, which routinely adopted a serial D-dimer measurement procedure to decide the duration of anticoagulant therapy in VTE patients treated with DOACs, if they were willing to centralize to the coordinating center the characteristics of the patients (in anonymous way), and the quantitative results of D-dimer measurements. A positive answer was obtained from 9 centers, which contributed to the study by sending data from examined patients (“cases”).Patients treated with warfarin were selected among patients enrolled in the DULCIS study  and those treated with DOACs were included in the START-Register (#NCT02219984). The DULCIS study and the START-Register have been approved by the Ethical Committee of the coordinating center . The local Ethics Committees approval was then obtained by all participating centers. All patients provided informed written consent to have data from their medical records used in research. Data were fully anonymized before transferring to the central analysis office.The cases (subjects treated with DOACs), gathered from the 9 participating centers, were listed onto an electronic page and printed to show only the fields to be used to select the appropriate matching controls (treated with warfarin as VKA), following this order: the commercial assay used to perform D-dimer measurements see , sex, agDifferently than in the DULCIS study, in the present report, positive or negative D-dimer results were established using the cut-off values indicated for VTE exclusion by the commercial D-dimer assays. Results were therefore considered positive when > 230 ng/ml for the assays expressing results as D-dimer units and > 500 ng/ml for those using fibrinogen equivalent units (FEU) as expression of results. D-dimer results were considered positive when above the mentioned cut-off values.Continuous variables are presented as median and interquartile range. The Mann-Whitney U-test and the Chi-square test (Yates corrected) were used for group comparison, as appropriate; all p values less than 0.05 were considered to indicate statistical significance. For statistical analysis the SPSS software package  and the GraphPad Software  were used.We collected the results of 527 VTE patients (“cases”), who were receiving a treatment with a DOAC. These patients had started a serial D-dimer measurement procedure to decide whether to continue or resume anticoagulation if and when D-dimer assay resulted positive. Among them, 66.8% were receiving Rivaroxaban (the first DOAC approved for this indication in our country), 19.5% Apixaban, 8.0% Dabigatran and 5.7% Edoxaban; 21/527 were treated with the corresponding low dose of DOACs. An equal number of VTE patients, receiving warfarin (“controls”), were selected by means of the matching procedure detailed in Methods section. The characteristics of the two cohorts are shown in As shown in When the results obtained at T0 (during treatment) were analyzed in details, it was found  that sigThe rates of positive D-dimer at different time-points resulted high in the small group of cases (21 subjects) treated with reduced DOAC doses . As expected, the age of these subjects was significantly higher than that of patients who received standard doses . After exclusion of the cases treated with reduced DOAC doses, the difference at T0 (during anticoagulation) between positive D-dimer rates in standard dose DOAC-treated cases and controls did not change .No differences in the rates of positive D-dimer at the different time-points were found between patients treated with once or twice per day DOAC dosing .This study investigates, for the first time, the course of D-dimer levels in patients with VTE treated with DOACs, measured during and after stopping anticoagulation. The rate of positive D-dimer assessed during anticoagulation was significantly higher in patients treated with DOACs than warfarin. After anticoagulation was stopped, the rates of positive D-dimer in the subsequent time measurements were still higher in DOACs than in warfarin, though difference reached a statistical significance only at the 30 days measurement control. While the higher prevalence of positive D-dimer during treatment with DOACs than with warfarin can be interpreted as a result of the completely different mechanism of action on coagulation balance of the two types of anticoagulant agents, more difficult is to hypothesize an explanation for the different prevalence of positive results that was detected at a later time after anticoagulation was stopped. It can be surmised that, similarly to what occurs in some warfarin-treated patients whose D-dimer measurements become positive at different time after the treatment is stopped, even in DOAC-treated patients laboratory signs of hypercoagulability may appear at a later time after treatment withdrawal, and more frequently than in warfarin-treated patients due to a putative higher baseline condition of activated coagulation. The high prevalence of positive D-dimer results among the few patients who were treated with reduced DOAC doses, was likely due to the selection of elderly patients  for the reduced dose-treatment. Focusing on results obtained during anticoagulation T0, , positivThe presence of high D-dimer plasma levels is in general considered a sign of hypercoagulability . D-dimerThe most important limitation of this study is that we do not have data about comparison of VTE recurrences according to D-dimer levels during and after stopping anticoagulant treatment, since we did not collect follow-up in patients treated with DOACs. Other important limitations are: the retrospective design, the indirect comparison with a warfarin-treated control group derived from a different study, the potential persisting effects of factors not included in the matching procedure, the imbalance between patients receiving the different DOAC drugs , the relatively not high number of examined patients, and the non-centralized D-dimer determination, that was performed in the participating centers using different commercial assays.The present study does not show any data regarding the risk of recurrent VTE after stopping anticoagulant therapy with either DOACs or warfarin according to the results of D-dimer measurements. Our results should, therefore, only be considered as hypothesis generating for specifically designed, prospective studies to assess the presence and potential clinical effects of signs of hypercoagulability during DOAC treatment in VTE patients; they also indicate that the use of D-dimer to predict the risk of VTE recurrence should be reassessed in patients treated with DOACs.


Anxiety disorders are the most common mental disorders in community settings, and they are associated with significant psychological distress, functional and social impairment. While cognitive behaviour therapy (CBT) is the most consistently efficacious psychological treatment for anxiety disorders, barriers preclude widespread implementation of CBT in primary care. Transdiagnostic group CBT (tCBT) focuses on cognitive and behavioural processes and intervention strategies common to different anxiety disorders, and could be a promising alternative to conventional CBT. This study aims to examine the effectiveness of a transdiagnostic group CBT for anxiety disorders program as a complement to treatment-as-usual (TAU) in primary mental health care.Treatment and control groups. a) tCBT ; b) TAU for anxiety disorders. Inclusion criteria comprise meeting DSM-5 criteria for primary Panic Disorder, Agoraphobia, Social Anxiety Disorder and/or Generalized Anxiety Disorder. Patients are recruited in three regions in the province of Quebec, Canada. The primary outcome measures are the self-reported Beck Anxiety Inventory and the clinician-administered Anxiety and Related Disorders Interview Schedule for DSM-5 (ADIS-5); secondary outcome measures include treatment responder status based on the ADIS-5, and self-reported instruments for specific anxiety and depression symptoms, quality of life, functioning, and service utilisation. Statistical analysis: Intention-to-treat analysis. A mixed effects regression model will be used to account for between- and within-subject variations in the analysis of the longitudinal effects of the intervention.The trial is a multicentre pragmatic randomized controlled trial with a pre-treatment, post-treatment, and follow-up at 4, 8 and 12-months design. This rigorous evaluation of tCBT in the real world will provide invaluable information to decision makers, health care managers, clinicians and patients regarding the effectiveness of the intervention. Widespread implementation of tCBT protocols in primary care could lead to better effectiveness, efficiency, access and equity for the large number of patients suffering from anxiety disorders that are currently not obtaining evidence-based psychotherapy.NCT02811458.ClinicalTrials.gov:  Anxiety disorders are the most common class of mental disorders , with a Low rates of treatment adequacy have been found for anxiety disorders in studies conducted in various countries and clinical settings –22. Whil. tCBT focuses on cognitive and behavioural processes that are shared among many disorders, as well as on common intervention strategies employed across the anxiety disorders . tCBT encompasses an overarching transdiagnostic treatment protocol rather than multiple evidence-based psychological treatment protocols that target specific anxiety disorders, which could facilitate training and supervision of psychotherapists [Transdiagnostic CBT (tCBT) is a promising intervention to improve access to evidence-based psychological treatments for patients with anxiety disorders , 36–38. erapists , 35. tCBerapists , 45. A nerapists –48. Fromerapists . tCBT grerapists , 47. Theerapists  has demoerapists , 51.Empirical data underscore the efficacy and feasibility of tCBT group approaches, which seem to be easily adaptable to the constraints of clinical settings and offer a promising solution to the challenges of comorbidity. Group tCBT should now be assessed in community-based primary mental health care, as transferability of the intervention from a specialized anxiety disorders clinic to community settings could contribute to improved access to evidence-based psychotherapy. In the context of the public mental health organization in the province of Quebec (Canada), community-based primary mental health care teams have been implemented in each administrative region since 2005 . It is iIn the present study, we aim to examine the effectiveness of group tCBT in the real world as it shows great potential to improve health outcomes for individuals with anxiety disorders. In the perspective of a pragmatic trial to examine the effectiveness of the intervention in terms of generalizability, feasibility and cost/effectiveness, we propose a comparative clinical effectiveness trial of group tCBT for anxiety disorders delivered in the primary care setting as a complement to usual care. Secondary objectives also encompass an economic evaluation as well as an embedded qualitative study to provide information to stakeholders on implementation issues.Primary question: When a group tCBT is added to TAU in primary care for a mixed group of patients with Panic Disorder, Agoraphobia, Social Anxiety Disorder and/or Generalized Anxiety Disorder, is it more effective to reduce anxiety symptoms than TAU alone? Hypothesis: Group tCBT will be more effective than TAU alone, showing the superiority of the tCBT intervention with usual care alone.The aim of the trial is to examine the effectiveness of group tCBT, as a complement to treatment-as-usual (TAU) in primary care, to reduce anxiety symptoms of adults with Panic Disorder, Agoraphobia, Social Anxiety Disorder and/or Generalized Anxiety Disorder compared to TAU. a) Considering clinically significant outcomes for patients with anxiety disorders, is there a significant difference between groups in terms of remission rates and high-end functioning rates based on a clinician-rated measure? b) Is there a significant difference between groups on functioning and quality of life? c) Is there a differential treatment effect size based on diagnostic-specific measures for subgroups of patients meeting DSM-5 criteria for specific anxiety disorders at baseline? d) Is there maintenance of gains at follow up? e) Does the severity of depressive symptoms at baseline moderate treatment effectiveness for the primary outcome measures? f) Does the presence of an antidepressant and/or benzodiazepine medication at baseline moderate treatment effectiveness for the primary outcome measures? g) Is there differential treatment effectiveness based on the principal anxiety disorder at baseline? h) Is there a differential compliance rate and treatment effect size based on gender? i) Is tCBT as a complement to TAU preferable to TAU only based on a cost-effectiveness and cost-utility analysis ? j) What are the acceptability and feasibility of the tCBT intervention for patients and therapists ?The trial is an investigator-initiated study designed as a two-arm parallel group multicentre pragmatic superiority RCT, with a 1:1 allocation at the level of the individual. The proposed trial conforms to the SPIRIT guidance for protocols of clinical trials .CIUSSS de la Capitale-Nationale) serves an urban and rural population of 737,000 inhabitants over a large territory of 18,600 KM2; the study site is in the Quebec City region (89% of the territory population). The health and social services centre for the region of Laval  serves a predominantly urban population of 435,000 inhabitants and is part of the Greater Montreal metropolitan area (over four million inhabitants). The health and social services centre for the Estrie region  serves a population of 474,000 inhabitants over a large territory of 13,000 km2; the study site is in Sherbrooke . All selected sites agreed to provide in-kind support for the study, including: 1- public sector psychologists and psychotherapists participation as co-therapists in treatment groups; 2- office space in primary care settings for participant’s assessment and treatment delivery. The institutional review boards at each site approved the protocol.The trial is being conducted in three health and social service administrative regions in the province of Québec, Canada. The network organization in Québec comprises regional integrated health and social services centres accountable for the delivery of care and services within a population responsibility framework. The universal health insurance system provides health care and social services coverage for the population. However, the organisation and delivery of mental health care varies considerably within each administrative region, and the same variability also applies to complementary mental health services available in the private sector . We purposefully selected the following three study sites based on diversity . The integrated health and social services centre for Quebec City and adjacent areas  program published by Norton 2012) . The tCB2 . The tGroups are being delivered by two psychologists or psychotherapists accredited by the provincial regulatory body for the practice of psychotherapy. Primary therapists are PhD level private practice psychologists with a CBT approach and at least 2 years of clinical experience to ensure basic CBT competence for treatment fidelity. In a pragmatic perspective on treatment delivery, the co-therapists are selected by the health care managers at each study site (in-kind contribution) to reflect the range of clinical backgrounds of therapists working in the public sector in Québec. The training of co-therapists also supports capacity building and mentorship in tCBT in public sector mental health care services. Therapists’ training was initially provided during a centralized two-day workshop with the tCBT protocol developer (PJN), and followed by ongoing supervision by investigators . In the event of the need to recruit more therapists after the initial training session, tailored individual training are provided to therapists (MDP). Supervision  is provided to co-therapists at predefined times during the delivery of the intervention , as well as as-needed. Fidelity to the tCBT program is monitored through the recording of all treatment sessions. Therapeutic treatment adherence and competence is assessed by a random review of 30% of audio recordings during all sessions with a 5-point treatment integrity rating scale developed by the author of the intervention (PJN)  and usedThe TAU control group continues receiving usual care as a comparator. For this pragmatic clinical trial, no restrictions are imposed upon participation regarding having a family physician or treatment of mental disorders, as we are interested in comparing the added value of tCBT in real world conditions. Service utilization is being documented at each assessment period throughout the trial. As in other pragmatic trials, it should be noted that participation in the study may be associated with uncontrolled variations in mental health care seeking among patients for several reasons .A description of patient assessment timeline is presented in Table Anxiety and Related Disorders Interview Schedule for DSM-5 (ADIS-5) [The (ADIS-5)  is a sem(ADIS-5)  for the (ADIS-5) . InterraWorld Health Organization Health and Work Performance Questionnaire (HPQ) [The initial interview also comprises a clinician-administered questionnaire on sociodemographic data, and a brief structured interview on health care costs used in previous studies  to obtaire (HPQ) .Beck Anxiety Inventory (BAI) [minimal anxiety (0–7), mild anxiety (8–15), moderate anxiety (16–25) and severe anxiety (26–63). Previous studies have established significant reliable improvement and clinically significant change cut-points for the BAI based on normative data and comparable samples of multiple anxiety disorders [CSR of the ADIS-5 for the principal anxiety disorder. Previous studies have used the ADIS-5 as a primary outcome measure for mixed anxiety disorders  , 62. Thexiety 26–. Previous .high end-state functioning as a post-treatment CSR of “2” or lower and treatment responder status as a post-treatment CSR < 4.As secondary outcome measures with the ADIS-5, we will examine Social Phobia Inventory (SPIN) [Penn State Worry Questionnaire (PSWQ) [Panic Disorder Severity Scale Self Report (PDSS-SR) [Mobility Inventory for Agoraphobia (MIA) [Patient Health Questionnaire (PHQ-9) [Insomnia Severity Index [Sheehan Disability Scale [EuroQoL EQ-5D [Centers for Disease Control Healthy Days Measures (CDC HRQOL-4) [Disease Burden Morbidity Assessment [Mental Health Continuum Short Form (MHC-SF) [Mental Health Self-Management Questionnaire (MHSQ) [Medical Outcomes Study Social Support Survey (MOS-SSS) [Participants also complete diagnostic-specific measures, quality of life and functioning measures, as well as other questionnaires related to anxiety disorders. The y (SPIN) , 66 consy (SPIN) . The Pene (PSWQ) , 68 is aPDSS-SR) , 70 asksia (MIA)  assessesia (MIA) . The Pat (PHQ-9)  is used ty Index , 74 is aty Scale  is a meaoL EQ-5D  is a 5-iHRQOL-4)  includessessment , 79 was (MHC-SF)  consistse (MHSQ)  assessesMOS-SSS) , 83 is aAnxiety Disorder Diagnostic Questionnaire - weekly (ADDQ-W) [Working Alliance Inventory (WAI) to assess the quality of the therapeutic relationship [Credibility Expectancy Questionnaire [Gross Cohesion Scale (GCS) [At the onset of each session, participants complete the (ADDQ-W) , a versi(ADDQ-W)  for sesstionship , 87. Thetionship . After sionnaire  which asle (GCS) , a 9-iteFor each participant, the therapists record the following information after each session: presence, homework completion, participation level, and clinical observations. The logbook content provides a better understanding of therapists’ experience, add to the evaluation of therapeutic integrity, and contribute to the optimization of the program for future large-scale implementation of tCBT. The therapists also complete a brief questionnaire comprising sociodemographic questions, items on academic and professional backgrounds, as well as experience with CBT, group therapy and treatment of anxiety disorders.Régie de l’assurance-maladie du Québec (RAMQ) for medical services, hospitalization’s registry, and medication data) after the 12 month follow-up (T4).Health care utilization data will be obtained retrospectively from provincial administrative databases  of 0.45 at T1, according to previous studies [It was not feasible to estimate the sample size required for a mixed regression model as current guidelines are only generalizable to particular data conditions and model structures . Therefo studies , 92, 93. studies . A samplWith an estimated 15% rate of loss at follow up factored in, the proposed final sample size is thus 215 patients in total (107 and 108 for each arm respectively). Such sample size will give us sufficient power to detect differences in the primary outcomes from a longitudinal perspective.As shown in Fig. Generalised Anxiety Disorder-7 (GAD-7) [Patient Health Questionnaire (PHQ-2) [CAGE , a widely used screening instrument [0).Filter 1: We advertise the study in the general population and primary care settings through the following strategies: 1- publicity in regional newspapers; 2- targeted ads to geographic locations with Facebook and Google AdWords; 3- advertisement posters on bulletin boards of medical clinics and pharmacies, via targeted mass mail-out including a letter from the research team and a recruitment poster; 4- convenience advertisement from the research team in diverse public locations. Self-referred individuals then acquire further information on the study by consulting the study’s website or through a telephone call or email to research coordinator (AB). Self-referred individuals have to complete a brief online survey with LimeSurvey that they access through the study’s website. The screening survey contains basic eligibility criteria as well as anxiety symptoms and comorbidity overview. The survey includes the  (GAD-7) , a brief (GAD-7) , 96. The (PHQ-2) , a very  (PHQ-2) . The itestrument , 99. It strument . General0; random pre-assignment) is conducted in person and comprises completion of the consent form, the administration of the ADIS-5 and the questionnaire on sociodemographic data, health care costs, medication and work performance by a trained PhD level evaluator. Patients meeting eligibility criteria are given a participant’s booklet with the self-reported questionnaires and a stamped envelope to return the questionnaires to the research team within 48 h, and only then do we have all required information to proceed with randomization. The same booklet is being used at T1, T2, T3 and T4. The follow-up assessments take place at post-treatment , 4 months , 8 months  and 12 months  follow-up.Data collection is managed independently of the treatment assignment by interviewers who are blind to the participant’s treatment assignment. The initial assessment  are offered to participants for each in-person assessment. The group tCBT intervention is also offered to participants in the TAU group at the 12-month follow up to increase perceived health benefits associated with the trial.Randomization is at the patient level. Contamination is unlikely because specific CBT treatments for anxiety disorders are rarely available in primary care in our health care context. To ensure that comparable groups are obtained, stratification based on site is implemented. To ensure a balance in the allocation for the strata and thus eliminate the risk of a secular trend in the composition of groups, blocks of four are used. This strategy also helps to avoid differences in the composition of the two groups, in the event of changes in clinical characteristics of those involved in the study over time. Randomization is being carried out using a code generated by a statistical software (manages the stratification and blocks) with a ratio of 1:1, set up by an independent statistician who is not be involved in the recruitment.Allocation concealment is ensured by an online computer tool for clinical trials (PIERCE) that only releases the randomization code to the principal investigator (PR) after the baseline assessment is completed. Upon review of data entry on the PIERCE computer tool from research coordinator and clinical evaluators concerning inclusion and exclusion criteria, written informed consent, agreement to accept the randomly assigned treatment and returned participant’s questionnaire booklet, a computer command allows release of the randomization code (PR). Each member of the team  has his or her own access code to the PIERCE system, designed with several access layers, and the randomization module is only accessible to the principal investigator (PR). She informs the research coordinator of each treatment assignment based on the allocation sequence, and the treatment allocation is be communicated to participants by telephone within 2 weeks after the initial clinical interview and reception of the booklet.Blinding of trial participants and therapists is not possible in this trial. Concealment of the treatment allocation is maintained for the clinical evaluators, research team and data analyst, with the exception of the research coordinator. Participants are asked not to discuss group participation with clinical evaluators. The randomization sequence will not be broken in the data set, with random codes (“A” and “B”), until the analyses for the primary outcomes are completed. The sequence for a specific participant will be broken in case of an incident if requested by the independent Data Safety and Monitoring Committee (DSMC).0, T1, T3) by trained PhD level evaluators at the three sites or by telephone  by the research coordinator (AB). The evaluators received a one-day training on the ADIS-5 as well as additional training to ensure optimal data collection . Regular supervision  is provided to clinical evaluators throughout the duration of the data collection, particularly regarding the ADIS-5 assessments. For the post-treatment and follow-up assessments, participants also receive a letter by mail reminding them of the upcoming clinical evaluation, including a booklet with a stamped envelope. The research coordinator manages contacts with participants for scheduling assessments.The clinical assessment of participants is conducted in person  at Université de Sherbrooke on a secure server with systematic backups. Double data entry is being conducted for 10% of patient questionnaires throughout the trial to promote data quality, and data entry is under the responsibility of a trained research assistant.The primary means to avoid bias include the randomization scheme; the masked data collection by clinical evaluators who enrol and evaluate participants throughout the project while being uninformed of treatment assignment (with an incident report and reassignment procedure if they become unmasked); the masked research hypotheses for participants.Statistical analysis of the data will follow intention-to-treat principles , i.e. “1Our pragmatic clinical trial will deliver important data to patients, clinicians, health care managers and decision makers to inform the implementation of optimal mental health services in real-world practice with clinically relevant outcomes. There is a major gap between knowledge and practice with regards to evidence-based psychotherapy for anxiety disorders, and a dissemination priority should be CBT, for which there is a substantial evidence base. While numerous studies have examined quality improvement approaches for the primary care management of depression, anxiety disorders have received limited attention. tCBT is a promising intervention for the large-scale implementation of CBT to improve access to evidence-based psychological treatments for patients with mixed anxiety disorders. In this pragmatic trial, we aim at examining the relative effectiveness of tCBT as a complement to usual care in the real world from a primary mental health care standpoint to generate evidence useful for decision-makers in the implementation of change in routine clinical practice for anxiety disorders. Currently, there is positive momentum to influence the organization of services given the resources invested in strengthening primary mental health care and the imperative to improve access to psychotherapy. A pragmatic trial of group tCBT will help to guide decision makers, managers and clinicians who are entrusted to develop mental health policies and implement mental health services. Among strengths of our pragmatic trial, the study will be rooted in the current reality of primary mental health care with a large sample of patients characteristic of primary care, for instance with multiple anxiety disorders, comorbid depression or concomitant pharmacological treatments. We will balance fidelity and pragmatism of treatment delivery with co-therapists that come from primary mental health care as well as CBT experts. The choice of usual care as a comparator will provide a better estimate of CBT effect size than a waiting-list condition , with noPatient enrolment began on September 12th 2016 and was completed February 19th 2018. The final treatment group is planned for completion in May 2018.


We report the case of a 3-year-old boy who presented with an upper respiratory tract infection and severe dyspnea. A chest X-ray revealed a left-sided tension pneumothorax with mediastinal shift and suspected enterothorax. After thoracic computed tomography (CT) scan, a chest tube was inserted, which drained fluid which had the same consistency and color as the one derived from the nasogastric (NG) tube. The boy underwent diagnostic laparoscopy for suspected bowel perforation, which confirmed a left-sided Bochdalek hernia with herniation of the viscera into the chest. After repositioning of the herniated organs into the abdomen, a gastric perforation was identified and repaired. This case demonstrates that the cause of a tension pneumothorax in an infant may be a rare combination of congenital diaphragmatic hernia (CDH) and perforation of a visceral hollow organ. Congenital diaphragmatic hernia (CDH) is a birth defect of the diaphragm caused by an insufficient closure of the pleuroperitoneal canal during fetal development.However, children with small defects may be asymptomatic postnatally and present later in life, when an increased intra-abdominal pressure facilitates herniation of organs into the chest.A 3-year-old boy presented to an outside hospital with a 5-day history of progressing respiratory distress and retching. The initial chest X-ray showed a left-sided tension pneumothorax with mediastinal shift and the suspicion of bowel loops in the left lower hemithorax . TherefOn admission, he showed severe dyspnea, a temperature of 39.5°C and tachycardia of 200/min. After immediate endotracheal intubation, a thoracic computed tomography (CT) scan was performed, which confirmed a left-sided enterothorax with mediastinal shift . A leftIntestinal symptoms of late presenting CDH can be nonspecific and may include abdominal pain or respiratory symptoms.Unusual in our case was the clinical presentation with tension pneumothorax, which has been described before; Ozkan et alCDH may be asymptomatic at birth and may present at a later age. The herniation of the viscera into the chest leads to respiratory symptoms. In case of both, enterothorax and tension pneumothorax, a gastric or bowel perforation in combination with CDH must be taken into consideration.