OBJECTIVE: To categorize, quantify and interpret findings documented in feedback letters of monitoring or auditing visits for an investigator-initiated, peer-review funded multicenter randomized trial testing probiotics for critically ill patients.
METHODS: In 37 Canadian centers, monitoring and auditing visits were performed by 3 trained individuals; findings were reported in feedback letters. At trial termination, we performed duplicate content analysis on letters, categorizing observations first into unique findings, followed by 10 pre-determined trial quality management domains. We further classified each observation into a) missing operational records, b) errors in process, and potential threats to c) data integrity, d) patient privacy or e) safety.
RESULTS: Across 37 monitoring or auditing visits, 75 unique findings were categorized into 10 domains. Most frequently, observations were in domains of training documentation (180/566 [32%]) and the informed consent process (133/566 [23%]). Most observations were missing operational records (438/566 [77%]) rather than errors in process (128/566 [23%]). Of 75 findings, 13 (62/566 observations [11%]) posed a potential threat to data integrity, 1 (1/566 observation [0.18%]) to patient privacy, and 9 (49/566 observations [8.7%]) to patient safety.
CONCLUSIONS: Monitoring and auditing findings predominantly concerned missing documentation with minimal threats to data integrity, patient privacy or safety.
BACKGROUND: PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial): NCT02462590.

In randomized trials with continuous-valued outcomes, the goal is often to estimate the difference in average outcomes between two treatment groups. However, the outcome in some trials is longitudinal, meaning that multiple measurements of the same outcome are taken over time for each subject. The target of inference in this case is often still the difference in averages at a given timepoint. One way to analyze these data is to ignore the measurements at intermediate timepoints and proceed with a standard covariate-adjusted analysis (e.g., ANCOVA) with the complete cases. However, it is generally thought that exploiting information from intermediate timepoints using mixed models for repeated measures (MMRM) (a) increases power and (b) more naturally \"handles\" missing data. Here, we prove that neither of these conclusions is entirely correct when baseline covariates are adjusted for without including time-by-covariate interactions. We back these claims up with simulations. MMRM provides benefits over complete-cases ANCOVA in many cases, but covariate-time interaction terms should always be included to guarantee the best results.

The objective was to evaluate whether including pregnant women in a preventive dental program prevented the appearance of caries in their children up to the age of 6, and whether the effect was similar in children of immigrant and non-immigrant women. In phase I, 90 pregnant women, 45 immigrants and 45 natives, were taught about the development and prevention of caries. In phase II the oral health of their children at the age of 6 (n = 90) was evaluated, along with a control group of children of natives and immigrants of the same age (n = 90). A survey was used to determine participants\' backgrounds and habits. A multivariate study of the results was performed using R-core software. The number of children without caries was 128 (71.1%), whereas 52 (28.9%) had caries, 15 from the protocol (16.67%) and 37 from the control group (41.11%), with statistically significant differences (p < 0.001). The mean number of caries for the children in the protocol was 0.62 ± 2 and in the control group it was 1.88 ± 2.9 (p = 0.001). In the multivariate analysis the risk of developing caries was higher for the condition of being the child of an immigrant (OR = 11.137), inadequate oral health (OR = 4.993), the children being overweight at the age of 6 (OR = 10.680), and the consumption of candies (OR = 5.042). In conclusion, the preventive protocols started during pregnancy reduced caries in participants\' children, which suggests that these protocols should be encouraged. Because immigrant children are more vulnerable to caries, they and their parents should be included in preventive programs once they arrive in the host country.

OBJECTIVE: 1. To compare the effectiveness of four different surveillance strategies in detecting COVID-19 within the homeless shelter population. 2. To assess the participant adherence over time for each surveillance method.
METHODS: This is a prospective cluster-randomized study to compare the effectiveness of four different surveillance regimens across eight homeless shelters in the city of Hamilton.
METHODS: Participants will include both residents of, and the staff working within, the homeless shelters. All participants aged 18 or older who consent to the study and are able to collect a swab sample (where relevant) are eligible for the study. The study will take place across eight homeless shelters (four men-only and four women-only) in the City of Hamilton in Ontario, Canada.
UNASSIGNED: The comparator group will receive active daily surveillance of symptoms and testing will only be completed in symptomatic participants (i.e. those who fail screening or who seek care for potential COVID-19 related symptoms). The three intervention arms will all receive active daily surveillance of symptoms and testing of symptomatic participants (as in the comparator group) in addition to one of the following: 1. Once weekly self-collected oral swabs (OS) regardless of symptoms using written and visual instructions. 2. Once weekly self-collected oral-nares swab (O-NS) regardless of symptoms using written and visual instructions. 3. Once weekly nurse collected nasopharyngeal swab (NPS) regardless of symptoms. Participants will follow verbal and written instructions for the collection of OS and O-NS specimens. For OS collection, participants are instructed to first moisten the swab on their tongue, insert the swab between the cheek and the lower gums and rotate the swab three times. This is repeated on the other side. For O-NS collection, after oral collection, the swab is inserted comfortably (about 2-3 cm) into one nostril, parallel to the floor and turned three times, then repeated in the other nostril. NPS specimens were collected by the nurse following standard of care procedure. All swabs were placed into a viral inactivation medium and transported to the laboratory for COVID-19 testing. Briefly, total nucleic acid was extracted from specimens and then amplified by RT-PCR for the UTR and Envelope genes of SARS-CoV-2 and the human RNase P gene, which is used as a sample adequacy marker.
RESULTS: 1.
METHODS: COVID-19 detection rate, i.e. the number of new positive cases over the study period of 8 weeks in each arm of the study. 2.
RESULTS: Qualitative assessment of study enrollment over 8 weeks. Percentage of participants who performed 50% or more of the weekly swabs in the intervention arms in the 8 week study period.
UNASSIGNED: We will use a computer-generated random assignment list to randomize the shelters to one of four interventions. Shelters were stratified by gender, and the simple randomization scheme was applied within each stratum. The randomization scheme was created using WinPEPI.
UNASSIGNED: This is an open-label study in which neither participants nor assessors are blinded.
UNASSIGNED: Since we are including our total sample frame, a sample size estimation at the cluster level is not required. However, if we succeed to enroll 50 participants per shelter from 8 shelters (n=400), and the detection rate is 3 times higher in the intervention groups (0.15) than in the comparator groups (0.05), we will have 90% power to detect a statistically significant and clinically important difference at a type I error rate of alpha=0.05 (one tailed), assuming an intraclass correlation of ~0.008. These computations were done using WinPEPI, and informed by conservative estimates from other studies on respiratory illness in the homeless (see Full protocol).
UNASSIGNED: The protocol version number is 3.0. Recruitment began on April 17, 2020 and is ongoing. Due to low numbers of COVID cases in the community and shelter system during the initial study period, the trial was extended. The estimated date for the end of the extended recruitment period is Feb 1, 2021.
BACKGROUND: The trial was registered with ClinicalTrials.gov on June 18, 2020 with the identifier NCT04438070 .
UNASSIGNED: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

UNASSIGNED: In their research reports, scientists are expected to discuss limitations that their studies have. Previous research showed that often, such discussion is absent. Also, many journals emphasize the importance of avoiding overstatement of claims. We wanted to see to what extent editorial handling and peer review affects self-acknowledgment of limitations and hedging of claims.
UNASSIGNED: Using software that automatically detects limitation-acknowledging sentences and calculates the level of hedging in sentences, we compared the submitted manuscripts and their ultimate publications of all randomized trials published in 2015 in 27 BioMed Central (BMC) journals and BMJ Open. We used mixed linear and logistic regression models, accounting for clustering of manuscript-publication pairs within journals, to quantify before-after changes in the mean numbers of limitation-acknowledging sentences, in the probability that a manuscript with zero self-acknowledged limitations ended up as a publication with at least one and in hedging scores.
UNASSIGNED: Four hundred forty-six manuscript-publication pairs were analyzed. The median number of manuscripts per journal was 10.5 (interquartile range 6-18). The average number of distinct limitation sentences increased by 1.39 (95% CI 1.09-1.76), from 2.48 in manuscripts to 3.87 in publications. Two hundred two manuscripts (45.3%) did not mention any limitations. Sixty-three (31%, 95% CI 25-38) of these mentioned at least one after peer review. Changes in mean hedging scores were negligible.
UNASSIGNED: Our findings support the idea that editorial handling and peer review lead to more self-acknowledgment of study limitations, but not to changes in linguistic nuance.

BACKGROUND: Personalizing medical care is becoming increasingly popular, particularly mental health care. There is growing interest in formalizing medical decision making based on evolving patient symptoms in an evidence-based manner. To determine optimal sequencing of treatments, the sequences themselves must be studied; this may be accomplished by using a sequential multiple assignment randomized trial (SMART). It has been hypothesized that SMART studies may improve participant retention and generalizability.
METHODS: We examine the hypotheses that SMART studies are more generalizable and have better retention than traditional randomized clinical trials via a case study of a SMART study of antipsychotic medications. We considered the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, comparing the trial participant characteristics and overall retention to those of comparable trials found via a review of all related trials conducted from 2000 onwards.
RESULTS: A MEDLINE search returned 6435 results for primary screening; ultimately, 48 distinct trials were retained for analysis. The study population in CATIE was similar to, although perhaps less symptomatic than, the study populations of traditional randomized clinical trials (RCTs), suggesting no large gains in generalizability despite the pragmatic nature of the trial. However, CATIE did see good month-by-month retention.
CONCLUSIONS: SMARTs offer the possibility of studying treatment sequences in a way that a series of traditional RCTs cannot. SMARTs may offer improved retention; however, this case study did not find evidence to suggest greater generalizability using this trial design.
BACKGROUND: ClinicalTrials.gov NCT00014001 . Registered on 6 April 2001.

With the advent of targeted agents, randomized phase II trials designed with explicit comparative intent, to allow a better interpretation of the results obtained with experimental treatment, have become a common approach for anti-cancer drug development. In the Cancer and Leukemia Group B (CALGB) 30504 randomized phase II trial, patients with extensive-stage small-cell lung cancer (SCLC), without progression after four to six cycles of standard chemotherapy with cisplatin or carboplatin plus etoposide, were randomized to sunitinib or placebo, until disease progression. Primary endpoint of the study was progression-free survival (PFS), and the results were formally positive [hazard ratio (HR) 0.62; one-sided P=0.02]. However, the prognosis of patients with extensive-stage SCLC is particularly bad, and even a relevant relative benefit (i.e., an encouraging HR) will likely correspond to a debatable absolute benefit: the difference in median PFS between patients treated with sunitinib and patients assigned to control arm was slightly higher than 1.5 months. Is this difference in median PFS big enough to predict a clinically relevant benefit in overall survival? Unfortunately, we do not know. From a \"clinical\" point of view, is this small absolute improvement in PFS relevant enough to further invest in the strategy? Probably not, also considering the absence of known predictive factors. If the results of the phase II trial had been really promising, the subsequent phase III study should have been promptly conducted, but this was not the case. It seems that, this time, the bar for enthusiasm was already raised in the phase II setting.

OBJECTIVE: To evaluate the effect of important trials on the practice of neurosurgery.
METHODS: We hypothesized that evidence from trials addressing the management of intracranial aneurysms (International Subarachnoid Aneurysm Trial [ISAT]) and nontraumatic intracerebral hemorrhages (Surgical Trial in Intracerebral Hemorrhage [STICH]) and vertebral augmentation for osteoporotic vertebral body fractures had a significant impact on the frequency of the corresponding neurosurgical procedures. A Medicare administrative database was queried for corresponding Common Procedural Terminology codes and units billed per calendar year. The effects of ISAT and STICH were evaluated using a generalized linear model. The effect of the vertebral augmentation study was evaluated using a t test.
RESULTS: After publication of ISAT in 2002, the rate of increase in proportion of cerebral aneurysms that were treated with embolization (Common Procedural Terminology code 61624) per year increased from 3.9% to 5.5% (P = 0.01). After publication of STICH in 2005, the number of craniotomies performed for intracerebral hematoma decreased from 2341 in 2002 to 1646 in 2011 (P = 0.03). After 2 publications in 2009, performance of vertebral augmentation decreased from a high of 99,961 in 2009 per year to 77,108 in 2013 (P = 0.002).
CONCLUSIONS: Randomized clinical trials remain the gold standard in the medical community to demonstrate efficacy, but their true impact relies on rapid and extensive assimilation into everyday medical practice. However, the described methodology establishes a temporal relationship only and does not prove causation. Nonetheless, trends in procedural volume suggest that the results of these select randomized clinical trials had a significant effect on neurosurgical practice affecting Medicare patients within an interval of a few years.

BACKGROUND: Obtaining accurate information about gastrointestinal (GI) symptoms is critical to achieving the goals of clinical research and practice. The accuracy of patient data is especially important for functional GI disorders (e.g., IBS) whose symptoms lack a biomarker and index illness severity and treatment response. Retrospective patient-reported data are vulnerable to forgetting and various cognitive biases whose impact has not been systematically studied in patients with GI disorders. The aim of this study was to document the accuracy of patient-reported GI symptoms over a reporting period (1 week) most representative of the time frame used in research and clinical care.
METHODS: Subjects were 273 Rome III-diagnosed IBS patients (mean age = 39 years, 89% F) who completed end of day GI symptom ratings for 7 days using an electronic diary. On Day 8, Subjects recalled the frequency and/or intensity of IBS symptoms over the past 7 days. Reports were then compared against a validation criterion based on aggregated end of day ratings.
RESULTS: At the group level, subjects recalled most accurately abdominal pain and urgency intensity at their worst, urgency days, and stool frequency. When data were analyzed at the individual level, a subgroup of subjects had difficulty recalling accurately symptoms that showed convergence between recall and real time reports at the group level.
CONCLUSIONS: Although many patients\' recollection for specific GI symptoms (e.g., worst pain, stool frequency) is reasonably accurate, a non-trivial number of other symptoms (e.g., typical pain) are vulnerable to distortion from recall biases that can reduce sensitivity of detecting treatment effects in clinical and research settings.