Development of a risk-tailored approach and dashboard for efficient management and monitoring of investigator-initiated trials.

BACKGROUND: Most randomized controlled trials (RCTs) in the academic setting have limited resources for clinical trial management and monitoring. Inefficient conduct of trials was identified as an important source of waste even in well-designed studies. Thoroughly identifying trial-specific risks to enable focussing of monitoring and management efforts on these critical areas during trial conduct may allow for the timely initiation of corrective action and to improve the efficiency of trial conduct. We developed a risk-tailored approach with an initial risk assessment of an individual trial that informs the compilation of monitoring and management procedures in a trial dashboard. METHODS: We performed a literature review to identify risk indicators and trial monitoring approaches followed by a contextual analysis involving local, national and international stakeholders. Based on this work we developed a risk-tailored management approach with integrated monitoring for RCTs and including a visualizing trial dashboard. We piloted the approach and refined it in an iterative process based on feedback from stakeholders and performed formal user testing with investigators and staff of two clinical trials. RESULTS: The developed risk assessment comprises four domains (patient safety and rights, overall trial management, intervention management, trial data). An accompanying manual provides rationales and detailed instructions for the risk assessment. We programmed two trial dashboards tailored to one medical and one surgical RCT to manage identified trial risks based on daily exports of accumulating trial data. We made the code for a generic dashboard available on GitHub that can be adapted to individual trials. CONCLUSIONS: The presented trial management approach with integrated monitoring enables user-friendly, continuous checking of critical elements of trial conduct to support trial teams in the academic setting. Further work is needed in order to show effectiveness of the dashboard in terms of safe trial conduct and successful completion of clinical trials.

Scoping review and characteristics of publicly available checklists for assessing clinical trial feasibility.

BACKGROUND: Whether there is sufficient capacity and capability for the successful conduct and delivery of a clinical trial should be assessed by several stakeholders according to transparent and evidence-based criteria during trial planning. For this openly shared, user-tested, and validated tools are necessary. Therefore, we systematically examined the public availability and content of checklists which assess the study-level feasibility in the planning phase of clinical trials. METHODS: In our scoping review we systematically searched Medline, EMBASE, and Google (last search, June 2021). We included all publicly available checklists or tools that assessed study level feasibility of clinical trials, examined their content, and checked whether they were user-tested or validated in any form. Data was analysed and synthesised using conventional content analysis. RESULTS: A total of 10 publicly available checklists from five countries were identified. The checklists included 48 distinct items that were classified according to the following seven different domains of clinical trial feasibility: regulation, review and oversight; participant recruitment; space, material and equipment; financial resources; trial team resources; trial management; and pilot or feasibility studies. None of the available checklists appeared to be user-tested or validated. CONCLUSIONS: Although a number of publicly available checklists to assess the feasibility of clinical trials exist, their reliability and usefulness remain unclear. Openly shared, user-tested, and validated feasibility assessment tools for a better planning of clinical trials are lacking.

The role of Clinical Trial Units in investigator- and industry-initiated research projects.

Six multidisciplinary competence centres (Clinical Trial Units, CTUs) in Basel, Berne, Geneva, Lausanne, St. Gallen and Zurich provide professional support to clinical researchers in the planning, implementation, conduct and evaluation of clinical studies. Through their coordinated network, these units promote high-quality, nationally harmonised and internationally standardised clinical research conduct in Switzerland. We will describe why this network has been established, how it has been successful in stilling the growing need for clinical research support, which training and education opportunities it offers, and how it created national awareness for the still-existing hurdles towards clinical research excellence in Switzerland. Taking the CTU Basel as an example, we show that a considerable number (25%) of the studies submitted for regulatory approval in 2013 were supported by the CTU, decreasing the number of findings in ethics reviews by about one-third. We conclude that these achievements, together with a Swiss national funding model for clinical research, and improved national coordination, will be critical factors to successfully position Swiss clinical research at the international forefront.

The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study.

OBJECTIVES: Ketamine is a well-known analgesic and dose-dependent anesthetic used in emergency and disaster medicine. Recently, a new formulation of S-ketamine, as an intranasal spray, was developed and tested in our institution in healthy volunteers. The authors investigated the effect of intranasal S-ketamine spray combined with midazolam intranasal spray in postoperative spinal surgery patients. MATERIALS AND METHODS: In this prospective, computer-randomized, double-blinded noninferiority study in spinal surgery patients, the effects of intranasal S-ketamine and midazolam were compared with standard morphine patient-controlled analgesia (PCA). The primary end point was the numeric rating scale pain score 24 hours after surgery. RESULTS: Twenty-two patients finished this study, eleven in each group. There were similar numeric rating scale scores in the morphine PCA and the S-ketamine-PCA groups at 1, 2, 4, 24, 48, and 72 hours after surgery during rest as well as in motion. There were no differences in the satisfaction scores at any time between the groups. The number of bolus demands and deliveries was not significantly different. DISCUSSION: In our study, we found that an S-ketamine intranasal spray combined with intra-nasal midazolam was similar in effectiveness, satisfaction, number of demands/deliveries of S-ketamine and morphine, and number/severity of adverse events compared with standard intravenous PCA with morphine. S-ketamine can be regarded as an effective alternative for a traditional intravenous morphine PCA in the postoperative setting.

Biplanar MRI for the assessment of the spinal cord in multiple sclerosis.

OBJECTIVE: To investigate the entire spinal cord (SC) of multiple sclerosis (MS) patients with biplanar MRI and to relate these MRI findings to clinical functional scores. METHODS: Two hundred and two patients (140 women, 62 men 24-74 years, Expanded Disability Status Scale (EDSS) scores 0-7.5) were investigated clinically and with biplanar MRI. Sagittal and axial proton density weighted (PDw) and T2 weighted (T2w) images of the whole SC were obtained employing parallel imaging. Data were analyzed by consensus reading using a standardized reporting scheme. Different combinations of findings were compared to EDSS scores with Spearman's rank correlation coefficient (ρ). RESULTS: The combined analysis of sagittal and axial planes demonstrated slightly differing results in 97/202 (48%) patients. There were 9% additional lesions identified, leading to a higher lesion count in 28% of these patients, but also rejection of equivocal abnormality leading to a lower lesion count in 11% of patients. Considering both sagittal and axial images, SC abnormalities were found in 167/202 (83%) patients. When compared with EDSS scores, the combination of focal lesions, signs of atrophy and diffuse abnormalities showed a moderate correlation (ρ=0.52), that precludes its use for individual patient assessment. CONCLUSION: Biplanar MRI facilitates a comprehensive identification, localization, and grading of pathological SC findings in MS patients. This improves the confidence and utility of SC imaging.

Converging seasonal prevalence dynamics in experimental epidemics.

BACKGROUND: Regular seasonal changes in prevalence of infectious diseases are often observed in nature, but the mechanisms are rarely understood. Empirical tests aiming at a better understanding of seasonal prevalence patterns are not feasible for most diseases and thus are widely lacking. Here, we set out to study experimentally the seasonal prevalence in an aquatic host-parasite system. The microsporidian parasite Hamiltosporidium tvärminnensis exhibits pronounced seasonality in natural rock pool populations of its host, Daphnia magna with a regular increase of prevalence during summer and a decrease during winter. An earlier study was, however, unable to test if different starting conditions (initial prevalence) influence the dynamics of the disease in the long term. Here, we aim at testing how the starting prevalence affects the regular prevalence changes over a 4-year period in experimental populations. RESULTS: In an outdoor experiment, populations were set up to include the extremes of the prevalence spectrum observed in natural populations: 5% initial prevalence mimicking a newly invading parasite, 100% mimicking a rock pool population founded by infected hosts only, and 50% prevalence which is commonly observed in natural populations in spring. The parasite exhibited similar prevalence changes in all treatments, but seasonal patterns in the 100% treatment differed significantly from those in the 5% and 50% treatments. Populations started with 5% and 50% prevalence exhibited strong and regular seasonality already in the first year. In contrast, the amplitude of changes in the 100% treatment was low throughout the experiment demonstrating the long-lasting effect of initial conditions on prevalence dynamics. CONCLUSIONS: Our study shows that the time needed to approach the seasonal changes in prevalence depends strongly on the initial prevalence. Because individual D. magna populations in this rock pool metapopulation are mostly short lived, only few populations might ever reach a point where the initial conditions are not visible anymore.

Statistical model for postoperative apnea-hypopnea index after multilevel surgery for sleep-disordered breathing.

The objective of the study was to formulate a statistical model for postoperative apnea-hypopnea index (AHI) 3 and 12 months after multilevel surgery using the predictors preoperative AHI, body mass index (BMI) and age. The study design was a prospective cohort study. Data of 144 patients were collected prospectively 3 and 12 months after multilevel surgery for obstructive sleep apnea syndrome (OSAS) or upper airway resistance syndrome with excessive daytime sleepiness. The primary endpoint postoperative AHI and the secondary endpoint success according to the Sher criteria (postoperative AHI <20 h and >50% reduction of preoperative AHI) were modeled with multiple linear and logistic regression using the predictors preoperative AHI, BMI, age and the indicator whether the patient had undergone a tonsillectomy. Preoperative AHI and tonsillectomy had a highly significant positive influence on postoperative AHI after 3 months, whereas the influence of preoperative BMI was only marginally significant but numerically rather large. Age was not a significant decisive factor. The success according to the Sher criteria was highly significantly determined by the circumstance whether the patient had undergone a tonsillectomy, but not by the other predictors preoperative BMI or age. The responder rate with and without tonsillectomy was 58 and 19%, respectively. The odds ratio to be a responder if a tonsillectomy was conducted was 5.7. This study provides statistical models predicting postoperative AHI and success according to the Sher criteria after multilevel surgery for OSAS.

Quality assessment of a randomly selected sample of Swiss medical expertises--a pilot study.

BACKGROUND: Considerable criticism has lately been raised by the media regarding the quality of Swiss medical expertises. The present investigation was therefore undertaken to assess the professional quality of Swiss medical expertises. The study was part of a market analysis of medical expertises (MGS study). METHODS: A sample of 97 anonymised expertises randomly chosen from a total of 3165, collected in the MGS study over a period of 3 months, were evaluated by an international board of medical experts and reviewers, using a stepwise developed questionnaire. Each expertise was independently evaluated by two experts. Data were then tested for plausibility (obvious errors and misunderstandings). The main outcome was the overall quality rating of the expertise that was graded from 1 (very poor) to 6 (excellent) in analogy to the Swiss school grading system. For analysis and interpretation the grades were divided into sufficient (grades >= 4) and insufficient (grades <4). RESULTS: Overall 19.6% (95% confidence interval: 13.1%; 28.3%) of the expertises were rated to be of insufficient quality. The quality was inversely related to the number of involved medical disciplines, the time relapsed since injury and positively related to the difficulty of the expertise. In addition, expertises in the French and Italian languages were rated superior to those in German. CONCLUSION: Our results confirm recent criticisms that the professional quality of expertises does not suffice. This is hardly acceptable in face of the financial and personal consequences. There is an obvious need for further research using larger samples and for educational programmes on all levels.

Dose calculation in opioid rotation: electronic calculator vs. manual calculation.

OBJECTIVE: To generate, validate and establish a web-based individualised opioid conversion calculator at the University Hospital Basel and to analyse its value and significance. SETTING: A 700-bed university hospital. METHOD: Published data were screened by a Medline search using the keywords: opioid, rotation, switching, potency and dose ratio. Based on this data, the criteria for the conversion calculator were defined. A prospective process validation was performed prior to the approval. Five months after the introduction of the tool, an online survey was performed in order to evaluate its acceptance by users. In the last step, a manual calculation using a written table was compared with the calculator in a cross-over trial with 72 participants in order to assess the findings of the survey. RESULTS: The opioid conversion calculator could be generated for 24 combinations of 6 opioids for 5 different routes of administration. The validation of the calculator was performed successfully without discovering any major or critical defects. The proportion of correct answers increased from 68% using the table to 81% using the calculator (P < 0.001), the median time necessary to answer the ten questions was 8.9 min using the table and 4.8 min using the calculator. CONCLUSION: A web-based opioid conversion calculator was planned, generated, validated and established at the hospital. Based on the results of the online survey and the results of our cross-over trial we conclude that the tool saves time compared to manual calculation and may contribute to patient safety by avoiding calculation errors. With this tool we contribute to the optimisation of processes in hospital and patient safety.

The anatomic reconstruction of acromioclavicular joint dislocations using 2 TightRope devices: a biomechanical study.

BACKGROUND: For the reconstruction of acromioclavicular (AC) joint separation, several operative procedures have been described; however, the anatomic reconstruction of both coracoclavicular ligaments has rarely been reported. PURPOSE: The aim of this biomechanical study is to describe a new procedure for anatomic reconstruction of the AC joint. STUDY DESIGN: Controlled laboratory study. MATERIALS AND METHODS: Forty fresh-frozen cadaveric shoulders were tested. Cyclic loading and a load-to-failure protocol was performed in vertical (native, n = 10; reconstructed, n = 10) and anterior directions (native, n = 10; reconstructed, n = 10) on 20 AC joints and repeated after anatomic reconstruction. Reconstruction of conoid and trapezoid ligaments was achieved by 2 TightRope devices (Arthrex, Naples, Florida). Dynamic, cyclic, and static loading until failure in vertical (n = 5) and horizontal (n = 5) directions were tested in native as well as reconstructed joints in a standardized setting. RESULTS: The native coracoclavicular ligaments in static load for vertical force measured 598 N (range, 409-687), elongation 10 mm (range, 6-14), and stiffness 99 N/mm (range, 67-130); static load for anterior force was 338 N (range, 186-561), elongation 4 mm (range, 3-7), and stiffness 140 N/mm (range, 70-210). The mean maximum static load until failure in reconstruction for vertical force was 982 N (range, 584-1330) (P =.001), elongation 4 mm (range, 3-6) (P < .001), and stiffness 80 N/mm (range, 66.6-105) (P = .091); and for anterior static force 627 N (range, 364-973) (P < .001), elongation 6.5 mm (range, 4-10) (P = .023), and stiffness 78 N/mm (range, 46-120) (P = .009). During dynamic testing of the native coracoclavicular ligaments, the mean amount of repetitions (100 repetitions per stage, stage 0-100 N, 100-200 N, 200-300 N, etc, and a frequency of 1.5 Hz) in native vertical direction was 593 repetitions (range, 426-683) and an average of 552 N (range, 452-683) load until failure. In vertical reconstructed testing, there were 742 repetitions (range, 488-893) (P = .222) with a load until failure of 768 N (range, 486-900) (P = .095). In the anterior direction load, the native ligament failed after an average of 365 repetitions (range, 330-475) and an average load of 360 N (range, 307-411), while reconstructed joints ended in 549 repetitions (range, 498-566) (P = .008) with a load until failure of 547 N (range, 490-585) (P = .008). In all testing procedures, a preload of 5 N was performed. CONCLUSION: The anatomic reconstruction of the AC joint using TightRope is a stable and functional anatomic reconstruction procedure. The reconstruction technique led to favorable in vitro results with equal or even higher forces than native ligaments. CLINICAL RELEVANCE: Through anatomic repair, stable function of the AC joint can be achieved in an anatomic manner.

The Dscam homologue of the crustacean Daphnia is diversified by alternative splicing like in insects.

In insects, the homologue of the Down syndrome cell adhesion molecule (Dscam) is a unique case of a single-locus gene whose expression has extensive somatic diversification in both the nervous and immune systems. How this situation evolved is best understood through comparative studies. We describe structural, expression, and evolutionary aspects of a Dscam homolog in 2 species of the crustacean Daphnia. The Dscam of Daphnia generates up to 13,000 different transcripts by the alternative splicing of variable exons. This extends the taxonomic range of a highly diversified Dscam beyond the insects. Additionally, we have identified 4 alternative forms of the cytoplasmic tail that generate isoforms with or without inhibitory or activating immunoreceptor tyrosine-based motifs (ITIM and ITAM respectively), something not previously reported in insect's Dscam. In Daphnia, we detected exon usage variability in both the brain and hemocytes (the effector cells of immunity), suggesting that Dscam plays a role in the nervous and immune systems of crustaceans, as it does in insects. Phylogenetic analysis shows a high degree of amino acid conservation between Daphnia and insects except in the alternative exons, which diverge greatly between these taxa. Our analysis shows that the variable exons diverged before the split of the 2 Daphnia species and is in agreement with the nearest-neighbor model for the evolution of the alternative exons. The genealogy of the Dscam gene family from vertebrates and invertebrates confirmed that the highly diversified form of the gene evolved from a nondiversified form before the split of insects and crustaceans.

Reliable confidence intervals in quantitative genetics: narrow-sense heritability.

Many quantitative genetic statistics are functions of variance components, for which a large number of replicates is needed for precise estimates and reliable measures of uncertainty, on which sound interpretation depends. Moreover, in large experiments the deaths of some individuals can occur, so methods for analysing such data need to be robust to missing values. We show how confidence intervals for narrow-sense heritability can be calculated in a nested full-sib/half-sib breeding design (males crossed with several females) in the presence of missing values. Simulations indicate that the method provides accurate results, and that estimator uncertainty is lowest for sampling designs with many males relative to the number of females per male, and with more females per male than progenies per female. Missing data generally had little influence on estimator accuracy, thus suggesting that the overall number of observations should be increased even if this results in unbalanced data. We also suggest the use of parametrically simulated data for prior investigation of the accuracy of planned experiments. Together with the proposed confidence intervals an informed decision on the optimal sampling design is possible, which allows efficient allocation of resources.

Pentatricopeptide repeat proteins in Trypanosoma brucei function in mitochondrial ribosomes.

The pentatricopeptide repeat (PPR), a degenerate 35-amino-acid motif, defines a novel eukaryotic protein family. Plants have 400 to 500 distinct PPR proteins, whereas other eukaryotes generally have fewer than 5. The few PPR proteins that have been studied have roles in organellar gene expression, probably via direct interaction with RNA. Here we show that the parasitic protozoan Trypanosoma brucei encodes 28 distinct PPR proteins, an extraordinarily high number for a nonplant organism. A comparative analysis shows that seven out of eight selected PPR proteins are mitochondrially localized and essential for oxidative phosphorylation. Six of these are required for the stabilization of mitochondrial rRNAs and, like ribosomes, are associated with the mitochondrial membranes. Furthermore, one of the PPR proteins copurifies with the large subunit rRNA. Finally, ablation of all of the PPR proteins that were tested induces degradation of the other PPR proteins, indicating that they function in concert. Our results show that a significant number of trypanosomal PPR proteins are individually essential for the maintenance and/or biogenesis of mitochondrial rRNAs.