Pragmatic trials in primary care. Methodological challenges and solutions demonstrated by the DIAMOND-study

Background  

Pragmatic randomised controlled trials are often used in primary care to evaluate the effect of a treatment strategy. In these trials it is difficult to achieve both high internal validity and high generalisability. This article will discuss several methodological challenges in designing and conducting a pragmatic primary care based randomised controlled trial, based on our experiences in the DIAMOND-study and will discuss the rationale behind the choices we made. From the successes as well as the problems we experienced the quality of future pragmatic trials may benefit.     

Major histocompatibility genes in cyprinid fishes: theory and practice

Summary: The first teleostean MHC sequences were described for carp. Subsequent studies in a number of cyprinid fishes showed that the class I sequences of these fishes are of particular interest. Two distinct lineages (Cyca-Z and Cyca-U) are found in the common and ginbuna crucian carp, but only the U lineage is present in zebrafish and other non-cyprinid species. The presence of the Z lineage is hypothesised to be the result of an allotetraploidisation event. Both phylogenetic analyses and amino acid sequence comparisons suggest that Cyca-Z sequences are non-classical class I sequences, probably similar to CD I. The comprehensive phylogenetic analyses of these sequences revealed different phylogenetic histories of the exons encoding the extracellular domains. The MHC genes were studied in laboratory and natural models. The natural model addressed the evolution of MHC genes in a Barbus species flock. Sequence analysis of class I and class II supported the species designation of the morphotypes present in the lake, and as a consequence the trans-species hypothesis of MHC polymorphism. The laboratory model involves the generation of gynogenetic clones, which can be divergently selected for traits such as high and low antibody response. The role of MHC molecules can be investigated further by producing a panel of isogenic lines.     

A Versatile Adaptive Dose-Finding Design Based on Multiple Endpoints

In drug development, assessment of the dose–response relationship gives essential insight into which doses are efficacious, yet safe. These relationships are often estimated by parametric, nonlinear models. A hurdle for trials that aim to estimate these models, is that the optimal study design depends on the unknown model parameters. A solution is to use adaptive designs. Ideally, such procedures evaluate a safety and an efficacy endpoint to get the best understanding of the therapeutic window. Many such designs have already been proposed. However, the outcomes are typically required to be of a specific type and the correlation between them has to be modeled explicitly. We propose a more general and simpler approach. Separate models can be specified for each endpoint, without restrictions on the type of model or outcome. The dependence between the outcomes is considered, without having to specify its structure. A new penalty function is introduced to balance the need for optimal precision and safe dose assignments. The method is illustrated by an example study in depression. Simulation results indicate that the adaptive design is more efficient than a fixed design. Use of the penalty function decreases estimation efficiency, but increases dose assignment to favorable doses. Supplementary materials for this article are available online.     

Contribution of Single-Fiber Evaluation on Monitoring Outcomes Following Injection of Botulinum Toxin-A: A Narrative Review of the Literature

Botulinum toxin-A (BoNT-A) blocks acetylcholine release at the neuromuscular junction (NMJ) and is widely used for neuromuscular disorders (involuntary spasms, dystonic disorders and spasticity). However, its therapeutic effects are usually measured by clinical scales of questionable validity. Single-fiber electromyography (SFEMG) is a sensitive, validated diagnostic technique for NMJ impairment such as myasthenia. The jitter parameter (µs) represents the variability of interpotential intervals of two muscle fibers from the same motor unit. This narrative review reports SFEMG use in BoNT-A treatment. Twenty-four articles were selected from 175 eligible articles searched in Medline/Pubmed and Cochrane Library from their creation until May 2020. The results showed that jitter is sensitive to early NMJ modifications following BoNT-A injection, with an increase in the early days’ post-injection and a peak between Day 15 and 30, when symptoms diminish or disappear. The reappearance of symptoms accompanies a tendency for a decrease in jitter, but always precedes its normalization, either delayed or nonexistent. Increased jitter is observed in distant muscles from the injection site. No dose effect relationship was demonstrated. SFEMG could help physicians in their therapeutic evaluation according to the pathology considered. More data are needed to consider jitter as a predictor of BoNT-A clinical efficacy.     

Sinus node function after cardiac surgery: is impairment specific for the maze procedure?

BACKGROUND: Maze surgery is a final solution for intractable atrial fibrillation (AF), but an adverse effect on postoperative sinus node function has been reported. Whether this also applies to other types of cardiac surgery is unclear. METHODS: We assessed postoperative rhythm by means of repeated exercise tolerance testing, ambulatory electrocardiography, and non-invasive testing of autonomic function between 1 and 12 months after four types of cardiac surgery. Fourteen patients without structural cardiac disease and medically refractory AF underwent the maze III procedure, 11 patients with mitral valve disease and preoperative AF underwent valvar surgery combined with a (simplified) maze III procedure, and 8 patients with mitral valve disease in sinus rhythm (SR) underwent isolated valvar surgery. The control group consisted of eight patients with sinus rhythm who underwent coronary artery bypass surgery (CABG). RESULTS: One month after surgery, the chronotropic response to exercise was depressed, mean heart rate was high, and heart rate variability (HRV) was low, especially after maze III, combined surgery, and isolated valvar surgery. Twelve months after surgery, moderate improvements were observed. After CABG, considerably fewer abnormalities were observed, and HRV parameters recovered to a large extent. Non-invasive testing of autonomic function indicated disturbed vagal modulation of heart rate in all three groups with atrial incision. CONCLUSION: Thus, attenuation of HRV and vagal modulation of sinus node function are not confined to maze surgery but also apply to isolated mitral valve surgery. Atrial incision therefore appears to be crucial and presumably produces autonomic nervous damage followed by partial reinnervation. Nevertheless, cardiac surgery in general seems initially to impair sinus node function with partial recovery in the consecutive 12 months.     

Efficacy of amodiaquine alone and combined with sulfadoxine-pyrimethamine and of sulfadoxine pyrimethamine combined with artesunate

The safety and the efficacy of amodiaquine (AQ) alone, AQ plus sulfadoxine-pyrimethamine (SP) (AQ plus SP), and artesunate (ART) plus SP (ART plus SP), three possible alternatives to chloroquine (CQ), were investigated in 379 Rwandan children 6-59 months old with uncomplicated Plasmodium falciparum malaria who visited one urban/peri-urban health center and two rural health centers. The three treatment regimens were well tolerated and no serious adverse effects were observed. Children treated with AQ plus SP had less clinical failures than those treated with ART plus SP (odds ratio [OR] = 0.25, 95% confidence interval [CI] = 0.06-0.81, P = 0.01) or AQ alone (OR = 0.33, 95% CI = 0.07-1.10, P = 0.08). Even after new infections were excluded, AQ plus SP was still significantly more efficacious than ART plus SP (P = 0.05). At day 14, the mean packed cell volume was significantly higher in the AQ plus SP group compared with the ART plus SP group (P = 0.02) and with the AQ alone group (P = 0.01). In Rwanda, AQ plus SP has been chosen to replace CQ as a first-line treatment. However, this is considered an interim measure and new combinations, possibly co-formulated, should be identified and tested.     

Reference values for spot urinary iodine concentrations in iodine-sufficient newborns using a new pad collection method.

BACKGROUND: Iodine deficiency in infancy can impair neurocognitive development, but there are few available indicators of iodine intake during this critical period. In many countries, access to newborns in maternity clinics in the first few days after birth is high. If spot urine samples could be collected, reference data for urinary iodine concentration (UIC) would be useful to evaluate their iodine status. The study objectives were 1) to develop and validate a simple pad system for collection of spot urine samples for iodine; 2) to establish a reference range for UIC in newborns in the first week after birth for use in monitoring iodine nutrition. METHODS: A two-stage cluster sampling was used to obtain a representative national sample of healthy, term Swiss infants, 0 to 5 days old (n = 634). Gestational information, whole blood for thyrotropin, and spot urine samples on two consecutive days were collected. RESULTS: The pad collection system was well-accepted and performed well during recovery and contamination testing. Median UIC in the total sample (n = 1224) was 77 (95% confidence interval; 76, 81) microg/L; there was a gradual increase in median UIC within the range of 70-100 microg/L from days 1 through 4. Because urinary creatinine concentrations were high and variable, the UI:creatinine ratio was not useful for standardization. CONCLUSIONS: The current WHO median UIC cut-off (> 100 microg/L) for iodine sufficiency in infancy may be too high for the first week after birth. Reference data from iodine-sufficient newborns and a simple collection system may facilitate use of UIC as an indicator of iodine status in this age group.