Ethics and practice of trials within cohorts: An emerging pragmatic trial design

BACKGROUND: With increasing emphasis on pragmatic trials, new randomized clinical trial designs are being proposed to enhance the "real world" nature of the data generated. We describe one such design, appropriate for unmasked pragmatic clinical trials in which the control arm receives usual care, called "Trials within Cohorts" that is increasingly used in various countries because of its efficiency in recruitment, advantages in reducing subject burden, and ability to better mimic real-world consent processes. METHODS: Descriptive, ethical, and US regulatory analysis of the Trials within Cohorts design. RESULTS: Trials within Cohorts design involves, after recruitment into a cohort, randomization of eligible subjects, followed by an asymmetric treatment of the two arms: those selected for the experimental arm provide informed consent for the intervention trial, while the data from the control arm are used based on prior broad permission. Thus, unlike the traditional Zelen post-randomization consent design, the cohort participants are informed about future research within the cohort; however, the extent of this disclosure currently varies among studies. Thus, ethical analysis is provided for two types of situations: when the pre-randomization disclosure and consent regarding the embedded trials are fairly explicit and detailed versus when they consist of only general statements about future data use. These differing ethical situations could have implications for how ethics review committees apply US research rules regarding waivers and alterations of informed consent. CONCLUSION: Trials within Cohorts is a promising new pragmatic randomized controlled trial design that is being increasingly used in various countries. Although the asymmetric consent procedures for the experimental versus control arm subjects can initially raise ethical concerns, it is ethically superior to previous post-randomization consent designs and can have important advantages over traditional trial designs

Atopic dermatitis and risk of atrial fibrillation or flutter: A 35-year follow-up study.

BACKGROUND: Atopic dermatitis is characterized by chronic inflammation, which is a risk factor for atrial fibrillation. OBJECTIVE: To examine the association between hospital-diagnosed atopic dermatitis and atrial fibrillation. METHODS: Using linked population-based Danish registries, we identified persons with an inpatient or outpatient hospital diagnosis of atopic dermatitis during 1977-2013 and a comparison cohort individually matched to the atopic dermatitis cohort. We followed cohorts until death, emigration, atrial fibrillation diagnosis, or end of study (January 1, 2013). We compared 35-year risk of atrial fibrillation and estimated hazard ratios with 95% confidence intervals using Cox regression, adjusting for birth year and sex. We validated 100 atopic dermatitis diagnoses from a dermatologic department through medical record review. RESULTS: We included 13,126 persons with atopic dermatitis and 124,211 comparators and followed them for a median of 19.3 years. The 35-year risk of atrial fibrillation was 0.81% and 0.67%, respectively. The positive predictive value of atopic dermatitis diagnoses was 99%. The hazard ratio was 1.2 (95% confidence interval 1.0-1.6) and remained increased after adjusting for various atrial fibrillation risk factors. LIMITATIONS: Analyses were limited to persons with moderate-to-severe atopic dermatitis, and we had no lifestyle data. CONCLUSION: Patients with hospital-diagnosed atopic dermatitis have a 20% increased long-term risk of atrial fibrillation, but the absolute risk remains low

All-Versus-Nothing Proof of Einstein-Podolsky-Rosen Steering

Einstein-Podolsky-Rosen steering is a form of quantum nonlocality intermediate between entanglement and Bell nonlocality. Although Schr\"odinger already mooted the idea in 1935, steering still defies a complete understanding. In analogy to "all-versus-nothing" proofs of Bell nonlocality, here we present a proof of steering without inequalities rendering the detection of correlations leading to a violation of steering inequalities unnecessary. We show that, given any two-qubit entangled state, the existence of certain projective measurement by Alice so that Bob's normalized conditional states can be regarded as two different pure states provides a criterion for Alice-to-Bob steerability. A steering inequality equivalent to the all-versus-nothing proof is also obtained. Our result clearly demonstrates that there exist many quantum states which do not violate any previously known steering inequality but are indeed steerable. Our method offers advantages over the existing methods for experimentally testing steerability, and sheds new light on the asymmetric steering problem.Comment: 7 pages, 2 figures. Accepted in Sci. Re

The response of perennial and temporary headwater stream invertebrate communities to hydrological extremes

The headwaters of karst rivers experience considerable hydrological variability, including spates and streambed drying. Extreme summer flooding on the River Lathkill (Derbyshire, UK) provided the opportunity to examine the invertebrate community response to unseasonal spate flows, flow recession and, at temporary sites, streambed drying. Invertebrates were sampled at sites with differing flow permanence regimes during and after the spates. Following streambed drying at temporary sites, dewatered surface sediments were investigated as a refugium for aquatic invertebrates. Experimental rehydration of these dewatered sediments was conducted to promote development of desiccation-tolerant life stages. At perennial sites, spate flows reduced invertebrate abundance and diversity, whilst at temporary sites, flow reactivation facilitated rapid colonisation of the surface channel by a limited number of invertebrate taxa. Following streambed drying, 38 taxa were recorded from the dewatered and rehydrated sediments, with Oligochaeta being the most abundant taxon and Chironomidae (Diptera) the most diverse. Experimental rehydration of dewatered sediments revealed the presence of additional taxa, including Stenophylax sp. (Trichoptera: Limnephilidae) and Nemoura sp. (Plecoptera: Nemouridae). The influence of flow permanence on invertebrate community composition was apparent despite the aseasonal high-magnitude flood events

GABA Maintains the Proliferation of Progenitors in the Developing Chick Ciliary Marginal Zone and Non-Pigmented Ciliary Epithelium

GABA is more than the main inhibitory neurotransmitter found in the adult CNS. Several studies have shown that GABA regulates the proliferation of progenitor and stem cells. This work examined the effects of the GABAA receptor system on the proliferation of retinal progenitors and non-pigmented ciliary epithelial (NPE) cells. qRT-PCR and whole-cell patch-clamp electrophysiology were used to characterize the GABAA receptor system. To quantify the effects on proliferation by GABAA receptor agonists and antagonists, incorporation of thymidine analogues was used. The results showed that the NPE cells express functional extrasynaptic GABAA receptors with tonic properties and that low concentration of GABA is required for a baseline level of proliferation. Antagonists of the GABAA receptors decreased the proliferation of dissociated E12 NPE cells. Bicuculline also had effects on progenitor cell proliferation in intact E8 and E12 developing retina. The NPE cells had low levels of the Cl–transporter KCC2 compared to the mature retina, suggesting a depolarising role for the GABAA receptors. Treatment with KCl, which is known to depolarise membranes, prevented some of the decreased proliferation caused by inhibition of the GABAA receptors. This supported the depolarising role for the GABAA receptors. Inhibition of L-type voltage-gated Ca2+ channels (VGCCs) reduced the proliferation in the same way as inhibition of the GABAA receptors. Inhibition of the channels increased the expression of the cyclin-dependent kinase inhibitor p27KIP1, along with the reduced proliferation. These results are consistent with that when the membrane potential indirectly regulates cell proliferation with hyperpolarisation of the membrane potential resulting in decreased cell division. The increased expression of p27KIP1 after inhibition of either the GABAA receptors or the L-type VGCCs suggests a link between the GABAA receptors, membrane potential, and intracellular Ca2+ in regulating the cell cycle

Observed Reductions in Schistosoma mansoni Transmission from Large-Scale Administration of Praziquantel in Uganda: A Mathematical Modelling Study

To date schistosomiasis control programmes based on chemotherapy have largely aimed at controlling morbidity in treated individuals rather than at suppressing transmission. In this study, a mathematical modelling approach was used to estimate reductions in the rate of Schistosoma mansoni reinfection following annual mass drug administration (MDA) with praziquantel in Uganda over four years (2003-2006). In doing this we aim to elucidate the benefits of MDA in reducing community transmission.Age-structured models were fitted to a longitudinal cohort followed up across successive rounds of annual treatment for four years (Baseline: 2003, TREATMENT: 2004-2006; n = 1,764). Instead of modelling contamination, infection and immunity processes separately, these functions were combined in order to estimate a composite force of infection (FOI), i.e., the rate of parasite acquisition by hosts.MDA achieved substantial and statistically significant reductions in the FOI following one round of treatment in areas of low baseline infection intensity, and following two rounds in areas with high and medium intensities. In all areas, the FOI remained suppressed following a third round of treatment.This study represents one of the first attempts to monitor reductions in the FOI within a large-scale MDA schistosomiasis morbidity control programme in sub-Saharan Africa. The results indicate that the Schistosomiasis Control Initiative, as a model for other MDA programmes, is likely exerting a significant ancillary impact on reducing transmission within the community, and may provide health benefits to those who do not receive treatment. The results obtained will have implications for evaluating the cost-effectiveness of schistosomiasis control programmes and the design of monitoring and evaluation approaches in general

Multilevel analysis of clinical parameters in chronic periodontitis after root planing/scaling, surgery, and systemic and local antibiotics: 2-year results

Aim: Find the periodontal treatment that best maintained clinical results over time evaluated by changes in pocket depth (PD) and clinical attachment level (CAL). Methods: 229 patients with chronic periodontitis from USA (n=134) and Sweden (n=95) were randomly assigned to eight groups receiving 1 scaling+root planing (SRP) alone or combined with 2 surgery (SURG)+systemic amoxicillin (AMOX)+systemic metronidazole (MET); 3 SURG+local tetracycline (TET); 4 SURG; 5 AMOX+MET+TET; 6 AMOX+MET; 7 TET; and 8 SURG+AMOX+MET+TET. Antibiotics were given immediately after SRP. Plaque, gingival redness, bleeding on probing, suppuration, PD, and CAL were recorded at baseline and after 3, 6, 12, 18, and 24 months. Treatment effects were evaluated by linear multilevel regression and logistic multilevel regression models. We considered only data from sites with a baseline PD of at least 5 mm of 187 patients completing the study. Results: Surgically treated patients experienced most CAL loss. Adjunctive therapy including SURG was most effective in reducing PD. Combining SURG with AMOX, MET, and TET gave significant clinical benefits. Past and current smoking habits were significant predictors of deeper PD. Only current smoking was a significant predictor of CAL loss. Bleeding, accumulation of plaque, gingival redness, and suppuration were significant predictors of further CAL loss and deeper PD. Conclusions: Both surgical and non-surgical therapies can be used to arrest chronic periodontitis. SURG+AMOX+MET+TET gave best maintenance of clinical results

Patent Human Infections with the Whipworm, Trichuris trichiura, Are Not Associated with Alterations in the Faecal Microbiota

Background: The soil-transmitted helminth (STH), Trichuris trichiura colonises the human large intestine where it may modify inflammatory responses, an effect possibly mediated through alterations in the intestinal microbiota. We hypothesised that patent T. trichiura infections would be associated with altered faecal microbiota and that anthelmintic treatment would induce a microbiota resembling more closely that observed in uninfected individuals. Materials and Methods: School children in Ecuador were screened for STH infections and allocated to 3 groups: uninfected, T. trichiura only, and mixed infections with T. trichiura and Ascaris lumbricoides. A sample of uninfected children and those with T. trichiura infections only were given anthelmintic treatment. Bacterial community profiles in faecal samples were studied by 454 pyrosequencing of 16 S rRNA genes. Results: Microbiota analyses of faeces were done for 97 children: 30 were uninfected, 17 were infected with T. trichiura, and 50 with T. trichiura and A. lumbricoides. Post-treatment samples were analyzed for 14 children initially infected with T. trichiura alone and for 21 uninfected children. Treatment resulted in 100% cure of STH infections. Comparisons of the microbiota at different taxonomic levels showed no statistically significant differences in composition between uninfected children and those with T. trichiura infections. We observed a decreased proportional abundance of a few bacterial genera from the Clostridia class of Firmicutes and a reduced bacterial diversity among children with mixed infections compared to the other two groups, indicating a possible specific effect of A. lumbricoides infection. Anthelmintic treatment of children with T. trichiura did not alter faecal microbiota composition. Discussion: Our data indicate that patent human infections with T. trichiura may have no effect on faecal microbiota but that A. lumbricoides colonisation might be associated with a disturbed microbiota. Our results also catalogue the microbiota of rural Ecuadorians and indicate differences with individuals from more urban industrialised societies

A human MAP kinase interactome.

Mitogen-activated protein kinase (MAPK) pathways form the backbone of signal transduction in the mammalian cell. Here we applied a systematic experimental and computational approach to map 2,269 interactions between human MAPK-related proteins and other cellular machinery and to assemble these data into functional modules. Multiple lines of evidence including conservation with yeast supported a core network of 641 interactions. Using small interfering RNA knockdowns, we observed that approximately one-third of MAPK-interacting proteins modulated MAPK-mediated signaling. We uncovered the Na-H exchanger NHE1 as a potential MAPK scaffold, found links between HSP90 chaperones and MAPK pathways and identified MUC12 as the human analog to the yeast signaling mucin Msb2. This study makes available a large resource of MAPK interactions and clone libraries, and it illustrates a methodology for probing signaling networks based on functional refinement of experimentally derived protein-interaction maps