Think twice before starting a new trial; what is the impact of recommendations to stop doing new trials?

ObjectivesIn evidence-based medicine, we base our conclusions on the effectiveness of interventions on the results of high-quality meta-analysis. If a new randomized controlled trial (RCT) is unlikely to change the pooled effect estimate, conducting the new trial is a waste of resources. We evaluated whether recommendations not to conduct further RCTs reduced the number of trials registered for two scenarios.MethodsAnalysis of registered trials on the World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP). We regarded trial protocols relevant if they evaluated the effectiveness of (1) exercise for chronic low back pain (LBP) and (2) cognitive behavioural therapy (CBT) for chronic pain. We calculated absolute and relative numbers and change of registered trials in a pre-set time window before and after publication of the recommendations, both published in 2012.ResultsWe found 1,574 trials registered in the WHO trial registry for exercise in LBP (459 before 2012; 1,115 after) and 5,037 trials on chronic pain (1,564 before 2012; 3,473 after). Before 2012, 13 trials on exercise for LBP (out of 459) fit the selection criteria, compared to 42 trials (out of 1,115) after, which represents a relative increase of 33%. Twelve trials (out of 1,564) regarding CBT for chronic pain, fit the selection criteria before 2012 and 18 trials (out of 3,473) after, representing a relative decrease of 32%. We found that visibility, media exposure and strength of the recommendation were related to a decrease in registered trials.ConclusionsRecommendations not to conduct further RCTs might reduce the number of trials registered if these recommendations are strongly worded and combined with social media attention

The experience of long-term opiate maintenance treatment and reported barriers to recovery: A qualitative systematic review

Background/Aim: To inform understanding of the experience of long-term opiate maintenance and identify barriers to recovery. Methods: A qualitative systematic review. Results: 14 studies in 17 papers, mainly from the USA (65%), met inclusion criteria, involving 1,088 participants. Studies focused on methadone prescribing. Participants reported stability; however, many disliked methadone. Barriers to full recovery were primarily ‘inward focused'. Conclusion: This is the first review of qualitative literature on long-term maintenance, finding that universal service improvements could be made to address reported barriers to recovery, including involving ex-users as positive role models, and increasing access to psychological support. Treatment policies combining harm minimisation and abstinence-orientated approaches may best support individualised recovery

Complete Equivalence Between Gluon Tree Amplitudes in Twistor String Theory and in Gauge Theory

The gluon tree amplitudes of open twistor string theory, defined as contour integrals over the ACCK link variables, are shown to satisfy the BCFW relations, thus confirming that they coincide with the corresponding amplitudes in gauge field theory. In this approach, the integration contours are specified as encircling the zeros of certain constraint functions that force the appropriate relation between the link variables and the twistor string world-sheet variables. To do this, methods for calculating the tree amplitudes using link variables are developed further including diagrammatic methods for organizing and performing the calculations.Comment: 38 page

What are the resourcing requirements for an Aboriginal and Torres Strait Islander primary healthcare research project?

Objective and importance To explore the role of resourcing during an Aboriginal and Torres Strait Islander primary healthcare research project. Study type Process evaluation using grounded theory approaches of a national Aboriginal and Torres Strait Islander research project (N=500) named Getting it Right: The validation study. Methods Qualitative semi-structured interviews with thirty-six primary healthcare staff and four community members from nine of ten primary healthcare services (participating services) involved in the research project. Interviews included questions about the resources needed to conduct the research project, including flexible reimbursement to participating services (allocated within services), human resources and reimbursement to research participants (vouchers). Qualitative data were triangulated with participant feedback (questions about the aPHQ-9 [depression screening tool under examination] and free-text feedback collected during the research project), study administrative data (budgets, contracts, communication logs and ethics correspondence) and field notes kept by the interviewer. Results Three themes were identified: 1) the influence of reimbursement on participating services and the research project: 2) the influence of human resources on the research project at participating services; and 3) the consequences of offering vouchers to reimburse research participants. Reimbursement was allocated to research expenses (human resources and logistics) or non-research expenses (service operations, equipment and conference attendance costs). Most services opted to offer vouchers to compensate participants for their time, which staff considered was appropriate recognition of participants’ contributions and facilitated recruitment. Some staff described some potential unintended negative consequences from vouchers, including creating a welfare mentality or the wrong precedent. Conclusion Primary healthcare research should have sufficient resourcing available, including human resource capacity, to achieve research targets. Research planning should include consideration of the existing commitments, priorities and human capacity needs of services and patients

Efficacy of three BCG strains (Connaught, TICE and RIVM) with or without secondary resection (re-TUR) for intermediate/high-risk non-muscle-invasive bladder cancers: results from a retrospective single-institution cohort analysis

Purpose: (I) To evaluate the clinical efficacy of three different BCG strains in patients with intermediate-/high-risk non-muscle-invasive bladder cancer (NMIBC). (II) To determine the importance of performing routine secondary resection (re-TUR) in the setting of BCG maintenance protocol for the three strains. Methods: NMIBCs who received an adjuvant induction followed by a maintenance schedule of intravesical immunotherapy with BCG Connaught, TICE and RIVM. Only BCG-naïve and those treated with the same strain over the course of follow-up were included. Cox proportional hazards model was developed according to prognostic factors by the Spanish Urological Oncology Group (CUETO) as well as by adjusting for the implementation of re-TUR. Results: n = 422 Ta-T1 patients (Connaught, n = 146; TICE, n = 112 and RIVM, n = 164) with a median (IQR) follow-up of 72 (60-85) were reviewed. Re-TUR was associated with improved recurrence and progression outcomes (HRRFS: 0.63; 95% CI 0.46-0.86; HRPFS: 0.55; 95% CI 0.31-0.86). Adjusting for CUETO risk factors and re-TUR, BGC TICE and RIVM provided longer RFS compared to Connaught (HRTICE: 0.58, 95% CI 0.39-0.86; HRRIVM: 0.61, 95% CI 0.42-0.87) while no differences were identified between strains for PFS and CSS. Sub-analysis of only re-TUR cases (n = 190, 45%) showed TICE the sole to achieve longer RFS compared to both Connaught and RIVM. Conclusion: Re-TUR was confirmed to ensure longer RFS and PFS in intermediate-/high-risk NMIBCs but did not influence the relative single BCG strain efficacy. When routinely performing re-TUR followed by a maintenance BCG schedule, TICE was superior to the other strains for RFS outcomes

Bridging Time Scales in Cellular Decision Making with a Stochastic Bistable Switch

Cellular transformations which involve a significant phenotypical change of the cell's state use bistable biochemical switches as underlying decision systems. In this work, we aim at linking cellular decisions taking place on a time scale of years to decades with the biochemical dynamics in signal transduction and gene regulation, occuring on a time scale of minutes to hours. We show that a stochastic bistable switch forms a viable biochemical mechanism to implement decision processes on long time scales. As a case study, the mechanism is applied to model the initiation of follicle growth in mammalian ovaries, where the physiological time scale of follicle pool depletion is on the order of the organism's lifespan. We construct a simple mathematical model for this process based on experimental evidence for the involved genetic mechanisms. Despite the underlying stochasticity, the proposed mechanism turns out to yield reliable behavior in large populations of cells subject to the considered decision process. Our model explains how the physiological time constant may emerge from the intrinsic stochasticity of the underlying gene regulatory network. Apart from ovarian follicles, the proposed mechanism may also be of relevance for other physiological systems where cells take binary decisions over a long time scale.Comment: 14 pages, 4 figure

Increasing confidence and changing behaviors in primary care providers engaged in genetic counselling.

BackgroundScreening and counseling for genetic conditions is an increasingly important part of primary care practice, particularly given the paucity of genetic counselors in the United States. However, primary care physicians (PCPs) often have an inadequate understanding of evidence-based screening; communication approaches that encourage shared decision-making; ethical, legal, and social implication (ELSI) issues related to screening for genetic mutations; and the basics of clinical genetics. This study explored whether an interactive, web-based genetics curriculum directed at PCPs in non-academic primary care settings was superior at changing practice knowledge, attitudes, and behaviors when compared to a traditional educational approach, particularly when discussing common genetic conditions.MethodsOne hundred twenty one PCPs in California and Pennsylvania physician practices were randomized to either an Intervention Group (IG) or Control Group (CG). IG physicians completed a 6 h interactive web-based curriculum covering communication skills, basics of genetic testing, risk assessment, ELSI issues and practice behaviors. CG physicians were provided with a traditional approach to Continuing Medical Education (CME) (clinical review articles) offering equivalent information.ResultsPCPs in the Intervention Group showed greater increases in knowledge compared to the Control Group. Intervention PCPs were also more satisfied with the educational materials, and more confident in their genetics knowledge and skills compared to those receiving traditional CME materials. Intervention PCPs felt that the web-based curriculum covered medical management, genetics, and ELSI issues significantly better than did the Control Group, and in comparison with traditional curricula. The Intervention Group felt the online tools offered several advantages, and engaged in better shared decision making with standardized patients, however, there was no difference in behavior change between groups with regard to increases in ELSI discussions between PCPs and patients.ConclusionWhile our intervention was deemed more enjoyable, demonstrated significant factual learning and retention, and increased shared decision making practices, there were few differences in behavior changes around ELSI discussions. Unfortunately, barriers to implementing behavior change in clinical genetics is not unique to our intervention. Perhaps the missing element is that busy physicians need systems-level support to engage in meaningful discussions around genetics issues. The next step in promoting active engagement between doctors and patients may be to put into place the tools needed for PCPs to easily access the materials they need at the point-of-care to engage in joint discussions around clinical genetics

Transkingdom Networks: A Systems Biology Approach to Identify Causal Members of Host-Microbiota Interactions

Improvements in sequencing technologies and reduced experimental costs have resulted in a vast number of studies generating high-throughput data. Although the number of methods to analyze these "omics" data has also increased, computational complexity and lack of documentation hinder researchers from analyzing their high-throughput data to its true potential. In this chapter we detail our data-driven, transkingdom network (TransNet) analysis protocol to integrate and interrogate multi-omics data. This systems biology approach has allowed us to successfully identify important causal relationships between different taxonomic kingdoms (e.g. mammals and microbes) using diverse types of data

New mutations at the imprinted Gnas cluster show gene dosage effects of Gsα in postnatal growth and implicate XLαs in bone and fat metabolism, but not in suckling

The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLαs, XLN1, and ALEX or a double dose of maternally expressed Gsα to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gsα, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsα and loss of expression of XLαs and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLαs, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLαs. This is, to our knowledge, the first report describing a role for XLαs in bone metabolism. We propose that XLαs is involved in the regulation of bone and adipocyte metabolism

Nitrogen uptake and internal recycling in Zostera marina exposed to oyster farming: eelgrass potential as a natural biofilter

Oyster farming in estuaries and coastal lagoons frequently overlaps with the distribution of seagrass meadows, yet there are few studies on how this aquaculture practice affects seagrass physiology. We compared in situ nitrogen uptake and the productivity of Zostera marina shoots growing near off-bottom longlines and at a site not affected by oyster farming in San Quintin Bay, a coastal lagoon in Baja California, Mexico. We used benthic chambers to measure leaf NH4 (+) uptake capacities by pulse labeling with (NH4)-N-15 (+) and plant photosynthesis and respiration. The internal N-15 resorption/recycling was measured in shoots 2 weeks after incubations. The natural isotopic composition of eelgrass tissues and vegetative descriptors were also examined. Plants growing at the oyster farming site showed a higher leaf NH4 (+) uptake rate (33.1 mmol NH4 (+) m(-2) day(-1)) relative to those not exposed to oyster cultures (25.6 mmol NH4 (+) m(-2) day(-1)). We calculated that an eelgrass meadow of 15-16 ha (which represents only about 3-4 % of the subtidal eelgrass meadow cover in the western arm of the lagoon) can potentially incorporate the total amount of NH4 (+) excreted by oysters (similar to 5.2 x 10(6) mmol NH4 (+) day(-1)). This highlights the potential of eelgrass to act as a natural biofilter for the NH4 (+) produced by oyster farming. Shoots exposed to oysters were more efficient in re-utilizing the internal N-15 into the growth of new leaf tissues or to translocate it to belowground tissues. Photosynthetic rates were greater in shoots exposed to oysters, which is consistent with higher NH4 (+) uptake and less negative delta C-13 values. Vegetative production (shoot size, leaf growth) was also higher in these shoots. Aboveground/belowground biomass ratio was lower in eelgrass beds not directly influenced by oyster farms, likely related to the higher investment in belowground biomass to incorporate sedimentary nutrients