Multi-arm multi-stage (MAMS) randomised selection designs:Impact of treatment selection rules on the operating characteristics

Background: Multi-arm multi-stage (MAMS) randomised trial designs have been proposed to evaluate multiple research questions in the confirmatory setting. In designs with several interventions, such as the 8-arm 3-stage ROSSINI-2 trial for preventing surgical wound infection, there are likely to be strict limits on the number of individuals that can be recruited or the funds available to support the protocol. These limitations may mean that not all research treatments can continue to accrue the required sample size for the definitive analysis of the primary outcome measure at the final stage. In these cases, an additional treatment selection rule can be applied at the early stages of the trial to restrict the maximum number of research arms that can progress to the subsequent stage(s).This article provides guidelines on how to implement treatment selection within the MAMS framework. It explores the impact of treatment selection rules, interim lack-of-benefit stopping boundaries and the timing of treatment selection on the operating characteristics of the MAMS selection design.Methods: We outline the steps to design a MAMS selection trial. Extensive simulation studies are used to explore the maximum/expected sample sizes, familywise type I error rate (FWER), and overall power of the design under both binding and non-binding interim stopping boundaries for lack-of-benefit.Results: Pre-specification of a treatment selection rule reduces the maximum sample size by approximately 25% in our simulations. The familywise type I error rate of a MAMS selection design is smaller than that of the standard MAMS design with similar design specifications without the additional treatment selection rule. In designs with strict selection rules - for example, when only one research arm is selected from 7 arms - the final stage significance levels can be relaxed for the primary analyses to ensure that the overall type I error for the trial is not underspent. When conducting treatment selection from several treatment arms, it is important to select a large enough subset of research arms (that is, more than one research arm) at early stages to maintain the overall power at the pre-specified level.Conclusions: Multi-arm multi-stage selection designs gain efficiency over the standard MAMS design by reducing the overall sample size. Diligent pre-specification of the treatment selection rule, final stage significance level and interim stopping boundaries for lack-of-benefit are key to controlling the operating characteristics of a MAMS selection design. We provide guidance on these design features to ensure control of the operating characteristics

Bioabsorbable mesh use in midline abdominal wall prophylaxis and repair achieving fascial closure:a cross-sectional review of stage of innovation

Background: Achieving stable closure of complex or contaminated abdominal wall incisions remains challenging. This study aimed to characterise the stage of innovation for bioabsorbable mesh devices used during both midline closure prophylaxis and complex abdominal wall reconstruction and to evaluate the quality of current evidence.Methods: A systematic review of published and ongoing studies was performed until 31st December 2019. Inclusion criteria were studies where bioabsorbable mesh was used to support fascial closure either prophylactically after midline laparotomy or for repair of incisional hernia with midline incision. Exclusion criteria were: (1) study design was a systematic review, meta-analysis, letter, review, comment, or conference abstract; (2) included less than p patients; (3) only evaluated biological, synthetic or composite meshes. The primary outcome measure was the IDEAL framework stage of innovation. The key secondary outcome measure was the risk of bias in non-randomised studies of interventions (ROBINS-I) criteria for study quality.Results: Twelve studies including 1287 patients were included. Three studies considered mesh prophylaxis and nine studies considered hernia repair. There were only two published studies of IDEAL 2B. The remainder was IDEAL 2A studies. The quality of the evidence was categorised as having a risk of bias of a moderate, serious or critical level in nine of the twelve included studies using the ROBINS-I tool.Conclusion: The evidence base for bioabsorbable mesh is limited. Better reporting and quality control of surgical techniques are needed. Although new trial results over the next decade will improve the evidence base, more trials in emergency and contaminated settings are required to establish the limits of indication

Ultraviolet Imaging Observations of the cD Galaxy in Abell 1795: Further Evidence for Massive Star Formation in a Cooling Flow

We present images from the Ultraviolet Imaging Telescope of the Abell 1795 cluster of galaxies. We compare the cD galaxy morphology and photometry of these data with those from existing archival and published data. The addition of a far--UV color helps us to construct and test star formation model scenarios for the sources of UV emission. Models of star formation with rates in the range \sim5-20M_{\sun}yr$^{-1}$ indicate that the best fitting models are those with continuous star formation or a recent ($\sim4$ Myr old) burst superimposed on an old population. The presence of dust in the galaxy, dramatically revealed by HST images complicates the interpretation of UV data. However, we find that the broad--band UV/optical colors of this cD galaxy can be reasonably matched by models using a Galactic form for the extinction law with $E_{B-V}=0.14$. We also briefly discuss other objects in the large UIT field of view.Comment: To appear in the Astrophysical Journal. 14 AAS preprint style pages plus 7 figure

South African Hypertension Guideline 2006

Outcomes. Extensive data from many randomised controlled trials have shown the benefit of treating hypertension. The target blood pressure (BP) for antihypertensive management should be systolic BP < 140 mmHg, diastolic BP < 90 mmHg, with minimal or no drug side-effects. However, a lesser reduction will elicit benefit although this is not optimal. The reduction of BP in the elderly should generally be achieved gradually over 6 months. Stricter BP control is required for patients with end-organ damage, co-existing risk factors and co-morbidity, e.g. diabetes mellitus. Co-existent risk factors should also be controlled. Benefits. Reduction in risk of stroke, cardiac failure, renal insufficiency and coronary artery disease. The major precautions and contraindications to each antihypertensive drug recommended are listed. Recommendations. Correct BP measurement procedure is described. Evaluation of cardiovascular risk factors and recommendations for antihypertensive therapy are stipulated. The total cardiovascular disease risk profile should be determined for all patients and this should inform management strategies. Lifestyle modification and patient education are cornerstones in the management of every patient. Drug therapy for the patient with uncomplicated hypertension should be as follows: first line – low-dose thiazide or thiazide-like diuretics; second line – add either an angiotensin-converting enzyme inhibitor (ACE-I) or a calcium channel blocker (CCB); third line – add another second-line drug not already used. In resistant hypertension where a fourth drug is needed, use either a centrally acting drug, vasodilator, alpha-blocker, or beta-blocker. The order of drug choice may change in those with compelling indications for a particular drug class. The guideline includes management of specific situations including hypertensive emergency and urgency, severe hypertension with target-organ damage and hypertension in diabetes mellitus, etc. Validity. The guideline was developed by a joint Southern African Hypertension Society and National Department of Health Directorate: Chronic Diseases, Disabilities and Geriatrics working group. Input was also obtained from representatives of the various related professional societies

The counterrotating core and the black hole mass of IC1459

The E3 giant elliptical galaxy IC1459 is the prototypical galaxy with a fast counterrotating stellar core. We obtained one HST/STIS long-slit spectrum along the major axis of this galaxy and CTIO spectra along five position angles. We present self-consistent three-integral axisymmetric models of the stellar kinematics, obtained with Schwarzschild's numerical orbit superposition method. We study the dynamics of the kinematically decoupled core (KDC) in IC1459 and we find it consists of stars that are well-separated from the rest of the galaxy in phase space. The stars in the KDC counterrotate in a disk on orbits that are close to circular. We estimate that the KDC mass is ~0.5% of the total galaxy mass or ~3*10^9 Msun. We estimate the central black hole mass M_BH of IC1459 independently from both its stellar and its gaseous kinematics. Some complications probably explain why we find rather discrepant BH masses with the different methods. The stellar kinematics suggest that M_BH = (2.6 +/- 1.1)*10^9 Msun (3 sigma error). The gas kinematics suggests that M_BH ~ 3.5*10^8 Msun if the gas is assumed to rotate at the circular velocity in a thin disk. If the observed velocity dispersion of the gas is assumed to be gravitational, then M_BH could be as high as ~1.0*10^9 Msun. These different estimates bracket the value M_BH = (1.1 +/- 0.3)*10^9 Msun predicted by the M_BH-sigma relation. It will be an important goal for future studies to assess the reliability of black hole mass determinations with either technique. This is essential if one wants to interpret the correlation between the BH mass and other global galaxy parameters (e.g. velocity dispersion) and in particular the scatter in these correlations (believed to be only ~0.3 dex). [Abridged]Comment: 51 pages, LaTeX with 19 PostScript figures. Revised version, with three new figures and data tables. To appear in The Astrophysical Journal, 578, 2002 October 2

Genetic Interaction between Mfrp and Adipor1 Mutations Affect Retinal Disease Phenotypes

Adipor1tm1Dgen and Mfrprd6 mutant mice share similar eye disease characteristics. Previously, studies established a functional relationship of ADIPOR1 and MFRP proteins in maintaining retinal lipidome homeostasis and visual function. However, the independent and/or interactive contribution of both genes to similar disease phenotypes, including fundus spots, decreased axial length, and photoreceptor degeneration has yet to be examined. We performed a gene-interaction study where homozygous Adipor1tm1Dgen and Mfrprd6 mice were bred together and the resulting doubly heterozygous F1 offspring were intercrossed to produce 210 F2 progeny. Four-month-old mice from all nine genotypic combinations obtained in the F2 generation were assessed for white spots by fundus photo documentation, for axial length by caliper measurements, and for photoreceptor degeneration by histology. Two-way factorial ANOVA was performed to study individual as well as gene interaction effects on each phenotype. Here, we report the first observation of reduced axial length in Adipor1tmlDgen homozygotes. We show that while Adipor1 and Mfrp interact to affect spotting and degeneration, they act independently to control axial length, highlighting the complex functional association between these two genes. Further examination of the molecular basis of this interaction may help in uncovering mechanisms by which these genes perturb ocular homeostasis

Regulation of the fibrosis and angiogenesis promoter SPARC/osteonectin in human adipose tissue by weight change, leptin, insulin, and glucose

This is the final version of the article. Available from the publisher via the DOI in this record.OBJECTIVE: Matricellular Secreted Protein, Acidic and Rich in Cysteine (SPARC), originally discovered in bone as osteonectin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines. RESEARCH DESIGN AND METHODS: Serum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 +/- 3.7 kg). Another six lean subjects underwent fast-food-based hyperalimentation for 4 weeks (weight gain: 7.2 +/- 1.6 kg). Finally, visceral adipose tissue explants were cultured with recombinant leptin, insulin, and glucose, and SPARC mRNA and protein expression determined by Western blot analyses. RESULTS: SPARC expression in human adipose tissue correlated with fat mass and was higher in SCAT. Weight loss induced by very-low-calorie diet lowered SPARC expression by 33% and increased by 30% in adipose tissue of subjects gaining weight after a fast-food diet. SPARC expression was correlated with leptin independent of fat mass and correlated with homeostasis model assessment-insulin resistance. In vitro experiments showed that leptin and insulin potently increased SPARC production dose dependently in visceral adipose tissue explants, while glucose decreased SPARC protein. CONCLUSIONS: Our data suggest that SPARC expression is predominant in subcutaneous fat and its expression and secretion in adipose tissue are influenced by fat mass, leptin, insulin, and glucose. The profibrotic effects of SPARC may contribute to metabolic dysregulation in obesity.This work was supported by Diabetes UK, Swedish Research Council (11285), University Hospital of Linkoping Research Funds; Diabetes Research Centre of Linkoping University; and the Gamla Tjaenarinnor Foundation. No potential conflicts of interest relevant to this article were reported. Parts of this study were presented in abstract form at the 69th Scientific Sessions of the American Diabetes Association, New Orleans, Louisiana, 5–9 June 2009