Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications.

OBJECTIVE To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. DESIGN Cohort of protocols of randomised controlled trial and subsequent full journal publications. SETTING Six research ethics committees in Switzerland, Germany, and Canada. DATA SOURCES 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. RESULTS Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. CONCLUSIONS Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

Notes on the diplomatic history of the Jewish question : with texts of protocols, treaty stipulations and other public acts and official documents

by Lucien Wolf

Evaluating gillnetting protocols to characterize lacustrine fish communities

Ecological research and monitoring of lacustrine ecosystems often requires a whole-lake assessment of fish communities. Gillnet sampling offers an efficient means of estimating abundance, biomass and fish community composition. However the choice of gillnet sampling protocol may influence lake characterization via physical properties of the nets and allocation of sampling effort between littoral, benthic and pelagic habitats. This paper compares two commonly used, whole-lake sampling protocols applied across 17 prealpine, subalpine and alpine European lakes ranging widely in size, depth and altitude to determine their relative strength for research and management applications. Effort-corrected estimates of abundance, biomass and species richness were correlated between the protocols and both distinguished the trout-dominated alpine communities from subalpine and prealpine lakes dominated by whitefish and perch. A considerable amount of variance remained unexplained between the two protocols however, which seemed to correspond with differences in the proportion of effort among benthic and pelagic habitats. We suggest that both the European standard (CEN) and vertical (VERT) netting protocols are suitable for assessing ecological status and monitoring changes in lake fish communities through time. However the details of each protocol should be kept in mind when comparing fish communities between lakes. Mesh sizes used in CEN nets produce a more even size frequency distribution, suggesting that this protocol is most appropriate for assessing size structure of fish assemblages. The high proportion of netting effort in benthic habitats shallower than 70 m depth under the CEN protocol means that, particularly in larger lakes, outcomes will be disproportionately influenced by the ecological condition of this habitat. The VERT protocol presumably provides a more accurate estimate of whole-lake CPUE and community composition because effort, in terms of net area, is more evenly distributed across the entire volume of the lake. This is particularly important in large and deep lakes where pelagic habitats occupy a high proportion of the lake volume.

Efficacy of patient-administered mechanical and/or chemical plaque control protocols in the management of peri-implant mucositis. A systematic review

AIM To systematically assess the efficacy of patient-administered mechanical and/or chemical plaque control protocols in the management of peri-implant mucositis (PM). MATERIAL AND METHODS Randomized (RCTs) and Controlled Clinical Trials (CCTs) were identified through an electronic search of three databases complemented by manual search. Identification, screening, eligibility and inclusion of studies was performed independently by two reviewers. Studies without professional intervention or with only mechanical debridement professionally administered were included. Quality assessment was performed by means of the Cochrane Collaboration's tool for assessing risk of bias. RESULTS Eleven RCTs with a follow-up from 3 to 24 months were included. Definition of PM was lacking or heterogeneously reported. Complete resolution of PM was not achieved in any study. One study reported 38% of patients with complete resolution of PM. Surrogate end-point outcomes of PM therapy were often reported. The choice of control interventions showed great variability. The efficacy of powered toothbrushes, a triclosan-containing toothpaste and adjunctive antiseptics remains to be established. High quality of methods and reporting was found in four studies. CONCLUSIONS Professionally- and patient-administered mechanical plaque control alone should be considered the standard of care in the management of PM. Therapy of PM is a prerequisite for the prevention of peri-implantitis.

Comparison of two protocols of periosteal distraction osteogenesis in a rabbit calvaria model

The regenerative pathways during periosteal distraction osteogenesis may be influenced by the local environment composed by cells, growth factors, nutrition and mechanical load. The aim of the present study was to evaluate the influence of two protocols of periosteal distraction on bone formation. Custom made distraction devices were surgically fixed onto the calvariae of 60 rabbits. After an initial healing period of 7 days, two groups of animals were submitted to distraction rates of 0.25 and 0.5 mm/24 h for 10 days, respectively. Six animals per group were sacrificed 10 (mid-distraction), 17 (end-distraction), 24 (1-week consolidation), 31 (2-week consolidation) and 77 days (2-month consolidation) after surgery. Newly formed bone was assessed by means of micro-CT and histologically. Expression of transcripts encoding tissue-specific genes (BMP-2, RUNX2, ACP5, SPARC, collagen I α1, collagen II α1 and SOX9) was analyzed by quantitative PCR. Two patterns of bone formation were observed, originating from the old bone surface in Group I and from the periosteum in Group II. Bone volume (BV) and bone mineral density (BMD) significantly increased up to the 2-month consolidation period within the groups (p < 0.05). Significantly more bone was observed in Group II compared to Group I at the 2-month consolidation period (p < 0.001). Expression of transcripts encoding osteogenic genes in bone depended on the time-point of observation (p < 0.05). Low level of transcripts reveals an indirect role of periosteum in the osteogenic process. Two protocols of periosteal distraction in the present model resulted in moderate differences in terms of bone formation.

An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules.

OBJECTIVES To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.

In vitro differentiation of mouse granulocytes. Programmed Cell Death: Methods and Protocols

Granulocytes are central players of the immune system and, once activated, a tightly controlled balance between effector functions and cell removal by apoptosis guarantees maximal host benefit with least possible collateral damage to healthy tissue. Granulocytes are end-differentiated cells that cannot be maintained in culture for prolonged times. Isolating primary granulocytes is inefficient and challenging when working with mice, and especially so for the lowly abundant eosinophil and basophils subtypes. Here we describe an in vitro protocol to massively expand mouse derived myeloid progenitors and to differentiate them ‘on demand’ and in large numbers into mature neutrophils or basophils.

A systematic review on the innervation of peri-implant tissues with special emphasis on the influence of implant placement and loading protocols

OBJECTIVES To systematically review the available literature on the influence of dental implant placement and loading protocols on peri-implant innervation. MATERIAL AND METHODS The database MEDLINE, Cochrane, EMBASE, Web of Science, LILACS, OpenGrey and hand searching were used to identify the studies published up to July 2013, with a populations, exposures and outcomes (PEO) search strategy using MeSH keywords, focusing on the question: Is there, and if so, what is the effect of time between tooth extraction and implant placement or implant loading on neural fibre content in the peri-implant hard and soft tissues? RESULTS Of 683 titles retrieved based on the standardized search strategy, only 10 articles fulfilled the inclusion criteria, five evaluating the innervation of peri-implant epithelium, five elucidating the sensory function in peri-implant bone. Three included studies were considered having a methodology of medium quality and the rest were at low quality. All those papers reported a sensory innervation around osseointegrated implants, either in the bone-implant interface or peri-implant epithelium, which expressed a particular innervation pattern. Compared to unloaded implants or extraction sites without implantation, a significant higher density of nerve fibres around loaded dental implants was confirmed. CONCLUSIONS To date, the published literature describes peri-implant innervation with a distinct pattern in hard and soft tissues. Implant loading seems to increase the density of nerve fibres in peri-implant tissues, with insufficient evidence to distinguish between the innervation patterns following immediate and delayed implant placement and loading protocols. Variability in study design and loading protocols across the literature and a high risk of bias in the studies included may contribute to this inconsistency, revealing the need for more uniformity in reporting, randomized controlled trials, longer observation periods and standardization of protocols.

Discrepancies in Outcome Reporting Exist Between Protocols and Published Oral Health Cochrane Systematic Reviews

OBJECTIVES To assess discrepancies in the analyzed outcomes between protocols and published reviews within Cochrane oral health systematic reviews (COHG) on the Cochrane Database of Systematic Reviews (CDSR). STUDY DESIGN AND SETTING All COHG systematic reviews on the CDSR and the corresponding protocols were retrieved in November 2014 and information on the reported outcomes was recorded. Data was collected at the systematic review level by two reviewers independently. RESULTS One hundred and fifty two reviews were included. In relation to primary outcomes, 11.2% were downgraded to secondary outcomes, 9.9% were omitted altogether in the final publication and new primary outcomes were identified in 18.4% of publications. For secondary outcomes, 2% were upgraded to primary, 12.5% were omitted and 30.9% were newly introduced in the publication. Overall, 45.4% of reviews had at least one discrepancy when compared to the protocol; these were reported in 14.5% reviews. The number of review updates appears to be associated with discrepancies between final review and protocol (OR: 3.18, 95% CI: 1.77, 5.74, p<0.001). The risk of reporting significant results was lower for both downgraded outcomes [RR: 0.52, 95% CI: 0.17, 1.58, p = 0.24] and upgraded or newly introduced outcomes [RR: 0.77, 95% CI: 0.36, 1.64, p = 0.50] compared to outcomes with no discrepancies. The risk of reporting significant results was higher for upgraded or newly introduced outcomes compared to downgraded outcomes (RR = 1.19, 95% CI: 0.65, 2.16, p = 0.57). None of the comparisons reached statistical significance. CONCLUSION While no evidence of selective outcome reporting was found in this study, based on the present analysis of SRs published within COHG systematic reviews, discrepancies between outcomes in pre-published protocols and final reviews continue to be common. Solutions such as the use of standardized outcomes to reduce the prevalence of this issue may need to be explored.

Design of a systematic approach to workplace exposure medical surveillance protocols

Current toxic tort cases have increased national awareness of health concerns and present an important avenue in which public health scientists can perform a vital function: in litigation, and in public health initiatives and promotions which may result. This review presents a systematic approach, using the paradigm of interactive public health disciplines, for the design of a matrix framework for medical surveillance of workers exposed to toxic substances. The matrix framework design addresses the required scientific bases to support the legal remedy of medical monitoring for workers injured as a result of their exposure to toxic agents. A background of recent legal developments which have a direct impact on the use of scientific expertise in litigation is examined in the context of toxic exposure litigation and the attainment of public health goals. The matrix model is applied to five different workplace exposures: dental mercury, firefighting, vinyl chloride manufacture, radon in mining and silica. An exposure matrix designed by the Department of Energy for government nuclear workers is included as a reference comparison to the design matrix. ^

Cryptographic properties of Boolean functions defining elementary cellular automata

In this work, the algebraic properties of the local transition functions of elementary cellular automata (ECA) were analysed. Specifically, a classification of such cellular automata was done according to their algebraic degree, the balancedness, the resiliency, nonlinearity, the propagation criterion and the existence of non-zero linear structures. It is shown that there is not any ECA satisfying all properties at the same time.

Fast measurement of cooling and heating rates in standard cryopreservation protocols based on vitrification

Estudio de la cinética de la crioconservación de tejidos vegetales