Publications

The inaugural round of merit review for the Patient-Centered Outcomes Research Institute (PCORI) in November 2012 included patients and other stakeholders, as well as scientists. This article examines relationships among scores of the 3 reviewer types, changes in scoring after in-person discussion, and the effect of inclusion of patient and stakeholder reviewers on the review process. In the first phase, 363 scientists scored 480 applications. In the second phase, 59 scientists, 21 patients, and 31 stakeholders provided a "prediscussion" score and a final "postdiscussion" score after an in-person meeting for applications. Bland-Altman plots were used to characterize levels of agreement among and within reviewer types before and after discussion. Before discussion, there was little agreement among average scores given by the 4 lead scientific reviewers and patient and stakeholder reviewers. After discussion, the 4 primary reviewers showed mild convergence in their scores, and the 21-member panel came to a much stronger agreement. Of the 25 awards with the best (and lowest) scores after phase 2, only 13 had ranked in the top 25 after the phase 1 review by scientists. Five percent of the 480 proposals submitted were funded. The authors conclude that patient and stakeholder reviewers brought different perspectives to the review process but that in-person discussion led to closer agreement among reviewer types. It is not yet known whether these conclusions are generalizable to future rounds of peer review. Future work would benefit from additional data collection for evaluation purposes and from long-term evaluation of the effect on the funded research.

The surface layers (S layers) of those bacteria and archaea that elaborate these crystalline structures have been studied for 40 years. However, most structural analysis has been based on electron microscopy of negatively stained S-layer fragments separated from cells, which can introduce staining artifacts and allow rearrangement of structures prone to self-assemble. We present a quantitative analysis of the structure and organization of the S layer on intact growing cells of the Gram-negative bacterium Caulobacter crescentus using cryo-electron tomography (CET) and statistical image processing. Instead of the expected long-range order, we observed different regions with hexagonally organized subunits exhibiting short-range order and a broad distribution of periodicities. Also, areas of stacked double layers were found, and these increased in extent when the S-layer protein (RsaA) expression level was elevated by addition of multiple rsaA copies. Finally, we combined high-resolution amino acid residue-specific Nanogold labeling and subtomogram averaging of CET volumes to improve our understanding of the correlation between the linear protein sequence and the structure at the 2-nm level of resolution that is presently available. The results support the view that the U-shaped RsaA monomer predicted from negative-stain tomography proceeds from the N terminus at one vertex, corresponding to the axis of 3-fold symmetry, to the C terminus at the opposite vertex, which forms the prominent 6-fold symmetry axis. Such information will help future efforts to analyze subunit interactions and guide selection of internal sites for display of heterologous protein segments.

Morbidity and mortality from preventable, non-communicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology and design thinking. The purpose of this paper is to summarise the results of a consensus meeting on NCD prevention sponsored by the IOC in April 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within healthcare systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: (1) Focus on behavioural change as the core component of all clinical programmes for the prevention and management of chronic disease. (2) Establish actual centres to design, implement, study and improve preventive programmes for chronic disease. (3) Use human-centred design in the creation of prevention programmes with an inclination to action, rapid prototyping and multiple iterations. (4) Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programmes for the prevention and treatment of chronic disease focused on physical activity, diet and lifestyle. (5) Mobilise resources and leverage networks to scale and distribute programmes of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programmes within healthcare. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad hoc Working Group charged with the responsibility of moving this agenda forward.

The seven-item Hospital Anxiety and Depression Scale Depression subscale (HADS-D) and the total score of the 14-item HADS (HADS-T) are both used for major depression screening. Compared to the HADS-D, the HADS-T includes anxiety items and requires more time to complete. We compared the screening accuracy of the HADS-D and HADS-T for major depression detection. We conducted an individual participant data meta-analysis and fit bivariate random effects models to assess diagnostic accuracy among participants with both HADS-D and HADS-T scores. We identified optimal cutoffs, estimated sensitivity and specificity with 95% confidence intervals, and compared screening accuracy across paired cutoffs via two-stage and individual-level models. We used a 0.05 equivalence margin to assess equivalency in sensitivity and specificity. 20,700 participants (2,285 major depression cases) from 98 studies were included. Cutoffs of ≥7 for the HADS-D (sensitivity 0.79 [0.75, 0.83], specificity 0.78 [0.75, 0.80]) and ≥15 for the HADS-T (sensitivity 0.79 [0.76, 0.82], specificity 0.81 [0.78, 0.83]) minimized the distance to the top-left corner of the receiver operating characteristic curve. Across all sets of paired cutoffs evaluated, differences of sensitivity between HADS-T and HADS-D ranged from -0.05 to 0.01 (0.00 at paired optimal cutoffs), and differences of specificity were within 0.03 for all cutoffs (0.02-0.03). The pattern was similar among outpatients, although the HADS-T was slightly (not nonequivalently) more specific among inpatients. The accuracy of HADS-T was equivalent to the HADS-D for detecting major depression. In most settings, the shorter HADS-D would be preferred. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Interconnect scaling to deep submicron processes presents many challenges to today's CAD flows. A recent analysis by Sylvester and Keutzer examined the behavior of average length wires under scaling, and controversially concluded that current CAD tools are adequate for future module-level designs. In our work, we show that average length wire scaling is sensitive to the technology assumptions, although the change in their behavior is small under all reasonable scaling assumptions. However, examining only average length wires is optimistic, since long wires are the ones that primarily cause CAD tool exceptions. In a module of fixed complexity, under both optimistic and pessimistic scaling assumptions, the number of long wires will increase slowly with scaling. More importantly, as the overall die capacity grows exponentially, the number of modules and thus the total number of wires in a design, will also increase exponentially. Thus, if the design team size and per-designer workload is to remain relatively constant, future CAD tools will need to handle long wires much better than current tools to reduce the percentage of wires that require designer intervention.

ABSTRACT Introduction Repetitive transcranial magnetic stimulation (rTMS) has been widely tested and promoted for use in multiple neuropsychiatric conditions, but as for many other medical devices, some gaps may exist in the literature and the evidence base for rTMS clinical efficacy remains under debate. We aimed to empirically test for an excess number of statistically significant results in the literature on rTMS therapeutic efficacy across a wide range of meta-analyses and to characterize the power of studies included in these meta-analyses. Methods Based on power calculations, we computed the expected number of “positive” datasets for a medium effect-size (standardized mean difference, SMD=0.30) and compared it with the number of observed “positive” datasets. Sensitivity analyses considered small (SMD=0.20), modest (SMD=0.50), and large (SMD=0.80) effect sizes. Results 14 meta-analyses with 228 datasets (110 for neurological disorders and 118 for psychiatric disorders) were assessed. For SMD=0.3, the number of observed “positive” studies (n=94) was larger than expected (n=35). We found evidence for an excess of significant findings overall (p<0.0001) and in 8/14 meta-analyses. Evidence for an excess of significant findings was also observed for SMD=0.5 for neurological disorders. 0 (0 %), 0 (0 %), 3 (1 %), and 53 (23 %) of the 228 datasets had power >0.80, respectively for SMDs of 0.30, 0.20, 0.50, and 0.80. Conclusion Most studies in the rTMS literature are underpowered. This results in fragmentation and waste of research efforts. The somewhat high frequency of “positive” results seems spurious and may reflect bias. Trial Registration: PROSPERO 2017 CRD42017056694