Abstract Objective GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large‐scale meta‐analysis of individual‐level data. Methods Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex‐specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed‐effects and random‐effects models for allele‐based effects, and also for haplotype effects for FRZB . Results A significant random‐effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) ( P = 9.4 × 10 −7 ), with no significant between‐study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between‐study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [ P = 0.016]) or absent (for OA of the hand [ P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA ( P = 0.019). Conclusion Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
Significance Science is said to be suffering a reproducibility crisis caused by many biases. How common are these problems, across the wide diversity of research fields? We probed for multiple bias-related patterns in a large random sample of meta-analyses taken from all disciplines. The magnitude of these biases varied widely across fields and was on average relatively small. However, we consistently observed that small, early, highly cited studies published in peer-reviewed journals were likely to overestimate effects. We found little evidence that these biases were related to scientific productivity, and we found no difference between biases in male and female researchers. However, a scientist’s early-career status, isolation, and lack of scientific integrity might be significant risk factors for producing unreliable results.
Journal Article Aspergillus fumigatus Infection of a Biloma Get access John P. A. Ioannidis, John P. A. Ioannidis From the Division of Geographic Medicine and Infectious Diseases, Departments of Medicine, Pathology, and Surgery, New England Medical Center, Boston, Massachusetts Reprints or correspondence: Dr. John P. A. Ioannidis, Department of Medicine, Division of Geographic Medicine and Infectious Diseases, New England Medical Center, Box 067, 750 Washington Street, Boston, Massachusetts 02111. Search for other works by this author on: Oxford Academic PubMed Google Scholar David R. Snydman, David R. Snydman From the Division of Geographic Medicine and Infectious Diseases, Departments of Medicine, Pathology, and Surgery, New England Medical Center, Boston, Massachusetts Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard J. Rohrer, Richard J. Rohrer From the Division of Geographic Medicine and Infectious Diseases, Departments of Medicine, Pathology, and Surgery, New England Medical Center, Boston, Massachusetts Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard B. Freeman, Richard B. Freeman From the Division of Geographic Medicine and Infectious Diseases, Departments of Medicine, Pathology, and Surgery, New England Medical Center, Boston, Massachusetts Search for other works by this author on: Oxford Academic PubMed Google Scholar Craig E. Haug Craig E. Haug From the Division of Geographic Medicine and Infectious Diseases, Departments of Medicine, Pathology, and Surgery, New England Medical Center, Boston, Massachusetts Search for other works by this author on: Oxford Academic PubMed Google Scholar Clinical Infectious Diseases, Volume 20, Issue 5, May 1995, Pages 1427–1428, https://doi.org/10.1093/clinids/20.5.1427 Published: 01 May 1995
Abstract : 1. Executive Summary. A summary of progress for the period April 1989 through October 1989 follows: (1) Parallel Architecture: The Stanford DASH multiprocessor advances the state of parallel computing by combining the programmability of shared-memory machines with the scalability of distributed-memory machines. (2) Parallel Software: We have developed a compiler algorithm that applies a large set of loop-level optimizations to improve data locality in programs. (3) Super-Scalar Design: We have investigated how much parallelism is available at the lowest level -- in the base instruction stream of a processor. (4) Multi-level Caches: The presence of a second-level cache can decrease the optimum size and cycle time of the first-level cache, and significantly improve performance beyond the best attainable with a single level of caching. (5) Testers: A single chip tester, called Testarossa, contains a dRAM for the test vector storage, a decompressor to increase the effective vector size, and the pin electronics for 16 DUT pins. (6) Computer Aided Design: In the area of algorithm and tool development for high-level synthesis we have targeted two goals: control generation for synthesized structures and relative scheduling techniques under timing constraints. (7) Simulation: The goal of this research is to provide application tools for the proposed scalable shared memory multiprocessor.
The extended GCD (XGCD) calculation, which computes Bézout coefficients ba, bb such that ba ∗ a0 + bb ∗ b0 = GCD(a0, b0), is a critical operation in many cryptographic applications. In particular, large-integer XGCD is computationally dominant for two applications of increasing interest: verifiable delay functions that square binary quadratic forms within a class group and constant-time modular inversion for elliptic curve cryptography. Most prior work has focused on fast software implementations. The few works investigating hardware acceleration build on variants of Euclid’s division-based algorithm, following the approach used in optimized software. We show that adopting variants of Stein’s subtraction-based algorithm instead leads to significantly faster hardware. We quantify this advantage by performing a large-integer XGCD accelerator design space exploration comparing Euclid- and Stein-based algorithms for various application requirements. This exploration leads us to an XGCD hardware accelerator that is flexible and efficient, supports fast average and constant-time evaluation, and is easily extensible for polynomial GCD. Our 16nm ASIC design calculates 1024-bit XGCD in 294ns (8x faster than the state-of-the-art ASIC) and constant-time 255-bit XGCD for inverses in the field of integers modulo the prime 2255−19 in 85ns (31× faster than state-of-the-art software). We believe our design is the first high-performance ASIC for the XGCD computation that is also capable of constant-time evaluation. Our work is publicly available at https://github.com/kavyasreedhar/sreedhar-xgcd-hardware-ches2022.
A phase-locked loop (PLL) and delay-locked loop (DLL) design with adaptively adjusting bandwidth enables optimal performance over a wide frequency range and across process, voltage, and temperature variations. A design methodology of such adaptive-bandwidth PLLs and DLLs is described. To assess the impact of each circuit parameter directly, we derive a discrete-time, open-loop dynamic model of the PLL/DLL that characterizes the change in output variables in response to the sampled error and we express the adaptive-bandwidth criteria in terms of the open-loop gains, instead of the traditional closed-loop parameters, /spl omega//sub n/ and /spl zeta/. Applying these criteria, we derive scaling equations for the charge-pump current and filter resistance that achieve adaptive bandwidth in charge-pump PLL/DLLs. We show that previously published adaptive-bandwidth PLL/DLLs, a self-biased PLL/DLL and a regulated-supply PLL/DLL, rely on the small-signal conductance tracking the large-signal conductance of the voltage-controlled oscillator/voltage-controlled delay-line and, thus, sustain constant /spl omega//sub n///spl omega//sub ref/ and /spl zeta/ only if the voltage swing is sufficiently higher than the device threshold voltage V/sub TH/. The paper also presents procedures to estimate the open-loop parameters from an open-loop impulse response of the PLL/DLL.
CFDP is a protocol that takes advantage of the broadcast nature of CSMA networks to speed up simultaneous one-to-many file transfers (e.g., when booting diskless workstations). The CFDP server listens and services requests for entire files or portions thereof. CFDP clients first determine whether the file they are interested in is already being transferred, in which case they "eavesdrop" and load as much of it as they can, or they initiate a new transfer. The clients timeout when the server stops transmitting, and if they are still missing parts of the file they request them with a block-transfer request. CFDP is a back-end protocol a front end is needed to handle naming and security issues. A simple such front end is also presented here.
Established guidelines for causal inference in epidemiological studies may be inappropriate for genetic associations. A consensus process was used to develop guidance criteria for assessing cumulative epidemiologic evidence in genetic associations. A proposed semi-quantitative index assigns three levels for the amount of evidence, extent of replication, and protection from bias, and also generates a composite assessment of 'strong', 'moderate' or 'weak' epidemiological credibility. In addition, we discuss how additional input and guidance can be derived from biological data. Future empirical research and consensus development are needed to develop an integrated model for combining epidemiological and biological evidence in the rapidly evolving field of investigation of genetic factors.
