Publications

Concordance between EMA Good Clinical Practice inspections and medical literature concerning drugs that have not received marketing authorization in the European Union: a meta-research survey

Abstract Objectives To describe the differences between European Medicine Agency (EMA) Good Clinical Practice (GCP) inspection reports and medical literature on drugs with withdrawn or refused applications. Design A retrospective study comparing studies included in European Public Assessment Reports (EPARs) and the corresponding articles published in the medical literature. Data sources We screened all EPARs released by the EMA from inception to April 2024 for drugs that were refused or had a withdrawn application. In those EPARs, we looked for mentions of GCP inspections and details about them, then we searched for related publications on the inspected studies on bibliographic databases. Eligibility criteria All EPARs mentioning good clinical practice inspection were included in this survey. Data extracted Two reviewers independently gathered information on the GCP inspections and their findings, including the EMA’s opinion on their impact on the study data. The reviewers checked related publications for mentions of the inspection and any subsequent correction, retraction, or expressions of concern related to its findings. Main outcome measures The main outcome was the mention of the GCP inspection findings in the publication of the inspected studies. We also assessed whether there was any mention of these findings in a correction, retraction, or expression of concern. Results Out of 285 EPARs screened, 57 (20%) mentioned a GCP inspection. 58 distinct studies with inspections had 61 publications. For 17 publications the inspection occurred after the publication, for 20 the inspection happened before the publication, and for 24 the date of the inspection was unknown. Only 1 publication (2%) addressed the inspection findings. Moreover, there were no corrections, retractions, or expressions of concern related to inspection findings. Among the 61 publications, 26 (43%) were related with 24 distinct studies that had an inspection that casted doubts on data reliability, but none mentioned the inspections at or after the time of publication. Conclusions This meta-research survey indicates that health authorities’ GCP inspections are not reflected in the published literature, even when the inspections have put the data reliability in doubt. Journals should clearly specify which aspects of those studies are trustworthy and which ones are not. Trial registration osf.io/pa9fq/

Twelve years after the ARRIVE guidelines: Animal research has not yet arrived at high standards

The reproducibility crisis across animal studies jeopardizes the credibility of the main findings derived from animal research, even though these findings are critical for informing human studies. To clarify and improve transparency among animal studies, the ARRIVE reporting guidelines were first announced in 2010 and upgraded to version 2.0 in 2020. However, compliance with and awareness of those reporting guidelines has remained suboptimal. Journal editors should encourage the authors to adhere to those guidelines. Authors, editors, referees, and reviewers should be aware of the ARRIVE guideline 2.0 when assessing and evaluating the methodology and findings of animal studies. However, we should also question whether reporting guidelines alone can change a research culture and improve the reproducibility of animal investigations. Reported research may not reflect actual research. Large segments of animal research efforts are wasted because of poor design choices and because of non-publication rather than suboptimal reporting. Better training of the scientific workforce, interventions at improving animal research at the design stage, registration practices, and alignment of the reward system with the publication of rigorous animal research may achieve more than reporting guidelines alone.

The Sparse Abstract Machine

We propose the Sparse Abstract Machine (SAM), an abstract machine model for targeting sparse tensor algebra to reconfigurable and fixed-function spatial dataflow accelerators. SAM defines a streaming dataflow abstraction with sparse primitives that encompass a large space of scheduled tensor algebra expressions. SAM dataflow graphs naturally separate tensor formats from algorithms and are expressive enough to incorporate arbitrary iteration orderings and many hardware-specific optimizations. We also present Custard, a compiler from a high-level language to SAM that demonstrates SAM's usefulness as an intermediate representation. We automatically bind from SAM to a streaming dataflow simulator. We evaluate the generality and extensibility of SAM, explore the performance space of sparse tensor algebra optimizations using SAM, and show SAM's ability to represent dataflow hardware.

The KeyNote Trust-Management System Version 2

This memo describes version 2 of the KeyNote trust-management system. It specifies the syntax and semantics of KeyNote `assertions', describes `action attribute' processing, and outlines the application architecture into which a KeyNote implementation can be fit. The KeyNote architecture and language are useful as building blocks for the trust management aspects of a variety of Internet protocols and services.

Large-scale Meta-analysis of Genome-wide Association (GWA) Scans for Osteoporosis Traits: the GEFOS Consortium

Supplementary Figure 8 from Collaborative Cancer Epidemiology in the 21st Century: The Model of Cancer Consortia

<p>PDF - 27KB, Percentage of CEC papers published each year that are linkage studies or GWAS.</p>

Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy

Achilles tendinopathy or rupture and anterior cruciate ligament (ACL) rupture are substantial injuries affecting athletes, associated with delayed recovery or inability to return to competition. To identify genetic markers that might be used to predict risk for these injuries, we performed genome-wide association screens for these injuries using data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort consisting of 102,979 individuals. We did not find any single nucleotide polymorphisms (SNPs) associated with either of these injuries with a p-value that was genome-wide significant (p<5x10-8). We found, however, four and three polymorphisms with p-values that were borderline significant (p<10-6) for Achilles tendon injury and ACL rupture, respectively. We then tested SNPs previously reported to be associated with either Achilles tendon injury or ACL rupture. None showed an association in our cohort with a false discovery rate of less than 5%. We obtained, however, moderate to weak evidence for replication in one case; specifically, rs4919510 in MIR608 had a p-value of 5.1x10-3 for association with Achilles tendon injury, corresponding to a 7% chance of false replication. Finally, we tested 2855 SNPs in 90 candidate genes for musculoskeletal injury, but did not find any that showed a significant association below a false discovery rate of 5%. We provide data containing summary statistics for the entire genome, which will be useful for future genetic studies on these injuries.

Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems

The dorsal raphe (DR) constitutes a major serotonergic input to the forebrain and modulates diverse functions and brain states, including mood, anxiety, and sensory and motor functions. Most functional studies to date have treated DR serotonin neurons as a single population. Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell-body distributions within the DR and differentially co-express a vesicular glutamate transporter. Further, amygdala- and frontal-cortex-projecting DR serotonin neurons have largely complementary whole-brain collateralization patterns, receive biased inputs from presynaptic partners, and exhibit opposite responses to aversive stimuli. Gain- and loss-of-function experiments suggest that amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal-cortex-projecting neurons promote active coping in the face of challenge. These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.

Reporting of demographic data and representativeness in machine learning models using electronic health records

Abstract Objective The development of machine learning (ML) algorithms to address a variety of issues faced in clinical practice has increased rapidly. However, questions have arisen regarding biases in their development that can affect their applicability in specific populations. We sought to evaluate whether studies developing ML models from electronic health record (EHR) data report sufficient demographic data on the study populations to demonstrate representativeness and reproducibility. Materials and Methods We searched PubMed for articles applying ML models to improve clinical decision-making using EHR data. We limited our search to papers published between 2015 and 2019. Results Across the 164 studies reviewed, demographic variables were inconsistently reported and/or included as model inputs. Race/ethnicity was not reported in 64%; gender and age were not reported in 24% and 21% of studies, respectively. Socioeconomic status of the population was not reported in 92% of studies. Studies that mentioned these variables often did not report if they were included as model inputs. Few models (12%) were validated using external populations. Few studies (17%) open-sourced their code. Populations in the ML studies include higher proportions of White and Black yet fewer Hispanic subjects compared to the general US population. Discussion The demographic characteristics of study populations are poorly reported in the ML literature based on EHR data. Demographic representativeness in training data and model transparency is necessary to ensure that ML models are deployed in an equitable and reproducible manner. Wider adoption of reporting guidelines is warranted to improve representativeness and reproducibility.

Access to data from clinical trials in the COVID-19 crisis: open, flexible, and time-sensitive

•Challenges of rapid COVID-19 drug development risk to compromise good scientific practice•Access to patient-level data especially urgent to address risks of protocol violations and rapid reviews.•Open access to data enables transparency, secondary analyses, and meta-analyses.•Politicization of scientific reports will be reduced by cross-checking and multilateral analyses.

Therapy and prevention for mental health: What if mental diseases are mostly not brain disorders?

Abstract Neurobiology-based interventions for mental diseases and searches for useful biomarkers of treatment response have largely failed. Clinical trials should assess interventions related to environmental and social stressors, with long-term follow-up; social rather than biological endpoints; personalized outcomes; and suitable cluster, adaptive, and n-of-1 designs. Labor, education, financial, and other social/political decisions should be evaluated for their impacts on mental disease.

Book Review

Tiny Tera: a packet switch core

Describes Tiny Tera: a small, high-bandwidth, single-stage switch. Tiny Tera has 32 ports switching fixed-size packets, each operating at over 10 Gbps (approximately the Sonet OC-192e rate, a telecom standard for system interconnects). The switch distinguishes four classes of traffic and includes efficient support for multicasting. We aim to demonstrate that it is possible to use currently available CMOS technology to build this compact switch with an aggregate bandwidth of approximately 1 terabit per second and a central hub no larger than a can of soda. Such a switch could serve as a core for an ATM switch or an Internet router. Tiny Tera is an input-buffered switch, which makes it the highest bandwidth switch possible given a particular CMOS and memory technology. The switch consists of three logical elements: ports, a central crossbar switch, and a central scheduler. It queues packets at a port on entry and optionally prior to exit. The scheduler, which has a map of each port's queue occupancy, determines the crossbar configuration every packet time slot. Input queueing, parallelism, and tight integration are the keys to such a high-bandwidth switch. Input queueing reduces the memory bandwidth requirements: When a switch queues packets at the input, the buffer memories need run no faster than the line rate. Thus, there is no need for the speedup required in output-queued switches.

DESMOPRESSIN FOR NOCTURNAL INCONTINENCE IN THE SPINA BIFIDA POPULATION

No AccessJournal of UrologyPediatric Urology1 Dec 1997DESMOPRESSIN FOR NOCTURNAL INCONTINENCE IN THE SPINA BIFIDA POPULATION Mark Horowitz, Andrew J. Combs, and Dawn Gerdes Mark HorowitzMark Horowitz More articles by this author , Andrew J. CombsAndrew J. Combs More articles by this author , and Dawn GerdesDawn Gerdes More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(01)68232-6AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We report our experience with the use of desmopressin in the spina bifida population that is dry during the day but wet at night. Materials and Methods: From 1994 to 1996, 18 patients with myelodysplasia were treated with desmopressin for persistent nocturnal enuresis. Initial dose was 40 mcg. before bedtime, decreased by intervals of 10 mcg. every 3 weeks. Patients were kept on the minimum dose required to keep them dry. We reviewed morning catheterized volumes, side effects and dosages needed to stay dry, and compared augmented patients with nonaugmented patients. Results: Of 18 patients 14 (78%) reported marked improvement in nocturnal enuresis. Of 6 augmented patients 5 (83%) are dry compared to 9 of 12 nonaugmented patients (75%). There were no adverse side effects from the use of desmopressin. Average dose to stay dry was 20 mcg. for augmented and 30 mcg. for nonaugmented patients. Of the 4 patients who had persistent nocturnal incontinence despite desmopressin 3 (75%) became dry with a single catheterization in the middle of the night. Conclusions: Desmopressin is successful in treating nocturnal enuresis in the spina bifida patient with diurnal continence. References 1 : DDAVP in the urological management of the difficult neurogenic bladder in spinal cord injury: preliminary report.. J. Amer. Paraplegia Soc.1994; 17: 165. Google Scholar From the State University of New York Health Science Center at Brooklyn, Brooklyn, New York.Accepted for publication June 27, 1997.(Horowitz) Requests for reprints: 450 Clarkson Ave., Box 79, Brooklyn, New York 11203.© 1997 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited byDEL GADO R, ACETO G, DEL GAIZO D, DEL GADO G, POLIDORI G and CHIOZZA M (2018) DESMOPRESSIN FOR THE TREATMENT OF NOCTURNAL BEDWETTING IN PATIENTS WITH NEURAL TUBE CLOSURE DEFECTSJournal of Urology, VOL. 171, NO. 4, (1656-1658), Online publication date: 1-Apr-2004. Volume 158Issue 6December 1997Page: 2267-2268 Advertisement Copyright & Permissions© 1997 by American Urological Association, Inc.Metrics Author Information Mark Horowitz More articles by this author Andrew J. Combs More articles by this author Dawn Gerdes More articles by this author Expand All Advertisement PDF downloadLoading ...

Conform and be funded

Guidelines Do Not Entangle Practitioners With Unavoidable Conflicts as Authors, and When There Is No Evidence, Just Say So

What is the vibration of effects?

International audience

Why Most Discovered True Associations Are Inflated

Newly discovered true (non-null) associations often have inflated effects compared with the true effect sizes. I discuss here the main reasons for this inflation. First, theoretical considerations prove that when true discovery is claimed based on crossing a threshold of statistical significance and the discovery study is underpowered, the observed effects are expected to be inflated. This has been demonstrated in various fields ranging from early stopped clinical trials to genome-wide associations. Second, flexible analyses coupled with selective reporting may inflate the published discovered effects. The vibration ratio (the ratio of the largest vs. smallest effect on the same association approached with different analytic choices) can be very large. Third, effects may be inflated at the stage of interpretation due to diverse conflicts of interest. Discovered effects are not always inflated, and under some circumstances may be deflated-for example, in the setting of late discovery of associations in sequentially accumulated overpowered evidence, in some types of misclassification from measurement error, and in conflicts causing reverse biases. Finally, I discuss potential approaches to this problem. These include being cautious about newly discovered effect sizes, considering some rational down-adjustment, using analytical methods that correct for the anticipated inflation, ignoring the magnitude of the effect (if not necessary), conducting large studies in the discovery phase, using strict protocols for analyses, pursuing complete and transparent reporting of all results, placing emphasis on replication, and being fair with interpretation of results.