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Currently, there is a growing interest in ensuring the transparency and reproducibility of the published scientific literature. According to a previous evaluation of 441 biomedical journals articles published in 2000-2014, the biomedical literature largely lacked transparency in important dimensions. Here, we surveyed a random sample of 149 biomedical articles published between 2015 and 2017 and determined the proportion reporting sources of public and/or private funding and conflicts of interests, sharing protocols and raw data, and undergoing rigorous independent replication and reproducibility checks. We also investigated what can be learned about reproducibility and transparency indicators from open access data provided on PubMed. The majority of the 149 studies disclosed some information regarding funding (103, 69.1% [95% confidence interval, 61.0% to 76.3%]) or conflicts of interest (97, 65.1% [56.8% to 72.6%]). Among the 104 articles with empirical data in which protocols or data sharing would be pertinent, 19 (18.3% [11.6% to 27.3%]) discussed publicly available data; only one (1.0% [0.1% to 6.0%]) included a link to a full study protocol. Among the 97 articles in which replication in studies with different data would be pertinent, there were five replication efforts (5.2% [1.9% to 12.2%]). Although clinical trial identification numbers and funding details were often provided on PubMed, only two of the articles without a full text article in PubMed Central that discussed publicly available data at the full text level also contained information related to data sharing on PubMed; none had a conflicts of interest statement on PubMed. Our evaluation suggests that although there have been improvements over the last few years in certain key indicators of reproducibility and transparency, opportunities exist to improve reproducible research practices across the biomedical literature and to make features related to reproducibility more readily visible in PubMed.

There is a growing movement to encourage reproducibility and transparency practices in the scientific community, including public access to raw data and protocols, the conduct of replication studies, systematic integration of evidence in systematic reviews, and the documentation of funding and potential conflicts of interest. In this survey, we assessed the current status of reproducibility and transparency addressing these indicators in a random sample of 441 biomedical journal articles published in 2000-2014. Only one study provided a full protocol and none made all raw data directly available. Replication studies were rare (n = 4), and only 16 studies had their data included in a subsequent systematic review or meta-analysis. The majority of studies did not mention anything about funding or conflicts of interest. The percentage of articles with no statement of conflict decreased substantially between 2000 and 2014 (94.4% in 2000 to 34.6% in 2014); the percentage of articles reporting statements of conflicts (0% in 2000, 15.4% in 2014) or no conflicts (5.6% in 2000, 50.0% in 2014) increased. Articles published in journals in the clinical medicine category versus other fields were almost twice as likely to not include any information on funding and to have private funding. This study provides baseline data to compare future progress in improving these indicators in the scientific literature.

Recent concerns about the reproducibility of science have led to several calls for more open and transparent research practices and for the monitoring of potential improvements over time. However, with tens of thousands of new biomedical articles published per week, manually mapping and monitoring changes in transparency is unrealistic. We present an open-source, automated approach to identify 5 indicators of transparency (data sharing, code sharing, conflicts of interest disclosures, funding disclosures, and protocol registration) and apply it across the entire open access biomedical literature of 2.75 million articles on PubMed Central (PMC). Our results indicate remarkable improvements in some (e.g., conflict of interest [COI] disclosures and funding disclosures), but not other (e.g., protocol registration and code sharing) areas of transparency over time, and map transparency across fields of science, countries, journals, and publishers. This work has enabled the creation of a large, integrated, and openly available database to expedite further efforts to monitor, understand, and promote transparency and reproducibility in science.

A signaling pathway that induces programmed necrotic cell death (necroptosis) was reported to be activated in cells by several cytokines and various pathogen components. The major proteins participating in that pathway are the protein kinases RIPK1 and RIPK3 and the pseudokinase mixed lineage kinase domain-like protein (MLKL). Recent studies have suggested that MLKL, once activated, mediates necroptosis by binding to cellular membranes, thereby triggering ion fluxes. However, our knowledge of both the sequence of molecular events leading to MLKL activation and the subcellular sites of these events is fragmentary. Here we report that the association of MLKL with the cell membrane in necroptotic death is preceded by the translocation of phosphorylated MLKL, along with RIPK1 and RIPK3, to the nucleus.

A wide variety of multivariable risk models have been developed to predict mortality in the setting of cardiac surgery; however, the relative utility of these models is unknown. This study investigated the literature related to comparisons made between established risk prediction models for perioperative mortality used in the setting of cardiac surgery. A systematic review was conducted to capture studies in cardiac surgery comparing the relative performance of at least 2 prediction models cited in recent guidelines (European System for Cardiac Operative Risk Evaluation [EuroSCORE II], Society for Thoracic Surgeons 2008 Cardiac Surgery Risk Models [STS] score, and Age, Creatinine, Ejection Fraction [ACEF] score) for the outcomes of 1-month or inhospital mortality. For articles that met inclusion criteria, we extracted information on study design, predictive performance of risk models, and potential for bias. Meta-analyses were conducted to calculate a summary estimate of the difference in AUCs between models. We identified 22 eligible studies that contained 33 comparisons among the above models. Meta-analysis of differences in AUCs revealed that the EuroSCORE II and STS score performed similarly (with a summary difference in AUC = 0.00), while outperforming the ACEF score (with summary differences in AUC of 0.10 and 0.08, respectively, p <0.05). Other metrics of discrimination and calibration were presented less consistently, and no study presented any metric of reclassification. Small sample size and absent descriptions of missing data were common in these studies. In conclusion, the EuroSCORE II and STS score outperform the ACEF score on discrimination.

Large-bodied animals play essential roles in ecosystem structuring and stability through both indirect and direct trophic effects. In recent times, humans have disrupted this trophic structure through both habitat destruction and active extirpation of large predators, resulting in large declines in numbers and vast contractions in their geographic ranges. Ripple et al. ( 10.1126/science.1241484 ; see the Perspective by Roberts ) review the status, threats, and ecological importance of the 31 largest mammalian carnivores globally. These species are responsible for a suite of direct and indirect stabilizing effects in ecosystems. Current levels of decline are likely to result in ecologically ineffective population densities and can lead to ecosystem instability. The preservation of large carnivores can be challenging because of their need for large ranges and their potential for human conflict. However, the authors demonstrate that the preservation of large carnivores is ecologically important and that the need for conservation action is immediate, given the severity of the threats they face. Large carnivores face serious threats and are experiencing massive declines in their populations and geographic ranges around the world. We highlight how these threats have affected the conservation status and ecological functioning of the 31 largest mammalian carnivores on Earth. Consistent with theory, empirical studies increasingly show that large carnivores have substantial effects on the structure and function of diverse ecosystems. Significant cascading trophic interactions, mediated by their prey or sympatric mesopredators, arise when some of these carnivores are extirpated from or repatriated to ecosystems. Unexpected effects of trophic cascades on various taxa and processes include changes to bird, mammal, invertebrate, and herpetofauna abundance or richness; subsidies to scavengers; altered disease dynamics; carbon sequestration; modified stream morphology; and crop damage. Promoting tolerance and coexistence with large carnivores is a crucial societal challenge that will ultimately determine the fate of Earth’s largest carnivores and all that depends upon them, including humans.

AbstractObjectiveTo characterize potential drug safety signals identified from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), from 2008 to 2019, to determine how often these signals resulted in regulatory action by the FDA and whether these actions were corroborated by published research findings or public assessments by the Sentinel Initiative.DesignCross sectional study.SettingUSA.PopulationSafety signals identified from the FAERS and publicly reported by the FDA between 2008 and 2019; and review of the relevant literature published before and after safety signals were reported in 2014-15. Literature searches were performed in November 2019, Sentinel Initiative assessments were searched in December 2021, and data analysis was finalized in December 2021.Main outcome measuresSafety signals and resulting regulatory actions; number and characteristics of published studies, including corroboration of regulatory action as evidenced by significant associations (or no associations) between the drug related to the signal and the adverse event.ResultsFrom 2008 to 2019, 603 potential safety signals identified from the FAERS were reported by the FDA (median 48 annually, interquartile range 41-61), of which 413 (68.5%) were resolved as of December 2021 (372 of 399 (93.2%) signals ≥3 years old were resolved). Among the resolved safety signals, 91 (22.0%) led to no regulatory action and 322 (78.0%) resulted in regulatory action, including 319 (77.2%) changes to drug labeling and 59 (14.3%) drug safety communications or other public communications from the FDA. For a subset of 82 potential safety signals reported in 2014-15, a literature search identified 1712 relevant publications; 1201 (70.2%) were case reports or case series. Among these 82 safety signals, 76 (92.7%) were resolved, of which relevant published research was identified for 57 (75.0%) signals and relevant Sentinel Initiative assessments for four (5.3%) signals. Regulatory actions by the FDA were corroborated by at least one relevant published research study for 17 of the 57 (29.8%) resolved safety signals; none of the relevant Sentinel Initiative assessments corroborated FDA regulatory action.ConclusionsMost potential safety signals identified from the FAERS led to regulatory action by the FDA. Only a third of regulatory actions were corroborated by published research, however, and none by public assessments from the Sentinel Initiative. These findings suggest that either the FDA is taking regulatory actions based on evidence not made publicly available or more comprehensive safety evaluations might be needed when potential safety signals are identified.

Non-Hodgkin lymphoma (NHL) is one of the most common haematologic malignancies in the world. Despite substantial efforts to identify causes and risk factors for NHL, its aetiology is largely unclear. Autoimmune diseases have long been considered potential risk factors for NHL. We carried out Mendelian randomisation (MR) analyses to examine whether genetically predicted susceptibility to ten autoimmune diseases (Behçet's disease, coeliac disease, dermatitis herpetiformis, lupus, psoriasis, rheumatoid arthritis, sarcoidosis, Sjögren's syndrome, systemic sclerosis, and type 1 diabetes) is associated with risk of NHL. Two-sample MR was performed using publicly available summary statistics from cohorts of European ancestry. For NHL and four NHL subtypes, we used data from UK Biobank, Kaiser Permanente cohorts, and FinnGen studies. Negative associations between type 1 diabetes and sarcoidosis and the risk of NHL were observed (odds ratio [OR] 0.95, 95% confidence interval [CI]: 0.92-0.98, p = 5 × 10 , and OR 0.92, 95% CI: 0.85-0.99, p = 2.8 × 10 , respectively). These findings were supported by the sensitivity analyses accounting for potential pleiotropy and weak instrument bias. No significant associations were found between the other eight autoimmune diseases and NHL risk. These findings suggest that genetically predicted susceptibility to type 1 diabetes, and to some extent sarcoidosis, might reduce the risk of NHL. However, future studies with different datasets, approaches, and populations are warranted to further examine the potential associations between these autoimmune diseases and the risk of NHL.

Large ‘apex’ predators influence ecosystems in profound ways, by limiting the density of their prey and controlling smaller ‘mesopredators’. The loss of apex predators from much of their range has lead to a global outbreak of mesopredators, a process known as ‘mesopredator release’ that increases predation pressure and diminishes biodiversity. While the classifications apex‐ and meso‐predator are fundamental to current ecological thinking, their definition has remained ambiguous. Trophic cascades theory has shown the importance of predation as a limit to population size for a variety of taxa (top–down control). The largest of predators however are unlikely to be limited in this fashion, and their densities are commonly assumed to be determined by the availability of their prey (bottom–up control). However, bottom–up regulation of apex predators is contradicted by many studies, particularly of non‐hunted populations. We offer an alternative view that apex predators are distinguishable by a capacity to limit their own population densities (self‐regulation). We tested this idea using a set of life‐history traits that could contribute to self‐regulation in the Carnivora, and found that an upper limit body mass of 34 kg (corresponding with an average mass of 13–16 kg) marks a transition between extrinsically‐ and self‐regulated carnivores. Small carnivores share fast reproductive rates and development and higher densities. Large carnivores share slow reproductive rates and development, extended parental care, sparsely populated territories, and a propensity towards infanticide, reproductive suppression, alloparental care and cooperative hunting. We discuss how the expression of traits that contribute to self‐regulation (e.g. reproductive suppression) depends on social stability, and highlight the importance of studying predator–prey dynamics in the absence of predator persecution. Self‐regulation in large carnivores may ensure that the largest and the fiercest do not overexploit their resources.