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The methods and results of health research are documented in study protocols, full study reports (detailing all analyses), journal reports, and participant-level datasets. However, protocols, full study reports, and participant-level datasets are rarely available, and journal reports are available for only half of all studies and are plagued by selective reporting of methods and results. Furthermore, information provided in study protocols and reports varies in quality and is often incomplete. When full information about studies is inaccessible, billions of dollars in investment are wasted, bias is introduced, and research and care of patients are detrimentally affected. To help to improve this situation at a systemic level, three main actions are warranted. First, academic institutions and funders should reward investigators who fully disseminate their research protocols, reports, and participant-level datasets. Second, standards for the content of protocols and full study reports and for data sharing practices should be rigorously developed and adopted for all types of health research. Finally, journals, funders, sponsors, research ethics committees, regulators, and legislators should endorse and enforce policies supporting study registration and wide availability of journal reports, full study reports, and participant-level datasets.

Tool condition monitoring can be employed to ensure safe and full utilization of the cutting tool. Hence, remaining useful life (RUL) prediction of a cutting tool is an important issue for an effective high-speed milling process-monitoring system. However, it is difficult to establish a mechanism model for the life decreasing process owing to the different wear rates in various stages of cutting tool. This study proposes a three-stage Wiener-process-based degradation model for the cutting tool wear estimation and remaining useful life prediction. Tool wear stages classification and RUL prediction are jointly addressed in this work in order to take full advantage of Wiener process, as this three-stage Wiener process definitely constitutes to describe the degradation processes at different wear stages, based on which the overall useful life can be accurately obtained. The numerical results obtained using extensive experiment indicate that the proposed model can effectively predict the cutting tool’s remaining useful life. Empirical comparisons show that the proposed model performs better than existing models in predicting the cutting tool RUL.

AbstractThe SPIRIT 2013 (The Standard Protocol Items: Recommendations for Interventional Trials) statement aims to improve the completeness of clinical trial protocol reporting, by providing evidence-based recommendations for the minimum set of items to be addressed. This guidance has been instrumental in promoting transparent evaluation of new interventions. More recently, there is a growing recognition that interventions involving artificial intelligence need to undergo rigorous, prospective evaluation to demonstrate their impact on health outcomes.The SPIRIT-AI extension is a new reporting guideline for clinical trials protocols evaluating interventions with an AI component. It was developed in parallel with its companion statement for trial reports: CONSORT-AI. Both guidelines were developed using a staged consensus process, involving a literature review and expert consultation to generate 26 candidate items, which were consulted on by an international multi-stakeholder group in a 2-stage Delphi survey (103 stakeholders), agreed on in a consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants).The SPIRIT-AI extension includes 15 new items, which were considered sufficiently important for clinical trial protocols of AI interventions. These new items should be routinely reported in addition to the core SPIRIT 2013 items. SPIRIT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention will be integrated, considerations around the handling of input and output data, the human-AI interaction and analysis of error cases.SPIRIT-AI will help promote transparency and completeness for clinical trial protocols for AI interventions. Its use will assist editors and peer-reviewers, as well as the general readership, to understand, interpret and critically appraise the design and risk of bias for a planned clinical trial.

This paper proposes four fundamental requirements for establishing PDEs (partial differential equations) modelling irreversible processes. We show that the PDEs derived via the CDF (conservation-dissipation formalism) meet all the requirements. In doing so, we find useful constraints on the freedoms of CDF and point out that a shortcoming of the formalism can be remedied with the help of the Maxwell iteration. It is proved that the iteration preserves the gradient structure and strong dissipativeness of the CDF-based PDEs. A refined formulation of the second law of thermodynamics is given to characterize the strong dissipativeness, while the gradient structure corresponds to nonlinear Onsager relations. Further advantages and limitations of CDF will also be presented. This article is part of the theme issue ‘Fundamental aspects of nonequilibrium thermodynamics’.

G protein-coupled receptors (GPCRs) are a large diverse family of cell surface signaling receptors implicated in various types of cancers. Several studies indicate that GPCRs control many aspects of cancer progression including tumor growth, invasion, migration, survival and metastasis. While it is known that GPCR activity can be altered in cancer through aberrant overexpression, gain-of-function activating mutations, and increased production and secretion of agonists, the precise mechanisms of how GPCRs contribute to cancer progression remains elusive. Protease-activated receptors (PARs) are a unique class of GPCRs implicated in cancer. PARs are a subfamily of GPCRs comprised of four members that are irreversibly activated by proteolytic cleavage induced by various proteases generated in the tumor microenvironment. Given the unusual proteolytic irreversible activation of PARs, expression of receptors at the cell surface is a key feature that influences signaling responses and is exquisitely controlled by endocytic adaptor proteins. Here, we discuss new survey data from the Cancer Genome Atlas and the Genotype-Tissue Expression projects analysis of expression of all PAR family member expression in human tumor samples as well as the role and function of the endocytic sorting machinery that controls PAR expression and signaling of PARs in normal cells and in cancer.

The risk of skin cancer associated with antihypertensive medication use is unclear, although thiazides have been implicated in regulatory safety warnings. We aimed to assess whether use of thiazides and other antihypertensives is associated with increased rates of keratinocyte carcinoma and melanoma. We conducted a population-based inception cohort study using linked administrative health data from Ontario, 1998–2017. We matched adults aged ≥ 66 years with a first prescription for an antihypertensive medication (thiazides, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, β-blockers) by age and sex to 2 unexposed adults who were prescribed a non-antihypertensive medication within 30 days of the index date. We evaluated each antihypertensive class in a separate cohort study. Our primary exposure was the cumulative dose within each class, standardized according to the World Health Organization’s Defined Daily Dose. Outcomes were time to first keratinocyte carcinoma, advanced keratinocyte carcinoma and melanoma. The inception cohorts included a total of 302 634 adults prescribed an antihypertensive medication and 605 268 unexposed adults. Increasing thiazide exposure was associated with an increased rate of incident keratinocyte carcinoma (adjusted hazard ratios [HRs] per 1 Defined Annual Dose unit 1.08, 95% confidence interval [CI] 1.03–1.14), advanced keratinocyte carcinoma (adjusted HR 1.07, 95% CI 0.93–1.23) and melanoma (adjusted HR 1.34, 95% CI 1.01–1.78). We found no consistent evidence of association between other antihypertensive classes and keratinocyte carcinoma or melanoma. Higher cumulative exposure to thiazides was associated with increased rates of incident skin cancer in people aged 66 years and older. Consideration of other antihypertensive treatments in patients at high risk of skin cancer may be warranted.

Global biomedical and public health research involves billions of dollars and millions of people. Although this vast enterprise has led to substantial health improvements, many more gains are possible if the waste and inefficiency in the ways that biomedical research is chosen, designed, done, analysed, regulated, managed, disseminated, and reported can be addressed.

Ferroptosis is a type of cell death characterized by the accumulation of intracellular iron and an increase in hazardous lipid peroxides. Ferroptosis and autophagy are closely related. Ionizing radiation is a frequently used cancer therapy to kill malignancies. We found that ionizing radiation induces both ferroptosis and autophagy and that there is a form of mutualism between the two processes. Ionizing radiation also causes lipid droplets to form in proximity to damaged mitochondria, which, through the action of mitophagy, results in the degradation of the peridroplet mitochondria by lysosomes and the consequent release of free fatty acids and a significant increase in lipid peroxidation, thus promoting ferroptosis. Ionizing radiation has a stronger, fatal effect on cells with a high level of mitophagy, and this observation suggests a novel strategy for tumor treatment.

Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available 1 – 3 . Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97) 4 – 6 , a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97–G o complexes bound to the anti-inflammatory drug beclomethasone or the steroid hormone cortisol revealed that glucocorticoids bind to a pocket within the transmembrane domain. The steroidal core of glucocorticoids is packed against the ‘toggle switch’ residue W 6.53 , which senses the binding of a ligand and induces activation of the receptor. Active GPR97 uses a quaternary core and HLY motif to fasten the seven-transmembrane bundle and to mediate G protein coupling. The cytoplasmic side of GPR97 has an open cavity, where all three intracellular loops interact with the G o protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the G o protein was found to be essential for efficient engagement with GPR97 but is not observed in other solved GPCR complex structures. Our work provides a structural basis for ligand binding to the seven-transmembrane domain of an adhesion GPCR and subsequent G protein coupling. The authors report on the structure of a glucocorticoid-bound adhesion G-protein-coupled receptor–G protein complex.

Systematic reviews of clinical trials aim to include all relevant studies conducted on a particular topic and to provide an unbiased summary of their results, producing the best evidence about the benefits and harms of medical treatments. Relevant studies, however, may not provide the results for all measured outcomes or may selectively report only some of the analyses undertaken, leading to unnecessary waste in the production and reporting of research, and potentially biasing the conclusions to systematic reviews. In this article, Kirkham and colleagues provide a methodological approach, with an example of how to identify missing outcome data and how to assess and adjust for outcome reporting bias in systematic reviews.