Are regulations safe? Reflections from developing a digital cancer decision support tool

PURPOSE Informatics solutions to early diagnosis of cancer in primary care are increasingly prevalent, but it is not clear whether existing and planned standards and regulations sufficiently address patients' safety nor whether these standards are fit for purpose. We use a patient safety perspective to reflect on the development of a computerized cancer risk assessment tool embedded within a UK primary care electronic health record system. METHODS We developed a computerized version of the CAncer Prevention in ExetER studies risk assessment tool, in compliance with the European Union's Medical Device Regulations. The process of building this tool afforded an opportunity to reflect on clinical concerns and whether current regulations for medical devices are fit for purpose. We identified concerns for patient safety and developed nine practical recommendations to mitigate these concerns. RESULTS We noted that medical device regulations (1) were initially created for hardware devices rather than software, (2) offer one-shot approval rather than supporting iterative innovation and learning, (3) are biased toward loss-transfer approaches that attempt to manage the fallout of harm instead of mitigating hazards becoming harmful, and (4) are biased toward known hazards, despite unknown hazards being an expected consequence of health care as a complex adaptive system. Our nine recommendations focus on embedding less-reductionist and stronger system perspectives into regulations and standards. CONCLUSION Our intention is to share our experience to support research-led collaborative development of health informatics solutions in cancer. We argue that regulations in the European Union do not sufficiently address the complexity of healthcare information systems with consequences for patient safety. Future standards and regulations should continue to follow a system-based approach to risk, safety, and accident avoidance

Snus use and rejection in the USA

OBJECTIVE: To determine whether snus might become a strategy for reducing the harm associated with cigarette smoking in the USA as appears to be the case in Sweden, we examined receptivity to snus use in two cities with the greatest exposure to the major brands. METHODS: A dual frame, telephone survey and a brief mail survey were conducted in 2011 and 2012 in Indianapolis, Indiana and Dallas/Fort Worth Texas. Over 5000 adults completed surveys. Trial, ever use, current use and reasons for using or quitting snus after trial were measured. RESULTS: Among male smokers, 29.9% had ever tried snus (CI 22.7 to 38.1) and 4.2% were current users (CI 1.6 to 10.7). Among female smokers, 8.5% ever tried snus (CI 4.4 to 15.7) and current use was unknown. Current use was virtually absent among former smokers and never smokers. A major predictor of any level of snus use was current use of conventional smokeless tobacco. Those who tried and gave up snus cited curiosity (41.3%) and the fact that it was available at low or no cost (30%) as reasons for trial; reasons for not continuing included preferring another form of tobacco (75.1%) and disliking the mouth feel (34.6%). Almost all current snus users indicated that they were trying to cut down on cigarettes, but few (3.9%) were using it to quit smoking entirely. CONCLUSIONS: The low rate of adoption of snus suggests that neither the hopes nor the fears surrounding this new product are likely to be realised in the USA with the current marketing patterns

System and Method for Providing a Climate Data Persistence Service

A system, method and computer-readable storage devices for providing a climate data persistence service. A system configured to provide the service can include a climate data server that performs data and metadata storage and management functions for climate data objects, a compute-storage platform that provides the resources needed to support a climate data server, provisioning software that allows climate data server instances to be deployed as virtual climate data servers in a cloud computing environment, and a service interface, wherein persistence service capabilities are invoked by software applications running on a client device. The climate data objects can be in various formats, such as International Organization for Standards (ISO) Open Archival Information System (OAIS) Reference Model Submission Information Packages, Archive Information Packages, and Dissemination Information Packages. The climate data server can enable scalable, federated storage, management, discovery, and access, and can be tailored for particular use cases

The spread of marine anoxia on the northern Tethys margin during the Paleocene-Eocene Thermal Maximum

Records of the paleoenvironmental changes that occurred during the Paleocene-Eocene Thermal Maximum (PETM) are preserved in sedimentary rocks along the margins of the former Tethys Ocean and Peri-Tethys. This paper presents new geochemical data that constrain paleoproductivity, sediment delivery, and seawater redox conditions, from three sites that were located in the Peri-Tethys region. Trace and major element, iron speciation, and biomarker data indicate that water column anoxia was established during episodes when inputs of land-derived higher plant organic carbon and highly weathered detrital clays and silts became relatively higher. Anoxic conditions are likely to have been initially caused by two primary processes: (i) oxygen consumption by high rates of marine productivity, initially stimulated by the rapid delivery of terrestrially derived organic matter and nutrients, and (ii) phosphorus regeneration from seafloor sediments. The role of the latter process requires further investigation before its influence on the spread of deoxygenated seawater during the PETM can be properly discerned. Other oxygen-forcing processes, such as temperature/salinity-driven water column stratification and/or methane oxidation, are considered to have been relatively less important in the study region. Organic carbon enrichments occur only during the initial stages of the PETM as defined by the negative carbon isotope excursions at each site. The lack of observed terminal stage organic carbon enrichment does not support a link between PETM climate recovery and the sequestration of excess atmospheric CO2 as organic carbon in this region; such a feedback may, however, have been important in the early stages of the PETM

Inorganic polyphosphate interacts with nucleolar and glycosomal proteins in trypanosomatids

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146806/1/mmi14131-sup-0001-FigS1-S9.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146806/2/mmi14131_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146806/3/mmi14131.pd

Bifactor analysis of motivation for charity sport event participation

The purpose of this study was to examine the utility of the existing subscales of charity sport events (CSEs) participation motivation by adopting both a second-order modeling and a bifactor modeling approaches. The results with 488 college students revealed that the bifactor model provided a better interpretation of the data compared to second-order model. The five-factor CSE motivation significantly predict the intention to participate in CSEs along with two domain-specific motivations, namely ‘sport and event’ and ‘cause’ while other three domain-specific motivations including ‘philanthropic’, ‘social interaction’, and ‘reference group’ are not statistically significant predictors. The results suggest that the bifactor model is more useful in predicting this group’s participation in charity sport events. © 2015, Springer-Verlag Berlin Heidelberg

A rare mutation in SMAD9 associated with high bone mass identifies the SMAD-dependent BMP signalling pathway as a potential anabolic target for osteoporosis

Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z-scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome-wide and gene-based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (P-GWAS = 6 x 10(-16); P-GENE = 8 x 10(-17)). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone-derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)-dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss-of-function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. (c) 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research

Climatic controls on C4 grassland distributions during the Neogene: A model-data comparison

Grasslands dominated by taxa using the C4photosynthetic pathway first developed on several continents during the Neogene and Quaternary, long after C4photosynthesis first evolved among grasses. The histories of these ecosystems are relatively well-documented in the geological record from stable carbon isotope measurements (of fossil vertebrate herbivores and paleosols) and the plant microfossil record (pollen and/or phytolith assemblages). The distinct biogeography and ecophysiology of modern C3and C4grasses have led to hypotheses explaining the origins of C4grasslands in terms of long-term changes in the Earth system, such as increased aridity and decreasing atmospheric pCO2. However, quantitative proxies for key abiotic drivers of these hypotheses (e.g., temperature, precipitation, pCO2) are still in development, not yet widely applied at the continental or global scale or throughout the late Cenozoic, and/or remain contentious. Testing these hypotheses globally therefore remains difficult. To understand better the potential links between changes in the Earth system and the origin of C4grasslands, we undertook a global-scale comparison between observational records of C4plant abundances in Miocene and Pliocene localities compiled from the literature and three increasingly complex models of C4physiology, dominance, and abundance. The literature compilation comprises > 2,600 δ13C-values each of fossil terrestrial vertebrates and of paleosol carbonates, which we interpret as primarily proxies for the abundance of C4grasses, based on the modern contribution of C4grasses to terrestrial net primary productivity. We forced the vegetation models with simulated monthly climates from the HadCM3 family of coupled ocean-atmosphere general circulation models (OAGCMs) over a range of pCO2-values for each epoch to model C4dominance or abundance in grid cells as: (1) months per year exceeding the temperature at which net carbon assimilation is greater for C4than C3photosynthesis (crossover temperature model); (2) the number of months per year exceeding the crossover temperature and having sufficient precipitation for growth (≥25 mm/month; Collatz model); and (3) the Sheffield Dynamic Global Vegetation Model (SDGVM), which models multiple plant functional types (PFTs) (C3and C4grasses, evergreen, and deciduous trees). Model-data agreement is generally weak, although statistically significant for many comparisons, suggesting that regional to local ecological interactions, continent-specific plant evolutionary histories, and/or regional to local climatic conditions not represented in global scale OAGCMs may have been equally strong or stronger in driving the evolution of C4grasslands as global changes in the Earth system such as decreases in atmospheric pCO2and late Cenozoic global cooling and/or aridification

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42\ub74% vs 44\ub72%; absolute difference \u20131\ub769 [\u20139\ub758 to 6\ub711] p=0\ub767; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5\u20138] vs 6 [5\u20138] cm H2O; p=0\ub70011). ICU mortality was higher in MICs than in HICs (30\ub75% vs 19\ub79%; p=0\ub70004; adjusted effect 16\ub741% [95% CI 9\ub752\u201323\ub752]; p<0\ub70001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0\ub780 [95% CI 0\ub775\u20130\ub786]; p<0\ub70001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. Funding: No funding