Clinician-in-the-Loop Annotation of ICU Bedside Alarm Data

In this work, we describe the state of clinical monitoring in the intensive care unit and operating room, where patients are at their most fragile and thus monitoring is most heightened. We describe how large amounts of data generated by monitoring patients’ physiologic signals, along with the ubiquitous aspecific threshold alarms in use today, cause dangerous alarm fatigue for medical caregivers. In order to build more specific, more useful alarms, we gathered a novel data set that would allow us to assess the number, types, and utility of alarms currently in use in the intensive care unit. To do this, we developed a system to collect physiologic monitor data, alarms, and annotations of those alarms provided electronically by clinicians. We describe the collection process for this novel data set and provide a preliminary description of the data

Comparison of central versus peripheral delivery of pregabalin in neuropathic pain states

<p>Abstract</p> <p>Background</p> <p>Although pregabalin therapy is beneficial for neuropathic pain (NeP) by targeting the CaVα₂δ-1 subunit, its site of action is uncertain. Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects.</p> <p>Results</p> <p>We used intranasal, intrathecal, and near-nerve chamber forms of delivery of varying concentrations of pregabalin or saline delivered over 14 days in rat models of experimental diabetic peripheral neuropathy and spinal nerve ligation. As well, radiolabelled pregabalin was administered to determine localization with different deliveries. We evaluated tactile allodynia and thermal hyperalgesia at multiple time points, and then analyzed harvested nervous system tissues for molecular and immunohistochemical changes in CaVα₂δ-1 protein expression. Both intrathecal and intranasal pregabalin administration at high concentrations relieved NeP behaviors, while near-nerve pregabalin delivery had no effect. NeP was associated with upregulation of CACNA2D1 mRNA and CaVα₂δ-1 protein within peripheral nerve, dorsal root ganglia (DRG), and dorsal spinal cord, but not brain. Pregabalin's effect was limited to suppression of CaVα₂δ-1 protein (but not CACNA2D1 mRNA) expression at the spinal dorsal horn in neuropathic pain states. Dorsal root ligation prevented CaVα₂δ-1 protein trafficking anterograde from the dorsal root ganglia to the dorsal horn after neuropathic pain initiation.</p> <p>Conclusions</p> <p>Either intranasal or intrathecal pregabalin relieves neuropathic pain behaviours, perhaps due to pregabalin's effect upon anterograde CaVα₂δ-1 protein trafficking from the DRG to the dorsal horn. Intranasal delivery of agents such as pregabalin may be an attractive alternative to systemic therapy for management of neuropathic pain states.</p

ACCOMMODATING MIXED-SEVERITY FIRE TO RESTORE AND MAINTAIN ECOSYSTEM INTEGRITY WITH A FOCUS ON THE SIERRA NEVADA OF CALIFORNIA, USA

Existing fire policy encourages the maintenance of ecosystem integrity in fire management, yet this is difficult to implement on lands managed for competing economic, human safety, and air quality concerns. We discuss a fire management approach in the mid-elevations of the Sierra Nevada, California, USA, that may exemplify similar challenges in other fire-adapted regions of the western USA. We also discuss how managing for pyrodiversity through mixed-severity fires can promote ecosystem integrity in Sierran mixed conifer and ponderosa pine (Pinus ponderosa Laws) forests. To illustrate, we show how coarse-filter (landscape-level) and complementary fine-filter (species-level) approaches can enhance forest management and conservation biology objectives as related to wildfire management. At the coarse-filter level, pyrodiverse mixed-severity fires provide landscape heterogeneity. Species and ecosystem characteristics associated with pyrodiversity can be maintained or enhanced by accommodating moderately severe fires, which hasten restoration by recreating a complex vegetation mosaic otherwise at risk from suppression. At the fine-filter level, managers can select focal species and species of conservation concern based on the degree to which those species depend on fire and accommodate their specific conservation needs. The black-backed woodpecker (Picoides arcticus [Swainson, 1832]) is an ideal focal species for monitoring the ecological integrity of forests restored through mixed-severity fire, and the California spotted owl (Strix occidentalis occidentalis [Xantus de Vesey, 1860]) is a species of conservation concern that uses post-fire habitat mosaics and is particularly vulnerable to logging. We suggest a comprehensive approach that integrates wildland fire for ecosystem integrity and species viability with strategic deployment of fire suppression and ecologically based restoration of pyrodiverse landscapes. Our approach would accomplish fire management goals while simultaneously maintaining biodiversity

Evolving Landscape of Carbapenem-Resistant

OBJECTIVES: The increased identification of carbapenem-resistant METHODS: A total of 169 CR-PA isolated from clinical specimens at a single centre in Houston, TX, USA were studied. Among them, 61 isolates collected between 1999 and 2005 were defined as historical strains, and 108 collected between 2017 and 2018 were defined as contemporary strains. Antimicrobial susceptibilities against selected β-lactams was determined. WGS data were used for the identification of antimicrobial resistance determinants and phylogenetic analysis. RESULTS: Non-susceptibility to ceftolozane/tazobactam and ceftazidime/avibactam increased from 2% (1/59) to 17% (18/108) and from 7% (4/59) to 17% (18/108) from the historical to the contemporary collection, respectively. Carbapenemase genes, which were not identified in the historical collection, were harboured by 4.6% (5/108) of the contemporary strains, and the prevalence of ESBL genes also increased from 3.3% (2/61) to 16% (17/108). Genes encoding acquired β-lactamases were largely confined to the high-risk clones. Among ceftolozane/tazobactam-resistant isolates, non-susceptibility to ceftazidime/avibactam, imipenem/relebactam and cefiderocol was observed in 94% (15/16), 56% (9/16) and 12.5% (2/16), respectively. Resistance to ceftolozane/tazobactam and imipenem/relebactam was primarily associated with the presence of exogenous β-lactamases. CONCLUSIONS: Acquisition of exogenous carbapenemases and ESBLs may be a worrisome trend i

Reduced fetal vitamin D status by maternal undernutrition during discrete gestational windows in sheep

Placental transport of vitamin D and other nutrients (e.g. amino acids, fats and glucose) to the fetus is sensitive to maternal and fetal nutritional cues. We studied the effect of maternal calorific restriction on fetal vitamin D status and the placental expression of genes for nutrient transport (aromatic T-type amino acid transporter-1 [TAT-1]; triglyceride hydrolase / lipoprotein uptake facilitator lipoprotein lipase [LPL]) and vitamin D homeostasis (CYP27B1; vitamin D receptor [VDR]), and their association with markers of fetal cardiovascular function and skeletal muscle growth. Pregnant sheep received 100% total metabolizable energy (ME) requirements (control), 40% total ME requirements peri-implantation (PI40, 1–31 days of gestation [dGA]) or 50% total ME requirements in late gestation (L, 104–127 dGA). Fetal, but not maternal, plasma 25-hydroxy-vitamin D (25OHD) concentration was lower in PI40 and L maternal undernutrition groups (p<0.01) compared with the control group at 0.86 gestation. PI40 group placental CYP27B1 mRNA levels were increased (p<0.05) compared with the control group. Across all groups, higher fetal plasma 25OHD concentration was associated with higher skeletal muscle myofibre and capillary density (p<0.05). In the placenta, higher VDR mRNA levels were associated with higher TAT-1 (p<0.05) and LPL (p<0.01) mRNA levels. In the PI40 maternal undernutrition group only, reduced fetal plasma 25OHD concentration may be mediated in part by altered placental CYP27B1. The association between placental mRNA levels of VDR and nutrient transport genes suggests a way in which the placenta may integrate nutritional cues in the face of maternal dietary challenges and alter fetal physiology

Cloud-Based Secure Logger for Medical Devices

A logger in the cloud capable of keeping a secure, time-synchronized and tamper-evident log of medical device and patient information allows efficient forensic analysis in cases of adverse events or attacks on interoperable medical devices. A secure logger as such must meet requirements of confidentiality and integrity of message logs and provide tamper-detection and tamper-evidence. In this paper, we propose a design for such a cloud-based secure logger using the Intel Software Guard Extensions (SGX) and the Trusted Platform Module (TPM). The proposed logger receives medical device information from a dongle attached to a medical device. The logger relies on SGX, TPM and standard encryption to maintain a secure communication channel even on an untrusted network and operating system. We also show that the logger is resilient against different kinds of attacks such as Replay attacks, Injection attacks and Eavesdropping attacks

The Distance To The Hyades Cluster Based On Hubble Space Telescope Fine Guidance Sensor Parallaxes

Trigonometric parallax observations made with the Hubble Space Telescope (HST) Fine Guidance Sensor (FGS) 3 of seven Hyades members in six fields of view have been analyzed along with their proper motions to determine the distance to the cluster. Knowledge of the convergent point and mean proper motion of the Hyades is critical to the derivation of the distance to the center of the cluster. Depending on the choice of the proper-motion system, the derived cluster center distance varies by 9%. Adopting a reference distance of 46.1 pc or m - M = 3.32, which is derived from the ground-based parallaxes in the General Catalogue of Trigonometric Stellar Parallaxes (1995 edition), the FK5/PPM proper-motion system yields a distance 4% larger, while the Hanson system yields a distance 2% smaller. The HST FGS parallaxes reported here yield either a 14% or 5% larger distance, depending on the choice of the proper-motion system. Orbital parallaxes (Torres et al.) yield an average distance 4% larger than the reference distance. The variation in the distance derived from the HST data illustrates the importance of the proper-motion system and the individual proper motions to the derivation of the distance to the Hyades center; therefore, a full utilization of the HST FGS parallaxes awaits the establishment of an accurate and consistent proper-motion system.NASA HST GTO, HF-1042.01-93A, HF-1046.01-93A, NAS526555Astronom

Identity-by-Descent Mapping Identifies Major Locus for Serum Triglycerides in Amerindians Largely Explained by an APOC3 Founder Mutation

Background—Identity-by-descent (IBD) mapping using empirical estimates of IBD allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization. Methods and Results—Through IBD mapping, using ~400,000 SNPs, of serum lipid profiles we identified a major linkage signal for triglycerides (TG) in 1,007 Pima Indians (LOD=9.23, p=3.5×10−11 on chromosome 11q). In subsequent fine-mapping and replication association studies in ~7,500 Amerindians, we determined that this signal reflects effects of a loss-of-function Ala43Thr substitution in APOC3 (rs147210663) and 3 established functional SNPs in APOA5. The association with rs147210663 was particularly strong; each copy of the Thr allele conferred 42% lower TG (β=−0.92±0.059 SD unit, p=9.6×10−55 in 4,668 Pimas and 2,793 Southwest Amerindians combined). The Thr allele is extremely rare in most global populations, but has a frequency of 2.5% in Pimas. We further demonstrated that 3 APOA5 SNPs with established functional impact could explain the association with the most well-replicated SNP (rs964184) for TG identified by genome-wide association studies (GWAS). Collectively these 4 SNPs account for 6.9% of variation in TG in Pimas (and 4.1% in Southwest Amerindians), and their inclusion in the original linkage model reduced the linkage signal to virtually null. Conclusions—APOC3/APOA5 constitutes a major locus for serum triglycerides in Amerindians, especially the Pimas, and these results provide an empirical example for the concept that population-based linkage analysis is a useful strategy to identify complex trait variants

The Southern Proper Motion Program IV. The SPM4 Catalog

We present the fourth installment of the Yale/San Juan Southern Proper Motion Catalog, SPM4. The SPM4 contains absolute proper motions, celestial coordinates, and (B,V) photometry for over 103 million stars and galaxies between the south celestial pole and -20 deg declination. The catalog is roughly complete to V=17.5 and is based on photographic and CCD observations taken with the Yale Southern Observatory's double-astrograph at Cesco Observatory in El Leoncito, Argentina. The proper-motion precision, for well-measured stars, is estimated to be 2 to 3 mas/yr, depending on the type of second-epoch material. At the bright end, proper motions are on the International Celestial Reference System by way of Hipparcos Catalog stars, while the faint end is anchored to the inertial system using external galaxies. Systematic uncertainties in the absolute proper motions are on the order of 1 mas/yr.Comment: 34 pages, 8 figures, 3 tables; accepted for publication in AJ; note - modified author list and acknowledgements sectio

Common Variants in 40 Genes Assessed for Diabetes Incidence and Response to Metformin and Lifestyle Intervention in the Diabetes Prevention Program

OBJECTIVE: Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions. RESEARCH DESIGN AND METHODS: We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates. RESULTS: We replicated the association of variants in the metformin transporter gene SLC47A1 with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene STK11, the AMPK subunit genes PRKAA1 and PRKAA2, and a missense SNP in SLC22A1, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene PRKAG2 (hazard ratio 1.24, 95% CI 1.09-1.40, P = 7 × 10(-4)). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest P values were consistent with experiment-wide 33% false discovery rates. CONCLUSIONS: We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples