Frequency Domain Functional Near-Infrared Spectrometer (fNIRS) for Crew State Monitoring

A frequency domain functional near-infrared spectrometer (fNIRS) and accompanying software have been developed by the NASA Glenn Research Center as part of the Airspace Operations and Safety Program (AOSP) Technologies for Airplane State Awareness (TASA)SE211 Crew State Monitoring (CSM) Project. The goal of CSM was to develop a suite of instruments to measure the cognitive state of operators while performing operational activities. The fNIRS was one of the instruments intended for the CSM, developed to measure changes in oxygen levels in the brain noninvasively

Sexually dimorphic effect of aging on skeletal muscle protein synthesis

BACKGROUND: Although there appear to be no differences in muscle protein turnover in young and middle aged men and women, we have reported significant differences in the rate of muscle protein synthesis between older adult men and women. This suggests that aging may affect muscle protein turnover differently in men and women. METHODS: We measured the skeletal muscle protein fractional synthesis rate (FSR) by using stable isotope-labeled tracer methods during basal postabsorptive conditions and during a hyperaminoacidemic-hyperinsulinemic-euglycemic clamp in eight young men (25–45 y), ten young women (25–45 y), ten old men (65–85 y) and ten old women (65–85 y). RESULTS: The basal muscle protein FSR was not different in young and old men (0.040 ± 0.004 and 0.043 ± 0.005%·h(-1), respectively) and combined insulin, glucose and amino acid infusion significantly increased the muscle protein FSR both in young (to 0.063 ± 0.006%·h(-1)) and old (to 0.051 ± 0.008%·h(-1)) men but the increase (0.023 ± 0.004 vs. 0.009 ± 0.004%·h(-1), respectively) was ~60% less in the old men (P = 0.03). In contrast, the basal muscle protein FSR was ~30% greater in old than young women (0.060 ± 0.003 vs. 0.046 ± 0.004%·h(-1), respectively; P < 0.05) and combined insulin, glucose and amino acid infusion significantly increased the muscle protein FSR in young (P < 0.01) but not in old women (P = 0.10) so that the FSR was not different between young and old women during the clamp (0.074 ± 0.006%·h(-1) vs. 0.072 ± 0.006%·h(-1), respectively). CONCLUSIONS: There is sexual dimorphism in the age-related changes in muscle protein synthesis and thus the metabolic processes responsible for the age-related decline in muscle mass

MitoNeoD:a mitochondria-targeted superoxide probe

Mitochondrial superoxide (O2⋅−) underlies much oxidative damage and redox signaling. Fluorescent probes can detect O2⋅−, but are of limited applicability in vivo, while in cells their usefulness is constrained by side reactions and DNA intercalation. To overcome these limitations, we developed a dual-purpose mitochondrial O2⋅− probe, MitoNeoD, which can assess O2⋅− changes in vivo by mass spectrometry and in vitro by fluorescence. MitoNeoD comprises a O2⋅−-sensitive reduced phenanthridinium moiety modified to prevent DNA intercalation, as well as a carbon-deuterium bond to enhance its selectivity for O2⋅− over non-specific oxidation, and a triphenylphosphonium lipophilic cation moiety leading to the rapid accumulation within mitochondria. We demonstrated that MitoNeoD was a versatile and robust probe to assess changes in mitochondrial O2⋅− from isolated mitochondria to animal models, thus offering a way to examine the many roles of mitochondrial O2⋅−production in health and disease

Daily low-dose prednisolone to prevent relapse of steroid-sensitive nephrotic syndrome in children with an upper respiratory tract infection:PREDNOS2 RCT

BACKGROUND: Most children with steroid-sensitive nephrotic syndrome have relapses that are triggered by upper respiratory tract infections. Four small trials, mostly in children already taking maintenance corticosteroid in countries of different upper respiratory tract infection epidemiology, showed that giving daily low-dose prednisone/prednisolone for 5-7 days during an upper respiratory tract infection reduces the risk of relapse. OBJECTIVES: To determine if these findings were replicated in a large UK population of children with relapsing steroid-sensitive nephrotic syndrome on different background medication or none. DESIGN: A randomised double-blind placebo-controlled trial, including a cost-effectiveness analysis. SETTING: A total of 122 UK paediatric departments, of which 91 recruited patients. PARTICIPANTS: A total of 365 children with relapsing steroid-sensitive nephrotic syndrome (mean age 7.6 ± 3.5 years) were randomised (1 : 1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively). INTERVENTIONS: At the start of an upper respiratory tract infection, children received 6 days of prednisolone (15 mg/m2) or an equivalent dose of placebo. MAIN OUTCOME MEASURES: The primary outcome was the incidence of first upper respiratory tract infection-related relapse following any upper respiratory tract infection over 12 months. The secondary outcomes were the overall rate of relapse, changes in background treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, change in Achenbach Child Behaviour Checklist score and quality of life. Analysis was by intention-to-treat principle. The cost-effectiveness analysis used trial data and a decision-analytic model to estimate quality-adjusted life-years and costs at 1 year, which were then extrapolated over 16 years. RESULTS: There were 384 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the prednisolone arm, and 407 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 (42.7%) and 58 (44.3%) in the prednisolone and placebo arms, respectively (adjusted risk difference -0.024, 95% confidence interval -0.14 to 0.09; p = 0.70). There was no evidence that the treatment effect differed when data were analysed according to background treatment. There were no significant differences in secondary outcomes between treatment arms. Giving daily prednisolone at the time of an upper respiratory tract infection was associated with increased quality-adjusted life-years (0.9427 vs. 0.9424) and decreased average costs (£252 vs. £254), when compared with standard care. The cost saving was driven by background therapy and hospitalisations after relapse. The finding was robust to sensitivity analysis. LIMITATIONS: A larger number of children than expected did not have an upper respiratory tract infection and the sample size attrition rate was adjusted accordingly during the trial. CONCLUSIONS: The clinical analysis indicated that giving 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of steroid-sensitive nephrotic syndrome in UK children. However, there was an economic benefit from costs associated with background therapy and relapse, and the health-related quality-of-life impact of having a relapse. FUTURE WORK: Further work is needed to investigate the clinical and health economic impact of relapses, interethnic differences in treatment response, the effect of different corticosteroid regimens in treating relapses, and the pathogenesis of individual viral infections and their effect on steroid-sensitive nephrotic syndrome. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10900733 and EudraCT 2012-003476-39. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 3. See the NIHR Journals Library website for further project information

HVAD to HeartMate 3 left ventricular assist device exchange: Best practices recommendations

The HeartWare HVAD System (Medtronic) is a durable implantable left ventricular assist device that has been implanted in approximately 20,000 patients worldwide for bridge to transplant and destination therapy indications. In December 2020, Medtronic issued an Urgent Medical Device Communication informing clinicians of a critical device malfunction in which the HVAD may experience a delay or failure to restart after elective or accidental discontinuation of pump operation. Moreover, evolving retrospective comparative effectiveness studies of patients supported with the HVAD demonstrated a significantly higher risk of stroke and all-cause mortality when compared with a newer generation of a commercially available durable left ventricular assist device. Considering the totality of this new information on HVAD performance and the availability of an alternate commercially available device, Medtronic halted the sale and distribution of the HVAD System in June 2021. The decision to remove the HVAD from commercial distribution now requires the use of the HeartMate 3 left ventricular assist system (Abbott, Inc) if a patient previously implanted with an HVAD requires a pump exchange. The goal of this document is to review important differences in the design of the HVAD and HeartMate 3 that are relevant to the medical management of patients supported with these devices, and to assess the technical aspects of an HVAD-to-HeartMate 3 exchange. This document provides the best available evidence that supports best practices

Depositional architecture, provenance, and tectonic/eustatic modulation of Miocene submarine fans in the Shikoku Basin: Results from Nankai Trough Seismogenic Zone Experiment

Seismostratigraphy, coring, and logging while drilling during Integrated Ocean Drilling Program Expeditions 319, 322, and 333 (Sites C0011/C0012) show three Miocene submarine fans in the NE Shikoku Basin, with broadly coeval deposits at Ocean Drilling Program Site 1177 and Deep Sea Drilling Project Site 297 (NW Shikoku Basin). The sediment dispersal patterns have major implications for paleogeographies at that time. The oldest, finer-grained (Kyushu) fan has sheet-like geometry; quartz-rich flows were fed mostly from an ancestral landmass in the East China Sea. During prolonged hemipelagic mud deposition at C0011-C0012 (~12.2 to 9.1 Ma), sand supply continued at Sites 1177 and 297. Sand delivery to much of the Shikoku Basin halted during a phase of sinistral strike slip to oblique plate motion, after which the Daiichi Zenisu Fan (~9.1 to 8.0 Ma) was fed by submarine channels. The youngest fan (Daini Zenisu; ~8.0 to 7.6 Ma) has sheet-like geometry with thick-bedded, coarse-grained pumiceous sandstones. The pumice fragments were fed from a mixed provenance that included the collision zone of the Izu-Bonin and Honshu Arcs. The shift from channelized to sheet-like flows was favored by renewal of relatively rapid northward subduction, which accentuated the trench as a bathymetric depression. Increased sand supply appears to correlate with long-term eustatic lowstands of sea level. The stratigraphic position and 3-D geometry of the sandbodies have important implications for subduction-related processes, including the potential for focused fluid flow and fluid overpressures above and below the plate boundary fault: In sheet-like sands, pathways for fluid flow have greater horizontal permeability compared with those in channel sands

Statins in Candidemia: clinical outcomes from a matched cohort study

<p>Abstract</p> <p>Background</p> <p>HMG CoA reductase inhibitors (statins) in patients with bacteremic sepsis have shown significant survival benefits in several studies. There is no data on the effect of statins in candidemic patients, however in-vitro models suggest that statins interfere with ergesterol formation in the wall of yeasts.</p> <p>Methods</p> <p>This retrospective matched- cohort study from 1/2003 to 12/2006 evaluated the effects of statins on patients with candidemia within intensive care units. Statin-users had candidemia as a cause of their systemic inflammatory response and were on statins throughout their antifungal therapy, while non-statin users were matched based on age +/- 5 years and co-morbid factors. Primary analysis was 30-day survival or discharge using bivariable comparisons. Multivariable comparisons were completed using conditional logistic regression. All variables with a p-value less than 0.10 in the bivariable comparisons were considered for inclusion in the conditional logistic model.</p> <p>Results</p> <p>There were 15 statin-users and 30 non-statin users that met inclusion criteria, all with similar demographics and co-morbid conditions except the statin group had more coronary artery disease (P < 0.01) and peripheral vascular disease (P = 0.03) and lower median APCAHE II scores (14.6 vs 17, p = 0.03). There were no differences in duration of candidemia, antifungal therapy or <it>Candida </it>species between the groups. Statins were associated with lower mortality on bivariable (OR 0.09, 95% CI 0.11-0.75, p = 0.03) and multivariable (OR 0.22, 95% CI 0.02-2.4, p = 0.21) analyses compared to controls; although, in the latter the protective effect lacked statistical signficance.</p> <p>Conclusion</p> <p>In our small, single-center matched-cohort study, statins may provide a survival benefit in candidemia, however further studies are warranted to validate and further explore this association.</p

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition