Broad-spectrum and sensitive screening of more than 1000 compounds in equine urine using liquid chromatography/high-resolution mass spectrometry.

RATIONALE: To uphold the integrity of horseracing and equestrian sports, it is critical for an equine doping control laboratory to develop a comprehensive screening method to cover a wide range of target substances at the required detection levels in equine urine. METHODS: The procedure involved the enzymatic hydrolysis of 3 mL urine samples followed by solid-phase extraction using HF Bond Elut C18 cartridge. The resulting extracts were then separated on a C18 reversed-phase column and analyzed using liquid chromatography/high-resolution mass spectrometry (LC/HRMS) in both electrospray ionization positive and negative modes in two separate injections. The analytical data were obtained in full scan and product ion scan (PIS) modes in an 11 min LC run. RESULTS: The method can detect 1011 compounds (in both positive and negative ion modes). Over 95% of the target compounds have limits of detections (LODs) ≤10 ng/mL, and more than 50% of the LODs are ≤0.5 ng/mL. The lowest LOD can reach down to 0.01 ng/mL. The applicability of the method was demonstrated by the successful detection of prohibited substances in overseas and domestic equine urine samples. CONCLUSIONS: We have successfully developed a regular screening method for equine urine samples that can detect more than 1000 compounds at sub-ppb levels in both positive and negative ion modes with full scan and PIS using LC/HRMS. Furthermore, this method can theoretically be expanded to accommodate an unlimited number of prohibited substances in full-scan mode.

Pharmacokinetic study of osilodrostat and identification of mono-hydroxylated metabolite in equine plasma for the purpose of doping control.

RATIONALE: Osilodrostat is an inhibitor of 11-beta-hydroxylase (CYP11B) and is used for the treatment of Cushing's disease but also categorized as an anabolic agent. The use of osilodrostat is prohibited in horseracing and equestrian sports. To the best of our knowledge, this is the first metabolic study of osilodrostat in equine plasma. METHODS: Potential metabolites of osilodrostat were identified by differential analysis using data acquired from pre- and post-administration plasma samples after protein precipitation with liquid chromatography electrospray ionization high-resolution mass spectrometry (LC/ESI-HRMS). [Correction added on 27 January 2023, after first online publication: In the preceding sentence, "C-HRMS" was changed to "LC/ESI-HRMS" in this version.] For quantification of osilodrostat, a strong cation exchange solid-phase extraction was employed, and the extracts were analyzed using LC/ESI-triple quadrupole tandem mass spectrometry (LC/ESI-QqQ-MS/MS) to establish its elimination profile. Such extracts were further analyzed using LC/ESI-HRMS to investigate the detectability of osilodrostat and its identified mono-hydroxylated metabolite over a 2-week sampling period. RESULTS: Mono-hydroxylated osilodrostat was identified based on the differential analysis and mass spectrometric interpretations, and it was found to be the most abundant metabolite in plasma. Elimination profile of osilodrostat in plasma was successfully established over the 24-h post-administration period. Both osilodrostat and its mono-hydroxylated metabolite were detected up to the last sampling point at 2 weeks using HRMS, and osilodrostat could be confirmed up to 8-day post-administration with its reference material using HRMS as well. CONCLUSIONS: For doping control, screening of both the parent drug osilodrostat and its mono-hydroxylated metabolite in equine plasma would be recommended due to their extended detection windows of up to 2 weeks. Given the availability of reference material for potential confirmation in forensic samples, osilodrostat is considered the most appropriate monitoring target.

Alteration of chronic inflammatory status by transarterial embolization in frozen shoulder evaluated by fluorine-18 fluorodeoxyglucose positron-emission tomography/computed tomography.

BACKGROUND: Frozen shoulder (FS) is speculated to have an inflammatory etiology. On angiography, abnormal angiogenesis is observed around the affected shoulder, suggesting a possible source of inflammation and pain. The effectiveness and safety of transarterial embolization (TAE) targeting abnormally proliferating blood vessels have been reported. This study investigated changes in chronic inflammatory and hypoxic status before and after TAE in FS by [18F]-fluoro-2-deoxyglucose (FDG) positron-emission tomography/computed tomography as a possible mechanism of the therapeutic response to TAE. METHODS: Fifteen patients with unilateral FS, persistent for more than 6 months, who were refractory to conservative treatments, underwent TAE using the temporary embolic agent imipenem/cilastatin. Patients underwent positron-emission tomography/computed tomography with FDG (as a biomarker of inflammation) before and 8 weeks after TAE. Regional uptake was evaluated by the maximum standardized uptake value. The lesion-side-to-(contralateral-) normal-side uptake ratio was also calculated. Pain and functional scales, range-of-motion, and laboratory tests, including white blood cell, C-reactive protein, interleukin 6, vascular endothelial growth factor, and tumor necrosis factor α were evaluated. RESULTS: On FDG-PET, the average maximum standardized uptake value of the lesion-side was significantly greater than that of the normal-side (maximum standardized uptake value before TAE: 3.11 ± 1.25 vs 1.95 ± 1.15, P = .0001; 8-weeks post-TAE: 2.36 ± 0.74 vs 1.78 ± 0.69, P = .0002). The mean lesion-side-to-(contralateral-) normal-side uptake ratios before TAE (1.71 ± 0.60) decreased after TAE (1.37 ± 0.29, P = .011). The decrease of FDG uptake (-21.1 ± 12.2%) showed a significant correlation with the change in the pain scale score (r = -0.56, P = .039) and extension score (r = -0.59, P = .026). CONCLUSION: Chronic inflammation in FS, as demonstrated by FDG uptake, was decreased after TAE. Thus, chronic inflammation is likely to be an underlying mechanism that should be targeted for symptomatic improvement of frozen shoulder.

Additional studies on nicotine exposure in horses: Accurate quantification and elimination profiles of potential biomarkers in plasma and urine.

RATIONALE: For the purpose of doping control, this is the first report of accurate quantification of four critical structural isomers of nicotine metabolites (trans-3'-hydroxycotinine, cis-3'-hydroxycotinine, 5'-hydroxycotinine, and N'-hydroxymethylnorcotinine) in equine plasma and urine for the establishment of their elimination profiles. Besides, the pharmacokinetic studies of trans-3'-hydroxycotinine and N'-hydroxymethylnorcotinine in equine plasma and urine are also presented for the first time. METHODS: The accurate quantification methods of the aforementioned four structural isomers in horse plasma and urine were successfully developed and validated using the solid-phase extractions followed by liquid chromatography/tandem mass spectrometry analysis. Baseline chromatographic separation was achieved to completely differentiate these isomers, which shared the same selected reaction monitoring transition. Such methods were applied to post-administration samples obtained from the nicotine and tobacco leaf administration studies for the establishment of pharmacokinetic profiles. RESULTS: N'-Hydroxymethylnorcotinine could be quantified for the longest period, ranging from 48 to 72 h in plasma and 96 h in urine after a single administration of 250 mg of nicotine and an equivalent amount of nicotine in tobacco leaves. In terms of detection, both N'-hydroxymethylnorcotinine and trans-3'-hydroxycotinine could be detected up to the last sample collection time point (96 h), indicating that they are the most appropriate biomarkers for nicotine exposure. CONCLUSIONS: N'-Hydroxymethylnorcotinine and trans-3'-hydroxycotinine were detected longest in plasma and urine samples after both nicotine and tobacco leaf administrations, and N'-hydroxymethylnorcotinine was deemed most appropriate as a monitoring target due to its relatively higher abundance and slower elimination rate. These two biomarkers could also be used to differentiate sample contamination by tobacco products and genuine nicotine exposure to horse regardless of intentionality.

Development of a Questionnaire to Evaluate Older Adults' Total Sedentary Time and Sedentary Time With Cognitive Activity.

This study aimed to develop a questionnaire for evaluating total sedentary time (ST) and ST with cognitive activity, and to examine the association between ST and cognitive function among Japanese older adults. The questionnaire to evaluate ST comprised 12 items regarding behavior in specific settings, including 8 items on ST with cognitive activity, in a usual week. Older adults aged ≥75 years who participated in a health check-up assessing cognitive function completed the developed questionnaire and subsequently wore an accelerometer and recorded a diary of ST with cognitive activity for a week as validity measures. Cognitive function was assessed with neuropsychological tests covering 4 domains: memory, attention, executive function, and processing speed. Fifty-two participants were included in the validity analysis. Spearman's correlation coefficient indicated fair-to-good agreement between the questionnaire-measured and the diary-measured time for ST with cognitive activity (r = 0.59, p < 0.001), but this was not the case for total ST. Bland-Altman plots showed that the questionnaire-measured total ST contained proportional bias (r = 0.51, p < 0.001). Multiple regression analysis (n = 49) showed longer questionnaire-measured ST with cognitive activity was significantly associated with better neuropsychological test scores (attention: ß = -0.38, p = 0.025; executive function: ß = -0.46, p = 0.003; and processing speed: ß = 0.31, p = 0.041), while total ST was not associated with better cognitive performance. The developed questionnaire showed acceptable validity to measure ST with cognitive activity, which was found to be protectively associated with cognitive function.

Generic approach for the discovery of drug metabolites in horses based on data-dependent acquisition by liquid chromatography high-resolution mass spectrometry and its applications to pharmacokinetic study of daprodustat.

In drug metabolism studies in horses, non-targeted analysis by means of liquid chromatography coupled with high-resolution mass spectrometry with data-dependent acquisition (DDA) has recently become increasingly popular for rapid identification of potential biomarkers in post-administration biological samples. However, the most commonly encountered problem is the presence of highly abundant interfering components that co-elute with the target substances, especially if the concentrations of these substances are relatively low. In this study, we evaluated the possibility of expanding DDA coverage for the identification of drug metabolites by applying intelligently generated exclusion lists (ELs) consisting of a set of chemical backgrounds and endogenous substances. Daprodustat was used as a model compound because of its relatively lower administration dose (100 mg) compared to other hypoxia-inducible factor stabilizers and the high demand in the detection sensitivity of its metabolites at the anticipated lower concentrations. It was found that the entire DDA process could efficiently identify both major and minor metabolites (flagged beyond the pre-set DDA threshold) in a single run after applying the ELs to exclude 67.7-99.0% of the interfering peaks, resulting in a much higher chance of triggering DDA to cover the analytes of interest. This approach successfully identified 21 metabolites of daprodustat and then established the metabolic pathway. It was concluded that the use of this generic intelligent "DDA + EL" approach for non-targeted analysis is a powerful tool for the discovery of unknown metabolites, even in complex plasma and urine matrices in the context of doping control.

The Association of Sleep Habits and Advancing Age in Japanese Older Adults: Results from the National Center for Geriatrics and Gerontology Study of Geriatric Syndromes.

BACKGROUND: The association of sleep habits with "advancing age among older adults" is not fully understood. OBJECTIVES: The purpose of the present study was to examine the association of sleep habits with advancing age among community-dwelling older adults in Japan. METHODS: A total of 18,005 older people (mean age: 73.2 ± 6.0 years; 8,070 men and 9,935 women) from the National Center for Geriatrics and Gerontology Study of Geriatric Syndromes were analyzed. Participants were asked in face-to-face interviews about the times they usually go to bed, fall asleep, wake-up, and get up. The amount of time spent in bed and self-reported sleep duration were then calculated from the differences between these times. As other parameters, the subjects were also asked about sleep latency, time spent in bed after waking up, number of nocturnal awakenings, and duration of napping in a typical day. RESULTS: The results of the Jonckheere-Terpstra test showed that all sleep parameters shifted to an earlier time (going to bed, falling asleep, waking up, and getting out of bed), longer duration (sleep duration, time spent in bed, sleep latency, time spent in bed after waking up, and napping), or more nocturnal awakenings with advancing age (all p < 0.01). Among the men, the time of waking up was not significantly associated with age, while among the women, the time of getting up was not significantly associated with age. CONCLUSION: These results from a large cohort show the age-related trends of sleep habits in community-dwelling older adults in Japan. Our results revealed that a longer duration and earlier timing of sleep are associated with advancing age.

Metabolic study of GW1516 in equine urine using liquid chromatography/electrospray ionization Q-Exactive high-resolution mass spectrometry for doping control.

RATIONALE: The use of GW1516, a peroxisome proliferator-activated receptor δ (PPAR δ) agonist, is strictly prohibited in both horseracing and equestrian competitions. However, little is known about its metabolic fate in horses. To the best of our knowledge, this is the first reported metabolic study of GW1516 in equine urine. METHODS: Urine samples obtained from a thoroughbred after nasoesophageal administration with GW1516 were protein-precipitated and the supernatants were subsequently analyzed by liquid chromatography/electrospray ionization high-resolution mass spectrometry (LC/ESI-HRMS) with a Q-Exactive mass spectrometer. Monoisotopic ions of GW1516 and its metabolites were monitored from the full-scan mass spectral data of pre- and post-administration samples. A quantification method was developed and validated to establish the excretion profiles of GW1516, its sulfoxide, and its sulfone in equine urine. RESULTS: GW1516 and its nine metabolites [including GW1516 sulfoxide, GW1516 sulfone, 5-(hydroxymethyl)-4-methyl-2-(4-trifluoromethylphenyl)thiazole (HMTT), methyl 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (MMTC), 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (MTTC), and M1 to M4] were detected in post-administration urine samples. GW1516 sulfoxide and GW1516 sulfone showed the longest detection times in post-administration urine samples and were therefore recommended as potential screening targets for doping control purposes. Quantitative analysis was also conducted to establish the excretion profiles of GW1516 sulfoxide and GW1516 sulfone in urine. CONCLUSIONS: For the purposes of doping control of GW1516, the GW1516 sulfoxide and GW1516 sulfone metabolites are recommended as the target analytes to be monitored in equine urine due to their high specificities, long detection times (1 and 4 weeks, respectively), and the ready availability of their reference materials.

Detection and longitudinal distribution of GW1516 and its metabolites in equine hair for doping control using liquid chromatography/high-resolution mass spectrometry.

RATIONALE: GW1516 is a peroxisome proliferator-activated receptor-δ (PPAR-δ) agonist that is banned in horseracing and equestrian sports. Long-term detection and longitudinal distribution of GW1516 in the mane of a horse are reported for the first time and this hair analysis could prolong the detection window of GW1516 for doping control. METHODS: Mane hairs were divided into three segments (0-7, 7-15, and >15 cm from the cut end) and completely pulverized and homogenized for analysis. The pulverized hair samples were extracted with methanol followed by further purification and the extracts were analyzed by liquid chromatography/electrospray ionization high-resolution mass spectrometry (LC/ESI-HRMS) using a Q-Exactive instrument. This method was successfully validated and applied to post-administration samples to confirm the presence of GW1516 and its metabolites and estimate the uptake amounts of GW1516. RESULTS: After administration of 150 mg of GW1516 to a thoroughbred mare, GW1516 was detected in one of two segments of all mane hairs, and four metabolites, namely GW1516 sulfoxide, GW1516 sulfone, 5-(hydroxymethyl)-4-methyl-2-(4-trifluoromethylphenyl)thiazole (HMTT), and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (MTTC), were also identified. The longitudinal distribution analysis results showed that the maximum uptake of GW1516 into hair (approximately 0.05 pg/mg) was observed at around 13 weeks post-administration and GW1516 could be detected and confirmed up to 6 months post-administration. CONCLUSIONS: The parent drug GW1516 was identified as the most appropriate monitoring target in equine hair for controlling its misuse in horses. The use of hair analysis could extend the detection time of GW1516 to at least 6 months after the administration of 150 mg of GW1516 to a thoroughbred mare.

Epidural Administration of Ropivacaine Reduces the Amplitude of Transcranial Electrical Motor-Evoked Potentials: A Double-Blinded, Randomized, Controlled Trial.

BACKGROUND: An epidurally administered local anesthetic acts primarily on the epidural nerve roots and can act directly on the spinal cord through the dural sleeve. We hypothesized that epidurally administered ropivacaine would reduce the amplitude of transcranial electrical motor-evoked potentials by blocking nerve conduction in the spinal cord. Therefore, we conducted a double-blind, randomized, controlled trial. METHODS: Thirty adult patients who underwent lung surgery were randomly allocated to 1 of 3 groups, based on the ropivacaine concentration: the 0.2% group, the 0.375% group, and the 0.75% group. The attending anesthesiologists, neurophysiologists, and patients were blinded to the allocation. The epidural catheter was inserted at the T5-6 or T6-7 interspace by a paramedian approach, using the loss of resistance technique with normal saline. General anesthesia was induced and maintained using propofol and remifentanil. Transcranial electrical motor-evoked potentials were elicited by a train of 5 pulses with an interstimulus interval of 2 milliseconds by using a constant-voltage stimulator and were recorded from the tibialis anterior muscle. Somatosensory-evoked potentials (SSEPs) were evoked by electrical tibial nerve stimulation at the popliteal fossa. After measuring the baseline values of these evoked potentials, 10 mL of epidural ropivacaine was administered at the 0.2%, 0.375%, or 0.75% concentration. The baseline amplitudes and latencies recorded before administering ropivacaine were defined as 100%. Our primary end point was the relative amplitude of the motor-evoked potentials at 60 minutes after the epidural administration of ropivacaine. We analyzed the amplitudes and latencies of these evoked potentials by using the Kruskal-Wallis test and used the Dunn multiple comparison test as the post hoc test for statistical analysis. RESULTS: The data are expressed as the median (interquartile range). Sixty minutes after epidurally administering ropivacaine, the motor-evoked potential amplitude was lower in the 0.75% group (7% [3%-18%], between-group difference P < .001) and in the 0.375% group (52% [43%-59%]) compared to that in the 0.2% group (96% [89%-105%]). The latency of SSEP was longer in the 0.75% group compared to that in the 0.2% group, but the amplitude was unaffected. CONCLUSIONS: Epidurally administered high-dose ropivacaine lowered the amplitude of motor-evoked potentials and prolonged the onset latencies of motor-evoked potentials and SSEPs compared to those in the low-dose group. High-dose ropivacaine can act on the motor pathway through the dura mater.

Physical Frailty and Future Costs of Long-Term Care in Older Adults: Results from the NCGG-SGS.

INTRODUCTION: Frailty is associated with adverse outcomes, but few studies have determined associations between the frailty phenotype and measures of healthcare burden, including long-term care insurance (LTCI) costs, in older community-dwelling populations. OBJECTIVE: The aim of this study was to examine the association between frailty status and subsequent LTCI costs in Japanese community-dwelling older adults. METHODS: The prospective data were from a cohort study (National Center for Geriatrics and Gerontology-Study of Geriatric Syndromes [NCGG-SGS]). The participants were community-dwelling older adults (mean age 71.8 years, women 50.7%) participating in an NCGG-SGS baseline examination held between August 2011 and February 2012 in Obu, Japan (N = 4,539). At baseline, we assessed the physical frailty phenotype using the Japanese version of the CHS criteria and categorized it as robust, pre-frail, or frail. We also ascertained care-needs certification and total costs using long-term care services in Japan's public LTCI system during the 29 months. RESULTS: During the 29-month follow-up period, 239 participants (5.3%) required the LTCI system's care-needs certification and 163 participants (3.6%) used LTCI services. Participants classified as frail (odds ratio 5.85, 95% confidence interval 3.54-9.66) or pre-frail (2.40, 1.58-3.66) at the baseline assessment had an increased risk of requiring care-needs certification compared with robust participants. The mean total costs for LTCI services during the 29 months were ¥6,434 ($63.1) for robust, ¥19,324 ($189.5) for pre-frail, and ¥147,718 ($1,448.2) for frail participants (1 US dollar = 102 Japanese yen in July 2014). There were significantly higher costs associated with advancing frailty status. Individual frailty components (slowness, weakness, exhaustion, low activity, and weight loss) were also associated with higher total costs for using LTCI services. DISCUSSION/CONCLUSION: Frail community-dwelling older adults had a higher risk of requiring the LTCI system's care-needs certification and the subsequent total LTCI costs.

Doping control analysis of GW1516 in equine plasma using liquid chromatography/electrospray ionization Q-Exactive high-resolution mass spectrometry.

RATIONALE: GW1516 is a peroxisome proliferator-activated receptor-δ agonist in the class of hormones and metabolic modulators. The use of GW1516 is banned in both horseracing and equestrian competitions. To the best of our knowledge, this is the first metabolic study of GW1516 in horses. METHODS: After protein precipitation of pre- and post-administration plasma GW1516 samples, the supernatants were analyzed using liquid chromatography/electrospray ionization Q-Exactive high-resolution mass spectrometry to detect GW1516 and its metabolites. Monoisotopic ions of GW1516 and its metabolites were monitored from the full-scan mass spectral data of pre- and post-administration samples. Quantification methods were developed and validated to establish the elimination profiles of GW1516, its sulfoxide, and its sulfone in equine plasma. RESULTS: GW1516 and its four metabolites GW1516 sulfoxide, GW1516 sulfone, 5-(hydroxymethyl)-4-methyl-2-(4-trifluoromethylphenyl)thiazole (HMTT), and M1 were detected in post-administration plasma samples. GW1516 sulfoxide, GW1516 sulfone, and HMTT were identified by comparison with their respective reference standards whereas M1 was tentatively identified as 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid by mass spectral interpretation. GW1516 had the longest detection time in post-administration plasma. The elimination profiles of GW1516, its sulfoxide, and its sulfone in plasma were established. CONCLUSIONS: For the purpose of doping control, GW1516 is recommended as the target analyte to be monitored in equine plasma due to its long detection time (around 1 week) and the ready availability of its reference material.

Car Accidents Associated with Physical Frailty and Cognitive Impairment.

INTRODUCTION: Age-related functional decline elevates the risk of car accidents. Whether specific cognitive impairments and physical frailty increase the risk of car accidents is still unclarified. OBJECTIVE: This study examines the association between car accidents, frailty, and cognitive function, owing to an increase in car accidents related to older adults. METHODS: Data were collected from 12,013 older adults (45.4% women, mean age: 71.7 years [min: 60, max: 96]) enrolled in the National Center for Geriatrics and Gerontology (NCGG) - Study of Geriatric Syndromes. A 2-year self-reported history of car accidents was assessed. The Japanese cardiovascular health study index was used as the criterion and included the following components of frailty: shrinking, weakness, exhaustion, low activity, and slowness. "Frailty" was assigned a value of 1 or more based on these components. Cognitive function was assessed using the NCGG Functional Assessment Tool, and cognitive impairment was assessed using a standardized value. RESULTS: Of the participants, 1,117 (9.3%) had a car accident history. The proportions of the frailty components' applicability were observed in the car accidents group compared to the non-car accidents group: shrinking (p = 0.006), exhaustion (p = 0.031), low activity (p = 0.034), and slowness (p = 0.030), but not weakness (p = 0.452). The proportion of cognitive impairment in executive function was also higher in the car accidents group (p = 0.011). A logistic regression analysis showed that both frailty (OR 1.26, 95% CI 1.11-1.43; p < 0.001) and cognitive impairment (OR 1.26, 95% CI 1.11-1.43, p < 0.001) are associated with car accidents. DISCUSSION: This study's findings contribute to enhancing the utility of risk assessments for older drivers. Further study is required to clarify the risk of car accidents.

Spatio-temporal gait variables predicted incident disability.

BACKGROUND: Assessing the risk of disability in older adults is important for developing prevention and intervention strategies to decrease potential disability and dependency. The aim of this study was to examine the association between spatio-temporal gait variables and disability among older adults. METHODS: We conducted a prospective study in a community setting. We collected data from 4121 subjects (≥ 65 years, mean age: 71.9 years). Gait speed, cadence, stride length, and stride length variability were measured at baseline. Participants were instructed to walk at their usual pace along a 6.4 m straight and flat path on which an electronic gait measuring device was mounted at mid 2.4 m. Subsequent disability was confirmed from long-term care insurance records. RESULTS: During follow-up duration (mean: 49.6 months), 425 participants had incident disability. The cut-off value to detect high or low function in each gait variable was determined using the Youden index. Cox proportional hazard analysis adjusted for covariates showed that disability was significantly predicted by low function in each gait variable using the cut-off values: gait speed (hazard ratio [95% confidential intervals]: 2.06 [1.65-2.57]), stride length (2.17 [1.72-2.73]), cadence (1.49 [1.20-1.86], and stride length variability (1.46 [1.19-1.80]). The number of gait variables that scored in the low function category were also cumulatively related to subsequent disability (p < .001). CONCLUSIONS: This study revealed that spatio-temporal gait variables had a significant predictive value for incident disability. Multifaceted and quantitative gait analysis can contribute to disability risk assessment.

An Overview on Denial-of-Service Attacks in Control Systems: Attack Models and Security Analyses.

In this paper, we provide an overview of recent research efforts on networked control systems under denial-of-service attacks. Our goal is to discuss the utility of different attack modeling and analysis techniques proposed in the literature for addressing feedback control, state estimation, and multi-agent consensus problems in the face of jamming attacks in wireless channels and malicious packet drops in multi-hop networks. We discuss several modeling approaches that are employed for capturing the uncertainty in denial-of-service attack strategies. We give an outlook on deterministic constraint-based modeling ideas, game-theoretic and optimization-based techniques and probabilistic modeling approaches. A special emphasis is placed on tail-probability based failure models, which have been recently used for describing jamming attacks that affect signal to interference-plus-noise ratios of wireless channels as well as transmission failures on multi-hop networks due to packet-dropping attacks and non-malicious issues. We explain the use of attack models in the security analysis of networked systems. In addition to the modeling and analysis problems, a discussion is provided also on the recent developments concerning the design of attack-resilient control and communication protocols.

Prevalence of sarcopenia and its association with activities of daily living among japanese nursing home residents.

Sarcopenia is an important predictor of adverse outcomes in elderly people. Based on a common clinical experience, sarcopenia may be associated with activities of daily living (ADL). To our knowledge, no study has investigated the association between sarcopenia and ADL in nursing home residents requiring long-term care. This cross-sectional study included 250 nursing home residents. Nutritional status, physical function, ADL and cognitive function were assessed using Mini Nutritional Assessment-Short Form (MNA-SF), Short Physical Performance Battery (SPPB), Barthel Index (BI) and Mini-Mental State Examination (MMSE). To examine the factors that may affect self-care capacity, a stepwise multiple linear regression analysis was performed. The prevalence of sarcopenia was 45.2%. Age, MMSE, MNA-SF, SPPB, and grip strength were independently associated with BI. A high prevalence of sarcopenia was observed among nursing home residents in Japan. However, sarcopenia was not associated with ADL.

A simultaneous determination method for 5-fluorouracil and its metabolites in human plasma with linear range adjusted by in-source collision-induced dissociation using hydrophilic interaction liquid chromatography-electrospray ionization-tandem mass spectrometry.

We applied a new technique for quantitative linear range shift using in-source collision-induced dissociation (CID) to complex biological fluids to demonstrate its utility. The technique was used in a simultaneous quantitative determination method of 5-fluorouracil (5-FU), an anticancer drug for various solid tumors, and its metabolites in human plasma by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS). To control adverse effects after administration of 5-FU, it is important to monitor the plasma concentration of 5-FU and its metabolites; however, no simultaneous determination method has yet been reported because of vastly different physical and chemical properties of compounds. We developed a new analytical method for simultaneously determining 5-FU and its metabolites in human plasma by LC/ESI-MS/MS coupled with the technique for quantitative linear range shift using in-source CID. Hydrophilic interaction liquid chromatography using a stationary phase with zwitterionic functional groups, phosphorylcholine, was suitable for separation of 5-FU from its nucleoside and interfering endogenous materials. The addition of glycerin into acetonitrile-rich eluent after LC separation improved the ESI-MS response of high polar analytes. Based on the validation results, linear range shifts by in-source CID is the reliable technique even with complex biological samples such as plasma. Copyright © 2016 John Wiley & Sons Ltd.

Shifting the Linear Range in Electrospray Ionization by In-Source Collision-Induced Dissociation.

The goal of this study was to demonstrate the utility of in-source collision-induced dissociation for shifting the linear range in liquid chromatography-electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS). The linear ranges for uracil, deoxyuridine, and uridine were shifted from 0.3-300, 1-100, and 10-1000 ng/mL to 10-1000, 30-3000, and 100-10000 ng/mL, respectively, by changing the declustering potential controlling in-source collision-induced dissociation. This technique should be considered for control of linear range in simultaneous quantitative measurements of extremely different amounts of compounds, drugs, and metabolites using LC/ESI-MS/MS.

Morphological spectrum of renal pathology and its correlation to clinical features in patients with disseminated intravascular coagulation: a study involving a series of 21 autopsy cases.

Disseminated intravascular coagulation (DIC), a thrombohemorrhagic disorder, occurs as a secondary complication in many diseases, but the histopathological features of kidneys in DIC have not been extensively characterized thus far. We reviewed 21 autopsy cases of patients with a clinical diagnosis of DIC and studied the repertoire of renal pathology. Eighteen patients had elevated serum creatinine levels and 15 patients had a variable degree of proteinuria. Underlying disorders included malignant neoplasms in 12 patients, and abdominal aortic aneurysm, acute myocardial infarction, and systemic infections in other patients. Coexistent glomerular pathology, such as focal segmental glomerulosclerosis (FSGS) with different morphological variants, and microthrombi formation, was present in many patients. The microthrombi were histologically similar to that seen in thrombotic microangiopathy, but characteristics associated with DIC were detected by special staining. The presence of FSGS correlated with the degree of urinary protein (P = 0.0044), and the presence of acute tubular injury (ATI) and the extent of global glomerulosclerosis both correlated with serum creatinine levels (P = 0.019 and 0.0003, respectively). FSGS was probably due to endothelial cell damage, another potential etiology for FSGS. Global glomerulosclerosis, a result of previous renal injury, can be a determinant of renal function during the acute phase of DIC.

[Anesthetic management of scoliosis surgery for a patient with congenital myasthenic syndrome].

Congenital myasthenic syndromes (CMS) are heterogeneous disorders of neurotransmission caused by genetic mutations of neuromuscular junction molecules. We report anesthetic management of a CMS patient who was a 14-year-old boy with endplate acetylcholinesterase deficiency. The patient used noninvasive positive pressure ventilation (NPPV) at night. He underwent a corrective maneuver for severe scoliosis under general anesthesia. General anesthesia was maintained using propofol and remifentanil. Intraoperative mechanical ventilation remained stable. Extubation was performed on the next day and NPPV was started. Several hours later, he complained of a stomachache and intense abdominal bloating. Computed tomography revealed a massive amount of air in the stomach and intestine. He recovered from abdominal bloating the next day without treatment for decompression. Lung-thoracic compliance has been reported to decrease immediately after a corrective maneuver for scoliosis patients. In our case, we suspected a relative increase of abdominal compliance to lung-thoracic compliance as a cause of intense abdominal bloating by air injection from NPPV with his daily setting. In CMS, symptoms, therapy and contraindicated drugs vary according to the location of dysfunction. Therefore, anesthetic management according to each genotype should be designed to avoid drugs that could either trigger or worsen CMS. Intensive respiratory care is advisable after surgery.