Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.

Increased adipose tissue lipogenesis is associated with enhanced insulin sensitivity. Mice overexpressing the Glut4 glucose transporter in adipocytes have elevated lipogenesis and increased glucose tolerance despite being obese with elevated circulating fatty acids. Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (FAHFAs) that were elevated 16- to 18-fold in these mice. FAHFA isomers differ by the branched ester position on the hydroxy fatty acid (e.g., palmitic-acid-9-hydroxy-stearic-acid, 9-PAHSA). PAHSAs are synthesized in vivo and regulated by fasting and high-fat feeding. PAHSA levels correlate highly with insulin sensitivity and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowers ambient glycemia and improves glucose tolerance while stimulating GLP-1 and insulin secretion. PAHSAs also reduce adipose tissue inflammation. In adipocytes, PAHSAs signal through GPR120 to enhance insulin-stimulated glucose uptake. Thus, FAHFAs are endogenous lipids with the potential to treat type 2 diabetes.

Radioembolization plus Immune Checkpoint Inhibitor Therapy Compared with Radioembolization plus Tyrosine Kinase Inhibitor Therapy for the Treatment of Hepatocellular Carcinoma.

PURPOSE: To investigate if combination therapy with immune checkpoint inhibitor (ICI) and yttrium-90 (90Y) radioembolization results in superior outcomes than those yielded by tyrosine kinase inhibitor (TKI) therapy and 90Y for the treatment of intermediate- to advanced-stage hepatocellular carcinoma (HCC). METHODS: A retrospective review of patients presented at an institutional multidisciplinary liver tumor board between January 1, 2012 and August 1, 2023 was conducted. In total, 44 patients with HCC who underwent 90Y 4 weeks within initiation of ICI or TKI therapy were included. Propensity score matching was conducted to account for baseline demographic differences. Kaplan-Meier analysis was used to compare median progression-free survival (PFS) and overall survival (OS), and univariate statistics identified disease response and control rate differences. Duration of imaging response was defined as number of months between the first scan after therapy and the first scan showing progression as defined by modified Response Evaluation Criteria in Solid Tumors (mRECIST) or immune Response Evaluation Criteria in Solid Tumors (iRECIST). Adverse events were analyzed per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: Patients in the 90Y+ICI therapy group had better objective response rates (ORRs) (89.5% vs 36.8%; P < .001) and disease control rates (DCRs) (94.7% vs 63.2%; P < .001) by mRECIST and iRECIST (ORR: 78.9% vs 36.8%; P < .001; DCR: 94.7% vs 63.2%; P < .001). Median PFS (8.3 vs 4.1 months; P = .37) and OS (15.8 vs 14.3 months; P = .52) were not statistically different. Twelve patients (63.1%) in the 90Y+TKI group did not complete systemic therapy owing to adverse effects compared with 1 patient (5.3%) in the 90Y+ICI group (P < .001). Grade 3/4 adverse events were not statistically different (90Y+TKI: 21.1%; 90Y+ICI: 5.3%; P = .150). CONCLUSIONS: Patients with HCC who received 90Y+ICI had better imaging response and fewer regimen-altering adverse events than those who received 90Y+TKI. No significant combination therapy adverse events were attributable to radioembolization.

Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System : A Population-Based Cohort Study.

BACKGROUND: In the EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) trial, nirmatrelvir plus ritonavir led to an 89% reduction in hospitalization or death among unvaccinated outpatients with early COVID-19. The clinical impact of nirmatrelvir plus ritonavir among vaccinated populations is uncertain. OBJECTIVE: To assess whether nirmatrelvir plus ritonavir reduces risk for hospitalization or death among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune-evasive SARS-CoV-2 lineages. DESIGN: Population-based cohort study analyzed to emulate a clinical trial using inverse probability-weighted models to account for anticipated bias in treatment. SETTING: A large health care system providing care for 1.5 million patients in Massachusetts and New Hampshire during the Omicron wave (1 January to 17 July 2022). PATIENTS: 44 551 nonhospitalized adults (90.3% with ≥3 vaccine doses) aged 50 years or older with COVID-19 and no contraindications for nirmatrelvir plus ritonavir. MEASUREMENTS: The primary outcome was a composite of hospitalization within 14 days or death within 28 days of a COVID-19 diagnosis. RESULTS: During the study period, 12 541 (28.1%) patients were prescribed nirmatrelvir plus ritonavir, and 32 010 (71.9%) were not. Patients prescribed nirmatrelvir plus ritonavir were more likely to be older, have more comorbidities, and be vaccinated. The composite outcome of hospitalization or death occurred in 69 (0.55%) patients who were prescribed nirmatrelvir plus ritonavir and 310 (0.97%) who were not (adjusted risk ratio, 0.56 [95% CI, 0.42 to 0.75]). Recipients of nirmatrelvir plus ritonavir had lower risk for hospitalization (adjusted risk ratio, 0.60 [CI, 0.44 to 0.81]) and death (adjusted risk ratio, 0.29 [CI, 0.12 to 0.71]). LIMITATION: Potential residual confounding due to differential access to COVID-19 vaccines, diagnostic tests, and treatment. CONCLUSION: The overall risk for hospitalization or death was already low (1%) after an outpatient diagnosis of COVID-19, but nirmatrelvir plus ritonavir reduced this risk further. PRIMARY FUNDING SOURCE: National Institutes of Health.

Safety Assessment of a Novel Intravenous Diclofenac Sodium Formulation Following 28-Day Repeated Administration in Wistar Rats.

These toxicity studies aimed to assess the safety and tolerability of a novel intravenous diclofenac sodium (37.5 mg/mL) formulation containing povidone K12 (80 mg/mL) as the key excipient in Wistar rats. This formulation was tested at doses of 3, 7, and 15 mg/kg/day and was administered daily for 28 days by intravenous route. Toxicokinetic estimation revealed a dose-proportional increase in plasma exposure to diclofenac. The formulation was well tolerated in males; however, mortality was observed in females (2/15) at the highest dose (15 mg/kg/day). Adverse gastrointestinal events related to NSAIDS and a few other treatment-related effects on clinical and anatomic pathology were noted at the 15 mg/kg/day dose, which normalized at the end of the 2-week recovery period. In addition, the excipient povidone K12 was present in a higher amount than the approved Inactive Ingredient Database (IID) limit in the proposed novel formulation. It was qualified through a separate 28-day repeated dose toxicity study by intravenous route in Wistar rats. Povidone K12 was found to be well tolerated and safe up to a dose of 165 mg/kg/day. No treatment-related adverse effects were observed in this study. In conclusion, repeated administration of a novel intravenous formulation containing diclofenac sodium was found to be safe up to the dose of 7 mg/kg/day in female rats and 15 mg/kg/day in male rats.

A Retrospective Comparison of Electrocardiographic Parameters in Ketamine and Tiletamine-Zolazepam Anesthetized Indian Rhesus Monkeys (Macaca mulatta).

Electrocardiographic evaluation is performed in rhesus monkeys to establish the cardiovascular safety of candidate molecules before progressing to clinical trials. These animals are usually immobilized chemically by ketamine (KTM) and tiletamine-zolazepam (TZ) to obtain a steady-state heart rate and to ensure adequate human safety. The present study aimed to evaluate the effect of these anesthetic regimens on different electrocardiographic parameters. Statistically significant lower HR and higher P-wave duration, RR, QRS, and QT intervals were observed in the KTM-anesthetized group in comparison to TZ-anesthetized animals. No significant changes were noticed in the PR interval and p-wave amplitude. Sex-based significance amongst these parameters was observed in male and female animals of TZ- and KTM-anesthetized groups. Regression analysis of four QTc formulas in TZ-anesthetized rhesus monkeys revealed that QTcNAK (Nakayama) better corrected the QT interval than QTcHAS (Hassimoto), QTcBZT (Bazett), and QTcFRD (Fridericia) formulas. QTcNAK exhibited the least correlation with the RR interval (slope closest to zero and r = .01) and displayed no statistical significance between male and female animals. These data will prove useful in the selection of anesthetic regimens for chemical restraint of rhesus monkeys in nonclinical safety evaluation studies.

Production of hydrogen-rich fuel gas from waste plastics using continuous plasma pyrolysis reactor.

There is a serious concern about the large amount of accumulated plastic waste all around the world. Synthetic polymers such as polyethylene terephthalate (PET), polypropylene (PP), and polyethylene (HDPE, LDPE) are substantially present in the plastic waste generated. There are various methods reported to minimise such plastics waste with certain limitations. To overcome such limitations the present study have been carried out in which thermal decomposition of plastic waste of PET, PP, HDPE, and LDPE studied using a novel plasma pyrolysis reactor. The major objective of this work is to investigate the viability of the continuous plasma pyrolysis process for the treatment of various plastic wastes with respect to waste volume reduction and production of combustible hydrogen-rich fuel gas. The effect of temperature and feed flow rate on product gas yield, product gas efficiency, solid residue yield, and H2/CO ratio has been evaluated. The experiments have been carried out at different temperatures within the range of 700-1000 °C. Plasma pyrolysis system exhibited combustible hydrogen-rich gas as a product and solid residue. Liquid products have not been observed during plasma pyrolysis, unlike conventional pyrolysis. The reaction mechanism of plastic cracking has been discussed based on literature and products obtained in the present work. The effects of feed flow rate and temperature on exergy efficiency were studied using the response surface method. The mass, energy, and exergy analyses have also been carried out for all the experiments, which are in the range of 0.95-0.99, 0.48 to 0.77, and 0.30 to 0.69, respectively.

Hypoosmosis alters hepatocyte mitochondrial morphology and induces selective release of carbamoyl phosphate synthetase 1.

Carbamoyl phosphate synthetase 1 (CPS1) is the most abundant hepatocyte mitochondrial matrix protein. Hypoosmotic stress increases CPS1 release in isolated mouse hepatocytes without cell death. We hypothesized that increased CPS1 release during hypoosmosis is selective and associates with altered mitochondrial morphology. Both ex vivo and in vivo models were assessed. Mouse hepatocytes and livers were challenged with isotonic or hypoosmotic (35 mosM) buffer. Mice were injected intraperitoneally with water (10% body weight) with or without an antidiuretic. Mitochondrial and cytosolic fractions were isolated using differential centrifugation, then analyzed by immunoblotting to assess subcellular redistribution of four mitochondrial proteins: CPS1, ornithine transcarbamylase (OTC), pyrroline-5-carboxylate reductase 1 (PYCR1), and cytochrome c. Mitochondrial morphology alterations were examined using electron microscopy. Hypoosmotic treatment of whole livers or hepatocytes led to preferential or increased mitochondrial release, respectively, of CPS1 as compared with two mitochondrial matrix proteins (OTC/PYCR1) and with the intermembrane space protein, cytochrome c. Mitochondrial apoptosis-induced channel opening using staurosporine in hepatocytes led to preferential CPS1 and cytochrome c release. The CPS1-selective changes were accompanied by dramatic alterations in ultrastructural mitochondrial morphology. In mice, hypoosmosis/hyponatremia led to increased liver vascular congestion and increased CPS1 in bile but not blood, coupled with mitochondrial structural alterations. In contrast, isotonic increase of intravascular volume led to a decrease in mitochondrial size with limited change in bile CPS1 compared with hypoosmotic conditions and absence of the hypoosmosis-associated histological alterations. Taken together, hepatocyte CPS1 is selectively released in response to hypoosmosis/hyponatremia and provides a unique biomarker of mitochondrial injury.NEW & NOTEWORTHY Exposure of isolated mouse livers, primary cultured hepatocytes, or mice to hypoosmosis/hyponatremia conditions induces significant mitochondrial shape alterations accompanied by preferential release of the mitochondrial matrix protein CPS1, a urea cycle enzyme. In contrast, the intermembrane space protein, cytochrome c, and two other matrix proteins, including the urea cycle enzyme ornithine transcarbamylase, remain preferentially retained in mitochondria. Therefore, hepatocyte CPS1 manifests unique mitochondrial stress response compartmentalization and is a sensitive sensor of mitochondrial hypoosmotic/hyponatremic injury.

Fertility after Transcatheter Arterial Embolization for Obstetric Hemorrhage: An Urban Health Care System Observational Study.

OBJECTIVE: This study aimed to investigate pregnancy rate, pregnancy outcomes, and resumption of menses after transcatheter arterial embolization (TAE) for obstetric hemorrhage (OH). STUDY DESIGN: Sixty-seven patients who underwent TAE for OH from 2006 to 2020 within an urban, multihospital health care system were identified retrospectively. Selected patients were interviewed by phone to complete a survey with a primary outcome of self-reported pregnancy in those seeking pregnancy. Secondary outcomes included pregnancy outcomes and resumption of menses. Univariate testing of association of pregnancy and miscarriage rate with embolic agent was performed using Fisher's exact test. RESULTS: Thirty-three of 50 patients (66%) meeting the inclusion criteria completed the survey on fertility, a median of 47 (range, 13-123) months after TAE for OH. Of the 13 patients who attempted pregnancy, there was a pregnancy rate of 77% and miscarriage rate of 38%. Those who delivered live newborns conceived spontaneously, carried to term, and delivered a healthy newborn via cesarean section at a weight appropriate for gestational age. Thirty (91%) patients resumed menstruation, and the majority with unchanged frequency. Most patients underwent bilateral uterine artery embolization with radial artery access (54%). The most common embolic agents used were gelfoam only (30%) and glue only (24%). There was no statistically significant association between embolic agent and pregnancy or miscarriage rate. CONCLUSION: Spontaneous pregnancy with live birth and resumption of menses can occur in a majority of patients after TAE for OH. KEY POINTS: · Most patients who attempted pregnancy after TAE for OH achieved pregnancy.. · Most patients who became pregnant conceived spontaneously and delivered healthy newborns at term.. · Most patients resumed menstruation after TAE for OH.. · There was no significant association between type of embolic and pregnancy or miscarriage rate..

In-depth analysis of the effect of catalysts on plasma technologies for treatment of various wastes.

Energy security and waste management are gaining global attention. The modern world is producing a large amount of liquid and solid waste as a result of the increasing population and industrialization. A circular economy encourages the conversion of waste to energy and other value-added products. Waste processing requires a sustainable route for a healthy society and clean environment. One of the emerging solutions for waste treatment is plasma technology. It converts waste into syngas, oil, and char/slag depending on the thermal/non-thermal processes. Most of all the types of carbonaceous wastes can be treated by plasma processes. The addition of a catalyst to the plasma process is a developing field as plasma processes are energy intensive. This paper covers the detailed concept of plasma and catalysis. It comprises various types of plasma (non-thermal and thermal) and catalysts (zeolites, oxides, and salts) which have been used for waste treatment. Catalyst addition improves gas yield and hydrogen selectivity at moderate temperatures. Depending on the properties of the catalyst and type of plasma, comprehensive points are listed for the selection of the right catalyst for a plasma process. This review offers an in-depth analysis of the research in the field of waste-to-energy using plasma-catalytic processes.

Development of an Automated and Scalable Virtual Assistant to Aid in PPE Adherence: A Study with Implications for Applications within Anesthesiology.

Virtual assistants (VAs) are conversational agents that are able to provide cognitive aid. We developed a VA device for donning and doffing personal protective equipment (PPE) procedures and compared it to live human coaching to explore the feasibility of using VAs in the anesthesiology setting. An automated, scalable, voice-enabled VA was built using the Amazon Alexa device and Alexa Skills application. The device utilized voice-recognition technology to allow a touch-free interactive user experience. Audio and video step-by-step instructions for proper donning and doffing of PPE were programmed and displayed on an Echo Show device. The effectiveness of VA in aiding adherence to PPE protocols was compared to traditional human coaching in a randomized, controlled, single-blinded crossover design. 70 anesthesiologists, anesthesia assistants, respiratory therapists, and operating room nurses performed both donning and doffing procedures, once under step-by-step VA instructional guidance and once with human coaching. Performance was assessed using objective performance evaluation donning and doffing checklists. More participants in the VA group correctly performed the step of "Wash hands for 20 seconds" during both donning and doffing tests. Fewer participants in the VA group correctly performed the steps of "Put cap on and ensure covers hair and ears" and "Tie gown on back and around neck". The mean doffing total score was higher in the VA group; however, the donning score was similar in both groups. Our study demonstrates that it is feasible to use commercially available technology to create a voice-enabled VA that provides effective step-by-step instructions to healthcare professionals.

Comparison of different QT correction methods for nonclinical safety assessment in ketamine-anesthetized Indian rhesus monkeys (Macaca mulatta).

Rhesus monkeys are a non-rodent species employed in the preclinical safety evaluation of pharmaceuticals and biologics. These nonhuman primate species have been increasingly used in biomedical research because of the similarity in their ionic mechanisms of repolarization with humans. Heart rate and QT interval are two primary endpoints in determining the pro-arrhythmic risk of drugs. As heart rate and QT interval have an inverse relationship, any change in heart rate causes a subsequent change in QT interval. This warrants for calculation of a corrected QT interval. This study aimed to identify an appropriate formula that best corrected QT for change in heart rate. We employed seven formulas based on source-species type, clinical relevance, and requirements of various international regulatory guidelines. Data showed that corrected QT interval values varied drastically for different correction formulas. Equations were compared on their slope values based on QTc versus RR plots. The rank order of the slope for different formulas was (closest to farthest from zero) QTcNAK, QTcHAS, QTcBZT, QTcFRD, QTcVDW, QTcHDG, and QTcFRM. QTcNAK emerged to be the best correcting formula in this study. It showed the least correlation with the RR interval (r = -0.01) and displayed no significant difference amongst the sexes. As there is no universally recognized formula for preclinical use, the authors recommend developing a best-case scenario model for specific study designs and individual organizations. The data from this research will be helpful in deciding an appropriate QT correction formula for the safety assessment of new pharmaceuticals and biologics.

Culturable heterotrophic bacterial diversity study from an Indian lignite mine habitat.

Diversity lifts the productivity of any ecosystem as all the species have a vital role to play that is present within the ecosystem. The characterization is essential to delve into the ecological functions of microbial communities and discover the type of microorganisms present within the ecosystem. As microbial diversity in ecosystems responds to environmental disturbances, it functions as a marker to indicate the change in such ecosystems. Mine ecology differs significantly from other habitats due to the presence of acidic runoff. This paper provides insight into the diversity of cultivable bacteria isolated from lignite mines located in south Gujarat. A total of 67 heterotrophic isolates were successfully cultivated from the collected solid and water samples of the Rajpardi and Tadkeshwar Lignite mine sites. The isolates were characterized morphologically and biochemically, and intra- and extracellular enzyme synthesis were studied. Moreover, the relative density and frequency of cultivated isolates from the samples were calculated. The similarity and evenness of the heterotrophic isolated were studied by calculating diversity indices such as Shannon and Simpson. Alpha diversity was calculated in PAST software to analyse the similarity between the selected two mine sites. This research also explored the relationship between the variance in heterotrophic microbial diversity and substrate utilization richness of the studied lignite mines of Gujarat.

Newborn screening and single nucleotide variation profiling of TSHR, TPO, TG and DUOX2 candidate genes for congenital hypothyroidism.

High prevalence of congenital hypothyroidism (CH) among Indian newborns prompted us to establish population-specific reference ranges of TSH and to explore the contribution of the common genetic variants in TSHR, TPO, TG and DUOX2 genes towards CH. A total of 1144 newborns (593 males and 551 females) were screened for CH. SNV profiling (n = 22) spanning three candidate genes, i.e. TSHR, TPO and TG was carried out in confirmed CH cases (n = 45). In screen negative cases (n = 700), ten TSHR variants were explored to establish association with CH. No mutation found in DUOX2. The 2.5th to 97.5th percentiles of TSH in these newborns were 0.5 to 12.2 mU/L. In newborns with optimal birth weight, the cut-off was 10 mU/L. Lower or higher birth weight resulted in slightly higher TSH. Two TSHR variants, i.e. rs7144481 and rs17630128 were associated with agenesis, hypoplasia and goiter. The rs2268477 was associated with agenesis and hypoplasia. The rs1991517, rs2075176 and rs2241119 were associated with agenesis only. The rs7144481, rs17630128, rs1991517 and rs2268477 were associated with 2.17, 4.62, 2.91 and 2.29-fold increased risk for CH, respectively. Among the TPO variants, rs867983 and rs2175977 were associated with agenesis and goiter, respectively. Among the TG variants, rs2076740 showed association with agenesis and goiter. Two rare variants i.e. TPO g.IVS14-19 G>C and TG c.1262 C>T were observed in CH cases. No genetic variant identified in the two exons of DUOX2. To conclude, the current study established Indian population-specific normative values for TSH and demonstrates specific genotype-phenotype correlations among three candidate genes.

Magnetocardiography for identification of coronary ischemia in patients with chest pain and normal resting 12-lead electrocardiogram.

BACKGROUND: Identification of coronary ischemia in patients presenting with chronic chest pain is difficult as resting ECG can be normal. Diagnosis of coronary ischemia requires evaluation during exercise or pharmacological stress. A noninvasive test to identify coronary ischemia at rest without the need for exercise is desirable. We studied the diagnostic accuracy of magnetocardiography (MCG) at rest to detect coronary ischemia in these patients. METHODS: Patients with chronic chest pain and suspected coronary ischemia with a normal ECG were included. Patients underwent treadmill test (TMT) and were divided into TMT positive and TMT negative groups. MCG was recorded in a magnetically shielded room. Iso-field contour maps generated at the T-wave peak were compared between the groups. From the magnetic field map (MFM), the magnetic field angle at T-wave peak was calculated and was also compared across the two groups. RESULTS: There were a total of 29 patients, 12 with positive TMT and 17 with negative TMT. An abnormal magnetic field angle was more common in the TMT positive group (72% vs. 6%). Abnormal contour maps in the form of nondipole patterns or abnormal orientation were seen in 81.8% (9/11) patients in TMT positive group and 6.8% (1/17) patients in the TMT negative group (p < .001). CONCLUSION: Abnormal magnetic field angle and abnormal magnetic field maps in MCG recorded at rest are able to identify the presence of coronary ischemia in patients with chronic chest pain and a normal resting ECG.

Does the evidence justify routine transfer of residents of aged care facilities for CT scan after minor head trauma?

BACKGROUND: In 2014, the South Australian coroner recommended that residents of residential aged care facilities (RACF) who had sustained a head injury should be transported to emergency departments (ED) for assessment and a head CT scan, with the view to preventing mortality. The evidence base for the recommendation is unclear. AIMS: To determine the rate of emergent intervention (neurosurgery, transfusion of blood products or reversal of anti-coagulation) in residents transferred to ED with minor head trauma who had their usual cognitive function on ED assessment. METHODS: This was a retrospective cohort study by medical records review at two university-affiliated community ED. Participants were patients from RACF attending ED who had suffered minor head trauma and had their usual cognitive function. Exclusions were altered conscious state, new neurological findings or associated orthopaedic injury requiring hospital admission. The primary outcome was rate of emergent intervention in residents transferred to ED with minor head trauma who had their usual cognitive function on ED assessment. RESULTS: A total of 366 patients was studied; median age 86 years, 45% taking anti-coagulant/anti-platelet medication. Eighty per cent underwent head CT. Six per cent had intracranial haemorrhage (ICH; 95% CI 4-8.9%). No patient underwent neurosurgery. One had emergent intervention, reversal of anti-coagulation (0.3%, 95% CI 0.05-1.5%). CONCLUSION: The rate of emergent intervention for ICH in patients from RACF who sustained a minor head trauma but had their normal cognitive function was <1%. None underwent neurosurgical intervention. The low rate of intervention seriously challenges the appropriateness of routine transfer and CT for this patient group.

An investigation on the influence of yogic methods on heart rate variability.

BACKGROUND: The role of underlying mechanisms of yogic strategies which exert beneficiary effects on cardiac autonomic control is poorly understood. We have performed heart rate variability (HRV) analysis on subjects performing yogic methods and control subjects who mimic them through paced breathing and focused attention tasks using external cues. METHODS: Heart rate (HR) time series is generated from electrocardiogram measured from subjects of yogic group (YG); performing yogic practices (n = 15), paced breathing group (PBG); involved in breathing exercises cued at breathing rates (BR) from 3 to 15 cycles per minute (cpm) (n = 23), normal breathing group (NBG) under regular breathing (n = 15), and subjects performing three different cognitive tasks designated as focused attention group (FAG), (n = 24). HRV is analyzed using coherence plots, spectrograms, HRV parameters, and instantaneous frequency recurrence plots (IFRP). RESULTS: HRV is similar among YG and PBG (at BR <12 cpm) and significantly different for YG vs. NBG (p < 0.001) and PBG vs. NBG (p < 0.001). Regularity of breathing oscillations observed in HR is quantified using IFRP and is identical among FAG, PBG, and YG and significantly different for YG vs. NBG (p < 0.01), PBG vs. NBG (p < 0.01), and FAG vs. NBG (p < 0.05). CONCLUSIONS: Low-frequency breathing (BR <12 cpm) plays a primary role in eliciting physiologically significant changes in HRV. By identifying a similarity in breathing oscillations of HR of FAG, YG, and PBG, the results recognize the coexistence of attention and breathing strategies and postulate their joint role in sustaining autonomic benefits, while effects induced by breathing alone on HRV could be attained even intermittently.

A Health System-Wide Initiative to Decrease Opioid-Related Morbidity and Mortality.

BACKGROUND: The opioid overdose crisis now claims more than 40,000 lives in the United States every year, and many hospitals and health systems are responding with opioid-related initiatives, but how best to coordinate hospital or health system-wide strategy and approach remains a challenge. METHODS: An organizational opioid stewardship program (OSP) was created to reduce opioid-related morbidity and mortality in order to provide an efficient, comprehensive, multidisciplinary approach to address the epidemic in one health system. An executive committee of hospital leaders was convened to empower and launch the program. To measure progress, metrics related to care of patients on opioids and those with opioid use disorder (OUD) were evaluated. RESULTS: The OSP created a holistic, health system-wide program that addressed opioid prescribing, treatment of OUD, education, and information technology tools. After implementation, the number of opioid prescriptions decreased (-73.5/month; p < 0.001), mean morphine milligram equivalents (MME) per prescription decreased (-0.4/month; p < 0.001), the number of unique patients receiving an opioid decreased (-52.6/month; p < 0.001), and the number of prescriptions ≥ 90 MME decreased (-48.1/month; p < 0.001). Prescriptions and providers for buprenorphine increased (+6.0 prescriptions/month and +0.4 providers/month; both p < 0.001). Visits for opioid overdose did not change (-0.2 overdoses/month; p = 0.29). CONCLUSION: This paper describes a framework for a new health system-wide OSP. Successful implementation required strong executive sponsorship, ensuring that the program is not housed in any one clinical department in the health system, creating an environment that empowers cross-disciplinary collaboration and inclusion, as well as the development of measures to guide efforts.

The effect of virtual reality bronchoscopy simulator training on performance of bronchoscopic-guided intubation in patients: A randomised controlled trial.

BACKGROUND: The use of a flexible optical bronchoscopic (FOB) for intubation is an essential airway management skill. OBJECTIVE(S): Our primary objective was to compare the effects of simulator training (ORSIM high-fidelity simulator) with no simulation training on the performance of FOB intubation in anaesthetised patients. DESIGN: Randomised controlled trial. SETTING: Single-centre tertiary hospital; trial conducted between April 2015 to May 2016. PARTICIPANTS: Medical students, anaesthesia assistants and anaesthesia residents with experience of less than five FOB intubations from whom informed consent was obtained. INTERVENTION: Students, anaesthesia assistants and anaesthesia residents viewed a didactic presentation before performing an initial FOB intubation in an anaesthetised patient. Intubations were recorded and evaluated using the Global Rating Scale (GRS) and checklist scores. Subsequently, participants were randomised to control group (Group CON) and had no simulation training, or to a simulation group (Group SIM) and underwent 60 min of simulation practice. Within a week, participants performed a second FOB intubation and were similarly evaluated. MAIN OUTCOME MEASURES: Pretraining and posttraining intubation time, GRS and checklist scores. RESULTS: Baseline characteristics were similar between groups. In Group SIM, there was significant improvement between pre and posttraining GRS [22.9 ±â€Š8.1 vs. 28.2 ±â€Š7.3, mean difference (95% CI) 5.3 (0.3 to 10.3), P = 0.04], and intubation time [177.6 ±â€Š77.6 vs. 119.3 ±â€Š52.2 s, mean difference (95% CI) -58.4 (-100.3 to -16.5) s, P = 0.01]. There was no difference in Group CON, between pre and posttraining intubation time, GRS or checklist. CONCLUSION: We conclude, posttraining performance of FOB intubation, as measured by intubation time and GRS, improved in Group SIM, while it was unchanged in the Group CON. The ORSIM simulator may be a useful adjunct in acquiring FOB intubation skills. CLINICAL TRIAL NUMBER AND REGISTRY: ClinicalTrials.gov ID: NCT02699242.

Carbon monoxide releasing molecule A-1 attenuates acetaminophen-mediated hepatotoxicity and improves survival of mice by induction of Nrf2 and related genes.

Acute liver injury is frequently associated with oxidative stress. Here, we investigated the therapeutic potential of carbon monoxide releasing molecule A-1 (CORM A-1) in oxidative stress-mediated liver injury. Overnight-fasted mice were injected with acetaminophen (APAP; 300 mg/kg; intraperitoneally) and were sacrificed at 4 and 12 h. They showed elevated levels of serum transaminases, depleted hepatic glutathione (GSH) and hepatocyte necrosis. Mice injected with CORM A-1 (20 mg/kg) 1 h after APAP administration, had reduced serum transaminases, preserved hepatic GSH and reduced hepatocyte necrosis. Mice that received a lethal dose of APAP (600 mg/kg), died by 10 h; but those co-treated with CORM A-1 showed a 50% survival. Compared to APAP-treated mice, livers from those co-treated with CORM A-1, had upregulation of Nrf2 and ARE genes (HO-1, GCLM and NQO-1). APAP-treated mice had elevated hepatic mRNA levels of inflammatory genes (Nf-κB, TNF-α, IL1-ß and IL-6), an effect blunted in those co-treated with CORM A-1. In tert-butyl hydroperoxide (t-BHP)-treated HepG2 cells, CORM A-1 augmented cell viability, reduced oxidative stress, activated the nuclear factor erythroid 2-related factor 2 (Nrf2) and anti-oxidant response element (ARE) genes. The molecular docking profile of CO in the kelch domain of Keap1 protein suggested that CO released from CORM A-1 mediated Nrf2 activation. Collectively, these data indicate that CORM A-1 reduces oxidative stress by upregulating Nrf2 and related genes, and restoring hepatic GSH, to reduce hepatocyte necrosis and thus minimize liver injury that contributes to an overall improved survival rate.

Endovascular Repair of Abdominal Aortic Aneurysm in Patients Physically Ineligible for Open Repair: Very Long-term Follow-up in the EVAR-2 Randomized Controlled Trial.

OBJECTIVE: The aim of the study was to compare long-term total and aneurysm-related mortality in physically frail patients with abdominal aortic aneurysm (AAA) randomized to either early endovascular aneurysm repair (EVAR) or no-intervention. SUMMARY BACKGROUND DATA: EVAR-2 remains the sole randomized trial to identify whether EVAR reduces mortality in patients physically ineligible for open repair. METHODS: Between September 1999 and August 2004, 404 patients from 33 centers in the United Kingdom aged ≥60 years with AAA >5.5 cm in diameter were randomized 1:1 using computer-generated sequences of randomly permuted blocks stratified by center to receive either EVAR (197) or no-intervention (207). The primary analysis compared total and aneurysm-related deaths in groups until June 30, 2015 (mean, 12.0 yrs; maximum 14.1 yrs). RESULTS: Mean follow-up until death or censoring was 4.2 years. There were 187 deaths (22.6 per 100 person-yrs) in the EVAR group and 194 (22.1 per 100 person-yrs) in the no-intervention group. By 12 years of follow-up the estimated survival was 5.3% [95% confidence interval (CI), 2.6-9.2] in the EVAR group and 8.5% (95% CI, 5.2-12.9) in the no-intervention group; there was no significant difference in life expectancy between the groups (both 4.2 yrs; P = 0.97). However, overall aneurysm-related mortality was significantly lower in the EVAR group [3.3 deaths per 100 person-yrs compared with 6.5 deaths per 100 person-yrs in the no-intervention group, adjusted hazard ratio 0.55 (95% CI, 0.34-0.91; P = 0.019)]. Patients surviving beyond 8 years were younger, with higher body mass index, estimated glomerular filtration rate, and forced expiratory volume in 1 second. CONCLUSIONS: EVAR does not increase overall life expectancy in patients ineligible for open repair, but can reduce aneurysm-related mortality.