13-Oxidation of long-chain fatty acids provides the major source of energy in the heart. Defects in enzymes of the 18-oxidation pathway cause sudden, unexplained death in childhood, acute hepatic encephalopathy or liver failure, skeletal myopathy, and cardiomyopathy. Verylong-chain acyl-CoA dehydrogenase [VLCAD; very-long-chainacyl-CoA:(acceptor) 2,3-oxidoreductase, EC 1.3.99.13] catalyzes the first step in 13-oxidation. We have isolated the human VLCAD cDNA and gene and determined the complete nucleotide sequences. Polymerase chain reaction amplification of VLCAD mRNA and genomic exons defined the molecular defects in two patients with VLCAD deficiency who presented with unexplained cardiac arrest and cardiomyopathy. In one, a homozygous mutation in the consensus dinucleotide of the donor splice site (g+1 --a) was associated with universal skipping of the prior exon (exon 11). The second patient was a compound heterozygote, with a missense mutation, C'837 > T, changing the arginine at residue 613 to tryptophan on one allele and a single base deletion at the intron-exon 6 boundary as the second mutation. This initial delineation of human mutations in VLCAD suggests that VLCAD deficiency reduces myocardial fatty acid 13-oxidation and energy production and is associated with cardiomyopathy and sudden death in childhood.Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first step in the mitochondrial (3-oxidation spiral that supplies the majority of energy in mature heart and is crucial to intermediary metabolism in the liver (1-3). This spiral requires four enzymatic activities, an initial fatty acyl-CoA dehydrogenase, a 2,3-enoyl-CoA hydratase reaction, a 3-hydroxy-acyl-CoA dehydrogenase step, and the final 3-ketoacylCoA thiolase cleavage step. Because fatty acids with different chain lengths are substrates in these reactions, several enzymes, encoded by distinct nuclear genes, are required for each step. For the initial fatty acyl-CoA dehydrogenase step, four enzymes with overlapping, but different, chain length specificities have been identified and designated as VLCAD, which acts on substrates of 14-20 carbons in length (1); long-chain acyl-CoA dehydrogenase (LCAD); medium-chain acyl-CoA dehydrogenase (MCAD); and short-chain acyl-CoA dehydrogenase (SCAD). Biochemical characterization of the last three soluble, matrix enzymes (4) revealed similar structures consisting of four identical 42-kDa subunits and FAD as a cofactor. The cloning of mRNAs encoding the subunits of MCAD, LCAD, and SCAD revealed similarity of their primary sequences (5, 6). The discovery, characterization, and cloning of rat VLCAD (1) demonstrated significant differences from the other three members of this CAD family. VLCAD is a homodimer of 70-kDa subunits and is associated with the inner mitochondrial membrane.The importance of the f-oxidation pathway for energy production is emphasized by inherited deficiencies of these enzyme activities (2, 3). Individuals with these disorders frequently become critically ill in infa...
Little is known about the associations between insomnia severity, insomnia symptoms, and key health outcomes. Using 2020 United States National Health and Wellness Survey (NHWS) data, we conducted a retrospective, cross-sectional analysis to determine the associations between insomnia severity and a number of health outcomes germane to patients (health-related quality of life (HRQoL), employers and government (workplace productivity), and healthcare payers (healthcare resource utilization (HCRU)). The Insomnia Severity Index (ISI) questionnaire was used to evaluate overall insomnia severity. HRQoL was assessed using the physical and mental component summary scores of the Short Form-36v2 (SF-36v2) questionnaire, and health utility status was measured using the Short Form-6D (SF-6D) and EuroQoL-5D (EQ-5D) questionnaires. Workplace productivity was measured using the Work Productivity and Activity Impairment (WPAI) questionnaire. After adjusting for confounders, greater insomnia severity was significantly associated with worsened quality of life, decreased productivity, and increased HCRU in an apparent linear fashion. These findings have important implications for future research, including the need for specific assessment of insomnia symptoms and their impact on key health outcomes.
Introduction Current pharmacologic treatments for insomnia are not universally effective, are associated with a range of adverse events, can cause daytime impairment, and have the potential to be abused. With no consistent standard of care, many patients with insomnia experience multiple dose changes and medication switches. The current study leveraged large-scale, real-world data to investigate the pharmacological treatment patterns of patients with insomnia. Methods Exploratory analyses were performed on claims data from the HealthVerity US primary care claims database. Data from 10/2015 to 3/2020 were obtained for patients aged 18+. Prescribing patterns, including initial treatment, switching, concomitant treatment, and discontinuation were explored. Results Of approximately 1.4 million individuals, 265,382 (~19%) had an insomnia diagnosis and 42.4% of that group were prescribed hypnotic medications. Among those, first prescriptions were most frequently a Z-drug (zolpidem, eszopiclone, zaleplon; 35.8%), trazodone (25.0%), a benzodiazepine (15.6%), or another class (23.6%; includes orexin receptor antagonists, antidepressants, melatonin agonists, etc.). For those receiving a benzodiazepine first, median treatment duration was 55 days, 80.4% of subjects discontinued, 11.6% were switched to a different medication, and 7.9% received concomitant treatment with another sleep medicine. For those first receiving a Z-drug, median treatment duration was 81 days, 87.3% discontinued, 8.2% were switched, and 4.4% received concomitant treatment. For those receiving trazodone first, median treatment duration was 104 days, 85.8% of patients eventually discontinued, 5.8% of patients received concomitant treatment with an additional hypnotic agent, and 8.4% switched to a different hypnotic. Furthermore, of those switched from trazodone, 22% were switched to a benzodiazepine, 31% to a Z-drug, and 47% to a medication of another class. Conclusion These results demonstrate a lack of a standard first-line treatment approach for insomnia; it is likely that physicians have their own preferences, or that they might tailor treatment choice to individual patient characteristics. Additionally, more insomnia patients are discontinued from medical treatment than are switched to a different medicine. Further study is needed to determine what proportion of treatment discontinuation is due to successful treatment, versus being due to adverse events or lack of efficacy. Support (If Any) Idorsia Pharmaceuticals, Ltd.
Background Insomnia disorder is a highly prevalent, significant public health concern associated with substantial and growing health burden. There are limited real-world data assessing the burden of insomnia disorder on daytime functioning and its association with comorbidities. The objective of this study was to leverage large-scale, real-world data to assess the burden of untreated insomnia disorder in terms of daytime impairment and clinical outcomes. Methods This United States medical claims database study compares patients diagnosed with insomnia disorder but not receiving treatment (‘untreated insomnia’ cohort) to patients without an insomnia disorder diagnosis and without treatment (‘non-insomnia’ cohort). International Classification of Disease, Tenth Revision codes were used as a proxy to represent the three symptom domains (Sleepiness, Alert/Cognition, Mood) of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), a newly developed and validated tool used in clinical studies to assess daytime functioning in insomnia disorder. Chronic Fatigue (R53.83) and Other Fatigue (R53.83), Somnolence (R40.0) and Disorientation (R41.0) were selected as categories representing one or more IDSIQ domains. Clinical outcomes included cardiovascular events, psychiatric disorders, cognitive impairment and metabolic disorders. Results Approximately 1 million patients were included (untreated insomnia: n = 139,959; non-insomnia: n = 836,975). Compared with the ‘non-insomnia’ cohort, the ‘untreated insomnia’ cohort was more likely to experience daytime impairments, with mean differences in occurrences per 100 patient-years for: (a) fatigue, at 27.35 (95% confidence interval [CI] 26.81, 27.77, p < 0.01); (b) dizziness, at 4.66 (95% CI 4.40, 4.90, p < 0.01); (c) somnolence, at 4.18 (95% CI 3.94, 4.43, p < 0.01); and (d) disorientation, at 0.92 (95% CI 0.77, 1.06, p < 0.01). During the 1-year look-back period, patients in the ‘untreated insomnia’ cohort were also more likely to have been diagnosed with arterial hypertension (40.9% vs. 26.3%), psychiatric comorbidities (40.1% vs. 13.2%), anxiety (29.2% vs. 8.5%), depression (26.1% vs. 8.1%) or obesity (21.3% vs. 11.1%) compared with those in the ‘non-insomnia’ cohort. Conclusions This large-scale study confirms the substantial burden of insomnia disorder on patients in a real-world setting, with significant daytime impairment and numerous comorbidities. This reinforces the need for timely insomnia disorder diagnosis and treatments that improve both sleep, as well as daytime functioning.
The conventional fossil fuels are being replaced by alternate energy sources very fast. This is mainly due to the limited resources left in the Nature and the polluting characteristic of fossil fuel. Only thirty additional years are left for the supply of fossil fuels. The extreme climate change is largely attributed to automotive fossil fuel burning. The advent of pure Electric vehicles has resulted in reduction of harmful greenhouse gas emissions. It addresses the answer to the concerns of oil resource depletion, air pollution and climate changes. The benefit of using electric power in automotive sector is immense. However, the outcome of hybrid EVs can surpass pure EVs due to its capability of charging on the go, hence no extra charging time. In absence of any moving parts in a fuel cell, the maintenance and noise are also minimal. PEM fuel cell is a most eligible power source having reduced emissions and high efficiency characteristics. The efficiency of hybrid vehicle is a result of charging effectiveness. Control Strategy plays an important role in conservating and elevating energy whenever required. These are the energy power banks to optimize battery sizing and minimize losses. This paper explains a control strategy to enhance efficiency of FCHV system along with reduction of hydrogen consumption. This is achieved by maximising fuel cell efficiency by balancing the power split between battery and fuel cell. The rule based strategy results in maximising fuel cell system efficiency by sustaining the state of charge (SOC) of the battery. The SOC is aimed to be kept around a value which can address extremely low charge and high charge condition of the battery. At the same time, load on fuel cell is switched in a manner so as not to have a sudden ascent or descent of power, which helps in preventing the terminal deterioration in the fuel cell.
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