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Background: Italy has one of the world’s oldest populations, and suffered one the highest death tolls from Coronavirus disease 2019 (COVID-19) worldwide. Older people with cardiovascular diseases (CVDs), and in particular hypertension, are at higher risk of hospitalization and death for COVID-19. Whether hypertensionmedicationsmay increase the risk for death in older COVID 19 inpatients at the highest risk for the disease is currently unknown. Methods: Data from 5,625 COVID-19 inpatients were manually extracted from medical charts from 61 hospitals across Italy. From the initial 5,625 patients, 3,179 were included in the study as they were either discharged or deceased at the time of the data analysis. Primary outcome was inpatient death or recovery. Mixed effects logistic regression models were adjusted for sex, age, and number of comorbidities, with a random effect for site. Results: A large proportion of participating inpatients were ≥65 years old (58%), male (68%), non-smokers (93%) with comorbidities (66%). Each additional comorbidity increased the risk of death by 35% [adjOR = 1.35 (1.2, 1.5) p < 0.001]. Use of ACE inhibitors, ARBs, beta-blockers or Ca-antagonists was not associated with significantly increased risk of death. There was a marginal negative association between ARB use and death, and a marginal positive association between diuretic use and death. Conclusions: This Italian nationwide observational study of COVID-19 inpatients, the majority of which ≥65 years old, indicates that there is a linear direct relationship between the number of comorbidities and the risk of death. Among CVDs, hypertension and pre-existing cardiomyopathy were significantly associated with risk of death. The use of hypertension medications reported to be safe in younger cohorts, do not contribute significantly to increased COVID-19 related deaths in an older population that suffered one of the highest death tolls worldwide.

Resource adequacy (RA) is the ability of an electricity system to reliably satisfy loads using its available resources. Assessing and maintaining RA is becoming more challenging due to increasing coal plant retirements, penetration of wind and solar resources, reliance on bilateral and market transactions, and emerging technologies. RA evaluation and planning have traditionally been conducted by utilities and overseen by their state regulators using integrated resource planning (IRP) processes. However, the Northwest Power Pool (NWPP) is developing a proposal for a regional RA program in the Western U.S. that would set and enforce capacity obligations for member utilities, and achieve RA more cost-effectively by pooling resources and load profiles from across the region. In this paper, we investigate the policy implications of a regional RA program for existing IRP regulations, with the proposed NWPP RA program as our main object of study. We compile the RA assessment practices of Western U.S. utilities, the proposed NWPP RA program design, and lessons from the historical experience of the Southwest Power Pool's RA program. Our analysis reveals that the IRP components which would be most heavily impacted by the regional program are RA targets, load forecasts, capacity accreditation factors, and transmission upgrades. We conclude by discussing the policy issues that RA program design and state IRP policy would have to address.

Resource adequacy (RA) is the ability of an electricity system to reliably satisfy loads using its available resources. Assessing and maintaining RA is becoming more challenging due to increasing coal plant retirements, penetration of wind and solar resources, reliance on bilateral and market transactions, and emerging technologies. RA evaluation and planning have traditionally been conducted by utilities and overseen by their state regulators using integrated resource planning (IRP) processes. However, the Northwest Power Pool (NWPP) is developing a proposal for a regional RA program in the Western U.S. that would set and enforce capacity obligations for member utilities, and achieve RA more cost-effectively by pooling resources and load profiles from across the region. In this paper, we investigate the policy implications of a regional RA program for existing IRP regulations, with the proposed NWPP RA program as our main object of study. We compile the RA assessment practices of Western U.S. utilities, the proposed NWPP RA program design, and lessons from the historical experience of the Southwest Power Pool's RA program. Our analysis reveals that the IRP components which would be most heavily impacted by the regional program are RA targets, load forecasts, capacity accreditation factors, and transmission upgrades. We conclude by discussing the policy issues that RA program design and state IRP policy would have to address.

Contains fulltext : 219560.pdf (publisher's version ) (Open Access), While the physical and behavioral symptomologies associated with a single mild traumatic brain injury (mTBI) are typically transient, repetitive mTBIs (RmTBI) have been associated with persisting neurological deficits. Therefore, this study examined the progressive changes in behaviour and the neuropathological outcomes associated with chronic RmTBI through adolescence and adulthood in male and female Sprague Dawley rats. Rats experienced 2 mTBIs/week for 15 weeks, and were periodically tested for changes in motor behaviour, cognitive function, emotional disturbances, and aggression. Brain tissue was examined for neuropathological changes in ventricle size, and presentation of Iba1 and GFAP. We did not see progressively worse behavioral impairments with the accumulation of injuries or time, but did find evidence for neurological and functional change (motor disturbance, reduced exploration, reduced aggression, alteration in depressive-like behaviour, deficits in short-term working memory). Neuropathological assessment of RmTBI animals identified an increase in ventricle size, prolonged changes in GFAP, and sex-differences in Iba1, in the corpus callosum, thalamus, and medial prefrontal cortex. Telomere length reduced exponentially as the injury load increased. Overall, chronic RmTBI did not result in accumulating behavioral impairment and there is a need to further investigate progressive behavioral changes associated with repeated injuries in adolescence and young adulthood.

Contains fulltext : 219560.pdf (publisher's version ) (Open Access), While the physical and behavioral symptomologies associated with a single mild traumatic brain injury (mTBI) are typically transient, repetitive mTBIs (RmTBI) have been associated with persisting neurological deficits. Therefore, this study examined the progressive changes in behaviour and the neuropathological outcomes associated with chronic RmTBI through adolescence and adulthood in male and female Sprague Dawley rats. Rats experienced 2 mTBIs/week for 15 weeks, and were periodically tested for changes in motor behaviour, cognitive function, emotional disturbances, and aggression. Brain tissue was examined for neuropathological changes in ventricle size, and presentation of Iba1 and GFAP. We did not see progressively worse behavioral impairments with the accumulation of injuries or time, but did find evidence for neurological and functional change (motor disturbance, reduced exploration, reduced aggression, alteration in depressive-like behaviour, deficits in short-term working memory). Neuropathological assessment of RmTBI animals identified an increase in ventricle size, prolonged changes in GFAP, and sex-differences in Iba1, in the corpus callosum, thalamus, and medial prefrontal cortex. Telomere length reduced exponentially as the injury load increased. Overall, chronic RmTBI did not result in accumulating behavioral impairment and there is a need to further investigate progressive behavioral changes associated with repeated injuries in adolescence and young adulthood.

Contains fulltext : 219560.pdf (publisher's version ) (Open Access), While the physical and behavioral symptomologies associated with a single mild traumatic brain injury (mTBI) are typically transient, repetitive mTBIs (RmTBI) have been associated with persisting neurological deficits. Therefore, this study examined the progressive changes in behaviour and the neuropathological outcomes associated with chronic RmTBI through adolescence and adulthood in male and female Sprague Dawley rats. Rats experienced 2 mTBIs/week for 15 weeks, and were periodically tested for changes in motor behaviour, cognitive function, emotional disturbances, and aggression. Brain tissue was examined for neuropathological changes in ventricle size, and presentation of Iba1 and GFAP. We did not see progressively worse behavioral impairments with the accumulation of injuries or time, but did find evidence for neurological and functional change (motor disturbance, reduced exploration, reduced aggression, alteration in depressive-like behaviour, deficits in short-term working memory). Neuropathological assessment of RmTBI animals identified an increase in ventricle size, prolonged changes in GFAP, and sex-differences in Iba1, in the corpus callosum, thalamus, and medial prefrontal cortex. Telomere length reduced exponentially as the injury load increased. Overall, chronic RmTBI did not result in accumulating behavioral impairment and there is a need to further investigate progressive behavioral changes associated with repeated injuries in adolescence and young adulthood.

Purpose: This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity.Experimental Design: Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent [4 days/week (4/7) or 2 days/week (2/7)] schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers.Results: MTDs were 320, 480, and 640 mg for continuous (n = 47), 4/7 (n = 21), and 2/7 (n = 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA-mutant cohort were met.Conclusions: At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA-mutant cancers treated with AZD5363. Clin Cancer Res; 24(9); 2050-9. ©2017 AACRSee related commentary by Costa and Bosch, p. 2029.

Ovarian cancer patients with germline or somatic pathogenic variants benefit from treatment with poly ADP ribose polymerase (PARP) inhibitors. Tumor BRCA1/2 testing is more challenging than germline testing as the majority of samples are formalin-fixed paraffin embedded (FFPE), the tumor genome is complex, and the allelic fraction of somatic variants can be low. We collaborated with 10 laboratories testing BRCA1/2 in tumors to compare different approaches to identify clinically important variants within FFPE tumor DNA samples. This was not a proficiency study but an inter-laboratory comparison to identify common issues. Each laboratory received the same tumor DNA samples ranging in genotype, quantity, quality, and variant allele frequency (VAF). Each laboratory performed their preferred next-generation sequencing method to report on the variants. No false positive results were reported in this small study and the majority of methods detected the low VAF variants. A number of variants were not detected due to the bioinformatics analysis, variant classification, or insufficient DNA. The use of hybridization capture or short amplicon methods are recommended based on a bioinformatic assessment of the data. The study highlights the importance of establishing standards and standardization for tBRCA testing particularly when the test results dictate clinical decisions regarding life extending therapies.

Ovarian cancer patients with germline or somatic pathogenic variants benefit from treatment with poly ADP ribose polymerase (PARP) inhibitors. Tumor BRCA1/2 testing is more challenging than germline testing as the majority of samples are formalin-fixed paraffin embedded (FFPE), the tumor genome is complex, and the allelic fraction of somatic variants can be low. We collaborated with 10 laboratories testing BRCA1/2 in tumors to compare different approaches to identify clinically important variants within FFPE tumor DNA samples. This was not a proficiency study but an inter-laboratory comparison to identify common issues. Each laboratory received the same tumor DNA samples ranging in genotype, quantity, quality, and variant allele frequency (VAF). Each laboratory performed their preferred next-generation sequencing method to report on the variants. No false positive results were reported in this small study and the majority of methods detected the low VAF variants. A number of variants were not detected due to the bioinformatics analysis, variant classification, or insufficient DNA. The use of hybridization capture or short amplicon methods are recommended based on a bioinformatic assessment of the data. The study highlights the importance of establishing standards and standardization for tBRCA testing particularly when the test results dictate clinical decisions regarding life extending therapies.

To describe the signalment, clinicopathological findings and outcome in dogs presenting with acute kidney injury (AKI) and skin lesions between November 2012 and March 2014, in whom cutaneous and renal glomerular vasculopathy (CRGV) was suspected and renal thrombotic microangiopathy (TMA) was histopathologically confirmed. The medical records of dogs with skin lesions and AKI, with histopathologically confirmed renal TMA, were retrospectively reviewed. Thirty dogs from across the UK were identified with clinicopathological findings compatible with CRGV. These findings included the following: skin lesions, predominantly affecting the distal extremities; AKI; and variably, anaemia, thrombocytopaenia and hyperbilirubinaemia. Known causes of AKI were excluded. The major renal histopathological finding was TMA. All thirty dogs died or were euthanised. Shiga toxin was not identified in the kidneys of affected dogs. Escherichia coli genes encoding shiga toxin were not identified in faeces from affected dogs. CRGV has previously been reported in greyhounds in the USA, a greyhound in the UK, without renal involvement, and a Great Dane in Germany. This is the first report of a series of non-greyhound dogs with CRGV and AKI in the UK. CRGV is a disease of unknown aetiology carrying a poor prognosis when azotaemia develops.

Silver birch (Betula pendula) and three Southeast Asian tropical plant species (Ficus cyathistipula, Ficus benjamina and Caryota millis) from the pantropical fig and palm genera were grown in a purpose-built and environment-controlled whole-tree chamber. The volatile organic compounds emitted from these trees were characterised and fed into a linked photochemical reaction chamber where they underwent photo-oxidation under a range of controlled conditions (relative humidity or RH ~65–89%, volatile organic compound-to-NOx or VOC / NOx ~3–9 and NOx ~2 ppbV). Both the gas phase and the aerosol phase of the reaction chamber were monitored in detail using a comprehensive suite of on-line and off-line chemical and physical measurement techniques. Silver birch was found to be a high monoterpene and sesquiterpene but low isoprene emitter, and its emissions were observed to produce measurable amounts of secondary organic aerosol (SOA) via both nucleation and condensation onto pre-existing seed aerosol (YSOA 26–39%). In contrast, all three tropical species were found to be high isoprene emitters with trace emissions of monoterpenes and sesquiterpenes. In tropical plant experiments without seed aerosol there was no measurable SOA nucleation, but aerosol mass was shown to increase when seed aerosol was present. Although principally isoprene emitting, the aerosol mass produced from tropical fig was mostly consistent (i.e. in 78 out of 120 aerosol mass calculations using plausible parameter sets of various precursor specific yields) with condensation of photo-oxidation products of the minor volatile organic compounds (VOCs) co-emitted; no significant aerosol yield from condensation of isoprene oxidation products was required in the interpretations of the experimental results. This finding is in line with previous reports of organic aerosol loadings consistent with production from minor biogenic VOCs co-emitted with isoprene in principally isoprene-emitting landscapes in Southeast

Silver birch (Betula pendula) and three Southeast Asian tropical plant species (Ficus cyathistipula, Ficus benjamina and Caryota millis) from the pantropical fig and palm genera were grown in a purpose-built and environment-controlled whole-tree chamber. The volatile organic compounds emitted from these trees were characterised and fed into a linked photochemical reaction chamber where they underwent photo-oxidation under a range of controlled conditions (relative humidity or RH ~65–89%, volatile organic compound-to-NOx or VOC / NOx ~3–9 and NOx ~2 ppbV). Both the gas phase and the aerosol phase of the reaction chamber were monitored in detail using a comprehensive suite of on-line and off-line chemical and physical measurement techniques. Silver birch was found to be a high monoterpene and sesquiterpene but low isoprene emitter, and its emissions were observed to produce measurable amounts of secondary organic aerosol (SOA) via both nucleation and condensation onto pre-existing seed aerosol (YSOA 26–39%). In contrast, all three tropical species were found to be high isoprene emitters with trace emissions of monoterpenes and sesquiterpenes. In tropical plant experiments without seed aerosol there was no measurable SOA nucleation, but aerosol mass was shown to increase when seed aerosol was present. Although principally isoprene emitting, the aerosol mass produced from tropical fig was mostly consistent (i.e. in 78 out of 120 aerosol mass calculations using plausible parameter sets of various precursor specific yields) with condensation of photo-oxidation products of the minor volatile organic compounds (VOCs) co-emitted; no significant aerosol yield from condensation of isoprene oxidation products was required in the interpretations of the experimental results. This finding is in line with previous reports of organic aerosol loadings consistent with production from minor biogenic VOCs co-emitted with isoprene in principally isoprene-emitting landscapes in Southeast

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Timothy P Carr, Mark M Ash, Andrew W BrownDepartment of Nutrition and Health Sciences, University of Nebraska, Lincoln, NE, USAAbstract: Phytosterols are essential components of plant cells and therefore naturally ­present in the human diet. When used therapeutically, phytosterols can significantly lower serum cholesterol concentrations. Meta-analyses of clinical trials indicate about 10% reduction of low-density lipoprotein cholesterol when phytosterols are consumed at the recommended dose of 2 g/d. Thus, phytosterols can be an important part of an overall dietary strategy to manage cholesterol levels, particularly for patients who cannot tolerate cholesterol-lowering drugs. Although other health benefits have been attributed to phytosterols, including anti-inflammatory, anticancer, and immune regulatory effects, this review will focus on the therapeutic use of phytosterols related to serum cholesterol, their mechanisms of action, and the various types of phytosterols available to consumers.Keywords: sterols, stanols phytosterols, cholesterol

The Kencana mine consists of two epithermal vein deposits, K1 and K2. The K1 deposit has a recent extensive mining history and development of the K2 deposit is in progress. The epithermal vein zones have a relatively simple planar geometry, dipping 25-45 degrees towards the east and extending 400 to 600 m along strike and down dip. True width ranges from 1 m to 20 m. Economic Au grades are generally associated with two distinct mineralisation styles, the Main Zone with continuous material characterised by classic epithermal vein textures typically grading 10-40 g/t Au, and the Bonanza zone, semi-continuous identifiable zones within the Main Zone characterised by brecciated quartz-adularia sulphide banded-vein ‘ginguro’ material typically grading 80-200 g/t Au. Associated with the Bonanza zone are Au grades averaging around ten times higher than in the surrounding Main Zone. Close-spaced sampling and mapping of the K1 orebody has shown that this style of mineralisation exhibits extreme short-scale geometric and spatial variability, and there is significant uncertainty in reporting these resources and reserves at relatively small reporting time-periods such as monthly production periods. The mining method often involves extracting the full width of the mineralised vein with multiple mining passes over several months. Geostatistical conditional simulation techniques have been applied in an attempt to model and quantify geological and grade variability in the K2 orebody, based on the experience to date with mining the K1 orebody. The results have provided a clearer understanding of the likely variances and risks associated with predicting Au metal production at key reporting time-periods from data at the resource model level of resolution., The Kencana mine consists of two epithermal vein deposits, K1 and K2. The K1 deposit has a recent extensive mining history and development of the K2 deposit is in progress. The epithermal vein zones have a relatively simple planar geometry, dipping 25-45 degrees towards the east and extending 400 to 600 m along strike and down dip. True width ranges from 1 m to 20 m. Economic Au grades are generally associated with two distinct mineralisation styles, the Main Zone with continuous material characterised by classic epithermal vein textures typically grading 10-40 g/t Au, and the Bonanza zone, semi-continuous identifiable zones within the Main Zone characterised by brecciated quartz-adularia sulphide banded-vein ‘ginguro’ material typically grading 80-200 g/t Au. Associated with the Bonanza zone are Au grades averaging around ten times higher than in the surrounding Main Zone. Close-spaced sampling and mapping of the K1 orebody has shown that this style of mineralisation exhibits extreme short-scale geometric and spatial variability, and there is significant uncertainty in reporting these resources and reserves at relatively small reporting time-periods such as monthly production periods. The mining method often involves extracting the full width of the mineralised vein with multiple mining passes over several months. Geostatistical conditional simulation techniques have been applied in an attempt to model and quantify geological and grade variability in the K2 orebody, based on the experience to date with mining the K1 orebody. The results have provided a clearer understanding of the likely variances and risks associated with predicting Au metal production at key reporting time-periods from data at the resource model level of resolution.

Rate equations modeling self-pulsating laser diodes have been investigated numerically by various groups. In this paper, we formulate dimensionless equations, which unifies these independent studies. The low values of the decay rates of the carriers motivate analytical approximations for the domain of self-pulsation. These approximations highlight the effect of some physical processes (diffusion of the carriers, radiative recombination rate) which are important for self-pulsating diode lasers., SCOPUS: ar.j, info:eu-repo/semantics/published

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Rate equations modeling self-pulsating laser diodes have been investigated numerically by various groups. In this paper, we formulate dimensionless equations, which unifies these independent studies. The low values of the decay rates of the carriers motivate analytical approximations for the domain of self-pulsation. These approximations highlight the effect of some physical processes (diffusion of the carriers, radiative recombination rate) which are important for self-pulsating diode lasers., SCOPUS: ar.j, info:eu-repo/semantics/published

info:eu-repo/semantics/published

A fundamental chaotic instability in a system of two coupled lasers is investigated both experimentally and theoretically. The amplitude instability and mutual coherence of the light emitted by the lasers is investigated as a function of the detuning and coupling parameters. A quantitative comparison of the intensity fluctuations is made with numerical simulations that include noise in the laser detuning., SCOPUS: ar.j, info:eu-repo/semantics/published

A fundamental chaotic instability in a system of two coupled lasers is investigated both experimentally and theoretically. The amplitude instability and mutual coherence of the light emitted by the lasers is investigated as a function of the detuning and coupling parameters. A quantitative comparison of the intensity fluctuations is made with numerical simulations that include noise in the laser detuning., SCOPUS: ar.j, info:eu-repo/semantics/published

The book is in three main sections. A summary of old mining and metallurgical techniques is copiously illustrated from 16th century woodcuts. The history of lead and silver mining in Cardiganshire is outlined, with reference to pre-Roman archaeological finds, the Cistercian abbey of Strata Florida which worked the lead mines in the Middle Ages, Sir Hugh Myddelton's operation of five royal mines from 1620, the dispute between Bushell and rebellious landowners, the new mint established at Aberystwyth in 1637, the capitalist era that folowed the repeal of the Mines Royal Act, the success of Cornish engineer John Taylor from 1822 to the 1860s, and the appalling labour conditions in the 19th century. The photographic section, which occupies more than half the book, illustrates the present-day remains of the workings and the various environmental problems associated with them; most of the pictures are coloured and are accompanied by grid references, descriptions, historical details and sketches of old equipment or maps. The locations of the mines and the main leats are shown on a map at the start of the work and a bibliography of 24 references concludes it., The book is in three main sections. A summary of old mining and metallurgical techniques is copiously illustrated from 16th century woodcuts. The history of lead and silver mining in Cardiganshire is outlined, with reference to pre-Roman archaeological finds, the Cistercian abbey of Strata Florida which worked the lead mines in the Middle Ages, Sir Hugh Myddelton's operation of five royal mines from 1620, the dispute between Bushell and rebellious landowners, the new mint established at Aberystwyth in 1637, the capitalist era that folowed the repeal of the Mines Royal Act, the success of Cornish engineer John Taylor from 1822 to the 1860s, and the appalling labour conditions in the 19th century. The photographic section, which occupies more than half the book, illustrates the present-day remains of the workings and the various environmental problems associated with them; most of the pictures are coloured and are accompanied by grid references, descriptions, historical details and sketches of old equipment or maps. The locations of the mines and the main leats are shown on a map at the start of the work and a bibliography of 24 references concludes it.