Clinical outcome of idiopathic juvenile ventricular arrhythmias in 25 dogs.

INTRODUCTION/OBJECTIVES: Juvenile ventricular arrhythmias in the absence of structural heart disease have been characterized in a small number of canine breeds with limited long-term follow up. The objective of this study was to describe the clinical outcome of dogs with JVA presenting to a university teaching hospital. ANIMALS, MATERIALS, METHODS: Twenty five dogs, less than two years old with idiopathic ventricular arrhythmias were retrospectively identified via a medical record search. Young dogs with ventricular arrhythmias were excluded if they had structural heart disease, systemic illness, or an abnormal troponin (if performed). Electrocardiographic and Holter monitor data was evaluated for arrhythmia frequency and complexity at the time of diagnosis and over time. Long-term follow up was achieved through client and primary veterinarian contact. RESULTS: Breeds included German Shepherd (eight), Boxer (four), Great Dane (three), mixed breed (two) and one each of the following: Anatolian Shepherd, French Bulldog, golden retriever, Great Pyrenees, Labrador retriever, Shiloh Shepherd, miniature Poodle and Siberian Husky. The average age at diagnosis was 7.9 months (range, 2-22 months). The overall median survival was 10.96 years (range, 1.75-15.66 years). There was an average reduction in the number of ventricular beats by 86.7 % per year (P value -0.0257) based on Holter data. CONCLUSION: In most cases, idiopathic juvenile ventricular arrhythmias had a favorable long-term prognosis with reduced ectopy over time in this case series. Juvenile ventricular arrhythmias remains a diagnosis of exclusion but can be considered in a broader range of dog breeds than previously described.

Two-Year Prognostic Utility of Plasma p217+tau across the Alzheimer's Continuum.

BACKGROUND: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid-ß (Aß) and tau in Alzheimer's Disease (AD). However, its association with longitudinal cognition and comparative performance to PET Aß and tau in predicting cognitive decline are unknown. OBJECTIVES: To evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on Aß (18F-NAV4694) and tau (18F-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost using p217+tau (pT+) as compared to PET Aß (A+) and tau (T+) with and without p217+tau pre-screening. DESIGN: A prospective observational cohort study. SETTING: Participants of the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Australian Dementia Network (ADNeT). PARTICIPANTS: 153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) individuals. MEASUREMENTS: Baseline p217+tau Simoa® assay, 18F-MK6240 tau-PET and 18F-NAV4694 Aß-PET with neuropsychological follow-up (MMSE, CDR-SB, AIBL-PACC) over 2.4 ± 0.8 years. RESULTS: In CI, p217+tau was a significant predictor of change in MMSE (ß = -0.55, p < 0.001) and CDR-SB (ß =0.61, p < 0.001) with an effect size similar to Aß Centiloid (MMSE ß = -0.48, p = 0.002; CDR-SB ß = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: ß = -0.62, p < 0.001; CDR-SB: ß = 0.65, p < 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC (ß = -0.22, p = 0.008). Screening pT+ CI participants into a trial could lead to 24% reduction in sample size compared to screening with PET for A+ and 6-13% compared to screening with PET for T+ (different regions). This would translate to an 81-83% biomarker test cost-saving assuming the p217+tau test cost one-fifth of a PET scan. In a trial requiring PET A+ or T+, p217+tau pre-screening followed by PET in those who were pT+ would cost more in the CI group, compared to 26-38% biomarker test cost-saving in the CU. CONCLUSIONS: Substantial cost reduction can be achieved using p217+tau alone to select participants with MCI or mild dementia for a clinical trial designed to slow cognitive decline over two years, compared to participant selection by PET. In pre-clinical AD trials, p217+tau provides significant cost-saving if used as a pre-screening measure for PET A+ or T+ but in MCI/mild dementia trials this may add to cost both in testing and in the increased number of participants needed for testing.

BLINCAR: a reusable bioluminescent and Cas9-based genetic toolset for repeatedly modifying wild-type Scheffersomyces stipitis.

Scheffersomyces stipitis is a yeast that robustly ferments the 5-carbon sugar xylose, making the yeast a valuable candidate for lignocellulosic ethanol fermentation. However, the non-canonical codon usage of S. stipitis is an obstacle for implementing molecular tools that were developed for other yeast species, thereby limiting the molecular toolset available for S. stipitis. Here, we developed a series of molecular tools for S. stipitis including BLINCAR, a Bio-Luminescent Indicator that is Nullified by Cas9-Actuated Recombination, which can be used repeatedly to add different exogenous DNA payloads to the wild-type S. stipitis genome or used repeatedly to remove multiple native S. stipitis genes from the wild-type genome. Through the use of BLINCAR tools, one first produces antibiotic-resistant, bioluminescent colonies of S. stipitis whose bioluminescence highlights those clones that have been genetically modified; then second, once candidate clones have been confirmed, one uses a transient Cas9-producing plasmid to nullify the antibiotic resistance and bioluminescent markers from the prior introduction, thereby producing non-bioluminescent colonies that highlight those clones which have been re-sensitized to the antibiotic and are therefore susceptible to another round of BLINCAR implementation. IMPORTANCE Cellulose and hemicellulose that comprise a large portion of sawdust, leaves, and grass can be valuable sources of fermentable sugars for ethanol production. However, some of the sugars liberated from hemicellulose (like xylose) are not easily fermented using conventional glucose-fermenting yeast like Saccharomyces cerevisiae, so engineering robust xylose-fermenting yeast that is not inhibited by other components liberated from cellulose/hemicellulose will be important for maximizing yield and making lignocellulosic ethanol fermentation cost efficient. The yeast Scheffersomyces stipitis is one such yeast that can ferment xylose; however, it possesses several barriers to genetic manipulation. It is difficult to transform, has only a few antibiotic resistance markers, and uses an alternative genetic code from most other organisms. We developed a genetic toolset for S. stipitis that lowers these barriers and allows a user to deliver and/or delete multiple genetic elements to/from the wild-type genome, thereby expanding S. stipitis's potential.

Using extended reality (XR) for medical training and real-time clinical support during deep space missions.

Medical events can affect space crew health and compromise the success of deep space missions. To successfully manage such events, crew members must be sufficiently prepared to manage certain medical conditions for which they are not technically trained. Extended Reality (XR) can provide an immersive, realistic user experience that, when integrated with augmented clinical tools (ACT), can improve training outcomes and provide real-time guidance during non-routine tasks, diagnostic, and therapeutic procedures. The goal of this study was to develop a framework to guide XR platform development using astronaut medical training and guidance as the domain for illustration. We conducted a mixed-methods study-using video conference meetings (45 subject-matter experts), Delphi panel surveys, and a web-based card sorting application-to develop a standard taxonomy of essential XR capabilities. We augmented this by identifying additional models and taxonomies from related fields. Together, this "taxonomy of taxonomies," and the essential XR capabilities identified, serve as an initial framework to structure the development of XR-based medical training and guidance for use during deep space exploration missions. We provide a schematic approach, illustrated with a use case, for how this framework and materials generated through this study might be employed.

Gold Nanoparticles Disrupt the IGFBP2/mTOR/PTEN Axis to Inhibit Ovarian Cancer Growth.

By exploiting the self-therapeutic properties of gold nanoparticles (GNPs) a molecular axis that promotes the growth of high-grade serous ovarian cancer (HGSOC), one of the deadliest gynecologic malignancies with poorly understood underlying molecular mechanisms, has been identified. The biodistribution and toxicity of GNPs administered by intravenous or intraperitoneal injection, both as a single dose or by repeated dosing over two weeks are first assessed; no biochemical or histological toxicity to vital organs is found. Using an orthotopic patient-derived xenograft (PDX) model of HGSOC, the authors then show that GNP treatment robustly inhibits tumor growth. Investigating the molecular mechanisms underlying the GNP efficacy reveals that GNPs downregulate insulin growth factor binding protein 2 (IGFBP2) by disrupting its autoregulation via the IGFBP2/mTOR/PTEN axis. This mechanism is validated by treating a cell line-based human xenograft tumor with GNPs and an mTOR dual-kinase inhibitor (PI-103), either individually or in combination with GNPs; GNP and PI-103 combination therapy inhibit ovarian tumor growth similarly to GNPs alone. This report illustrates how the self-therapeutic properties of GNPs can be exploited as a discovery tool to identify a critical signaling axis responsible for poor prognosis in ovarian cancer and provides an opportunity to interrogate the axis to improve patient outcomes.

Association of diet with clinical outcomes in dogs with dilated cardiomyopathy and congestive heart failure.

INTRODUCTION: Dilated cardiomyopathy (DCM) in dogs has been associated with feeding of grain-free (GF), legume-rich diets. Some dogs with presumed diet-associated DCM have shown improved myocardial function and clinical outcomes following a change in diet and standard medical therapy. HYPOTHESIS: Prior GF (pGF) diet influences reverse cardiac remodeling and clinical outcomes in dogs with DCM and congestive heart failure (CHF). ANIMALS AND METHODS: A retrospective study was performed with 67 dogs with DCM and CHF for which diet history was known. Dogs were grouped by diet into pGF and grain-inclusive (GI) groups. Dogs in the pGF group were included if diet change was a component of therapy. Survival was analyzed using Kaplan-Meier curves and the Cox proportional-hazards model. RESULTS: The median survival time was 344 days for pGF dogs vs. 253 days for GI dogs (P = 0.074). Statistically significant differences in median survival were identified when the analysis was limited to dogs surviving longer than one week (P = 0.033). Prior GF dogs had a significantly worse outcome the longer a GF diet was fed prior to diagnosis (P = 0.004) or if they were diagnosed at a younger age (P = 0.017). Prior GF dogs showed significantly greater improvement in normalized left ventricular internal diastolic diameter (P = 0.038) and E-point septal separation (P = 0.031) measurements and significant decreases in their furosemide (P = 0.009) and pimobendan (P < 0.005) dosages over time compared to GI dogs. CONCLUSIONS: Prior GF dogs that survived at least one week after diagnosis of DCM, treatment of CHF, and diet change had better clinical outcomes and showed reverse ventricular remodeling compared to GI dogs.

From the clinic to the street: the changing role of benzodiazepines in the Scottish overdose epidemic.

Drug-related deaths in Scotland increased for seven years in a row between 2014 and 2020 consolidating Scotland's place at the top of the United Kingdom and European drug-related mortality charts. One of the defining features of this recent and rapid rise has been the role of benzodiazepines which are now involved in two-thirds of all cases. Policy decisions over four decades have contributed to the supply and demand drivers of this unique element of the Scottish overdose crisis. An illicit market once populated by diverted prescription medications is now dominated by a toxic supply of NPS-type benzodiazepines or so-called 'street benzos' which have increased the risk environment for people who use drugs. In response, Scotland needs to urgently expand its harm reduction infrastructure and implement safer supply, drug testing and drug consumption rooms. Such a response should be made in parallel to addressing the socioeconomic inequalities which are fuelling an epidemic of global significance.

Diverging trends for onset of acute myocardial infarction, heart failure, stroke and mortality in young males: role of changes in obesity and fitness.

BACKGROUND: As opposed to the decreasing overall rates of coronary heart disease (CHD) incidence and overall cardiovascular disease (CVD) mortality, heart failure (HF) and stroke incidence are increasing in young people, potentially due to rising rates of obesity and reduced cardiorespiratory fitness (CRF). OBJECTIVES: We investigated trends in early major CVD outcomes in a large cohort of young men. METHODS: Successive cohorts of Swedish military conscripts from 1971 to 1995 (N = 1,258,432; mean age, 18.3 years) were followed, using data from the National Inpatient and Cause of Death registries. Cox proportional hazard models were used to analyse changes in 21-year CVD event rates. RESULTS: 21-year CVD and all-cause mortality and incidence of acute myocardial infarction (AMI) decreased progressively. Compared with the cohort conscripted in 1971-1975 (reference), the hazard ratios (HRs) for the last 1991-1995 cohort were 0.50 [95% confidence interval (CI) 0.42-0.59] for CVD mortality; 0.57 (95% CI 0.54-0.60) for all-cause mortality; and 0.63 (95% CI 0.53-0.75) for AMI. In contrast, the incidence of ischaemic stroke, intracerebral haemorrhage and HF increased with HRs of 1.43 (95% CI 1.17-1.75), 1.30 (95% CI 1.01-1.68) and 1.84 (95% CI 1.47-2.30), respectively. During the period, rates of obesity increased from 1.04% to 2.61%, whilst CRF scores decreased slightly. Adjustment for these factors influenced these secular trends only moderately. CONCLUSION: Secular trends of young-onset CVD events demonstrated a marked shift from AMI and CVD mortality to HF and stroke incidence. Trends were significantly, though moderately, influenced by changing baseline BMI and CRF.

Experiments with a prototype titanium hot cavity surface ionization source intended for electromagnetic separation of radioactive samarium and other lanthanide elements.

This paper reports experimental results of a prototype titanium surface ionization source. For the first time, a lanthanide ion beam has been produced with a surface ionizer composed completely of titanium metal. Titanium does not readily activate with neutron irradiation. This offers the potential for inserting an ion source made of titanium directly into a reactor with a pre-loaded non-radioactive lanthanide target. This seamlessly integrates target irradiation with isotope separation, eliminating post irradiation sample manipulation. Samarium ion beam currents up to 960 nA have been produced in an off-line test bench equipped with rudimentary beam optics. This is a crucial step toward the development of an ionization source adopted for the electromagnetic isotope separator (EMIS) facility, which has been designed for high throughput separations of radioactive 153Sm and other lanthanides of interest in the field of nuclear medicine. The ion current and important factors affecting the performance of the ion source, such as the ionizer temperature and thermal gradient, are discussed. The experimental results are presented together with a discussion of future modifications to optimize the overall surface ionization source performance.

Scotland's 2009-2015 methadone-prescription cohort: Quintiles for daily dose of prescribed methadone and risk of methadone-specific death.

AIMS: As methadone clients age, their drug-related death (DRD) risks increase, more than doubling at 45+ years for methadone-specific DRDs. METHODS: Using Community Health Index (CHI) numbers, mortality to 31 December 2015 was ascertained for 36 347 methadone-prescription clients in Scotland during 2009-2015. Cohort entry, quantity of prescribed methadone and daily dose (actual or recovered by effective, simple rules) were defined by clients' first CHI-identified methadone prescription after 30 June 2009 and used in proportional hazards analysis. As custodian of death records, National Records of Scotland identified non-DRDs from DRDs. Methadone-specific DRD means methadone was implicated but neither heroin nor buprenorphine. RESULTS: The cohort's 192 928 person-years included 1857 non-DRDs and 1323 DRDs (42%), 546 of which were methadone specific. Actual/recovered daily dose was available for 26 533 (73%) clients who experienced 420 methadone-specific DRDs. Top quintile for daily dose at first CHI-identified methadone prescription was >90 mg. Age 45+ years at cohort-entry (hazard ratio vs 25-34 years: 3.1, 95% confidence interval: 2.4-4.2), top quintile for baseline daily dose of prescribed methadone (vs 50-70 mg: 1.9, 1.1-3.1) and being female (1.3, 1.0-1.6) significantly increased clients' risk of methadone-specific DRD. CONCLUSION: Extra care is needed when methadone daily dose exceeds 90 mg. Females' higher risk for methadone-specific DRD is new and needs validation. Further analyses of prescribed daily dose linked to mortality for large cohorts of methadone clients are needed internationally, together with greater pharmacodynamic and pharmacokinetic understanding of methadone by age and sex. Balancing age-related risks is challenging for prescribers who manage chronic opiate dependency against additional uncertainty about the nature, strength and pharmacological characteristics of drugs from illegal markets.

Effect of zinc on oropharyngeal mucositis in children with acute leukemia undergoing chemotherapy.

BACKGROUND: Oropharyngeal mucositis (OM) is one of the main side-effects of oncological therapy. There is no treatment to prevent its occurrence, but some zinc-based therapies have been proven to help in decreasing its intensity. The objective of this study was to determine the effect of zinc in OM in children with acute leukemia in the early stages of oncological treatment. MATERIAL AND METHODS: This quasi-experimental study evaluated OM in 2 groups (control group: conventional hospital management, and experimental group: administration of 50 mg of zinc gluconate daily plus conventional hospital management). OM severity was recorded at a two-month follow-up. RESULTS: Forty-nine patients (26 in the control group and 23 in the experimental group) were included. The mean age of the patients was 11.1 ± 2.7 years; 65.3% had a diagnosis of pre-B acute lymphoblastic leukemia. The incidences of OM in the control group and the experimental group were 46.2% and 26.1%, respectively, but the difference was not significant. Based on a negative binomial regression model, females had, on average, 1.5 more days with OM (p = 0.002), and patients assigned to the experimental group had, on average, 2 less days with OM than the control group (p = 0.001). The pain score was higher in the control group (p = 0.0009), as was the mean score on the WHO scale (p = 0.0012). CONCLUSIONS: Zinc facilitated a reduction in the severity and duration of OM; further studies focusing on children are needed to confirm the effects of this trace element.

Eukaryotic cell biology is temporally coordinated to support the energetic demands of protein homeostasis.

Yeast physiology is temporally regulated, this becomes apparent under nutrient-limited conditions and results in respiratory oscillations (YROs). YROs share features with circadian rhythms and interact with, but are independent of, the cell division cycle. Here, we show that YROs minimise energy expenditure by restricting protein synthesis until sufficient resources are stored, while maintaining osmotic homeostasis and protein quality control. Although nutrient supply is constant, cells sequester and store metabolic resources via increased transport, autophagy and biomolecular condensation. Replete stores trigger increased H+ export which stimulates TORC1 and liberates proteasomes, ribosomes, chaperones and metabolic enzymes from non-membrane bound compartments. This facilitates translational bursting, liquidation of storage carbohydrates, increased ATP turnover, and the export of osmolytes. We propose that dynamic regulation of ion transport and metabolic plasticity are required to maintain osmotic and protein homeostasis during remodelling of eukaryotic proteomes, and that bioenergetic constraints selected for temporal organisation that promotes oscillatory behaviour.

A bioluminescent reporter for the halophilic archaeon Haloferax volcanii.

Haloarchaea have evolved to thrive in hypersaline environments. Haloferax volcanii is of particular interest due to its genetic tractability; however, few in vivo reporters exist for halophiles. Haloarchaeal proteins evolved characteristics that promote proper folding and function at high salt concentrations, but many mesophilic reporter proteins lack these characteristics. Mesophilic proteins that acquire salt-stabilizing mutations, however, can lead to proper function in haloarchaea. Using laboratory-directed evolution, we developed and demonstrated an in vivo luciferase that functions in the hypersaline cytosol of H. volcanii.

Out-of-office blood pressure measurement for the diagnosis of hypertension in pregnancy: Survey of Canadian Obstetric Medicine and Maternal Fetal Medicine specialists.

BACKGROUND: Multiple hypertension guidelines recommend out-of-office measurements for the diagnosis of hypertension in non-pregnant adults, whereas pregnancy guidelines recommend in-office blood pressure measurements. The objective of our study was to determine how Canadian Obstetric Medicine and Maternal Fetal Medicine specialists measure blood pressure in pregnancy. METHODS: An email survey was sent to 69 Canadian Obstetric Medicine and Maternal Fetal Medicine specialists in academic centers across Canada to explore the practice patterns of blood pressure measurement in pregnant women. RESULTS: The response rate was 48%. The majority of respondents (63.6%) preferred office blood pressure measurement for diagnosing hypertension, but relied on home blood pressure readings for ongoing monitoring and management of hypertension during pregnancy (59.4%). The preferred method of out-of-office blood pressure measurement was home monitoring; 24-hour ambulatory blood pressure monitoring was not used due to limited availability and cost. CONCLUSIONS: There is wide practice variation in methods of measuring blood pressure among Canadian specialists managing hypertension in pregnancy.

Obesity in adolescent men increases the risk of venous thromboembolism in adult life.

BACKGROUND: As the population of obese and severely obese young adults grows, it is becoming increasingly important to recognize the long-term risks associated with adolescent obesity. OBJECTIVES: This study aimed to determine the association between body mass index (BMI) in young men at enlistment for military service and later risk of venous thromboembolism (VTE). METHODS: Nationwide register-based prospective cohort study of men enlisting 1969 to 2005, followed through the Swedish National Patient and Cause of Death registries. We identified 1 639 838 men (mean age, 18.3 years) free of prior venous thromboembolism, of whom 29 342 were obese (BMI 30 to <35 kg m-2 ) and 7236 severely obese (BMI ≥ 35 kg m-2 ). The participants were followed until a first registered diagnosis of VTE. RESULTS: During a median follow-up of 28 years (interquartile interval, 20 to 36 years), 11 395 cases of deep vein thrombosis and 7270 cases of pulmonary embolism were recorded. Compared with men with a BMI of 18.5 to <20 kg m-2 , men with higher BMI in young adulthood showed an incrementally increasing risk of VTE that was moderately but significantly increased already at normal BMI levels. Adolescent obese men with a BMI of 30 to 35 kg m-2 had an adjusted hazard ratio of 2.93 (95% confidence interval, 2.65 to 3.24) for VTE. Severely obese men with a BMI of ≥35 kg m-2 had a hazard ratio of 4.95 (95% confidence interval, 4.16 to 5.90). CONCLUSIONS: Men who were obese or severely obese in young adulthood had a marked increase in risk of VTE.

Harvesting 48V at the National Superconducting Cyclotron Laboratory.

As part of an effort to develop aqueous isotope harvesting techniques at radioactive beam facilities, 48V and a cocktail of primary- and secondary-beam ions created by the fragmentation reaction of a 160 MeV/nucleon 58Ni beam were stopped in an aqueous target cell. After collection, 48V was separated from the mixture of beam ions using cation-exchange chromatography. The extraction efficiency from the aqueous solution was (47.0 ± 2.5)%, and the isolated 48V had a radiochemical purity of 95.8%. This proof-of-concept work shows that aqueous isotope harvesting could provide significant quantities of rare isotopes which are currently unavailable at conventional facilities.

Targeting Pancreatic Cancer Cells and Stellate Cells Using Designer Nanotherapeutics in vitro.

INTRODUCTION AND OBJECTIVE: Pancreatic cancer (PC) is characterized by a robust desmoplastic environment, which limits the uptake of the standard first-line chemotherapeutic drug gemcitabine. Enhancing gemcitabine delivery to the complex tumor microenvironment (TME) is a major clinical challenge. Molecular crosstalk between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) plays a critical role in desmoplastic reaction in PCs. Herein, we report the development of a targeted drug delivery system to inhibit the proliferation of PCCs and PSCs in vitro. Using gold nanoparticles as the delivery vehicle, the anti-EGFR antibody cetuximab (C225/C) as a targeting agent, gemcitabine as drug and polyethylene glycol (PEG) as a stealth molecule, we created a series of targeted drug delivery systems. METHODS: Fabricated nanoconjugates were characterized by various physicochemical techniques such as UV-Visible spectroscopy, transmission electron microscopy, HPLC and instrumental neutron activation analysis (INAA). RESULTS AND CONCLUSION: Targeted gemcitabine delivery systems containing mPEG-SH having molecular weights of 550 Da or 1000 Da demonstrated superior efficacy in reducing the viability of both PCCs and PSCs as compared to their non-targeted counterparts. EGFR-targeted pathway was further validated by pre-treating cells with C225 followed by determining cellular viability. Taken together, in our current study we have developed a PEGylated targeted nanoconjugate ACG44P1000 that showed enhanced selectivity towards pancreatic cancer cells and pancreatic stellate cells, among others, for gemcitabine delivery. We will investigate the ability of these optimized conjugates to inhibit desmoplasia and tumor growth in vivo in our future studies.