Search

AbstractThe adenosine analogue GS-441524 has demonstrated efficacy in treatment of feline infectious peritonitis (FIP). With no commercially registered formulations of GS-441524 available, global focus shifted to its pro-drug remdesivir, as it became more accessible throughout the COVID-19 pandemic. This study developed and validated a simple liquid chromatography equipped with a fluorescence detector to quantify plasma concentrations of GS-441524 applicable for routine therapeutic monitoring of remdesivir or GS-441524 therapy for FIP infected cats. A Waters X-Bridge C18, 5 µm, 150 × 4.6 mm, column was used and mixtures of 20 mM ammonium acetate (pH 4.5) with acetonitrile of 5% and 70% were prepared for gradient mobile phase. With a simple protein precipitation using methanol to clean plasma sample, GS-441524 was monitored at excitation and emission wavelengths of 250 nm and 475 nm, respectively. Using an external standard, the lowest and highest limits of quantification were 19.5 ng/mL to 10,000 ng/mL, respectively. The intra- and inter day trueness of the quality controls (QCs) were within 10% of their nominal concentrations and intra- and inter day precision of the QCs (expressed as the coefficient of variation) ranged from 1.7 to 5.7%, This assay was able to quantify plasma trough levels of GS-441524 (23.7–190.1 ng/mL) after the administration of remdesivir (9.9–15.0 mg/kg BW, IV or SC) in FIP cats (n = 12). Accordingly, this study generated an alternative and cost-effective way to quantify GS-441524 in feline biological fluids at least up to 24 hr after administrations of remdesivir.

The level of each RNA species depends on the balance between its rates of production and decay. Although previous studies have measured RNA decay across the genome in tissue culture and single-celled organisms, few experiments have been performed in intact complex tissues and organs. It is therefore unclear whether the determinants of RNA decay found in cultured cells are preserved in an intact tissue, and whether they differ between neighboring cell types and are regulated during development. To address these questions, we measured RNA synthesis and decay rates genome wide via metabolic labeling of whole cultured Drosophilalarval brains using 4-thiouridine. Our analysis revealed that decay rates span a range of more than 100-fold, and that RNA stability is linked to gene function, with mRNAs encoding transcription factors being much less stable than mRNAs involved in core metabolic functions. Surprisingly, among transcription factor mRNAs there was a clear demarcation between more widely used transcription factors and those that are expressed only transiently during development. mRNAs encoding transient transcription factors are among the least stable in the brain. These mRNAs are characterized by epigenetic silencing in most cell types, as shown by their enrichment with the histone modification H3K27me3. Our data suggest the presence of an mRNA destabilizing mechanism targeted to these transiently expressed transcription factors to allow their levels to be regulated rapidly with high precision. Our study also demonstrates a general method for measuring mRNA transcription and decay rates in intact organs or tissues, offering insights into the role of mRNA stability in the regulation of complex developmental programs.

BackgroundIn February 2020, Canada implemented plain packaging without any changes to the size and content of health warning labels (HWLs), which were last updated in 2012 (pictorial HWLs on 75% of the pack front and back). This pre-post evaluation study assessed the impact of plain packaging in Canada on: (1) pack appeal; (2) HWL effectiveness; and (3) support for plain packaging. Additionally, a quasi–experimental design was used to assess the Canadian results relative to two comparator countries: Australia, where plain packaging (with new larger HWLs) was implemented in 2012, and the United States (USA), where plain packaging has not been implemented and the same text warnings have appeared on cigarette packs since 1985.MethodsData are from adult smokers who participated in the 2018 and/or 2020 International Tobacco Control Smoking and Vaping Surveys in Canada (n=4600), Australia (n=1834) and the USA (n=3046). Online surveys were conducted before (February to July 2018) and after (February to June 2020) the implementation of plain packaging in Canada. Adjusted regression analyses were conducted on weighted data.ResultsPlain packaging was associated with a significant increase in the percentage of Canadian smokers who did not like the look of their cigarette pack (2018: 28.6% vs 2020: 44.7%, p<0.001), whereas no change in pack appeal was observed among smokers in Australia and the USA over the same period. Plain packaging was not associated with changes in HWL effectiveness in Canada. Support for plain packaging increased significantly among Canadian smokers (2018: 25.6% vs 2020: 33.7%, p<0.001).ConclusionsPlain packaging in Canada substantially reduced pack appeal and increased support for the policy among adult smokers; however, there was no increase in the effectiveness of Canada’s 8-year-old HWLs. The impact of plain packaging on health warning effectiveness may depend on the design of the warnings and length of time since implementation.

IntroductionBetween 2015 and 2018, Canada banned menthol cigarettes. This study pooled data from two pre–post cohort studies (the Ontario Menthol Ban Study, and the International Tobacco Control Policy Evaluation (ITC) Canada Survey, conducted in seven provinces) to derive more precise estimates of the impact of Canada’s menthol ban on quitting and to apply these estimates to project the impact of a menthol ban in the USA.MethodsWeighted multivariable logistic analyses compared post-ban quit success of menthol smokers with non-menthol smokers (for daily smokers and for all (daily + non-daily) smokers), controlling for sex, age, ethnicity, education, baseline smoking status, baseline cigarettes per day and study regions. Projections to the USA were created by multiplying the effect size of the Canadian menthol ban on quitting (percentage of increased quitting among menthol smokers) by the number of menthol smokers overall and among African Americans, from the 2019 National Survey on Drug Use and Health.ResultsAfter the menthol cigarette ban, menthol smokers were more likely than non-menthol smokers to have quit smoking among daily smokers (difference=8.0%; 95% CI: 2.4% to 13.7%,p=0.005) and all (daily+non-daily) smokers (difference=7.3%; 95% CI: 2.1% to 12.5%,p=0.006). The projected number of smokers who would quit after a US menthol ban would be 789 724 daily smokers (including 199 732 African Americans) and 1 337 988 daily+non-daily smokers (including 381 272 African Americans).ConclusionsThis pooled analysis of Canada’s menthol cigarette ban provides the foundation for estimating the impact of menthol bans in the USA and other countries. Projections suggest that a US menthol cigarette ban would have a substantial impact on increasing quitting.

Occupational therapists support the occupational participation of people who are dying yet remain underutilized in end-of-life care. The purpose of this article was to explore how occupational therapists develop their role in end-of-life care to provide strategies to address underutilization. Using a grounded-theory method, semi-structured interviews were conducted with 21 occupational therapists. Three themes emerged which demonstrate participants’ role development process. Participants’ experiences with dying (Close Experience of Loss) often instilled the importance of end-of-life care. Led by these convictions (Willing to Do It), participants developed skills for end-of-life care. Reflecting on their experiences and treatment outcomes (Making a Difference), participants self-validated their role. The Model of Occupational Therapists’ Role Development in End-of-Life Care captured this process. Personal experiences and critical self-reflection may provide an adaptive means to drive role development and appropriately increase end-of-life care occupational therapy utilization.

The researchers identified and described parents' expectations and perceptions of therapy services received by their children with Down syndrome.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy with a highly favorable overall prognosis. Central nervous system (CNS) relapse of B-ALL is relatively rare and is associated with inferior survival outcomes. We present two patients with B-ALL who developed isolated CNS relapse following confirmed infection with severe acute respiratory syndrome coronavirus 2. In addition to individual and disease factors, we posit that delays in therapy together with immune system modulation because of severe acute respiratory syndrome coronavirus 2 may account for these 2 cases of CNS relapsed B-ALL. We report on this clinical observation to raise awareness of this potential association.

Large B cell lymphomas (LBCL) are a heterogeneous group of diseases with variable presentations and prognoses. Rarely, LBCLs arise in the sinonasal tract and are distinct from extranodal NK/T-cell lymphoma which is more typical in this anatomic location. We hypothesized that large B cell lymphoma primary to the sinonasal tract (snLBCL) would be heterogeneous and include high-grade B cell lymphomas (HGBCL) described in the revised 4thedition WHO classification of lymphomas. We retrospectively evaluated cases of snLBCL at our center, and performed additional immunohistochemical and in situ hybridization studies where needed for modern WHO classification. Our cohort consisted of 25 cases, 15 males and 10 female patients, aged 14 to 87 years, with predominantly nasopharyngeal disease (n= 11), Ann Arbor stage IIE (n= 15), and immunocompetence (n= 24). According to revised 2016 WHO criteria, 20 of the 25 cases were DLBCL-NOS (80%, two-thirds germinal center phenotype), 3 were HGBCL-NOS (8%, one with MYCrearrangement without BCL2rearrangement), and 2 were EBV-LBCL (8%). Among DLBCL-NOS, those arising in the nasopharynx all showed a germinal center B cell (GCB) phenotype, whereas both evaluable maxillary sinus tumors showed non-GCB characteristics (p= 0.02). These data show that large B cell lymphoma primary to the sinonasal tract is histopathologically heterogeneous as systemic large B cell lymphoma. The observation that GCB and non-GCB tumors differs in anatomic location suggests that microenvironmental factors in sinonasal anatomic sites may drive lymphoma characteristics.

Urinary bladder diseases are common in dogs and cats; however, there is little published work on urinary bladder disease in Australian pets. We identified pathology records of Australian dogs and cats with urinary bladder tissue submitted to the University of Queensland Veterinary Laboratory Service during 1994–2016 (n= 320). We described the proportion of bladder diseases in dogs and cats, and applied the less-commonly used logistic regression procedure to quantify associations between signalment variables and disease diagnosis that were evident using descriptive statistics alone. After preliminary analysis, both species were combined because of similar results. Spayed/castrated animals were 74% less likely to be diagnosed with cystitis compared with intact animals. Animals 4–11 y old were also at lower risk of being diagnosed with cystitis compared with younger or older animals. Male animals were at increased risk of neoplasia compared to females, which contrasts with reports from North America and Europe. There was increased risk for developing neoplasia with progressive age, with up to 20 times higher odds in the > 11-y age group. Logistic regression modeling provided unique insight into proportionate morbidity of urinary bladder diseases in Australian dogs and cats.

Dire wolves are considered to be one of the most common and widespread large carnivores in Pleistocene America1, yet relatively little is known about their evolution or extinction. Here, to reconstruct the evolutionary history of dire wolves, we sequenced five genomes from sub-fossil remains dating from 13,000 to more than 50,000 years ago. Our results indicate that although they were similar morphologically to the extant grey wolf, dire wolves were a highly divergent lineage that split from living canids around 5.7 million years ago. In contrast to numerous examples of hybridization across Canidae2,3, there is no evidence for gene flow between dire wolves and either North American grey wolves or coyotes. This suggests that dire wolves evolved in isolation from the Pleistocene ancestors of these species. Our results also support an early New World origin of dire wolves, while the ancestors of grey wolves, coyotes and dholes evolved in Eurasia and colonized North America only relatively recently.

Background/aimsMotor strategies change with age, resulting in balance deficits. Clinical options for objectively measuring motor strategies are limited. The use of two-dimensional kinematic analysis through smart devices and applications may provide a cost-effective portable solution for measuring differences in motor strategy use between older and younger adults. The aims of this study were to investigate the concurrent validity of a two-dimensional software and two-dimensional application and to determine whether the application could capture the difference in ankle motor strategy use by older and younger adults (construct validity).MethodsVideo clips captured by Sony and iPad Air cameras were used to assess concurrent validity between the two-dimensional software and application. A total of 30 older (72.6 ± 4.0 years) and 30 younger (26.5±4.5 years) adults performed forward and backward stepping. A two-dimensional applicationmeasured the ankle position in degrees and time taken in seconds to initiate and complete a compensatory step.ResultsThe two-dimensional software and app demonstrated excellent reliability (ICC2,1≥0.994). The ankle forward stop angle differed significantly between older and younger adults (P=0.012). No differences were observed in time taken to initiate and complete a compensatory step.ConclusionsThe two-dimensional application appears to be a valid alternative to two-dimensional software for measuring ankle motor strategies. Further investigation for clinical use is warranted.

The measurement of RNA abundance derived from massively parallel sequencing experiments is an essential technique. Methods that reduce ribosomal RNA levels are usually required prior to sequencing library construction because ribosomal RNA typically comprises the vast majority of a total RNA sample. For some experiments, ribosomal RNA depletion is favored over poly(A) selection because it offers a more inclusive representation of the transcriptome. However, methods to deplete ribosomal RNA are generally proprietary, complex, inefficient, applicable to only specific species, or compatible with only a narrow range of RNA input levels. Here, we describe Ribo-Pop (ribosomal RNA depletion for popular use), a simple workflow and antisense oligo design strategy that we demonstrate works over a wide input range and can be easily adapted to any organism with a sequenced genome. We provide a computational pipeline for probe selection, a streamlined 20-min protocol, and ready-to-use oligo sequences for several organisms. We anticipate that our simple and generalizable “open source” design strategy would enable virtually any laboratory to pursue full transcriptome sequencing in their organism of interest with minimal time and resource investment.

Classification of viral- and immunodeficiency-associated lymphoproliferative disorders continues to evolve. Entities in these categories recognized in the 2016 revision of the World Health Organization Classification of Lymphoid Neoplasms show considerable morphologic overlap, and it is unclear whether the current classification conceptualizes the scenarios in which these lesions arise and how they might be best managed. Here, we report two cases of lymphoproliferative disorders meeting histologic criteria for lymphomatoid granulomatosis that arose following solid organ transplant. In reviewing the clinicopathologic features of these examples and those of similar cases in the literature, we highlight challenges in current classification and opportunities for their refinement.

BackgroundRecent studies show that greater price variability and more opportunities for tax avoidance are associated with tax structures that depart from a specific uniform one. These findings indicate that tax structures other than a specific uniform one may lead to more cigarette consumption.ObjectiveThis paper aims to examine how cigarette tax structure is associated with cigarette consumption.MethodsWe used survey data taken from the International Tobacco Control Policy Evaluation Project in 17 countries to conduct the analysis. Self-reported cigarette consumption was aggregated to average measures for each surveyed country and wave. The effect of tax structures on cigarette consumption was estimated using generalised estimating equations after adjusting for sociodemographic characteristics, average taxes and year fixed effects.FindingsOur study provides important empirical evidence of a relationship between tax structure and cigarette consumption. We find that a change from a specific to an ad valorem structure is associated with a 6%–11% higher cigarette consumption. In addition, a change from uniform to tiered structure is associated with a 34%–65% higher cigarette consumption. The results are consistent with existing evidence and suggest that a uniform and specific tax structure is the most effective tax structure for reducing tobacco consumption.

To determine the feasibility of Headpod use to improve head control in children with cerebral palsy classified as GMFCS level V.

Abstract:During 1918, the “Spanish Flu” took millions of lives worldwide and remains the worst influenza pandemic in history. The worldwide transmission and the number of deaths from this flu were increased due to the conditions of World War I. In September 1918, the first cases of flu in Kentucky appeared at Camp Zachary Taylor, Louisville. At the time, over forty thousand troops were stationed at the camp. Within a week of the first cases being diagnosed, thousands of soldiers were ill, and the base hospital was quickly overwhelmed. By the end of September, 20 percent of the barracks had been converted to emergency hospitals, and urgent appeals went out for additional nurses. During many previous health crises within Kentucky, dating back to the early 1800s, Catholic sisters had volunteered to work as caregivers. A Roman Catholic Army chaplain at the base requested help from various orders of Kentucky nuns, and within days, eighty-eight sisters from seven orders arrived to help, despite knowing they were placing themselves at great personal risk. The majority of the sisters were teachers rather than professional nurses. The care and vigilant observation provided by the sisters was vital to saving many soldiers’ lives, yet they received little recognition for their contribution. In this year of the centenary of the flu pandemic and the end of the war, it is appropriate to acknowledge the work of the sisters who sacrificed to help the stricken soldiers.

Design for Manufacturing and Assembly (DfMA) has great potential for minimizing late engineering changes (ECs) that impede high-speed product development and delay time-to-profit. However, our understanding of DfMA and its implementation in industry is still incomplete. This paper presents an industrial case study on late ECs in high-speed product development and compares the results to other examples from the literature. It then proposes a framework with sets of key performance indicators (KPIs) to measure and improve producability and product quality throughout the product development process.

Objective: The ITC EUREST-PLUS Spain Survey is a longitudinal study of a representative sample of adult (≥18 years old) smokers in Spain. This protocol describes the methods of the 2021 follow-up survey.

Background/Aims:Dual tasking exacerbates gait deficits in people with Parkinson's disease. This pilot study aimed to examine the effect of aerobic exercise on dual-task gait in individuals with Parkinson's disease and begin to identify the impact of volitional pedal rate.Methods:Twenty people with Parkinson's disease were recruited and tested at baseline, post-intervention, and follow-up for motor (Unified Parkinson's Disease Rating Scale) and cognitive function (Repeatable Battery for the Assessment of Neuropsychological Status) and dual-task gait (Time Up and Go) conditions (manual and cognitive). A 12-week aerobic exercise intervention of cycle ergometry was carried out three times a week for 60 minutes each session. To assess our intervention, separate repeated measures of analysis of variance were conducted. As determined a priori, to assess the impact of volitional pedal rate, participants were divided after the intervention into a high-pedal rate group (>60 rpm) and a low-pedal rate group (≤60 rpm) based upon average maximal pedal rate throughout the intervention and analysed with the Mann Whitney U test and Related Samples Wilcoxon Signed Rank Test.Findings:Overall, motor function (P=0.580), cognitive function (P=0.077), and motor-cognitive interplay (P=0.168) did not improve after aerobic exercise. However, pedal rate groups were different for TUGmanual and TUGcognitive, but not on motor or cognitive function. Only low-pedal rate group improved over time (P=0.028 on TUGmanual) and demonstrated reduced dual task cost after the aerobic exercise (>Minimal Detectible Change of 18.1%).Conclusions:Though the low-pedal rate group experienced greater motor-cognitive interference, persons who pedalled at the slower rate demonstrated the most improvement in dual-task activities.