First analytical confirmation of drug-induced crystal nephropathy in felines caused by GS-441524, the active metabolite of Remdesivir.

GS-441524 is an adenosine nucleoside antiviral demonstrating significant efficacy in the treatment of feline infectious peritonitis (FIP), an otherwise fatal illness, resulting from infection with feline coronavirus. However, following the emergence of COVID-19, veterinary development was halted, and Gilead pursued clinical development of a GS-441524 pro-drug, resulting in the approval of Remdesivir under an FDA emergency use authorization. Despite lack of regulatory approval, GS-441524 is available without a prescription through various unlicensed online distributors and is commonly purchased by pet owners for the treatment of FIP. Herein, we report data obtained from the analytical characterization of two feline renal calculi, demonstrating the propensity for GS-441524 to cause renal toxicity through drug-induced crystal nephropathy in vivo. As definitive diagnosis of drug-induced crystal nephropathy requires confirmation of the lithogenic material to accurately attribute a mechanism of toxicity, renal stone composition and crystalline matrix were characterized using ultra-performance liquid chromatography photodiode array detection (UPLC-PDA), ultra-performance liquid chromatography mass spectrometry (LCMS), nuclear magnetic resonance (NMR) spectroscopy, X-ray powder diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR). This work serves to provide the first analytical confirmation of GS-441524-induced crystal nephropathy in an effort to support toxicologic identification of adverse renal effects caused by administration of GS-441524 or any pro-drug thereof.

Host range characterization of Phytophthora sansomeana across corn, soybean, wheat, winter cereal rye, dry bean and oats, and an in vitro assessment of seed treatment sensitivity.

Formally described in 2009, Phytophthora sansomeana is a pathogen of increasing interest in native, agricultural, and horticulturally important plant species. The objective of this study was to elucidate the symptomatic and asymptomatic host range of P. sansomeana on six agricultural crop species commonly used in field crop rotations in Michigan. In addition, sensitivity to oomicides commonly used in seed treatments including, oxathiapiprolin, mefenoxam, ethaboxam, and pyraclostrobin was performed to aid in disease management recommendations. Plant biomass, quantity of P. sansomeana DNA in roots, and reisolations were used to assess pathogenicity and virulence of eighteen isolates of P. sansomeana on each plant species using an inoculated seedling growth chamber assay. Isolates displayed varying levels of virulence to the hosts tested. Reisolations were completed for each plant species tested, and varying quantities of P. sansomeana DNA were found within all plant species root samples. Corn, wheat, soybean, dry bean, and winter cereal rye plants were symptomatic hosts with significant reduction observed in total plant biomass. No significant reduction in total plant biomass was observed in oats, and oat roots harbored the least amount of P. sansomeana DNA. No P. sansomeana isolates were insensitive to the oomicide compounds tested with mean absolute EC50 values of 7.8 x 10-2 µg/ml for mefenoxam, 1.13 x 10-1 µg/ml for ethaboxam, 2.6 x 10-2 µg/ml for oxathiapiprolin, and 3.04 x 10-1 µg/ml for pyraclostrobin. These results suggest that common crop rotations in Michigan may not be a viable option to reduce soilborne inoculum accumulation and oomicide seed treatments should be considered for early season management of P. sansomeana.

Social determinants and participation in fecal occult blood test based colorectal cancer screening: A qualitative systematic review and meta-synthesis.

ISSUE ADDRESSED: Colorectal cancer (CRC) screening through fecal occult blood testing (FOBT) has saved thousands of lives globally with multiple countries adopting comprehensive population wide screening programs. Participation rates in FOBT based CRC screening for the socially and economically disadvantaged remains low. The aim of this systematic review is to explore empirical evidence that will guide targeted interventions to improve participation rates within priority populations. METHODS: PubMed, Embase, Scopus, Cinahl and PsycInfo were systematically searched from inception to 22 June 2022. Eligible studies contained qualitative evidence identifying barriers to FOBT based CRC screening for populations impacted by the social determinants of health. An inductive thematic synthesis approach was applied using grounded theory methodology, to explore descriptive themes and interpret these into higher order analytical constructs and theories. RESULTS: A total of 8,501 publications were identified and screened. A total of 48 studies from 10 countries were eligible for inclusion, representing 2,232 subjects. Coding within included studies resulted in 30 key descriptive themes with a thematic frequency greater than 10%. Coded themes applied to four overarching, interconnected barriers driving inequality for priority populations: social, behavioural, economic and technical/interfaces. SO WHAT?: This study has highlighted the need for stronger patient/provider relationships to mitigate barriers to FOBT screening participation for diverse groups. Findings can assist health professionals and policy makers address the systemic exclusion of priority populations in cancer screening by moving beyond the responsibility of the individual to a focus on addressing the information asymmetry driving low value perceptions.

Uroliths composed of antiviral compound GS-441524 in 2 cats undergoing treatment for feline infectious peritonitis.

Feline infectious peritonitis (FIP) historically has been a fatal disease in cats. Recent unlicensed use of antiviral medication has been shown to markedly improve survival of this infection. An 8-month-old female spayed domestic short-haired cat undergoing treatment for presumptive FIP with the antiviral nucleoside analog GS-441524 developed acute progressive azotemia. Abdominal ultrasound examination identified multifocal urolithiasis including renal, ureteral, and cystic calculi. Unilateral ureteral obstruction progressed to suspected bilateral ureteral obstruction and subcutaneous ureteral bypass (SUB) was performed along with urolith removal and submission for analysis. A 2-year-old male neutered domestic medium-haired cat undergoing treatment for confirmed FIP with GS-441524 developed dysuria (weak urine stream, urinary incontinence, and difficulty expressing the urinary bladder). This cat also was diagnosed sonographically with multifocal urolithiasis requiring temporary tube cystostomy after cystotomy and urolith removal. In both cases, initial urolith analysis showed unidentified material. Additional testing confirmed the calculi in both cats to be 98% consistent with GS-441524. Additional clinical studies are required to determine best screening practices for cats presented for urolithiasis during treatment with GS-441524.

SMARTERscreen protocol: a three-arm cluster randomised controlled trial of patient SMS messaging in general practice to increase participation in the Australian National Bowel Cancer Screening Program.

BACKGROUND: Australia persistently has one of the highest rates of colorectal cancer (CRC) in the world. Australia's National Bowel Cancer Screening Program (NBCSP) sends a biennial Faecal Immunochemical Test (FIT)-the 'NBCSP kit'-to everyone eligible for the programme between 50 and 74 years old; however, participation in the programme is low, especially in the 50- to 60-year-old age group. Our previous efficacy trial ('SMARTscreen') demonstrated an absolute increase in uptake of 16.5% (95% confidence interval = 2.02-30.9%) for people sent an SMS with motivational and instructional videos, from their general practice prior to receiving their NBCSP kit, compared to those receiving usual care. Building on the strengths of the SMARTscreen trial and addressing limitations, the 'SMARTERscreen' trial will test the effect on participation in the NBCSP of sending either an SMS only or an SMS with online video material to general practice patients due to receive their NBCSP compared to 'usual care'. METHODS: SMARTERscreen is a three-arm stratified cluster randomised controlled trial involving 63 general practices in two states in Australia. Eligible patients are patients who are aged 49-60 years and due to receive their NBCSP kit within the next 2 weeks during the intervention period. General practices will be equally randomised to three trial arms (21:21:21, estimated average 260 patients/practice). The two interventions include (i) an SMS with an encouraging message from their general practice or (ii) the same SMS with weblinks to additional motivational and instructional videos. The control arm will receive 'usual care'. Using the intention-to-treat approach, primary analysis will estimate the three pair-wise between-arm differences in the proportion of eligible patients who participate in the NBCSP within 6 months of when their kit is sent, utilising screening data from the Australian National Cancer Screening Register (NCSR). Patient intervention adherence to the interventions will also be evaluated. Findings will be incorporated into the Policy1-Bowel microsimulation model to estimate the long-term health benefits and cost-effectiveness of the interventions. DISCUSSION: SMARTERscreen will provide high-level evidence determining whether an SMS or an SMS with web-based material sent to general practice patients prior to receiving their NBCSP kit increases participation in bowel cancer screening. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12623000036617. Registered on 13 January 2023. Trial URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385119&isClinicalTrial=False.

First Reported Case of a Pyrophosphate Kidney Stone in a Human.

Urolithiasis composed of pyrophosphate salts has only been reported in animals, in the form of potassium magnesium pyrophosphate. However, there have been no reports of pyrophosphate stones in humans. Hypophosphatasia is an inherited disease characterized by low alkaline phosphatase activity and elevated levels of pyrophosphate in blood and urine. Urolithiasis is a part of the hypophosphatasia phenotype. The role of elevated urine pyrophosphate levels in the formation of stones in hypophosphatasia is unknown. Here, we report a case of a 60-year-old man with recurrent urolithiasis. The patient's most recent presentation was gross hematuria and his computed tomography scan showed bilateral kidney stones. Stones were removed via retrograde intrarenal surgery. Stone analysis revealed a composition of potassium magnesium pyrophosphate. The patient also has a long history of fracturing bone disease which led to the consideration of hypophosphatasia as the cause of both his bone disease and pyrophosphate stones. Hypophosphatasia was confirmed by genetic analysis. Pyrophosphate has been of interest in the fields of mineral metabolism because of its action as a crystallization inhibitor. However, pyrophosphate at elevated concentrations in the presence of divalent cations can exceed its solubility. Nephrocalcinosis and stone disease have been described in hypophosphatasia; stones have been assumed to be calcium phosphate but no compositional analysis has been reported. This is the first report of human stones composed of pyrophosphate salts, which led to the subsequent diagnosis of hypophosphatasia in this patient.

Perceptions and implications for cervical screening and self-collection: A qualitative exploration of never and under-screened Queensland women.

BACKGROUND: Over 70% of cervical cancers are detected in women not currently screening. Queensland Health wanted to better understand the drivers of screening to inform our planning and capitalise on self-collection as an option to reach under-screened women. In 2020 Queensland Health commissioned qualitative research to explore barriers and enablers to cervical screening with never-screened and under-screened women in Queensland (with under-screeners defined as having last screened more than 4 years ago and being more than 2 years overdue). Additionally, the research explored the acceptability of self-collection amongst this cohort. METHODS: A mixed methods qualitative approach of online focus groups and in-depth interviews was employed. Online focus groups were conducted with under-screeners. In-depth telephone interviews were conducted with never-screeners due to the anticipated personal nature of their reasons for not screening. RESULTS: A total of 51 Queensland women aged 30 to 50 years participated in the research. CONCLUSIONS: Queensland women cited several negative experiences and aspects of the current program, as well as barriers in their social and personal lives that limited screening intention and behaviour. Barriers and enablers to cervical screening identified in this research have been classified into four categories: structural, knowledge and attitudinal, social, and personal. The research identified more factors associated with nonparticipation than participation. However, the research did uncover a range of potential enablers to encourage screening, some of which related to the program design. SO WHAT?: The concept of self-collection was broadly well accepted by research participants, particularly by never-screeners. Recommendations resulting from this research include communications, systems, and eligibility changes, particularly regarding the availability and benefits of self-collection.

Influence of Age and Geography on Chemical Composition of 98043 Urinary Stones from the USA.

BACKGROUND: Urolithiasis is a growing issue globally, but it is heterogeneous, with a different epidemiology and pathophysiology for each different stone composition. OBJECTIVE: The purpose of this study is to describe the incidence of urinary stones in the USA from 2016 to 2019 by chemical composition and to investigate the influence of age and geography on these stone types. DESIGN SETTING AND PARTICIPANTS: We obtained compositional analyses for all urinary stones submitted to a national laboratory over an approximately 3-yr period. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data collected included the chemical constituents of a stone, patient age, and geographical origin. We describe the incidence of each stone type by frequency. Statistical testing was performed to determine the influence of age and geographical region on overall incidence of each stone composition. RESULTS AND LIMITATIONS: In total, 99 908 specimens were analyzed. When pure stones were ordered by frequency, we found that the most common stone type was calcium oxalate (CaOx) (79.2%), followed by uric acid (UA; 14.3%), calcium phosphate (CaPO4; 3.7%), cystine (0.51%), drug induced (0.12%), and magnesium ammonium phosphate (0.04%). CaOx, UA, and CaPO4 were often mixed with one another. Among CaOx stones, the plurality (28.0%) was made of pure calcium oxalate monohydrate (COM), and only 0.002% was pure calcium oxalate dihydrate. There was an overall association between stone composition and both geographical distribution and age (p < 0.001). CONCLUSIONS: CaOx stones comprise the majority of urinary stones in the USA, of which almost 28% were pure COM. Additionally, age and geographical region are significantly associated with variations in stone composition. PATIENT SUMMARY: We evaluated the incidence of urinary stones in the USA based on their chemical composition. The most common stone type was calcium oxalate, the majority of which was pure calcium oxalate monohydrate. We also found age and geographical region to be significantly associated with variations in stone composition.

Codesigning Parks for Increasing Park Visits and Physical Activity in a Low-Socioeconomic Community: The Active By Community Design Experience.

The purpose of the Active By Community Design (ABCD) project was to engage residents in the redesign of two public open spaces to increase park visits and park-based physical activity (PBPA). It was anticipated that by adding local preferences to park design considerations along with collected data and available evidence, the study would achieve increased levels of community engagement and subsequent increases in park visits and PBPA. This study summarizes two case studies outlining the community engagement and research translation process. Utilizing a pre-post evaluation design, baseline measures were completed with a series of validated tools for park use and park quality. Baseline data, evidence, community and stakeholder input were synthesized and presented to a "design subcommittee" to translate into "real-world" park redesigns. Park audits, a household survey, and park open days identified the spaces were not designed for the activities residents wanted, while park observations identified usage was low, and those observed were mostly children and adults walking. Park redesigns focused on maximizing access, infrastructure to enable physical activity (PA), PA programs and enhancements to improve aesthetics and safety concerns. The ABCD project successfully demonstrated a process of combining data and community and stakeholder engagement input to translate evidence into the creation of more supportive environments for PA. Stakeholder and resident input to the redesign processes contributed to satisfaction and ownership that residents reported on the redesigned parks, which may increase the likelihood of increased park usage and park-based physical activity.

A model for oxygen conservation associated with titration during pediatric oxygen therapy.

BACKGROUND: Continuous oxygen treatment is essential for managing children with hypoxemia, but access to oxygen in low-resource countries remains problematic. Given the high burden of pneumonia in these countries and the fact that flow can be gradually reduced as therapy progresses, oxygen conservation through routine titration warrants exploration. AIM: To determine the amount of oxygen saved via titration during oxygen therapy for children with hypoxemic pneumonia. METHODS: Based on published clinical data, we developed a model of oxygen flow rates needed to manage hypoxemia, assuming recommended flow rate at start of therapy, and comparing total oxygen used with routine titration every 3 minutes or once every 24 hours versus no titration. RESULTS: Titration every 3 minutes or every 24 hours provided oxygen savings estimated at 11.7% ± 5.1% and 8.1% ± 5.1% (average ± standard error of the mean, n = 3), respectively. For every 100 patients, 44 or 30 kiloliters would be saved-equivalent to 733 or 500 hours at 1 liter per minute. CONCLUSIONS: Ongoing titration can conserve oxygen, even performed once-daily. While clinical validation is necessary, these findings could provide incentive for the routine use of pulse oximeters for patient management, as well as further development of automated systems.

Reservoir Cannulas for Pediatric Oxygen Therapy: A Proof-of-Concept Study.

Hypoxemia is a complication of pneumonia-the leading infectious cause of death in children worldwide. Treatment generally requires oxygen-enriched air, but access in low-resource settings is expensive and unreliable. We explored use of reservoir cannulas (RCs), which yield oxygen savings in adults but have not been examined in children. Toddler, small child, and adolescent breathing profiles were simulated with artificial lung and airway models. An oxygen concentrator provided flow rates of 0 to 5 L/min via a standard nasal cannula (NC) or RC, and delivered oxygen fraction (FdO2) was measured. The oxygen savings ratio (SR) and absolute flow savings (AFS) were calculated, comparing NC and RC. We demonstrated proof-of-concept that pendant RCs could conserve oxygen during pediatric therapy. SR mean and standard deviation were 1.1 ± 0.2 to 1.4 ± 0.4, 1.1 ± 0.1 to 1.7 ± 0.3, and 1.3 ± 0.1 to 2.4 ± 0.3 for toddler, small child, and adolescent models, respectively. Maximum AFS observed were 0.3 ± 0.3, 0.2 ± 0.1, and 1.4 ± 0.3 L/min for the same models. RCs have the potential to reduce oxygen consumption during treatment of hypoxemia in children; however, further evaluation of products is needed, followed by clinical analysis in patients.

Translating research to practice: using the RE-AIM framework to examine an evidence-based physical activity intervention in primary school settings.

Although there has been an increase in the availability of effective, evidence-based physical activity interventions in school settings during the past decade, there is a paucity of published research focusing on the translation of these effective interventions into real-world practice. The purpose of this research was to examine the translatability of an existing school-based physical activity intervention. More specifically, this research sought to identify the barriers and facilitators in adopting, implementing, and maintaining a school-based physical activity intervention using RE-AIM as a theoretical evaluation framework. It was concluded that interventions that consider issues around complexity and compatibility with the school setting are more likely to be adopted, implemented, and maintained. It was recommended that future evaluations of physical activity interventions should not be limited to testing internal validity, but should consider external validity and ecological aspects, relevant to increasing dissemination in real-world settings.

Magnetic resonance imaging of SILCS diaphragm: anatomical considerations and corroboration with clinical fit.

BACKGROUND: We performed a pilot study to evaluate in vivo the fit of the new SILCS diaphragm, a single-size cervical barrier, using magnetic resonance imaging (MRI) in a group of women varying in body mass and parity. STUDY DESIGN: Two healthy premenopausal women were recruited for each of the following groups: body mass index (BMI)<25, BMI=25-30 and BMI>30. One woman in each group was nulliparous and one was multiparous. Subjects were instructed on the placement of the SILCS diaphragm. Each subject underwent three MRI scans: baseline, with the SILCS diaphragm in place and after placement of intravaginal contrast and simulated intercourse. RESULTS: The SILCS diaphragm was easily identified on MRI. In all subjects, the diaphragm covered the cervix. The position of the diaphragm did not change after simulated intercourse. The appropriate position of the diaphragm, as assessed by the subjects and the practitioner, was corroborated by the MR images. The intravaginal contrast was not readily visible on the images, precluding assessment of the diaphragm's barrier properties. CONCLUSION: MRI confirms the anatomic position of the SILCS diaphragm in vivo, among a sample of women varying in body mass and parity.

Short-term acceptability of the PATH Woman's Condom among couples at three sites.

PURPOSE: The objective of this study is to evaluate acceptability of the PATH Woman's Condom among user populations in Mexico, South Africa and Thailand. METHODS: A nonrandomized, nonblinded, nonsignificant risk study was conducted among 20 couples per site. Data were collected via structured questionnaires after the first, second and third condom uses and through in-depth interviews after all condoms were used. RESULTS: Women from all sites reported that the PATH Woman's Condom was easy and comfortable to insert, and the pouch and ring were very stable during use. Both women and men reported that the comfort and sensation of sex while using the condom was acceptable. CONCLUSIONS: The PATH Woman's Condom is easy to use, stable during use, comfortable and satisfactory during sex among users from diverse populations and cultures. The iterative user-driven product development process helped ensure that this new product addresses a wide range of user preferences.

Effect of methylphenidate on Stroop Color-Word task performance in children with attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric syndrome common in the pediatric population. It is associated with multiple nonspecific deficits on neuropsychological tests of executive function, and a beneficial response to pharmacotherapy with methylphenidate (MPH) and other psychostimulants. The Stroop Color-Word task is used empirically as an aid in diagnosis and treatment monitoring of ADHD; however, data on the sensitivity of the Stroop interference score to the effects of MPH are limited. To address this issue, we studied Stroop performance in a cohort of 18 MPH-treated prepubescent boys with ADHD and six healthy controls on and off MPH treatment conditions. MPH significantly improved performance in both groups, with the ADHD participants consistently displaying worse scores than those of controls both on and off MPH. These results suggest that though the diagnostic value of the Stroop task in ADHD remains controversial, it has heuristic value for monitoring clinical responses to MPH treatment. More research is needed to ascertain the clinical significance of our findings and to replicate this relatively small effect in a larger cohort, to determine whether MPH effects on Stroop performance are specific to ADHD symptoms or they generalize to other forms of symptomatology.

Effects of methylphenidate discontinuation on cerebral blood flow in prepubescent boys with attention deficit hyperactivity disorder.

UNLABELLED: Methylphenidate (MPH) is an effective symptomatic treatment of attention deficit hyperactivity disorder (ADHD), but the mechanisms of its therapeutic action have not been fully elucidated. To address this issue, we assessed the effects of discontinuation of chronic MPH treatment on regional cerebral blood flow (rCBF) in ADHD patients. METHODS: Twenty-two prepubescent boys with ADHD (age range, 8.2-11.5 y) and 7 healthy volunteers were studied with SPECT on and off MPH. Their rCBF data were automatically normalized to whole-brain counts and coregistered with standard anatomic space. rCBF changes were evaluated with statistical parametric mapping based on voxel-by-voxel ANOVA. RESULTS: When the subjects were not taking MPH, rCBF was higher in the motor, premotor, and the anterior cingulate cortices (Brodmann's areas 4, 6, and 32). CONCLUSION: Brief discontinuation of MPH treatment is associated with increased motor and anterior cingulate cortical activity. Our findings suggest that MPH treatment modulates motor and anterior cingulate cortical activity directly or indirectly. Alternatively, our findings may be related to MPH withdrawal. These data provide novel information on the potential mechanisms of the therapeutic action of MPH. Furthermore, they are clinically relevant to the commonly occurring brief interruptions in MPH treatment.