Publications by authors named "Michael Walsh"

925 Publications

Using Biomarkers to Predict Memantine Effects in Alzheimer's Disease: A Proposal and Proof-Of-Concept Demonstration.

J Alzheimers Dis 2021 Oct 19. Epub 2021 Oct 19.

Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, CA, USA.

Memantine's benefits in Alzheimer's disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual's clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20 mg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10 mg bid). Study participation was well tolerated. Subgroups based on memantine sensitivity on specific laboratory measures differed in their clinical response to memantine, some by large effect sizes. It appears feasible to use biomarkers to predict clinical sensitivity to memantine.
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http://dx.doi.org/10.3233/JAD-215029DOI Listing
October 2021

Clinical and Functional Significance of TP53 Exon 4-Intron 4 Splice Junction Variants.

Mol Cancer Res 2021 Oct 21. Epub 2021 Oct 21.

Dept of Pathology, St Jude Children's Research Hosp.

Germline TP53 splicing variants are uncommon, and their clinical relevance is unknown. However, splice-altering variants at exon 4-intron 4 junctions are relatively enriched in pediatric adrenocortical tumors (ACTs). Nevertheless, family histories of cancer compatible with classic Li-Fraumeni syndrome are rarely seen in these patients. We used conventional and in-silico assays to determine protein stability, splicing, and transcriptional activity of ten TP53 variants at exon 4-intron 4 junctions and analyzed their clinical correlates. We reviewed public databases that report the impact of TP53 variants in human cancer and examined individual reports, focusing on family history of cancer. TP53 exon 4-intron 4 junctions germline variants were identified in 9 of 75 pediatric ACTs enrolled in the International Pediatric Adrenocortical Tumor Registry and Children's Oncology Group ARAR0332 study. An additional 8 independent TP53 variants involving exon 4 splicing were identified in the Pediatric Cancer Genome Project (n=5213). These variants resulted in improper expression due to ineffective splicing, protein instability, altered subcellular localization and loss of function. Clinical case review of carriers of TP53 exon 4-intron 4 junctions variants revealed a high incidence of pediatric ACTs and atypical tumor types not consistent with classic Li-Fraumeni Syndrome. Germline variants involving TP53 exon 4-intron 4 junctions are frequent in ACT and rare in other pediatric tumors. The collective impact of these germline TP53 variants on the fidelity of splicing, protein structure and function must be considered in evaluating cancer susceptibility. Implications: Taken together, the data indicate that splice variants at TP53 codon 125 and surrounding bases differentially impacted p53 gene expression and function.
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http://dx.doi.org/10.1158/1541-7786.MCR-21-0583DOI Listing
October 2021

Impact of Bioelectrical Impedance-Guided Fluid Management and Vitamin D Supplementation on Left Ventricular Mass in Patients Receiving Peritoneal Dialysis: A Randomized Controlled Trial.

Am J Kidney Dis 2021 Oct 14. Epub 2021 Oct 14.

Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada.

Rationale & Objectives: Hypervolemia and vitamin D (Vit D) deficiency occur frequently in patients receiving peritoneal dialysis and may contribute to left ventricular hypertrophy (LVH). The effect of bioimpedance analysis-guided volume management or Vit D supplementation on LV mass among those receiving peritoneal dialysis is uncertain.

Study Design: Two-by-two factorial randomized controlled trial.

Setting & Participants: Sixty-five patients receiving chronic peritoneal dialysis.

Intervention: BIA-guided volume management versus usual care and oral cholecalciferol 50,000u weekly for 8 weeks followed by 10,000u weekly for 44 weeks or matching placebo.

Outcomes: Change in left ventricular mass at one-year measured by cardiac magnetic resonance imaging.

Results: Total body water decreased by 0.9L (standard deviation: 2.4) in the BIA group compared to a 1.5L (± 3.4) increase in the usual care group (adjusted between group difference: -2.4L [95% confidence interval: -4.1, -0.68], p=0.01). Left ventricular mass increased by 1.3g (± 14.3) in the BIA group and decreased by 2.4g (±37.7) in the usual care group (between group difference; +2.2g [-13.9, 18.3], p=0.78). Serum 25-OH Vit D concentration increased by a mean of 17.2 nmol/L (standard deviation: 30.8 nmol/L) in the cholecalciferol group and declined by 8.2 nmol/L (±24.3 nmol/L) in the placebo group (between group difference: 28.3 nmol/L [95% confidence interval 17.2, 39.4]; p<0.001). Left ventricular mass decreased by 3.0g (± 28.1g) in the cholecalciferol group and increased by 2.0g (±31.2g) in the placebo group (between group difference; -4.5g [-20.4, 11.5], p=0.58).

Limitations: Relatively small sample size with larger than expected variation in change in left ventricular mass.

Conclusions: BIA-guided volume management had a modest impact on volume status with no effect on the change in LV mass. Vitamin D supplementation increased serum Vit D concentration but had no effect on left ventricular mass.
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http://dx.doi.org/10.1053/j.ajkd.2021.08.022DOI Listing
October 2021

Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing.

Eur Urol Oncol 2021 Oct 12. Epub 2021 Oct 12.

Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: Despite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking.

Objective: To define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing.

Design, Setting, And Participants: We retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020.

Outcome Measurement And Statistical Analysis: The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher's exact or χ test).

Results And Limitations: Of 232 patients with early-onset RCC, 50% had non-clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non-RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non-clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non-RCC-associated genes was 0% and 9.9%, respectively.

Conclusions: Patients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing.

Patient Summary: In this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.
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http://dx.doi.org/10.1016/j.euo.2021.09.005DOI Listing
October 2021

MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Front Neurol 2021 9;12:722237. Epub 2021 Sep 9.

Menzies Health Institute Queensland, Gold Coast, Griffith University, Southport, QLD, Australia.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.
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http://dx.doi.org/10.3389/fneur.2021.722237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458658PMC
September 2021

Comparing accuracy of bedside ultrasound examination with physical examination for detection of pleural effusion.

Ultrasound J 2021 Sep 6;13(1):40. Epub 2021 Sep 6.

Division of General Internal Medicine, University of Calgary, Calgary, AB, Canada.

Background: In detecting pleural effusion, bedside ultrasound (US) has been shown to be more accurate than auscultation. However, US has not been previously compared to the comprehensive physical examination. This study seeks to compare the accuracy of physical examination with bedside US in detecting pleural effusion.

Methods: This study included a convenience sample of 34 medical inpatients from Calgary, Canada and Spokane, USA, with chest imaging performed within 24 h of recruitment. Imaging results served as the reference standard for pleural effusion. All patients underwent a comprehensive lung physical examination and a bedside US examination by two researchers blinded to the imaging results.

Results: Physical examination was less accurate than US (sensitivity of 44.0% [95% confidence interval (CI) 30.0-58.8%], specificity 88.9% (95% CI 65.3-98.6%), positive likelihood (LR) 3.96 (95% CI 1.03-15.18), negative LR 0.63 (95% CI 0.47-0.85) for physical examination; sensitivity 98% (95% CI 89.4-100%), specificity 94.4% (95% CI 72.7-99.9%), positive LR 17.6 (95% CI 2.6-118.6), negative LR 0.02 (95% CI 0.00-0.15) for US). The percentage of examinations rated with a confidence level of 4 or higher (out of 5) was higher for US (85% of the seated US examination and 94% of the supine US examination, compared to 35% of the PE, P < 0.001), and took less time to perform (P < 0.0001).

Conclusions: US examination for pleural effusion was more accurate than the physical examination, conferred higher confidence, and required less time to complete.
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http://dx.doi.org/10.1186/s13089-021-00241-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421481PMC
September 2021

MyTEMP: Statistical Analysis Plan of a Registry-Based, Cluster-Randomized Clinical Trial.

Can J Kidney Health Dis 2021 27;8:20543581211041182. Epub 2021 Aug 27.

ICES, London, ON, Canada.

Background: Major Outcomes with Personalized Dialysate TEMPerature (MyTEMP) is a 4-year cluster-randomized clinical trial comparing the effect of using a personalized, temperature-reduced dialysate protocol versus a dialysate temperature of 36.5°C on cardiovascular-related death and hospitalization. Randomization was performed at the level of the dialysis center ("the cluster").

Objective: The objective is to outline the statistical analysis plan for the MyTEMP trial.

Design: MyTEMP is a pragmatic, 2-arm, parallel-group, registry-based, open-label, cluster-randomized trial.

Setting: A total of 84 dialysis centers in Ontario, Canada.

Patients: Approximately 13 500 patients will have received in-center hemodialysis at the 84 participating dialysis centers during the trial period (April 3, 2017, to March 1, 2021, with a maximum follow-up to March 31, 2021).

Methods: Patient identification, baseline characteristics, and study outcomes will be obtained primarily through Ontario administrative health care databases held at ICES. Covariate-constrained randomization was used to allocate the 84 dialysis centers (1:1) to the intervention group or the control group. Centers in the intervention group used a personalized, temperature-reduced dialysate protocol, and centers in the control group used a fixed dialysate temperature of 36.5°C.

Outcomes: The primary outcome is a composite of cardiovascular-related death or major cardiovascular-related hospitalization (defined as a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke) recorded in administrative health care databases. The key secondary outcome is the mean drop in intradialytic systolic blood pressure, defined as the patients' predialysis systolic blood pressure minus their nadir systolic blood pressure during the dialysis treatment. Anonymized data on patients' predialysis and intradialytic systolic blood pressure were collected at monthly intervals from each dialysis center.

Analysis Plan: The primary analysis will follow an intent-to-treat approach. The primary outcome will be analyzed at the patient level as the hazard ratio of time-to-first event, estimated from a subdistribution hazards model. Within-center correlation will be accounted for using a robust sandwich estimator. In the primary analysis, patients' observation time will end if they experience the primary outcome, emigrate from Ontario, or die of a noncardiovascular cause (which will be treated as a competing risk event). The between-group difference in the mean drop in intradialytic systolic blood pressure obtained during the dialysis sessions throughout the trial period will be analyzed at the center level using an unadjusted random-effects linear mixed model.

Trial Status: The MyTEMP trial period is April 3, 2017, to March 31, 2021. We expect to analyze and report results by 2023 once the updated data are available at ICES.

Trial Registration: MyTEMP is registered with the US National Institutes of Health at clincaltrials.gov (NCT02628366).

Statistical Analytic Plan: Version 1.1 June 15, 2021.
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http://dx.doi.org/10.1177/20543581211041182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404662PMC
August 2021

Health reference intervals and values for common bottlenose dolphins (Tursiops truncatus), Indo-Pacific bottlenose dolphins (Tursiops aduncus), Pacific white-sided dolphins (Lagenorhynchus obliquidens), and beluga whales (Delphinapterus leucas).

PLoS One 2021 30;16(8):e0250332. Epub 2021 Aug 30.

Conservation Science and Animal Welfare Research, Chicago Zoological Society-Brookfield Zoo, Brookfield, IL, United States of America.

This study reports comprehensive clinical pathology data for hematology, serum, and plasma biochemistry reference intervals for 174 apparently healthy common bottlenose dolphins (Tursiops truncatus) and reference values for 27 Indo-Pacific bottlenose dolphins (Tursiops aduncus), 13 beluga whales (Delphinapterus leucas), and 6 Pacific white-sided dolphins (Lagenorhynchus obliquidens) in zoos and aquariums accredited by the Alliance for Marine Mammal Parks and Aquariums and the Association of Zoos & Aquariums. Blood samples were collected as part of a larger study titled "Towards understanding the welfare of cetaceans in zoos and aquariums" (colloquially called the Cetacean Welfare Study). Two blood samples were collected following a standardized protocol, and two veterinarian examinations were conducted approximately six months apart between July to November 2018 and January to April 2019. Least square means, standard deviations, and 95% confidence intervals were calculated for hematology, serum, and plasma biochemical variables. Comparisons by age, gender, and month revealed statistically significant differences (p < 0.01) for several variables. Reference intervals and values were generated for samples tested at two laboratories for up to 56 hematologic, serum, and plasma biochemical variables. To apply these data, ZooPhysioTrak, an iOS mobile software application, was developed to provide a new resource for cetacean management. ZooPhysioTrak provides species-specific reference intervals and values based on user inputs of individual demographic and sample information. These data provide a baseline from which to compare hematological, serum, and plasma biochemical values in cetaceans in zoos and aquariums.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250332PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405036PMC
August 2021

Reference intervals and values for fecal cortisol, aldosterone, and the ratio of cortisol to dehydroepiandrosterone metabolites in four species of cetaceans.

PLoS One 2021 30;16(8):e0250331. Epub 2021 Aug 30.

Biology Department, Portland State University, Portland, OR, United States of America.

The goal of the current study was to create reference intervals and values for several common and one potential novel physiological indicators of animal welfare for four species of cetaceans. The subjects included 189 bottlenose dolphins (Tursiops truncatus), 27 Indo-Pacific bottlenose dolphins (Tursiops aduncus), eight Pacific white-sided dolphins (Lagenorhynchus obliquidens), and 13 beluga whales (Delphinapterus leucas) at Alliance of Marine Mammal Parks and Aquariums and/or Association of Zoos and Aquariums accredited facilities. During two sampling time periods between July and November of 2018 and between January and April of 2019, fecal samples were collected weekly for five weeks from all animals. Samples were processed and analyzed using enzyme immunoassay for fecal cortisol, aldosterone, and dehydroepiandrosterone (DHEA) metabolites. Linear mixed models were used to examine demographic and time factors impacting hormone metabolite concentrations. Age, sex, and time of year were all significant predictors for some of the models (p < 0.01). An iOS mobile application ZooPhysioTrak was created for easy access to species-specific reference intervals and values accounting for significant predictors. For facilities without access to this application, additional reference intervals and values were constructed without accounting for significant predictors. Information gained from this study and the use of the application can provide reference intervals and values to make informed management decisions for cetaceans in zoological facilities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250331PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404979PMC
August 2021

Bottlenose dolphin habitat and management factors related to activity and distance traveled in zoos and aquariums.

PLoS One 2021 30;16(8):e0250687. Epub 2021 Aug 30.

Conservation Science and Animal Welfare Research, Chicago Zoological Society - Brookfield Zoo, Brookfield, Illinois, United States of America.

High-resolution non-invasive cetacean tagging systems can be used to investigate the influence of habitat characteristics and management factors on behavior by quantifying activity levels and distance traveled by bottlenose dolphins (Tursiops truncatus and Tursiops aduncus) in accredited zoos and aquariums. Movement Tags (MTags), a bio-logging device, were used to record a suite of kinematic and environmental information outside of formal training sessions as part of a larger study titled "Towards understanding the welfare of cetaceans in zoos and aquariums" (colloquially called the Cetacean Welfare Study). The purpose of the present study was to explore if and how habitat characteristics, environmental enrichment programs, and training programs were related to the distance traveled and energy expenditure of dolphins in accredited zoos and aquariums. Bottlenose dolphins in accredited zoos and aquariums wore MTags one day per week for two five-week data collection periods. Overall dynamic body acceleration (ODBA), a proxy for energy expenditure, and average distance traveled per hour (ADT) of 60 dolphins in 31 habitats were examined in relation to demographic, habitat, and management factors. Participating facilities were accredited by the Alliance for Marine Mammal Parks and/or Aquariums and the Association of Zoos & Aquariums. Two factors were found to be related to ADT while six factors were associated with ODBA. The results showed that enrichment programs were strongly related to both ODBA and ADT. Scheduling predictable training session times was also positively associated with ADT. The findings suggested that habitat characteristics had a relatively weak association with ODBA and were not related to ADT. In combination, the results suggested that management practices were more strongly related to activity levels than habitat characteristics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250687PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405030PMC
August 2021

Towards understanding the welfare of cetaceans in accredited zoos and aquariums.

PLoS One 2021 30;16(8):e0255506. Epub 2021 Aug 30.

Conservation Science and Animal Welfare Research, Chicago Zoological Society - Brookfield Zoo, Brookfield, Illinois, United States of America.

Cetaceans are long-lived, social species that are valued as ambassadors inspiring the public to engage in conservation action. Under professional care, they are critical partners with the scientific community to understanding the biology, behavior, physiology, health, and welfare requirements of this taxonomic group. The Cetacean Welfare Study was a highly collaborative research effort among zoos and aquariums accredited by the Alliance for Marine Mammal Parks and Aquariums and/or the Association of Zoos & Aquariums that provided important empirical and comparative information on the care and management of cetaceans. The goal was to identify factors that were related to the welfare of bottlenose dolphins and to develop reference intervals and values for common and novel indicators of health and welfare for common bottlenose dolphins (Tursiops truncatus), Indo-Pacific bottlenose dolphins (Tursiops aduncus), beluga whales (Delphinapterus leucas), and Pacific white-sided dolphins (Lagenorhynchus obliquidens). Data were collected from cetaceans at 43 accredited zoos and aquariums in seven countries in 2018 and 2019. This overview presents a summary of findings from the initial research articles that resulted from the study titled "Towards understanding the welfare of cetaceans in zoos and aquariums." With multiple related objectives, animal-based metrics were used to advance frameworks of clinical care and target key conditions that were associated with good welfare of cetaceans in zoo and aquarium environments. As a result of this collaboration, species-specific reference intervals and values for blood variables and fecal hormone metabolites were developed and are freely available in an iOS application called ZooPhysioTrak. The results suggested that environmental enrichment programs and social management factors were more strongly related to behaviors likely indicative of positive welfare than habitat characteristics for common and Indo-Pacific bottlenose dolphins. These findings can be widely applied to optimize care and future science-based welfare practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255506PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404978PMC
August 2021

Relationships between animal management and habitat characteristics with two potential indicators of welfare for bottlenose dolphins under professional care.

PLoS One 2021 30;16(8):e0252861. Epub 2021 Aug 30.

Institute for interdisciplinary Salivary Bioscience Research, University of California, Irvine, CA, United States of America.

Accredited zoos and aquariums continually strive to ensure high levels of animal welfare for the animals under their professional care. Best management practices include conducting research to better understand factors that lead to optimal welfare and then turning findings into practice. The current study is part of the larger Cetacean Welfare Study or more formally, "Towards understanding the welfare of cetaceans in zoos and aquariums." Facilities participating in the study were accredited by the Alliance of Marine Mammal Parks and Aquariums and/or the Association of Zoos and Aquariums. Animal management factors and habitat characteristics were examined in relation to two potential indicators of welfare for common (Tursiops truncatus) and Indo-Pacific (Tursiops aduncus) bottlenose dolphins. Specifically, we examined environmental enrichment, animal training, and habitat characteristics that were significantly related to behavioral diversity and route tracing, a form of stereotypic behavior. Behavior was recorded from 47 animals at 25 facilities around the world. Overall, the rate of route tracing behavior observed during the study was very low and few animal management factors or habitat characteristics were found to be related to this behavior. One factor, enrichment diversity, had a significant positive relationship with route tracing and an inverse relationship with behavioral diversity. This finding may be a product of a response mounted by animal care specialists to the behavior as opposed to a cause. Animals that engaged in this behavior were likely provided more diverse enrichment in attempts to ameliorate the stereotypic behavior. However, multiple factors were found to significantly relate to behavioral diversity, a potential positive indicator of welfare for bottlenose dolphins. Dolphins that were trained on a predictable schedule had higher behavioral diversity than those on a semi-predictable schedule. There was a positive significant relationship between behavioral diversity and the number of habitats to which an animal had access, and a significant inverse relationship with the maximum depth of the habitat. Finally, animals that were split into groups and reunited or rotated between subgroups had higher behavioral diversity than animals managed in the same group. Information gained from the current study suggested that animal management techniques may be more important in ensuring good welfare for bottlenose dolphins than focusing on habitat size.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252861PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405007PMC
August 2021

Assessment of animal management and habitat characteristics associated with social behavior in bottlenose dolphins across zoological facilities.

PLoS One 2021 30;16(8):e0253732. Epub 2021 Aug 30.

Institute for interdisciplinary Salivary Bioscience Research, University of California, Irvine, CA, United States of America.

Bottlenose dolphins are a behaviorally complex, social species that display a variety of social behaviors. Because of this, it is important for zoological facilities to strive to ensure animals display species-appropriate levels of social behavior. The current study is part of the multi-institutional study entitled "Towards understanding the welfare of cetaceans in zoos and aquariums" commonly referred to as the Cetacean Welfare Study. All participating facilities were accredited by the Alliance of Marine Mammal Parks and Aquariums and/or the Association of Zoos and Aquariums. Behavioral data were collected on 47 bottlenose dolphins representing two subspecies, Tursiops truncatus and Tursiops aduncus, at 25 facilities. The social behaviors of group related activity (group active) as well as interacting with conspecifics (interact with conspecific) were examined for their relationships to both animal management factors and habitat characteristics. The behavioral state of group active and the rate of interact with conspecific were both positively related to the frequency of receiving new forms of environmental enrichment. Both were inversely related to the random scheduling of environmental enrichment. Additional results suggested interact with conspecific was inversely related with daytime spatial experience and that males displayed group active more than females. Overall, the results suggested that animal management techniques such as the type and timing of enrichment may be more important to enhance social behavior than habitat characteristics or the size of the habitat. Information gained from this study can help facilities with bottlenose dolphins manage their enrichment programs in relation to social behaviors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253732PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405028PMC
August 2021

Behavioral diversity as a potential positive indicator of animal welfare in bottlenose dolphins.

PLoS One 2021 30;16(8):e0253113. Epub 2021 Aug 30.

Institute for Interdisciplinary Salivary Bioscience Research, University of California, Irvine, California, United States of America.

Accredited zoological facilities are committed to fully understanding the behavioral, mental, and physical needs of each species to continuously improve the welfare of the animals under their professional care and detect when welfare has diminished. In order to accomplish this goal, internally consistent and externally valid indicators of animal welfare are necessary to advance our understanding of the current welfare status of individual animals. Historically, efforts have focused on monitoring visible or observable signs of poor health or problem behavior, but lack of signs or problems does not necessarily demonstrate that an individual animal is thriving. The current study examined fecal hormone metabolite levels and behavior for two species of bottlenose dolphins (Tursiops truncatus and Tursiops aduncus) from 25 different accredited zoological facilities. At the time of the study, all facilities were accredited by the Alliance of Marine Mammal Parks and Aquariums and/or the Association of Zoos and Aquariums. This was part of the multi-institutional study 'Towards understanding of the welfare of cetaceans in zoos and aquariums" commonly referred to as the Cetacean Welfare Study. Behavioral diversity was calculated using the Shannon Diversity Index on species-appropriate behavioral events. Behavioral diversity was compared to the fecal metabolites of cortisol, aldosterone, and the ratio of cortisol to dehydroepiandrosterone (DHEA) as well as the stereotypic behavior of route tracing. Similar to previous studies on other species, there was a significant inverse relationship between behavioral diversity and both fecal cortisol metabolites and route tracing. Additionally, a significant inverse relationship also exists between behavioral diversity and the ratio of fecal cortisol to DHEA metabolites. Behavioral diversity and fecal aldosterone metabolites were not associated. Additional research is still needed to validate behavioral diversity as an indicator of positive animal welfare for bottlenose dolphins and across species. However, based on current results, facilities could utilize behavioral diversity combined with other measures of welfare to more comprehensively evaluate the welfare of bottlenose dolphins.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253113PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405024PMC
August 2021

Habitat characteristics and animal management factors associated with habitat use by bottlenose dolphins in zoological environments.

PLoS One 2021 30;16(8):e0252010. Epub 2021 Aug 30.

Conservation Science and Animal Welfare Research, Chicago Zoological Society-Brookfield Zoo, Brookfield, IL, United States of America.

The way an animal uses its habitat can serve as an indicator of habitat appropriateness for the species and individuals. Bottlenose dolphins (Tursiops truncatus and Tursiops aduncus) in accredited zoos and aquariums experience a range of habitat types and management programs that provide opportunities for dolphins to engage in species-appropriate behaviors and potentially influence their individual and group welfare. Data in the present study were collected as part of a larger study titled "Towards understanding the welfare of cetaceans in zoos and aquariums" (colloquially called the Cetacean Welfare Study). Non-invasive bio-logging devices (Movement Tags) recorded the diving behavior and vertical habitat movements of 60 bottlenose dolphins at 31 zoos and aquariums that were accredited by the Alliance for Marine Mammal Parks and Aquariums and/or the Association of Zoos & Aquariums. Bottlenose dolphins wore a Movement Tag one day per week for two five-week data collection periods. Demographic variables, environmental enrichment programs, training programs, and habitat characteristics were associated with habitat usage. Longer dive durations and use of the bottom third of the habitat were associated with higher enrichment program index values. Dolphins receiving new enrichment on a monthly/weekly schedule also used the bottom third of the habitat more often than those receiving new enrichment on a yearly/year+ schedule. Dolphins that were managed in a group that was split into smaller subgroups during the day and were reunited into one group at night spent less time in the top third of the habitat than those who remained in a single group with consistent members at all times. Dolphins that were managed as subgroups with rotating members but were never united as one group spent less time in the bottom third of the habitat than those who remained in a single group with consistent members at all times. Taken together, the results suggested that management practices, such as enrichment and training programs, played a greater role in how dolphins interacted with their environment relative to the physical characteristics of the habitat.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252010PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404980PMC
August 2021

Environmental enrichment, training, and habitat characteristics of common bottlenose dolphins (Tursiops truncatus) and Indo-Pacific bottlenose dolphins (Tursiops aduncus).

PLoS One 2021 30;16(8):e0253688. Epub 2021 Aug 30.

Conservation Science and Animal Welfare Research, Chicago Zoological Society - Brookfield Zoo, Brookfield, Illinois, United States of America.

In recent decades, animal welfare science has evolved to utilize a multidisciplinary approach to assess the welfare of animals in accredited zoos and aquariums. Science-based animal welfare assessments have become an essential component of management programs and widespread application is expected by animal care professionals. Management practices for bottlenose dolphins in accredited facilities incorporate several programs that potentially impact animal welfare including environmental enrichment and animal training. Additionally, habitat characteristics, such as the dimensions of the habitat, have been proposed to affect welfare. While accredited facilities are required to meet high standards of care, habitat characteristics and management practices are not standardized across locations. Knowledge and subsequent application of these practices and habitat characteristics can enhance our understanding of factors associated with positive welfare. As part of a larger study of dolphin welfare titled "Towards understanding the welfare of cetaceans in zoos and aquariums" (colloquially called the Cetacean Welfare Study), survey data were collected from 86 bottlenose dolphins in 40 habitats at 38 facilities in seven countries. The major aims of this paper are to provide general descriptive information regarding dolphin management in accredited zoos and aquariums and to provide supplemental context to the other research published from the Cetacean Welfare Study data set. This paper provides a review of current habitat characteristics and management practices at those 38 accredited zoos and aquariums. These data enabled the identification and quantification of how cetacean management practices differed between participating facilities accredited by the Alliance for Marine Mammal Parks and Aquariums and the Association of Zoos & Aquariums. Variables were selected based on their potential association with welfare including the physical habitat, environmental enrichment, and training programs. The variables were also used for subsequent research in this collection of related papers to investigate important connections between potential indicators of welfare and habitat characteristics, environmental enrichment, and training programs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253688PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404999PMC
August 2021

The Remarkable Journey of a Weed: Biology and Management of Annual Ryegrass () in Conservation Cropping Systems of Australia.

Plants (Basel) 2021 Jul 22;10(8). Epub 2021 Jul 22.

Weed Research Unit, The University of Sydney, Camden, NSW 2570, Australia.

Annual ryegrass ( Gaud.), traditionally utilised as a pasture species, has become the most problematic and difficult-to-control weed across grain production regions in Australia. Annual ryegrass has been favoured by the adoption of conservation tillage systems due to its genetic diversity, prolific seed production, widespread dispersal, flexible germination requirements and competitive growth habit. The widespread evolution of herbicide resistance in annual ryegrass has made its management within these systems extremely difficult. The negative impacts of this weed on grain production systems result in annual revenue losses exceeding $93 million (AUD) for Australian grain growers. No single method of management provides effective and enduring control hence the need of integrated weed management programs is widely accepted and practiced in Australian cropping. Although annual ryegrass is an extensively researched weed, a comprehensive review of the biology and management of this weed in conservation cropping systems has not been conducted. This review presents an up-to-date account of knowledge on the biology, ecology and management of annual ryegrass in an Australian context. This comprehensive account provides pragmatic information for further research and suitable management of annual ryegrass.
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http://dx.doi.org/10.3390/plants10081505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400064PMC
July 2021

Low mammalian species richness is associated with Kyasanur Forest disease outbreak risk in deforested landscapes in the Western Ghats, India.

One Health 2021 Dec 5;13:100299. Epub 2021 Aug 5.

Department of Microbiology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India.

Kyasanur forest disease virus (KFDV) is a rapidly expanding tick-borne zoonotic virus with natural foci in the forested region of the Western Ghats of South India. The Western Ghats is one of the world's most important biodiversity hotspots and, like many such areas of high biodiversity, is under significant pressure from anthropogenic landscape change. The current study sought to quantify mammalian species richness using ensemble models of the distributions of a sample of species extant in the Western Ghats and to explore its association with KFDV outbreaks, as well as the modifying effects of deforestation on this association. Species richness was quantified as a composite of individual species' distributions, as derived from ensembles of boosted regression tree, random forest, and generalised additive models. Species richness was further adjusted for the potential biotic constraints of sympatric species. Both species richness and forest loss demonstrated strong positive associations with KFDV outbreaks, however forest loss substantially modified the association between species richness and outbreaks. High species richness was associated with increased KFDV risk but only in areas of low forest loss. In contrast, lower species richness was associated with increased KFDV risk in areas of greater forest loss. This relationship persisted when species richness was adjusted for biotic constraints at the taluk-level. In addition, the taluk-level species abundances of three monkey species (, , and ) were also associated with outbreaks. These results suggest that increased monitoring of wildlife in areas of significant habitat fragmentation may add considerably to critical knowledge gaps in KFDV epidemiology and infection ecology and should be incorporated into novel One Health surveillance development for the region. In addition, the inclusion of some primate species as sentinels of KFDV circulation into general wildlife surveillance architecture may add further value.
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http://dx.doi.org/10.1016/j.onehlt.2021.100299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367838PMC
December 2021

Wilms Tumor (Nephroblastoma), Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2021 08 1;19(8):945-977. Epub 2021 Aug 1.

National Comprehensive Cancer Network.

The NCCN Guidelines for Wilms Tumor focus on the screening, diagnosis, staging, treatment, and management of Wilms tumor (WT, also known as nephroblastoma). WT is the most common primary renal tumor in children. Five-year survival is more than 90% for children with all stages of favorable histology WT who receive appropriate treatment. All patients with WT should be managed by a multidisciplinary team with experience in managing renal tumors; consulting a pediatric oncologist is strongly encouraged. Treatment of WT includes surgery, neoadjuvant or adjuvant chemotherapy, and radiation therapy (RT) if needed. Careful use of available therapies is necessary to maximize cure and minimize long-term toxicities. This article discusses the NCCN Guidelines recommendations for favorable histology WT.
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http://dx.doi.org/10.6004/jnccn.2021.0037DOI Listing
August 2021

Improvement of kidney function in patients with chronic kidney disease and severe obesity after bariatric surgery: A systematic review and meta-analysis.

Nephrology (Carlton) 2021 Aug 10. Epub 2021 Aug 10.

Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada.

The general management for chronic kidney disease (CKD) includes treating reversible causes, including obesity, which may be both a driver and comorbidity for CKD. Bariatric surgery has been shown to reduce the likelihood of CKD progression and improve kidney function in observational studies. We performed a systematic review and meta-analysis of patients with at least stage 3 CKD and obesity receiving bariatric surgery. We searched Embase, MEDLINE, CENTRAL and identified eligible studies reporting on kidney function outcomes in included patients before and after bariatric surgery with comparison to a medical intervention control if available. Risk of bias was assessed with the Newcastle-Ottawa Risk of Bias score. Nineteen studies were included for synthesis. Bariatric surgery showed improved eGFR with a mean difference (MD) of 11.64 (95%CI: 5.84 to 17.45, I  = 66%) ml/min/1.73m and reduced SCr with MD of -0.24 (95%CI -0.21 to -0.39, I  = 0%) mg/dl after bariatric surgery. There was no significant difference in the relative risk (RR) of having CKD stage 3 after bariatric surgery, with a RR of -1.13 (95%CI: -0.83 to -2.07, I  = 13%), but there was reduced likelihood of having uACR >30 mg/g or above with a RR of -3.03 (95%CI: -1.44 to -6.40, I  = 91%). Bariatric surgery may be associated with improved kidney function with the reduction of BMI and may be a safe treatment option for patients with CKD. Future studies with more robust reporting are required to determine the feasibility of bariatric surgery for the treatment of CKD.
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http://dx.doi.org/10.1111/nep.13958DOI Listing
August 2021

Discharging select patients without an escort after ambulatory anesthesia: identifying return to baseline function.

Authors:
Michael T Walsh

Curr Opin Anaesthesiol 2021 Aug 6. Epub 2021 Aug 6.

Mayo Clinic, Department of Anesthesiology and Perioperative Medicine, Rochester, Minnesota, USA.

Purpose Of Review: The current standard of care requires ambulatory surgical patients to have an escort for discharge. Recent studies have started to challenge this dogma. Modern ultrashort acting anesthetics have minimal psychomotor effects after a couple of hours. Driving simulator performance and psychomotor testing return to baseline as soon as 1 h following propofol sedation.

Recent Findings: Two recent reports of actual experience with thousands of patients found no increase in complications in patients who were discharged without escort or drove themselves from a sedation center. These studies suggest discharge without escort may be safe in select patients but a method to identify appropriate patients remains undefined.

Summary: A reliable test to document return of function might allow safe discharge without an escort. Currently, there is intense interest in developing reliable, inexpensive, easy to administer psychomotor function testing to improve workplace safety and legally define the effects of drugs on driving impairment. Future studies may be able to adapt this technology and develop a validated test for residual anesthetic impairment.
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http://dx.doi.org/10.1097/ACO.0000000000001051DOI Listing
August 2021

Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.

Nat Cancer 2021 Mar 15;2:357-365. Epub 2021 Feb 15.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, New York, 10065, USA.

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.
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http://dx.doi.org/10.1038/s43018-021-00172-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294573PMC
March 2021

Incidence and Outcomes of Acute Kidney Injury in Patients Admitted to Hospital With COVID-19: A Retrospective Cohort Study.

Can J Kidney Health Dis 2021 11;8:20543581211027759. Epub 2021 Jul 11.

Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.

Background: The incidence of acute kidney injury (AKI) in patients with COVID-19 and its association with mortality and disease severity is understudied in the Canadian population.

Objective: To determine the incidence of AKI in a cohort of patients with COVID-19 admitted to medicine and intensive care unit (ICU) wards, its association with in-hospital mortality, and disease severity. Our aim was to stratify these outcomes by out-of-hospital AKI and in-hospital AKI.

Design: Retrospective cohort study from a registry of patients with COVID-19.

Setting: Three community and 3 academic hospitals.

Patients: A total of 815 patients admitted to hospital with COVID-19 between March 4, 2020, and April 23, 2021.

Measurements: Stage of AKI, ICU admission, mechanical ventilation, and in-hospital mortality.

Methods: We classified AKI by comparing highest to lowest recorded serum creatinine in hospital and staged AKI based on the Kidney Disease: Improving Global Outcomes (KDIGO) system. We calculated the unadjusted and adjusted odds ratio for the stage of AKI and the outcomes of ICU admission, mechanical ventilation, and in-hospital mortality.

Results: Of the 815 patients registered, 439 (53.9%) developed AKI, 253 (57.6%) presented with AKI, and 186 (42.4%) developed AKI in-hospital. The odds of ICU admission, mechanical ventilation, and death increased as the AKI stage worsened. Stage 3 AKI that occurred during hospitalization increased the odds of death (odds ratio [OR] = 7.87 [4.35, 14.23]). Stage 3 AKI that occurred prior to hospitalization carried an increased odds of death (OR = 5.28 [2.60, 10.73]).

Limitations: Observational study with small sample size limits precision of estimates. Lack of nonhospitalized patients with COVID-19 and hospitalized patients without COVID-19 as controls limits causal inferences.

Conclusions: Acute kidney injury, whether it occurs prior to or after hospitalization, is associated with a high risk of poor outcomes in patients with COVID-19. Routine assessment of kidney function in patients with COVID-19 may improve risk stratification.

Trial Registration: The study was not registered on a publicly accessible registry because it did not involve any health care intervention on human participants.
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http://dx.doi.org/10.1177/20543581211027759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278450PMC
July 2021

Mapping the Edmonton Symptom Assessment System-Revised: Renal to the EQ-5D-5L in patients with chronic kidney disease.

Qual Life Res 2021 Jul 19. Epub 2021 Jul 19.

School of Public Health, University of Alberta, Edmonton, AB, Canada.

Purpose: The Edmonton Symptom Assessment System-Revised: Renal (ESAS-r: Renal) is a disease-specific patient-reported outcome measure (PROM) that assesses symptoms common in chronic kidney disease (CKD). There is no preference-based scoring system for the ESAS-r: Renal or a mapping algorithm to predict health utility values. We aimed to develop a mapping algorithm from the ESAS-r: Renal to the Canadian EQ-5D-5L index scores.

Methods: We used data from a multi-centre cluster randomized-controlled trial of the routine measurement and reporting of PROMs in hemodialysis units in Northern Alberta, Canada. In two arms of the trial, both the ESAS-r: Renal and the EQ-5D-5L were administered to CKD patients undergoing hemodialysis. We used data from one arm for model estimation, and data from the other for validation. We explored direct and indirect mapping models; model selection was based on statistical fit and predictive power.

Results: Complete data were available for 506 patient records in the estimation sample and 242 in the validation sample. All models tended to perform better in patients with good health, and worse in those with poor health. Generalized estimating equations (GEE) and generalized linear model (GLM) on selected ESAS-r: Renal items were selected as final models as they fitted the best in estimation and validation sample.

Conclusion: When only ESAS-r: Renal data are available, one could use GEE and GLM to predict EQ-5D-5L index scores for use in economic evaluation. External validation on populations with different characteristics is warranted, especially where renal-specific symptoms are more prevalent.
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http://dx.doi.org/10.1007/s11136-021-02948-5DOI Listing
July 2021

Genetic syndromes predisposing to pediatric brain tumors.

Neurooncol Pract 2021 Aug 13;8(4):375-390. Epub 2021 Feb 13.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

The application of high-throughput sequencing approaches including paired tumor/normal sampling with therapeutic intent has demonstrated that 8%-19% of pediatric CNS tumor patients harbor a germline alteration in a classical tumor predisposition gene (, ). In addition, large-scale germline sequencing studies in unselected cohorts of pediatric neuro-oncology patients have demonstrated novel candidate tumor predisposition genes ( alterations in sonic hedgehog medulloblastoma). Therefore, the possibility of an underlying tumor predisposition syndrome (TPS) should be considered in all pediatric patients diagnosed with a CNS tumor which carries critical implications including accurate prognostication, selection of optimal therapy, screening, risk reduction, and family planning. The Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) recently published consensus screening recommendations for children with the most common TPS. In this review, we provide an overview of the most relevant as well as recently identified TPS associated with the most frequently encountered pediatric CNS tumors with an emphasis on pathogenesis, genetic testing, clinical features, and treatment implications.
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http://dx.doi.org/10.1093/nop/npab012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278355PMC
August 2021

Prevalence and Characterization of Biallelic and Monoallelic and Variant Carriers From a Pan-Cancer Patient Population.

JCO Precis Oncol 2021 26;5. Epub 2021 Feb 26.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.

and have been implicated as autosomal recessive cancer predisposition genes. Although individuals with biallelic and pathogenic variants (PVs) have increased cancer and polyposis risk, risks for monoallelic carriers are uncertain. We sought to assess the prevalence and characterize and from a large pan-cancer patient population.

Materials And Methods: Patients with pan-cancer (n = 11,081) underwent matched tumor-normal sequencing with consent for germline analysis. Medical records and tumors were reviewed and analyzed. Prevalence of PVs was compared with reference controls (Genome Aggregation Database).

Results: -PVs were identified in 40 patients including 39 monoallelic carriers (39/11,081 = 0.35%) and one with biallelic variants (1/11,081 = 0.009%) and a diagnosis of isolated early-onset breast cancer. -associated mutational signature 30 was identified in the tumors of the biallelic patient and two carriers. Colonic polyposis was not identified in any patient. -PVs were identified in 13 patients, including 12 monoallelic carriers (12/11,081 = 0.11%) and one with biallelic variants (1/11,081 = 0.009%) and diagnoses of later-onset cancers, attenuated polyposis, and abnormal MSH3-protein expression. Of the 12 carriers, two had early-onset cancer diagnoses with tumor loss of heterozygosity of the wild-type allele. Ancestry-specific burden tests demonstrated that and prevalence was not significantly different in this pan-cancer population versus controls.

Conclusion: and germline alterations were not enriched in this pan-cancer patient population. However, tumor-specific findings, such as mutational signature 30 and loss of heterozygosity of the wild-type allele, suggest the potential contribution of monoallelic variants to tumorigenesis in a subset of patients.
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http://dx.doi.org/10.1200/PO.20.00443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232072PMC
February 2021

Paired Tumor-Normal Sequencing Provides Insights into TP53-Related Cancer Spectrum in Li-Fraumeni Patients.

J Natl Cancer Inst 2021 Jul 7. Epub 2021 Jul 7.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.

Background: Li-Fraumeni syndrome (LFS) genetic testing is performed using blood specimens from patients selected based on phenotype-dependent guidelines. This approach is problematic for understanding LFS clinical spectrum, because patients with non-classical presentations are missed, clonal hematopoiesis (CH)-related somatic blood mutations cannot be distinguished from germline variants, and unrelated tumors cannot be differentiated from those driven by germline TP53 defects.

Methods: To provide insights into LFS-related cancer spectrum, we analyzed paired tumor-blood DNA sequencing results in 17,922 cancer patients, and distinguished CH-related, mosaic, and germline TP53 variants. Loss-of-heterozygosity (LOH) and TP53 mutational status were assessed in tumors, followed by immunohistochemistry for p53 expression on a subset to identify those lacking biallelic TP53 inactivation.

Results: Pathogenic/likely pathogenic TP53 variants were identified in 50 patients, 12 (24.0%) of which were CH-related and four (8.0%) were mosaic. Twelve (35.3%) of 34 patients with germline TP53 variants did not meet LFS testing criteria. LOH of germline TP53 variant was observed in 96.0% (95% CI = 79.7-99.9%) of core LFS-spectrum type tumors versus 45.5% (95% CI = 16.8-76.6%) of other tumors, and 91.3% (95% CI = 72.0-98.9%) of tumors from patients who met LFS testing criteria versus 61.5% (95% CI = 31.6-86.1%) of tumors from patients who did not. Tumors retaining wild-type TP53 allele exhibited wild-type p53 expression.

Conclusions: Our results indicate that some TP53 variants identified in blood-only sequencing are not germline and a substantial proportion of LFS patients are missed by current testing guidelines. Additionally, a subset of tumors from LFS patients do not have biallelic TP53 inactivation and may represent cancers unrelated to their germline TP53 defect.
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http://dx.doi.org/10.1093/jnci/djab117DOI Listing
July 2021

Azole-resistant Aspergillus fumigatus is highly prevalent in the environment of Vietnam, with marked variability by land use type.

Environ Microbiol 2021 Jul 7. Epub 2021 Jul 7.

Faculty of Medicine and Health, The University of Sydney, Sydney, 2145, Australia.

Azole-resistant environmental Aspergillus fumigatus presents a threat to public health but the extent of this threat in Southeast Asia is poorly described. We conducted environmental surveillance in the Mekong Delta region of Vietnam, collecting air and ground samples across key land-use types, and determined antifungal susceptibilities of Aspergillus section Fumigati (ASF) isolates and azole concentrations in soils. Of 119 ASF isolates, 55% were resistant (or non-wild type) to itraconazole, 65% to posaconazole and 50% to voriconazole. Azole resistance was more frequent in A. fumigatus sensu stricto isolates (95%) than other ASF species (32%). Resistant isolates and agricultural azole residues were overrepresented in samples from cultivated land. cyp51A gene sequence analysis showed 38/56 resistant A. fumigatus sensu stricto isolates carried known resistance mutations, with TR /L98H most frequent (34/38).
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http://dx.doi.org/10.1111/1462-2920.15660DOI Listing
July 2021

Seed Shattering: A Trait of Evolutionary Importance in Plants.

Front Plant Sci 2021 16;12:657773. Epub 2021 Jun 16.

Department of Soil and Crop Sciences, Texas A&M University, College Station, TX, United States.

Seed shattering refers to the natural shedding of seeds when they ripe, a phenomenon typically observed in wild and weedy plant species. The timing and extent of this phenomenon varies considerably among plant species. Seed shattering is primarily a genetically controlled trait; however, it is significantly influenced by environmental conditions, management practices and their interactions, especially in agro-ecosystems. This trait is undesirable in domesticated crops where consistent efforts have been made to minimize it through conventional and molecular breeding approaches. However, this evolutionary trait serves as an important fitness and survival mechanism for most weeds that utilize it to ensure efficient dispersal of their seeds, paving the way for persistent soil seedbank development and sustained future populations. Weeds have continuously evolved variations in seed shattering as an adaptation under changing management regimes. High seed retention is common in many cropping weeds where weed maturity coincides with crop harvest, facilitating seed dispersal through harvesting operations, though some weeds have notoriously high seed shattering before crop harvest. However, high seed retention in some of the most problematic agricultural weed species such as annual ryegrass (), wild radish (), and weedy amaranths (s spp.) provides an opportunity to implement innovative weed management approaches such as harvest weed seed control, which aims at capturing and destroying weed seeds retained at crop harvest. The integration of such management options with other practices is important to avoid the rapid evolution of high seed shattering in target weed species. Advances in genetics and molecular biology have shown promise for reducing seed shattering in important crops, which could be exploited for manipulating seed shattering in weed species. Future research should focus on developing a better understanding of various seed shattering mechanisms in plants in relation to changing climatic and management regimes.
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http://dx.doi.org/10.3389/fpls.2021.657773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248667PMC
June 2021

The WISHED Randomized Controlled Trial: Impact of an Interactive Health Communication Application on Home Dialysis Use in People With Chronic Kidney Disease.

Can J Kidney Health Dis 2021 4;8:20543581211019631. Epub 2021 Jun 4.

Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON, Canada.

Background: While home dialysis therapies are more cost effective and may offer improved health-related quality of life, uptake compared to in-center hemodialysis remains low.

Objective: To test whether a web-based interactive health communication application (IHCA) compared to usual care would increase home dialysis use.

Design: Randomized control trial.

Setting: Patients were recruited from 3 multidisciplinary kidney clinics across Ontario, Canada (Hamilton, Kingston, London).

Patients: We included adults with advanced chronic kidney disease (CKD) followed in multidisciplinary kidney clinics. Patients who had not completed dialysis modality education, who did not have access to a home computer or the internet, who had significant hearing or vision impairment, who could not read/write/speak English, who had a medical contraindication for home dialysis, or who had selected conservative kidney care were excluded.

Measurements: The primary outcome was any use of home dialysis (peritoneal dialysis or home hemodialysis) within 90 days of dialysis initiation. Secondary outcomes were social support, decision conflict and dialysis knowledge measured at baseline, 6 months and 1 year.

Methods: Eligible patients were randomized to either usual care or the IHCA in addition to usual care in a 1:1 ratio. As part of usual care, all patients received education about dialysis modalities and kidney transplantation delivered by clinic nurses according to local practices. Randomization was performed using a computer-generated sequence in randomly permuted block sizes, stratified by site, and allocation occurred using sequentially numbered sealed, opaque envelopes. Participants, care providers, and outcome assessors were not blinded to the intervention. All analyses were performed blinded using an intention to treat approach. We estimated the effect of the ICHA on the odds of the primary outcome using unadjusted logistic regression models. Linear mixed models for repeated measures over time were used to analyze the impact of the IHCA on the secondary outcomes of interest.

Results: We randomized 140 (usual care, n = 71; IHCA, n = 69) out of a planned 264 patients (mean [SD] age 61 [14.5] years, 65% men). Among patients randomized to the IHCA group that completed 6-month and 1-year follow-up visits, 56.8% and 71.4%, respectively, had not accessed the IHCA website within the past month. There were 23 (32.4%) and 26 (37.7%) patients in the usual care and IHCA groups who received a home dialysis therapy within 90 days of dialysis initiation (odds ratio, OR = 1.3, 95% CI = [0.6-2.5], = .5). Among the 78 patients who initiated dialysis (n = 38 usual care, n = 40 IHCA), 60.5% and 65% in the usual care and IHCA groups received a home therapy within 90 days of dialysis initiation (OR = 1.2, 95% CI = [0.5-3.0], = .7). Secondary outcomes did not differ by intervention group over time.

Limitations: The trial was underpowered due to poor recruitment and use of the IHCA was low.

Conclusions: We did not find evidence of a difference in home dialysis uptake with IHCA use, but our analyses were notably underpowered. The incorporation of greater patient engagement, qualitative research and design research, and pilot implementation may help future evaluations of strategies to improve home dialysis uptake.

Trial Registration: NCT01403454, registration date: Jul 21, 2011.
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http://dx.doi.org/10.1177/20543581211019631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182179PMC
June 2021
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