The pre-transplant evaluation: Considerations for trainees and early career transplant infectious diseases clinician.

Transplant infectious disease (TID) clinicians are integral to the pre-transplantation evaluation. Pre-transplant evaluations allow clinicians to assess risk factors for latent infections and relevant exposures to potential pathogens, address immunizations, and optimize patients' health and understanding of life after transplant. However, there is not a standardized approach to the pre-transplant evaluation. This article reviews the details of performing successful pre-transplant evaluations, including updated recommendations on available vaccines and contemporary opinions on marijuana use. This resource can be used for teaching with trainees or for early career TID clinicians.

Psychosocial burden after the death of a child from cancer: Results of a bereaved parent survey.

Parents experience lasting psychological distress after a child's death from cancer. Limited evidence exists regarding difficult life events, duration of psychosocial impacts, and associated risk factors among bereaved parents. Alex's Lemonade Stand Foundation surveyed self-selected, bereaved parents regarding difficult life events and psychosocial wellbeing (life satisfaction, unanswered questions, and missing the care team) through a public, cross-sectional survey. 176 bereaved parents (89% mothers) participated a median of 7 y after their child's death. The most difficult events were family vacations (80%), their child's birthday (80%), and anniversary of their child's death (76%). Only the latter did not improve with time. Greater life satisfaction was associated with male sex (ARR = 1.2, 95% CI:1.1-1.4) and being married/partnered (ARR = 1.2, 95% CI = 1.0-1.3). Having unanswered questions and missing the child's team were associated with annual income <$50,000 (ARR = 1.2, 95% CI:1.1-1.2; ARR = 1.2, 95% CI:1.0-1.3, respectively). Pediatric oncology programs need robust bereavement programs that include prolonged contact with families.

SARS-CoV-2 Polymerase Chain Reaction Cycle Threshold Trends in Patients Who Are Immunocompromised and Implications for Isolation Precautions.

Among 495 patients who were immunocompromised and tested positive for SARS-CoV-2, polymerase chain reaction cycle thresholds remained <33 beyond 20 days more frequently in patients with hematologic malignancies, particularly those receiving B-cell-depleting or Bruton tyrosine kinase inhibitor therapy, as compared with those with solid organ malignancy (26% vs 5%).

Do All Postoperative Vancouver B2 Fractures Require Revision Arthroplasty With Cementless Stems?

Background: Management of periprosthetic fractures has been guided by the Vancouver classification, which recommends revision for fractures around a loose femoral implant (B2). New studies have challenged this approach, demonstrating acceptable outcomes with internal fixation. This study evaluates our experience with Vancouver B2 fractures, comparing internal fixation to femoral revision. We hypothesized that in select cases with cementless stems, internal fixation would provide acceptable results with reduced morbidity. Methods: A retrospective review was performed of periprosthetic hip fractures treated at our institution between 1 January 2012 and 4 November 2022. We excluded patients who did not have prior radiographs and evidence of stem subsidence, suggestive of a Vancouver B2 fracture. Thirteen patients were included in the analysis. Results: Four patients (31%) underwent revision of the femoral component, 4 patients (31%) underwent plating, and 5 patients (38%) underwent internal fixation with cerclage cabling. The average operative duration was 158 minutes, 203 minutes, and 62 minutes for the revision, plating, and cabling cohorts, respectively (P = .009). Blood loss was 463 cc, 510 cc, and 90 cc for the revision, plating, and cabling cohorts, respectively (P = .036). Three patients in both the revision and plating cohorts each received a transfusion (75%), whereas no patients in the cabling cohort required a transfusion (P = .033). All patients demonstrated fracture healing on the postoperative radiographs. No patients required additional surgery during the follow-up period. Conclusions: We have demonstrated that Vancouver B2 periprosthetic fractures with intact lateral cortices may be treated with internal fixation with cerclage cabling with excellent results.

Insights into Brominated Flame Retardant Neurotoxicity: Mechanisms of Hippocampal Neural Cell Death and Brain Region-Specific Transcriptomic Shifts in Mice.

Brominated Flame Retardants (BFRs) reduce flammability in a wide range of products including electronics, carpets, and paint, but leach into the environment to result in continuous, population-level exposure. Epidemiology studies have correlated BFR exposure with neurological problems, including alterations in learning and memory. This study investigated the molecular mechanisms mediating BFR-induced cell death in hippocampal cells and clarified the impact of HBCD exposure on gene transcription in the hippocampus, dorsal striatum, and frontal cortex of male mice. Exposure of hippocampus derived HT-22 cells to various flame retardants, including tetrabromobisphenol-A (TBBPA, current use), hexabromocyclododecane (HBCD, phasing out), or 2,2',4,4'-tetrabromodiphenyl ether (BDE-47, phased out) resulted in time, concentration, and chemical-dependent cellular and nuclear morphology alterations, alterations in cell cycle and increases in annexin V staining. All three BFRs increased p53 and p21 expression; however, inhibition of p53 nuclear translocation using pifthrin-α did not decrease cell death. Transcriptomic analysis upon low (10 nM) and cytotoxic (10 µM) BFR exposure indicated that HBCD and BDE-47 altered genes mediating autophagy-related pathways. Further evaluation showed BFR exposure increased LC3-II conversion and autophagosome formation, and co-exposure with the autophagy inhibitor 3-methyladenine (3-MA) attenuated cytotoxicity. Transcriptomic assessment of select brain regions from subchronically HBCD-exposed male mice demonstrated alteration of genes mediating vesicular transport, with greater impact on the frontal cortex and dorsal striatum compared to the dorsal and ventral hippocampus. Immunoblot analysis demonstrated no increases in cell death or autophagy markers, but did demonstrate increases in the SNARE binding complex SNAP29, specifically in the dorsal hippocampus. These data demonstrate that BFRs can induce chemical-dependent autophagy in neural cells in vitro and provide evidence that BFRs induce region-specific transcriptomic and protein expression in the brain suggestive of change in vesicular trafficking.

A decision methodology for site-level ecosystem accounting.

The United Nations System of Environmental-Economic Accounting Ecosystem Accounting (SEEA EA) framework is the international standard for ecosystem accounting. To date, application of SEEA EA has been predominantly at large scales, usually at landscape and national levels. However, many environmental management decisions are taken locally, in site-specific contexts. While the use of SEEA EA continues to develop at all scales, there is currently no widely endorsed methodology for employing SEEA EA at local scales, such as the site level. We present a methodology for developing site-level ecosystem accounts, describing the important decisions at each step of the process. We also provide two case studies that demonstrate the context-dependent nature of the decision-making process of ecosystem accounting at small scales. The two major challenges for site-level accounting are stakeholder engagement and data availability. As the use of SEEA EA continues to increase in policy and decision-making processes worldwide, there is a need for local-scale case studies that adapt this methodology across a broad range of contexts. Our case studies provide some of the first published examples of the application of SEEA EA at the site level and are intended to promote consistent implementation of ecosystem accounting across scales.

The effects of socioeconomic status on complex ventral hernia repair operative decision-making and outcomes.

BACKGROUND: Patients from low socioeconomic backgrounds have greater rates of morbidity and mortality across disease processes. The Distressed Communities Index identified several socioeconomic components that were used to create a Distressed Communities Index score for every ZIP code, then broken into quintiles from prosperous to distressed. We aimed to explore whether socioeconomic distress as defined by the Distressed Communities Index affects the outcome of complex ventral hernia repair in the elderly population. METHODS: Retrospective analysis was performed using the Abdominal Core Health Collaborative data. Included were adults aged 65+ years undergoing elective complex ventral hernia repair from 2013 to 2021. Primary outcomes were postoperative outcomes and composite hernia recurrence by Distressed Communities Index quintile. The Cox proportional hazards model was used for composite recurrence, and logistic regression was used for postoperative outcomes. RESULTS: A total of 4,172 patients were included. Patients in distressed communities were more likely to identify as female or racial minority and had greater body mass index and American Society of Anesthesiologists class. Lower Distressed Communities Index quintile was associated with larger hernia (P = .012), open repair (P = .019), and 30-day complication (P = .05). There was no association between time to recurrence and Distressed Communities Index quintile (P = .24). After adjusted analysis, there was no significant difference for readmission, reoperation, recurrence, and complications. CONCLUSION: Patients from more distressed communities presented in worse clinical status with larger hernias. This likely contributed to greater rates of open repair and complications. However, when adjusted for these variables, outcomes were similar across Distressed Communities Index quintile. This supports the efficacy of complex hernia repair across socioeconomic classes.

Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells.

OBJECTIVES: Mutations in Tissue Inhibitor of Metalloproteinases 3 (TIMP3) cause Sorsby's Fundus Dystrophy (SFD), a dominantly inherited, rare form of macular degeneration that results in vision loss. TIMP3 is synthesized primarily by retinal pigment epithelial (RPE) cells, which constitute the outer blood-retinal barrier. One major function of RPE is the synthesis and transport of vital nutrients, such as glucose, to the retina. Recently, metabolic dysfunction in RPE cells has emerged as an important contributing factor in retinal degenerations. We set out to determine if RPE metabolic dysfunction was contributing to SFD pathogenesis. METHODS: Quantitative proteomics was conducted on RPE of mice expressing the S179C variant of TIMP3, known to be causative of SFD in humans. Proteins found to be differentially expressed (P<0.05) were analyzed using statistical overrepresentation analysis to determine enriched pathways, processes, and protein classes using g:profiler and PANTHER Gene Ontology. We examined the effects of mutant TIMP3 on RPE metabolism using human ARPE-19 cells expressing mutant S179C TIMP3 and patient-derived induced pluripotent stem cell-derived RPE (iRPE) carrying the S204C TIMP3 mutation. RPE metabolism was directly probed using isotopic tracing coupled with GC/MS analysis. Steady state [U-13C6] glucose isotopic tracing was preliminarily conducted on S179C ARPE-19 followed by [U-13C6] glucose and [U-13C5] glutamine isotopic tracing in SFD iRPE cells. RESULTS: Quantitative proteomics and enrichment analysis conducted on RPE of mice expressing mutant S179C TIMP3 identified differentially expressed proteins that were enriched for metabolism-related pathways and processes. Notably these results highlighted dysregulated glycolysis and glucose metabolism. Stable isotope tracing experiments with [U-13C6] glucose demonstrated enhanced glucose utilization and glycolytic activity in S179C TIMP3 APRE-19 cells. Similarly, [U-13C6] glucose tracing in SFD iRPE revealed increased glucose contribution to glycolysis and the TCA cycle. Additionally, [U-13C5] glutamine tracing found evidence of altered malic enzyme activity. CONCLUSION: This study provides important information on the dysregulation of RPE glucose metabolism in SFD and implicates a potential commonality with other retinal degenerative diseases, emphasizing RPE cellular metabolism as a therapeutic target.

Unplanned Emergency Department or Inpatient Acute Care Within 1 Week After Administration of Peptide Receptor Radionuclide Therapy: Frequency of Occurrence and Standard Operating Procedures for Radioprotection in These Situations.

Peptide receptor radionuclide therapy (PRRT) is a rapidly developing treatment modality. These treatments are indicated for patients who are either heavily pretreated and/or may have neurohormonal active disease, increasing risk of acute adverse effects and the need for unplanned acute care. The goals of this report were to characterize the frequency of unplanned acute care utilization after PRRT infusion and to detail a comprehensive standard operating procedure (SOP) for radioprotection during unplanned post-PRRT acute care. The records of patients treated with PRRT were reviewed. The event of interest was emergency department (ED) utilization and/or inpatient admission within 7 days of PRRT infusion. A multidisciplinary group developed a radioprotection SOP for all phases of unplanned acute care including the clinical infusion space, emergency medical services (EMS) transport to the ED, within the ED, and on the inpatient floor. A total of 232 patients received 814 infusions of PRRT, with 134 (58%) receiving Lutathera and 98 (42%) receiving Pluvicto. Nineteen patients received unplanned acute care at an ED within 7 days of PRRT infusion (8% of patients, 2% of infusions), of which 10 received Lutathera (8% of patients, 2% of infusions). Two patients (2% of patients, 0.5% of infusions) experienced carcinoid crises within 24 hours of Lutathera infusion. The median and average interval between infusion and ED visit was 0.5 days and 1.3 days, respectively. Nine patients received Pluvicto (9% of patients, 3% of infusions). The median and average interval between infusion and ED visit was 4 days and 4.7 days, respectively. Emergency room utilization and/or inpatient admission after PRRT administration are relatively infrequent events, but not unexpected. Centers that administer PRRT should have a comprehensive SOP in place to effectively care for radioactive patient emergencies while maximizing medical staff protection.

Single-cell analysis reveals transcriptional dynamics in healthy primary parathyroid tissue.

Studies on human parathyroids are generally limited to hyperfunctioning glands owing to the difficulty in obtaining normal human tissue. We therefore obtained non-human primate (NHP) parathyroids to provide a suitable alternative for sequencing that would bear a close semblance to human organs. Single-cell RNA expression analysis of parathyroids from four healthy adult M. mulatta reveals a continuous trajectory of epithelial cell states. Pseudotime analysis based on transcriptomic signatures suggests a progression from GCM2 hi progenitors to mature parathyroid hormone (PTH)-expressing epithelial cells with increasing core mitochondrial transcript abundance along pseudotime. We sequenced, as a comparator, four histologically characterized hyperfunctioning human parathyroids with varying oxyphil and chief cell abundance and leveraged advanced computational techniques to highlight similarities and differences from non-human primate parathyroid expression dynamics. Predicted cell-cell communication analysis reveals abundant endothelial cell interactions in the parathyroid cell microenvironment in both human and NHP parathyroid glands. We show abundant RARRES2 transcripts in both human adenoma and normal primate parathyroid cells and use coimmunostaining to reveal high levels of RARRES2 protein (also known as chemerin) in PTH-expressing cells, which could indicate that RARRES2 plays an unrecognized role in parathyroid endocrine function. The data obtained are the first single-cell RNA transcriptome to characterize nondiseased parathyroid cell signatures and to show a transcriptomic progression of cell states within normal parathyroid glands, which can be used to better understand parathyroid cell biology.

Astrocytes require perineuronal nets to maintain synaptic homeostasis in mice.

Perineuronal nets (PNNs) are densely packed extracellular matrices that cover the cell body of fast-spiking inhibitory neurons. PNNs stabilize synapses inhibiting synaptic plasticity. Here we show that synaptic terminals of fast-spiking interneurons localize to holes in the PNNs in the adult mouse somatosensory cortex. Approximately 95% of holes in the PNNs contain synapses and astrocytic processes expressing Kir4.1, glutamate and GABA transporters. Hence, holes in the PNNs contain tripartite synapses. In the adult mouse brain, PNN degradation causes an expanded astrocytic coverage of the neuronal somata without altering the axon terminals. The loss of PNNs impairs astrocytic transmitter and potassium uptake, resulting in the spillage of glutamate into the extrasynaptic space. Our data show that PNNs and astrocytes cooperate to contain synaptically released signals in physiological conditions. Their combined action is altered in mouse models of Alzheimer's disease and epilepsy where PNNs are disrupted.

Relating gut microbiome composition and life history metrics for pronghorn (Antilocapra americana) in the Red Desert, Wyoming.

Host microbial communities (hereafter, the 'microbiome') are recognized as an important aspect of host health and are gaining attention as a useful biomarker to understand the ecology and demographics of wildlife populations. Several studies indicate that the microbiome may contribute to the adaptive capacity of animals to changing environments associated with increasing habitat fragmentation and rapid climate change. To this end, we investigated the gut microbiome of pronghorn (Antilocapra americana), an iconic species in an environment that is undergoing both climatic and anthropogenic change. The bacterial composition of the pronghorn gut microbiome has yet to be described in the literature, and thus our study provides important baseline information about this species. We used 16S rRNA amplicon sequencing of fecal samples to characterize the gut microbiome of pronghorn-a facultative sagebrush (Artemisia spp.) specialist in many regions where they occur in western North America. We collected fecal pellets from 159 captured female pronghorn from four herds in the Red Desert of Wyoming during winters of 2013 and 2014. We found small, but significant differences in diversity of the gut microbiome relative to study area, capture period, and body fat measurements. In addition, we found a difference in gut microbiome composition in pronghorn across two regions separated by Interstate 80. Results indicated that the fecal microbiome may be a potential biomarker for the spatial ecology of free-ranging ungulates. The core gut microbiome of these animals-including bacteria in the phyla Firmicutes (now Bacillota) and Bacteroidota-remained relatively stable across populations and biological metrics. These findings provide a baseline for the gut microbiome of pronghorn that could potentially be used as a target in monitoring health and population structure of pronghorn relative to habitat fragmentation, climate change, and management practices.

ARFID Parent Training Protocol ("ARFID-PTP"): Results of a Randomized Pilot Trial Evaluating a Brief, Parent-Training Program for Avoidant/Restrictive Food Intake Disorder.

OBJECTIVE: Accessible treatment options for avoidant/restrictive food intake disorder (ARFID) in children are limited. The current study sought to assess acceptability, feasibility, and preliminary efficacy of a brief, virtual intervention for ARFID in children ("ARFID-PTP"). METHOD: Families of children ages 5-12 with ARFID (n = 30) were randomized to immediate or waitlist treatment groups, with both groups ultimately receiving ARFID-PTP. ARFID-PTP consists of two, 2-h individual treatment sessions with an optional booster session at 4-week follow-up. Families completed acceptability and feasibility measures at end-of-treatment, as well as preliminary efficacy measures at 4-week, 3-month, and 6-month follow-up. RESULTS: Of 30 families who completed an intake session, 27 (90%) completed treatment. Families rated acceptability as high (MCEQ-C = 7.75). Treatment was feasible by participant retention. Exposure adherence was lower than expected, and booster session requests were higher than expected, indicating that achieving feasibility across measures may require treatment modifications. Regarding preliminary efficacy, children in the immediate treatment group had a decrease in ARFID symptoms compared to those on the waitlist. Overall, at 6-month follow-up linear mixed models showed participants had significantly reduced ARFID symptoms by presentation (p < 0.05) and in follow-up completers, children incorporated eight new foods on average. DISCUSSION: ARFID-PTP is acceptable and preliminarily efficacious. The protocol may benefit from modifications to increase feasibility; however, booster session content and treatment outcomes suggest a priori feasibility markers may not accurately capture the utility of ARFID-PTP. Further work should continue to examine the efficacy ARFID-PTP, particularly in diverse samples where treatment accessibility is urgently needed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04913194.

Patient-Reported Outcome Measures Within a National Multispecialty Surgical Quality Improvement Program.

Importance: Patient-reported outcome measures (PROMs) are increasingly recognized for their ability to promote patient-centered care, but concerted health information technology (HIT)-enabled PROM implementations have yet to be achieved for national surgical quality improvement. Objective: To evaluate the feasibility of collecting PROMs within a national surgical quality improvement program. Design, Setting, and Participants: This was a pragmatic implementation cohort study conducted from February 2020 to March 2023. Hospitals in the US participating in the American College of Surgeons National Surgical Quality Improvement Program and their patients were included in this analysis. Exposures: Strategies to increase PROM collection rates were identified using the Institute for Healthcare Improvement (IHI) Framework for Spread and the Consolidated Framework for Implementation Research and operationalized with the IHI Model for Improvement's Plan-Do-Study-Act (PDSA) cycles. Main Outcomes and Measures: The primary goal was to accrue more than 30 hospitals and achieve collection rates of 30% or greater in the first 3 years. Logistic regression was used to identify hospital-level factors associated with achieving collection rates of 30% or greater and to identify patient-level factors associated with response to PROMs. Results: At project close, 65 hospitals administered PROMs to 130 365 patients (median [IQR] age, 60.1 [46.2-70.0] years; 77 369 female [59.4%]). Fifteen PDSA cycles were conducted to facilitate implementation, primarily targeting the Consolidated Framework for Implementation Research domains of Inner Setting (ie, HIT platform) and Individuals (ie, patients). The target collection rate was exceeded in quarter 3 (2022). Fifty-eight hospitals (89.2%) achieved collection rates of 30% or greater, and 9 (13.8%) achieved collection rates of 50% or greater. The median (IQR) maximum hospital-level collection rate was 40.7% (34.6%-46.7%). The greatest increases in collection rates occurred when both email and short-message service text messaging were used, communications to patients were personalized with their surgeon's and hospital's information, and the number of reminders increased from 2 to 5. No identifiable hospital characteristic was associated with achieving the target collection rate. Patient age and insurance status contributed to nonresponse. Conclusions and Relevance: Results of this cohort study suggest that the large-scale electronic collection of PROMs into a national multispecialty surgical registry was feasible. Findings suggest that HIT platform functionality and earning patient trust were the keys to success; although, iterative opportunities to increase collection rates and address nonresponse remain. Future work to drive continuous surgical quality improvement with PROMs are ongoing.

Wavelet transform of single-trial vestibular short-latency evoked potential reveals temporary reduction in signal detectability and temporal precision following noise exposure.

The vestibular short-latency evoked potential (VsEP) reflects the activity of irregular vestibular afferents and their target neurons in the brain stem. Attenuation of trial-averaged VsEP waveforms is widely accepted as an indicator of vestibular dysfunction, however, more quantitative analyses of VsEP waveforms could reveal underlying neural properties of VsEP waveforms. Here, we present a time-frequency analysis of the VsEP with a wavelet transform on a single-trial basis, which allows us to examine trial-by-trial variability in the strength of VsEP waves as well as their temporal coherence across trials. Using this method, we examined changes in the VsEP following 110 dB SPL noise exposure in rats. We found detectability of head jerks based on the power of wavelet transform coefficients was significantly reduced 1 day after noise exposure but recovered nearly to pre-exposure level in 3 - 7 days and completely by 28 days after exposure. Temporal coherence of VsEP waves across trials was also significantly reduced on 1 day after exposure but recovered with a similar time course. Additionally, we found a significant reduction in the number of calretinin-positive calyces in the sacculi collected 28 days after noise exposure. Furthermore, the number of calretinin-positive calyces was significantly correlated with the degree of reduction in temporal coherence and/or signal detectability of the smallest-amplitude jerks. This new analysis of the VsEP provides more quantitative descriptions of noise-induced changes as well as new insights into potential mechanisms underlying noise-induced vestibular dysfunction. Significance Statement: Our study presents a new method of VsEP quantification using wavelet transform on a single-trial basis. It also describes a novel approach to determine the stimulus threshold of the VsEP based on signal-detection theory and Rayleigh statistics. The present analysis could also be applied to analysis of auditory brain stem response (ABR). Thus, it has the potential to provide new insights into the physiological properties that underlie peripheral vestibular and auditory dysfunction.

Relation between ARFID symptomatology and picky eating onset and duration.

BACKGROUND: Picky eating (PE) is common in early childhood, peaking between ages 1 and 5 years. However, PE may persist beyond this normative period and pose threats to health and psychosocial functioning. Avoidant/restrictive food intake disorder (ARFID) involves restrictive eating driven by appetite, preference/selectivity, and/or fear of eating, leading to significant medical and/or psychosocial impairment. This retrospective study examined the relation between early childhood PE onset/duration and ARFID eating restrictions and symptoms. METHOD: Parents of children ages 6-17 (N = 437) completed a survey about their child's eating behavior, including the Nine-item ARFID Screen (NIAS) and questions about PE onset and impacts. Children were then categorized into groups based on PE onset (before or after age 5) and duration: never picky, normative picky, persistent picky, and late-onset picky. RESULTS: The groups differed (all p < .05) in mean NIAS subscales (picky eating, NIAS-PE; appetite, NIAS-A; fear, NIAS-F) and total scores (NIAS-T). Tukey post-hoc tests found that persistent PEs had significantly higher NIAS-PE, NIAS-A, and NIAS-T scores than never or normative PEs (all p < .05). Chi-Square tests found that persistent PEs were significantly more likely than all other groups to endorse ARFID criteria. CONCLUSION: Findings from this study suggest that PE that persists beyond or is identified after the normative period is associated with elevated ARFID symptoms compared to normative and never PEs. Persistent PE increases risk of impairment from PE and other ARFID eating restrictions. Given the health and psychosocial risks associated with ARFID, early identification and intervention for this group is warranted.

Genetic variation near GRB10 associated with bone growth and osteosarcoma risk in canine and human populations.

BACKGROUND: Canine and human osteosarcoma are similar in clinical presentation and tumor genomics. Giant breed dogs experience elevated osteosarcoma incidence, and taller stature remains a consistent risk factor for human osteosarcoma. Whether evolutionarily conserved genes contribute to both human and canine osteosarcoma predisposition merits evaluation. METHODS: A multi-center sample of childhood osteosarcoma patients and controls underwent genome-wide genotyping and imputation. Ancestry-adjusted SNP associations were calculated within each dataset using logistic regression, then meta-analyzed across the three datasets, totaling 1091 patients and 3026 controls. Ten regions previously associated with canine osteosarcoma risk were mapped to the human genome, spanning ∼6 Mb. We prioritized association testing of 5985 human SNPs mapping to candidate osteosarcoma risk regions detected in Irish wolfhounds, the largest dog breed studied. Secondary analyses explored 6289 additional human SNPs mapping to candidate osteosarcoma risk regions identified in Rottweilers and greyhounds. RESULTS: Fourteen SNPs were associated with human osteosarcoma risk after adjustment for multiple comparisons, all within a 42 kb region of human Chromosome 7p12.1. The lead variant was rs17454681 (OR=1.25, 95 %CI: 1.12-1.39; P=4.1×10-5), and independent risk variants were not observed in conditional analyses. While the associated region spanned 2.1 Mb and contained eight genes in Irish wolfhounds, associations were localized to a 50-fold smaller region of the human genome and strongly implicate GRB10 (growth factor receptor-bound protein 10) in canine and human osteosarcoma predisposition. PheWAS analysis in UK Biobank data identified noteworthy associations of the rs17454681 risk allele with varied measures of height and pubertal timing. CONCLUSIONS: Our comparative oncology analysis identified a novel human osteosarcoma risk allele near GRB10, a growth inhibitor that suppresses activated receptor tyrosine kinases including IGF1R, PDGFRB, and EGFR. Epidemiologists may benefit from leveraging cross-species comparisons to identify haplotypes in highly susceptible but genetically homogenous populations of domesticated animals, then fine-mapping these associations in diverse human populations.

Dexamethasone, Glycemic Control, and Outcomes in Patients With Type 2 Diabetes Mellitus Undergoing Elective, Primary Total Joint Arthroplasty.

Background: Dexamethasone (DEX) has been shown to reduce pain and postoperative nausea and vomiting for patients undergoing elective total joint arthroplasty (TJA). We investigated the impact of DEX on glycemic control and outcomes in patients with type 2 diabetes mellitus undergoing elective primary TJA. Methods: All patients with type 2 diabetes mellitus undergoing primary elective TJA between January 2016 and December 2021 at 4 sites within 1 hospital system were identified. Propensity scores were calculated to match patients receiving or not receiving DEX. Primary outcomes were perioperative blood glucose levels and the incidence of hyperglycemia. Secondary outcomes were the amount of insulin administered, the occurrence of 30-day postoperative surgical site infections, hospital readmission, and mortality. Results: After matching, we identified 1372 patients. DEX administration was associated with a significant increase in mean blood glucose levels in mg/dL on postoperative days (PODs) 0 to 2: POD 0 (28.4, 95% confidence interval [CI]: 24.6-32.1), POD 1 (14.4, 95% CI: 10.1-18.8), POD 2 (12.4, 95% CI: 7.5-17.2) when comparing patients who did or did not receive DEX. Additionally, patients receiving DEX, compared to patients who did not receive DEX, had increased odds of experiencing hyperglycemia on POD 0 (odds ratio: 4.0, 95% CI: 3.1-5.2). DEX was not associated with a significant difference in insulin administration, surgical site infections, hospital readmission, or mortality. Conclusions: In our review of 1372 patients with propensity-matched type 2 diabetes mellitus undergoing elective, primary TJA, we found that DEX administration was associated with an increased risk of elevated mean glucose on POD 0-2, hyperglycemia on POD 0, but was not associated with an increase in total insulin dose administered nor occurrence of surgical site infections, hospital readmission, or mortality within 30 days of surgery in patients who received DEX compared to patients who did not receive DEX. Level of Evidence: IV.