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.

Folate metabolism and risk of childhood acute lymphoblastic leukemia: a genetic pathway analysis from the Childhood Cancer and Leukemia International Consortium.

BACKGROUND: Prenatal folate supplementation has been consistently associated with a reduced risk of childhood lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity, and led to inconclusive results. METHODS: We evaluated whether ~2,900 single nucleotide polymorphisms (SNPs) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control-studies in the Childhood Cancer and Leukemia International Consortium (n=9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data, and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software. RESULTS: None of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni p-value of 5x10-6 and less stringent p-value of 3.5x10-5 accounting for the number of "independent" SNPs). None of the 10 top (non-significant) SNPs and corresponding genes overlapped across ancestry groups. CONCLUSION: This large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups. IMPACT: Genetic variants in the folate pathway alone do not appear to substantially influence childhood ALL risk. Other mechanisms such as gene-folate interaction, DNA methylation or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

Robotic-assisted Laparoscopic Repair of Kidney Transplant Ureteral Strictures.

OBJECTIVE: To evaluate outcomes of robotic-assisted transplant ureteral repair (RATUR) for the management of kidney transplant ureteral strictures (TUS). METHODS: We retrospectively analyzed 41 consecutive patients who underwent RATUR for TUS at multiple tertiary referral centers between January 2016 and December 2022. RATUR was performed utilizing a robotic-assisted transperitoneal approach. The primary outcome was stricture recurrence rate and secondary outcomes included postoperative complicate rate, determining factors impacting with allograft functional recovery, and rate of conversion to open surgery. Categorical and continuous variables are displayed as total number (Percentage) or median [Interquartile Range], respectively. Pearson correlation coefficient was utilized to assess categorical variable correlation with creatinine. RESULTS: The median age was 56years [44,66]. The female-to-male ratio was 1.1:1. Approximately 66% of patients were dialysis-dependent prior to kidney transplantation. TUS was identified at a median time of 4months [2, 15.5] following kidney transplant. Median stricture length was 2 cm [1.22, 2.9 cm]. There were no TUS recurrences with a median follow-up of 36months [24,48]. There were 3 Clavien grade 2 and 1 Clavien grade 3 complications (9.5%). No baseline characteristics or preoperative diagnostics were correlated with a long-term decline in renal allograft function. CONCLUSION: RATUR has excellent and durable outcomes with low complication rates. These findings encourage the use of a minimally invasive definitive repair as a first-line treatment option for the management of TUS.

The Effect of Socioeconomic Status and Race/Ethnicity on the Risk of Presenting With Advanced Stage at Diagnosis in Embryonal Tumors.

We evaluated whether socioeconomic status (SES), race/ethnicity, and their interaction were associated with the presentation of advanced stage at diagnosis in embryonal tumors. Children 0 to 19 years of age diagnosed with embryonal tumors between 2006 and 2018 were identified from the US Surveillance, Epidemiology, and End Results program database specialized with Census Tract SES/Rurality. SES quintile was derived from a composite index for census tracts. We performed logistic regression to estimate odds ratios (ORs) and 95% confidence intervals by SES and race/ethnicity, adjusting for sex, age, and diagnosis year. Overall, no significant associations were found between either SES or race/ethnicity and the risk of presenting with advanced stage at diagnosis, although patterns of risk reductions were observed in atypical teratoid/rhabdoid tumors and embryonal rhabdomyosarcoma with increasing SES. In the stratified analysis, decreased odds of presenting with advanced-stage embryonal rhabdomyosarcoma were observed for Hispanics with higher SES (OR: 0.24, 95% Confidence Interval: 0.08-0.75) compared with Hispanics with lower SES. Future studies incorporating individual-level SES, cancer-specific staging information, and potential demographic, clinical, epidemiological, and genetic risk factors are warranted to confirm our findings.

An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma.

BACKGROUND: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA. MATERIALS AND METHODS: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430). RESULTS: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME. CONCLUSIONS: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours.

Secondary Lipid Oxidation Products as Modulators of Calpain-2 Functionality In Vitro.

The objective was to understand the impacts of secondary lipid oxidation products on calpain-2 activity and autolysis and, subsequently, to determine the quantity and localization of modification sites. 2-Hexenal and 4-hydroxynonenal incubation significantly decreased calpain-2 activity and slowed the progression of autolysis, while malondialdehyde had minimal impact on calpain-2 activity and autolysis. Specific modification sites were determined with LC-MS/MS, including distinct malondialdehyde modification sites on the calpain-2 catalytic and regulatory subunits. 2-Hexenal modification sites were observed on the calpain-2 catalytic subunit. Intact protein mass analysis with MALDI-MS revealed that a significant number of modifications on the calpain-2 catalytic and regulatory subunits are likely to exist. These observations confirm that specific lipid oxidation products modify calpain-2 and may affect the calpain-2 functionality. The results of these novel experiments have implications for healthy tissue metabolism, skeletal muscle growth, and post-mortem meat tenderness development.

Sex differences in osteosarcoma survival across the age spectrum: A National Cancer Database analysis (2004-2016).

BACKGROUND: Osteosarcoma displays a bimodal peak in incidence in adolescence and later adulthood. Males are more frequently diagnosed with osteosarcoma in both periods. Males have worse survival than females, which is generally poor at 30-70% 5-years post diagnosis, depending on age, but treatment received is often unaccounted for in survival analyses. METHODS: Therefore, we estimated sex differences in survival for children and adults stratifying by treatment received and other disease characteristics using the National Cancer Database (2004-2016, n=9017). We estimated sex differences in long-term survival using Kaplan Meier survival curves and Log-Rank p-values. We also estimated hazard ratios (HR) and 95% confidence intervals (CIs) as the measure of association between sex and death using Cox regression. RESULTS: In all age groups, cases were predominantly male (52-58%). In Kaplan-Meier analyses, males had worse overall survival than females for 0-19, 20-39, and ≥60-year-olds (Log-Rank p<0.05). Females had higher 5- and 10-year survival percentages in all age groups. In adjusted Cox models, males had a higher risk of death among 0-19-year-olds (HRoverall: 1.24, 95% CI: 1.06-1.44; HRnon-metastatic disease: 1.35, 95% CI: 1.12, 1.63, HRlower limb tumors: 1.31, 95% CI: 1.09-1.59). Among 20-39-year-olds, males had an increased risk of death when receiving surgery only (HR: 4.67, 95% CI: 1.44, 15.09). Among those ≥60-year-olds, males had a suggestive increased risk of death overall (HR: 1.17, 95% CI: 0.99-1.39) and a higher risk of death based on some tumor locations, (HRupper limb: 2.52, 95% CI: 1.24, 5.11; HRmidline: 1.36, 95% CI: 1.02, 1.82). CONCLUSIONS: Our findings suggest that the worse survival among young males compared to females with osteosarcoma persisted after accounting for many major disease characteristics, including treatment received. Collectively, our work points toward other unexplored mechanisms beyond treatment, potentially biologic or otherwise, which may be driving the observed sex differences in long-term survival.

Addressing the Rhino in the Room: ChatGPT Creates "Novel" Patent Ideas for Rhinoplasty.

Background: OpenAI's ChatGPT can generate novel ideas for a number of applications. The aim of this study was to prompt the chatbot to generate possible innovations in aesthetic surgery relating to rhinoplasty. Methods: ChatGPT was prompted to develop rhinoplasty patents. The resulting outputs were tabulated and categorized based on technology domain and anatomic location. A Google Patents search was conducted to find uses of the term "rhinoplasty" between 2021 and 2023. Patents not pertaining to rhinoplasty were excluded. Filed patents were compared with those generated by ChatGPT to determine predictive power. Results: A total of 40 patents resulted from ChatGPT and 42 Google Patents from 2021 to 2023 were included. Patents generated without a detailed description command were related to preoperative planning (35%), intraoperative tools (30%), functional evaluation (15%), and 3D printing and implants (10%). Patents with a detailed description command resulted in the majority being postoperative tools (40%), followed by intraoperative tools (30%), 3D printing and implants (10%), and nonsurgical (10%) categories. The anatomic locations included the airway, dorsum, septum, and nasal tip. ChatGPT's predictive power yielded 45% for the detailed prompting, which was higher than the prompt without the detail command. Conclusions: ChatGPT has reasonable potential to generate ideas for innovations in plastic surgery with the assistance of an experienced surgeon-innovator. With new artificial intelligence generations and updates, chatbots will continue to improve. Determining whether these technologies can assist in the later portions of the patent process beyond idea generation will be crucial.

Predicting Peak Productivity in Urologic Medicare Practice via Work-Relative Value Units.

OBJECTIVE: To explore factors associated with productivity in urologic practice. Work-relative value units (wRVUs), the basis for Center for Medicare & Medicaid Services (CMS) and private payer reimbursements, commonly serve to estimate physician productivity. Limited data describes which practice factors predict increased wRVU productivity. METHODS: The 2017 and 2018 CMS databases were retrospectively queried for urologic Medicare provider demographics and procedural/service details. Medical school graduation year was used to estimate years in practice and generation (Millennial, Gen X, Baby Boomer, or Post-War). Treated patients' demographics were obtained. Adjusted and unadjusted linear mixed models were performed to predict wRVU production. RESULTS: Included were 6773 Medicare-participating urologists across the United States. Millennials produced 1115 wRVUs per year, while Gen X and Baby Boomers produced significantly more (1997 and 2104, respectively, P <.01). Post-War urologists produced numerically more (1287, P = .88). In adjusted analyses, predictors of Medicare wRVU productivity included female and pelvic medicine and reconstructive surgery (exponentiated beta estimate (ß) 1.46, 95% CI 1.32-1.60), men's health (ß 1.22, 95% CI 1.13-1.32), and oncologic subspecialization (ß 1.08, 95% CI 1.02-1.14), female gender (ß 0.87, 95% CI 0.82-0.92), wRVUs generated from inpatient procedures (ß 1.08, 95% CI 1.06-1.09) and office visits (ß 0.88, 95% CI 0.87-0.89), and the level of education (ß 1.10, 95% CI 1.07-1.14) and percent impoverished patients (ß 0.85, 95% CI 0.83-0.88) in provider's practice zip code. CONCLUSION: Urologic experience, specialization, demographics, practice patterns, and patient demographics are significantly associated with wRVU productivity in Medicare settings. Further work should incorporate quality metrics into wRVUs and ensure patient demographics do not affect reimbursement.

TMR Using a Free Rectus Flap after Transhumeral Amputation.

Targeted muscle reinnervation offers an approach to regain use of the affected extremity through electronic prosthesis while limiting phantom pain and neuroma limb production or pain. In this case report, we present the first reported case of leveraging the rectus flap for targeted muscle reinnervation. The case herein is of a 28-year-old woman who sustained a severe right upper extremity crush injury while being involved in a vehicular roll-over collision requiring right transhumeral amputation. Plastic surgery, orthopedic surgery, and vascular surgery were consulted to manage the right upper extremity injury.

In Utero Origins of Acute Leukemia in Children.

Acute leukemias, mainly consisting of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), comprise a major diagnostic group among hematologic cancers. Due to the early age at onset of ALL, particularly, it has long been suspected that acute leukemias of childhood may have an in utero origin. This supposition has motivated many investigations seeking direct proof of prenatal leukemogenesis, in particular, twin and "backtracking studies". The suspected in utero origin has also focused on gestation as a critical window of risk, resulting in a rich literature on prenatal risk factors for pediatric acute leukemias. In this narrative review, we recount the circumstantial and direct evidence for an in utero origin of childhood acute leukemias.

The hardware is the software.

Human brains and bodies are not hardware running software: the hardware is the software. We reason that because the physics of artificial intelligence hardware and of human biological "hardware" is distinct, neuromorphic engineers need to be selective in the inspiration we take from neuroscience.

Genetic analyses identify evidence for a causal relationship between Ewing sarcoma and hernias.

Knowledge of Ewing sarcoma (EWS) risk factors is exceedingly limited; however, multiple small, independent studies have suggested a possible connection between hernia and EWS. By leveraging hernia summary statistics from the UK Biobank and a recently published genome-wide association study of EWS (733 EWS cases and 1,346 controls), we conducted a genetic investigation of the relationship of 5 hernia types (diaphragmatic, inguinal, umbilical, femoral, and ventral) and EWS. We discovered a positive causal relationship between inguinal hernia and EWS (OR 1.27, 95% confidence interval [CI] 1.01-1.59, and p = 0.041) through Mendelian randomization analysis. Further analyses suggested shared pathways through three genes: HMGA2, LOX, and FBXW7. Diaphragmatic hernia showed a stronger causal relationship with EWS among all of the hernia types (OR 2.26, 95% CI 1.30-3.95, p = 0.004), but no statistically significant local correlation pattern was observed. No evidence of a causal or genetic relationship was observed between EWS and the other three hernia types, including umbilical hernia, despite a previous report indicating an OR as high as 3.3. The finding of our genetic analysis provided additional support to the hypothesis that EWS and hernias may share a common origin.

Preoperative Planning Software Does Not Accurately Predict Range of Motion in Reverse Total Shoulder Arthroplasty.

BACKGROUND: The purpose of this study was to determine whether preoperative planning software (PPS) accurately predicts clinical range of motion (ROM) in patients with reverse total shoulder arthroplasty 1 year postoperatively with preoperative and postoperative computed tomography (CT) scans. METHODS: This was a retrospective study of 16 reverse total shoulder arthroplasty patients with preoperative and postoperative (CT) scans obtained at least 1 year postoperatively. Clinical ROM was measured in abduction, external rotation at resting abduction, extension, and flexion at a minimum of 1 year postoperatively. All clinical measurements were obtained before generation of PPS ROM values. Using postoperative CT scans, the achieved implant component positions were quantified and then replicated in PPS on the preoperative CT scans. The preoperative predicted ROM was then recorded, both with and without osteophyte removal. Bland-Altman plots were generated within each motion comparing the differences between clinically measured motion and software-predicted motion. RESULTS: The variation in clinically measured ROM in abduction, external rotation at resting abduction, extension, and flexion were 118 ± 27 (65° to 180°), 33 ± 16 (10° to 75°), 56 ± 8 (50° to 65°), and 137 ± 25 (80° to 160°), respectively. Clinically measured motion differed greatly from PPS-predicted ROM, with mean differences of 33 ± 29 (-32 to 93) for abduction, 44 ± 25 (-38 to 57) for external rotation, 44 ± 25 (-35 to 65) for extension, and 54 ± 50 (-51 to 147) for flexion with no significant correlations between clinically measured and PPS-predicted ROM ( P > 0.05). With humeral or humeral and glenoid osteophyte resection, correlations for only flexion became significant ( P = 0.002 for both). CONCLUSION: The passive glenohumeral impingement-free ROM generated from PPS incompletely predicts clinically measured active humerothoracic ROM, possibly because of the unmeasured factors of soft-tissue tension, muscular strength, humeral torsion, resting scapular posture, and, most importantly, scapulothoracic motion. LEVEL OF EVIDENCE: IV.

Sympathetic remodeling and altered angiotensin-converting enzyme 2 localization occur in patients with cardiac disease but are not exacerbated by severe COVID-19.

PURPOSE: Remodeling of sympathetic nerves and ACE2 has been implicated in cardiac pathology, and ACE2 also serves as a receptor for SARS-CoV-2. However, there is limited histological knowledge about the transmural distribution of sympathetic nerves and the cellular localization and distribution of ACE2 in human left ventricles from normal or diseased hearts. Goals of this study were to establish the normal pattern for these parameters and determine changes that occurred in decedents with cardiovascular disease alone compared to those with cardiac pathology and severe COVID-19. METHODS: We performed immunohistochemical analysis on sections of left ventricular wall from twenty autopsied human hearts consisting of a control group, a cardiovascular disease group, and COVID-19 ARDS, and COVID-19 non-ARDS groups. RESULTS: Using tyrosine hydroxylase as a noradrenergic marker, we found substantial sympathetic nerve loss in cardiovascular disease samples compared to controls. Additionally, we found heterogeneous nerve loss in both COVID-19 groups. Using an ACE2 antibody, we observed robust transmural staining localized to pericytes in the control group. The cardiovascular disease hearts displayed regional loss of ACE2 in pericytes and regional increases in staining of cardiomyocytes for ACE2. Similar changes were observed in both COVID-19 groups. CONCLUSIONS: Heterogeneity of sympathetic innervation, which occurs in cardiac disease and is not increased by severe COVID-19, could contribute to arrhythmogenesis. The dominant localization of ACE2 to pericytes suggests that these cells would be the primary target for potential cardiac infection by SARS-CoV-2. Regional changes in ACE2 staining by myocytes and pericytes could have complex effects on cardiac pathophysiology.

Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Role of non-chromosomal birth defects on the risk of developing childhood Hodgkin lymphoma: A Children's Oncology Group study.

BACKGROUND: Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk. PROCEDURE: Information on cases (n = 517) diagnosed with HL (ages of 0-14) at Children's Oncology Group Institutions for the period of 1989-2003 was obtained. Control children without a history of cancer (n = 784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including whether their child had been born with a non-chromosomal birth defect. To test the association between birth defects and HL risk, conditional logistic regression was applied to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: Children born with any non-chromosomal birth defect were not more likely to be diagnosed with HL at 0-14 years of age (aOR: 0.91; 95% CI: 0.69-1.21). No associations were detected between major or minor birth defects and HL (aOR: 1.34; 95% CI: 0.67-2.67 and aOR: 0.88; 95% CI: 0.57-1.34, respectively). Similarly, no association was observed for children born with any birth defect and EBV-positive HL (aOR: 0.57; 95% CI: 0.25-1.26). CONCLUSIONS: Previous assessments of HL in children with non-chromosomal birth defects have been limited. Using data from the largest case-control study of HL in those <15 years of age, we did not observe strong associations between being born with a birth defect and HL risk.

Combined TMR and RPNI in a vasculopathy patient: A case report.

TMR (targeted muscle reinnervation) or RPNI (regenerative peripheral nerve interface) have been the standard after nerve injuries. In this case report, we explain our approach in combining these two techniques (TMRpni) for a patient undergoing left above-the-knee amputation. Using this method, both phantom and nerve pain were reduced in our patient's case. As this technique becomes more well understood and widely adopted, amputee patients may achieve a greater quality of life post operation.