Transposon-based oncogene integration in Abcb4(Mdr2)-/- mice recapitulates high susceptibility to cholangiocarcinoma in primary sclerosing cholangitis.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC), difficult to diagnose and associated with high mortality. Lack of animal models of CCA recapitulating the hepatic microenvironment of sclerosing cholangitis hinders development of novel treatments. Here we sought to develop such PSC-associated CCA model in mice. METHODS: Ten-week-old Mdr2-/- mice with congenital PSC-like disease, and healthy wild-type littermates were subjected to either modified retrograde biliary instillation or hydrodynamic tail vein injection of sleeping beauty transposon-transposase plasmid system with activated AKT (myr-AKT) and Yap (YapS127A) protooncogenes (SB AKT/YAP1). The role of TGFß was interrogated via ALK5 inhibitor (SB-525334) administration. Tumor phenotype, burden and desmoplastic reaction were analyzed histologically and via RNA-seq. RESULTS: While SB AKT/YAP1 plasmids via retrograde biliary injection caused tumors in Mdr2-/-, only 26.67% (4/15) of these tumors were CCA. Alternatively, hydrodynamic tail vein injection of SB AKT/YAP1 resulted in robust tumorigenesis in all fibrotic Mdr2-/- mice with high CCA burden compared to healthy mice. Tumors phenotypically resembled human CCA, expressed multiple CCA (but not hepatocellular carcinoma) markers, and exhibited a profound desmoplastic reaction. RNA-seq analysis revealed profound transcriptional changes in CCA evolving in PSC-like context, with specific alterations in multiple immune pathways. Pharmacological TGFß inhibition led to enhanced immune cell tumor infiltration, reduced tumor burden and suppressed desmoplastic collagen accumulation compared to placebo CONCLUSION: We established a new high-fidelity cholangiocarcinoma model in mice, termed SB CCA.Mdr2-/-, which recapitulates the increased susceptibility to CCA in the setting of biliary injury and fibrosis observed in PSC. Through transcriptomics and pharmacological studies, we show dysregulation of multiple immune pathways and TGFß signaling as potential drivers of CCA in PSC-like microenvironment. IMPACT AND IMPLICATIONS: There is a lack of animal models for primary sclerosing cholangitis (PSC) related cholangiocarcinoma (PSC-CCA). We have developed and characterized a new mouse model of PSC-CCA, termed SB CCA.Mdr2-/-, which features reliable tumor induction in PSC-like background of biliary injury and fibrosis. Global gene expression alterations were identified and standardized tools, including automated whole slide image analysis methodology for tumor burden and feature analysis, were established to enable systematic research into PSC-CCA biology and formal pre-clinical drug testing.

Fluid and electrolyte pathophysiology in common febrile illness in children and the implications for clinical management.

Achieving fluid homeostasis and the management of fluid and electrolyte complications are constants in the treatment of seriously ill children worldwide. Consensus on the most appropriate fluid strategy for unwell children has been difficult to achieve and has evolved over the last two decades, most notably in high-income countries where adverse events relating to poor fluid management were identified more readily, and official robust inquiries were possible. However, this has not been the situation in many low-income settings where fluids that are prohibited from use in high-income countries may be all that are available, local guidelines and processes to recognise adverse events are not developed, and there has been limited training on safe fluid management for front-line healthcare workers. This narrative review outlines the fluid and electrolyte pathophysiology of common febrile illnesses in children, describes the evolution of this field and concludes with implications and principles of a fluid management strategy for seriously ill children. This review was prepared as a physiological background paper to support evidence presented to the WHO Guideline Development Group for Fluid Guidelines in Children, Geneva, March 2024.

Systematic loss-of-function screens identify pathway-specific functional circular RNAs.

Circular RNA (circRNA) is covalently closed, single-stranded RNA produced by back-splicing. A few circRNAs have been implicated as functional; however, we lack understanding of pathways that are regulated by circRNAs. Here we generated a pooled short-hairpin RNA library targeting the back-splice junction of 3,354 human circRNAs that are expressed at different levels (ranging from low to high) in humans. We used this library for loss-of-function proliferation screens in a panel of 18 cancer cell lines from four tissue types harbouring mutations leading to constitutive activity of defined pathways. Both context-specific and non-specific circRNAs were identified. Some circRNAs were found to directly regulate their precursor, whereas some have a function unrelated to their precursor. We validated these observations with a secondary screen and uncovered a role for circRERE(4-10) and circHUWE1(22,23), two cell-essential circRNAs, circSMAD2(2-6), a WNT pathway regulator, and circMTO1(2,RI,3), a regulator of MAPK signalling. Our work sheds light on pathways regulated by circRNAs and provides a catalogue of circRNAs with a measurable function.

Home environment factors associated with child BMI changes during COVID-19 pandemic.

BACKGROUND: The influence of home obesogenic environments, as assessed by the validated Family Nutrition and Physical Activity (FNPA) tool, and child obesity during the COVID pandemic were evaluated using electronic health records in this retrospective cohort study. METHODS: Historical data on BMI and the FNPA screening tool were obtained from annual well-child visits within the Geisinger Health System. The study examined youth ages 2-17 that had a BMI record and an FNPA assessment prior to the pandemic (BMI 3/1/19-2/29/20), 1 BMI record 3 months into the pandemic (6/1/20-12/31/20) and 1 BMI in the second year of the pandemic (1/1/21-12/31/21). Tertiles of obesity risk by FNPA score were examined. Mixed-effects linear regression was used to examine change in BMI slope (kg/m2 per month) pre-pandemic to pandemic using FNPA summary and subscales scores as predictors and adjusting for confounding factors. RESULTS: The analyses included 6,746 children (males: 51.7%, non-Hispanic white: 86.6%, overweight:14.8%, obesity:10.3%, severe obesity: 3.9%; mean(SD) age: 5.7(2.8) years). The rate of BMI change in BMI was greatest from early pandemic compared to pre-pandemic for children in lowest versus highest tertiles of FNPA summary score (0.079 vs. 0.044 kg/m2), FNPA-Eating (0.068 vs. 0.049 kg/m2), and FNPA-Activity (0.078 vs. 0.052 kg/m2). FNPA summary score was significantly associated with change in BMI from the pre-pandemic to early pandemic period (p = 0.014), but not associated with change in BMI during the later pandemic period. CONCLUSIONS: This study provides additional insight into the changes in the rate of BMI change observed among children and adolescents in the United States during the COVID-19 pandemic. The FNPA provides ample opportunity to continue our exploration of the negative impact of the COVID-19 pandemic on the longitudinal growth patterns among children and adolescents.

Adverse events associated with robotic-assistance in total hip arthroplasty: an analysis based on the FDA MAUDE database.

BACKGROUND: The Food and Drug Administration (FDA) maintains the Manufacturer and User Facility Device Experience (MAUDE) database for reporting adverse events associated with medical devices, including emerging technologies, such as robotic-assisted total hip arthroplasty (THA). Aim of this study was to evaluate the variation of adverse events associated with robotics in THA. METHODS: Medical device reports (MDRs) within the MAUDE database were identified between 2017 and 2021. For MDR identification the product class "orthopaedic stereotaxic equipment" and terms associated with THA were used. Individual adverse events were identified and organised by type and consequences, such as patient injury, surgical delay, or conversion to the manual technique. RESULTS: 521 MDRs constituting 546 discrete events were found. The most common reported complication was intraoperative hardware failure (304/546, 55.7%), among which the most common failure was a broken impaction handle/platform (110, 20.1%). Inaccurate cup placement was the second most common reported complication (63, 11.5%). Abandoning the robot occurred in 13.0% (71/521) of reports. A surgical delay was noted in 28% (146/521) of reports, with an average delay of 17.9 (range 1-60) minutes. CONCLUSIONS: Identifying complications that may occur with robotics in THA is an important first step in preventing adverse events and surgical delays. Database analysis provide an overview of the range of complications.

A High Capacity Gas Diffusion Electrode for Li-O2 Batteries.

The very high theoretical specific energy of the lithium-air (Li-O2) battery (3500 Wh kg-1) compared with other batteries makes it potentially attractive, especially for the electrification of flight. While progress has been made in realizing the Li-air battery, several challenges remain. One such challenge is achieving a high capacity to store charge at the positive electrode at practical current densities, without which Li-air batteries will not outperform lithium-ion. The capacity is limited by the mass transport of O2 throughout the porous carbon positive electrode. Here it is shown that by replacing the binder in the electrode by a polymer with the intrinsic ability to transport O2, it is possible to reach capacities as high as 31 mAh cm-2 at 1 mA cm-2 in a 300 µm thick electrode. This corresponds to a positive electrode energy density of 2650 Wh L-1 and specific energy of 1716 Wh kg-1, exceeding significantly Li-ion batteries and previously reported Li-O2 cells. Due to the enhanced oxygen diffusion imparted by the gas diffusion polymer, Li2O2 (the product of O2 reduction on discharge) fills a greater volume fraction of the electrode and is more homogeneously distributed.

Randomized double-blind placebo-controlled study to evaluate the effect of long-acting mesalamine on postinfectious irritable bowel syndrome with diarrhea.

BACKGROUND: A subset of patients with irritable bowel syndrome (IBS) develop their symptoms after gastroenteritis, referred to as postinfectious IBS (PI-IBS). PI-IBS is associated with low-grade intestinal inflammation. Previous studies have evaluated mesalamine, an anti-inflammatory drug, in patients with IBS. We evaluated the efficacy of long-acting mesalamine in patients with PI-IBS. METHODS: Sixty-one patients who developed diarrhea-predominant IBS (IBS-D) after gastroenteritis were randomized to receive either 2.4 g of long-acting mesalamine or placebo daily for 8-weeks. The symptoms assessed were abdominal pain, bloating, stool frequency, stool consistency, severity of diarrhea and constipation, satisfaction with bowel habits, and IBS affecting or interfering with life. Quality-of-life (QOL) was assessed using the IBS-QOL questionnaire. The prespecified primary outcome variable was the overall bowel symptom score (BSS) after 8-weeks of treatment. Effect sizes were expressed as standardized mean differences (Cohen's d). RESULTS: Fifty-four patients completed the 8-week treatment (n = 28 mesalamine, n = 26 placebo), 49 (91%) were male, and age range 23-71 years (mean ± SD 43 ± 13). Mesalamine demonstrated superior efficacy compared to placebo on the primary outcome variable, overall BSS (Cohen's d = 0.57, p = 0.042). Mesalamine was also superior for the secondary outcome of how much IBS affects your life in general (d = 0.72, p = 0.01). For the secondary outcomes of IBS symptoms, 7 of the 7 symptoms had trends of mesalamine superiority. For the secondary outcomes of IBS-QOL subscales, 8 of 9 had trends of mesalamine superiority. CONCLUSION: In patients with PI-IBS, long-acting mesalamine demonstrated to be effective in reducing IBS symptoms and improving QOL.

Transplantation Within 6 Months of Registration does not Enhance Survival for Patients with Perihilar Cholangiocarcinoma.

OBJECTIVES: Determine if timing of transplantation affects patient mortality. BACKGROUND: Neoadjuvant therapy and liver transplantation has emerged as an excellent treatment option for select patients with perihilar cholangiocarcinoma (pCCA). However, the optimal timing of transplantation is not known. METHODS: We reviewed all patients registered for a standardized pCCA protocol between 1996 - 2020 at our center. After adjusting for confounders, we examined the association of waiting time with patient mortality in an intention-to-treat cohort (n=392) and those who received a liver transplant (n=256). RESULTS: The median (interquartile range) time from registration to transplant or drop out was 5.74 (3.25-7.06) months. Compared to a short wait time (0-3 months), longer waiting times did not affect all-cause mortality: (3-6 months) hazard ratio (HR) 0.98; 95% CI 0.52-1.84; (6-9 months) HR 0.80; 95% CI 0.39-1.65; (9-12 months) HR 0.56; 95% CI 0.26-1.22. Subgroups with a shorter waiting time had similar survival to those with long waiting times: living donor available HR 0.97; 95% CI 0.67-1.42; AB or B blood group HR 0.93; 95% CI 0.62-1.39. Longer waiting times were associated with decreased all-cause mortality after transplantation (HR 0.92; 95% CI 0.87-0.97). This benefit began after a 6 month waiting time minimum (HR 0.53; 95% CI 0.26-1.10) and increased further after 9 months (HR; 0.43 95% CI 0.20-0.93). Waiting time was not associated with residual adenocarcinoma in the explant (odds ratio 0.99; 95% CI 0.98-1.00). CONCLUSIONS: A waiting time of at least 6 months will optimize results with transplantation without affecting overall (intention-to-treat) patient survival.

Helping ourselves, helping others: the Young Women's Breast Cancer Study (YWS) - a multisite prospective cohort study to advance the understanding of breast cancer diagnosed in women aged 40 years and younger.

PURPOSE: Compared with older women diagnosed with breast cancer, younger women are more likely to die of breast cancer and more likely to suffer psychosocially in both the short-term and long term. The Young Women's Breast Cancer Study (YWS) is a multisite prospective cohort study established to address gaps in our knowledge about this vulnerable and understudied population. PARTICIPANTS: The YWS enrolled 1302 women newly diagnosed with stages 0-IV breast cancer at age 40 years or younger at 13 academic and community sites in North America between 2006 and 2016. Longitudinal patient-reported outcome data are complemented by clinical data abstraction and biospecimen collection at multiple timepoints. FINDINGS TO DATE: Key findings related to fertility include that nearly 40% of participants were interested in pregnancy following diagnosis; of those who reported interest, 10% pursued fertility preservation. Overall, approximately 10% of YWS participants became pregnant in the first 5 years after diagnosis; follow-up is ongoing for pregnancies after 5 years. Studies focused on psychosocial outcomes have characterised quality of life, post-traumatic stress and fear of recurrence, with findings detailing the factors associated with the substantial psychosocial burden many young women face during and following active treatment. Multiple studies have leveraged YWS biospecimens, including whole-exome sequencing of tumour analyses that revealed that select somatic alterations occur at different frequencies in young (age≤35) versus older women with luminal A breast cancer, and a study that explored clonal hematopoiesis of indeterminate potential found it to be rare in young survivors. FUTURE PLANS: With a median follow-up of approximately 10 years, the cohort is just maturing for many relevant long-term outcomes and provides outstanding opportunities to further study and build collaborations to address gaps in our knowledge, with the ultimate objective to improve care and outcomes for young women with breast cancer. TRIAL REGISTRATION NUMBER: NCT01468246.

First-Generation OTC Antihistamine Use and Voice Function in Individuals with Allergic Rhinitis: A Preliminary Report of Clinically Impactful Findings.

PURPOSE: The primary goal of this investigation was to characterize the effect of the first-generation, over-the-counter antihistamine Chlor-Trimeton on laryngeal structure and function in a previously unstudied population - individuals diagnosed with allergic rhinitis who routinely take over-the-counter antihistamines and deny the experience or diagnosis of voice disorder. STUDY DESIGN: Prospective within-participant multimodality repeated measures design. METHODS: Eight consented participants (seven females, one male) previously diagnosed with allergic rhinitis and without history of voice disorder who routinely took over-the-counter antihistamines completed the study. Volunteers completed the following measures before and 2hours after antihistamine administration: perceptual vocal function measures, phonation threshold pressure (PTP), acoustic measures, and laryngeal imaging. All pre- and post-administration data were descriptively analyzed for clinically significant change. RESULTS: No clinically significant differences were identified for any acoustic or aerodynamic measures taken. Analyses of laryngeal imaging data indicated that all participants had evidence of mucosal changes in one or more of the following parameters: increased vascularity, mucus in the anterior commissure, and vocal fold color changes, all of which are consistent with prior descriptions of allergy larynx. CONCLUSIONS: Empirical study of laryngeal appearance in individuals diagnosed with allergic rhinitis, affirmed clinical observations of laryngeal tissue changes consistent with allergy larynx. Stable PTP suggests potential vocal fold cover adaptations from routine use of over-the-counter antihistamines that may buffer the typical desiccating effect on voice function observed in prior studies of healthy individuals.

The relationship between intraosseous catheter tip placement, flow rates, and infusion pressures in a high bone density cadaveric swine (Sus scrofa) model.

Background: Intraosseous (IO) infusion is a life-preserving technique when intravenous access is unobtainable. Successful IO infusion requires sufficiently high flow rates to preserve life but at low enough pressures to avoid complications. However, IO catheter tips are often misplaced, and the relative flow rates and pressures between IO catheter tips placed in medullary, trabecular, and cortical bone are not well described, which has important implications for clinical practice. Objectives: We developed the Zone Theory of IO Catheter Tip Placement based on bone density and proximity to the venous central sinus and then tested the influence of catheter tip placement locations on flow rates and pressures in a cadaveric swine model. Methods: Three cross-trained participants infused 500 mL of crystalloid fluid into cadaveric swine humerus and sternum (N = 210 trials total) using a push‒pull method with a 60 cm3 syringe. Computed tomography scans were scored by radiologists and categorized as zone 1 (medullary space), zone 2 (trabecular bone), or zone 3 (cortical bone) catheter tip placements. Differences between zones in flow rates, mean pressures, and peak pressures were assessed using analysis of variance and analysis of covariance to account for participant and site differences at the p < 0.05 threshold. Results: Zone 1 and zone 2 placements were essentially identical in flow rates, mean pressures, and peak pressures (each p > 0.05). Zone 1 and zone 2 placements were significantly higher in flow rates and lower in pressures than zone 3 placements (each p < 0.05 or less). Conclusion: Within the limitations of an unpressurized cadaveric swine model, the present findings suggest that IO catheter tip placements need not be perfect to acquire high flow rates at low pressures, only accurate enough to avoid the dense cortical bone of zone 3. Future research using in vivo animal and human models is needed to better define the clinical impact of IO catheter placement on infusion flow rates and pressures.

Identification of Data-Driven Preoperative Hemoglobin Strata That Predict the Likelihood of Blood Transfusion and the Risk of Major Complications and Prosthetic Joint Infection After Total Hip Arthroplasty.

INTRODUCTION: Preoperative anemia is an independent risk factor of complications after primary total hip arthroplasty (THA). Currently used hemoglobin thresholds are not developed for risk stratification of arthroplasty patients and do not provide surgery-specific information on postoperative complication risk. Thus, we aimed to calculate THA-specific preoperative hemoglobin strata that observe the likelihood of 90-day blood transfusion and determine whether these strata are associated with increased risk of 90-day complications and 2-year prosthetic joint infection (PJI). METHODS: A retrospective cohort analysis identified 56,101 patients who underwent primary THA from 2013 to 2022. Using the lowest hemoglobin value for each patient one month before THA, stratum-specific likelihood ratio (SSLR) analysis calculated sex-based hemoglobin strata associated with the likelihood of 90-day postoperative blood transfusion. Propensity score matching was performed. Incidence rates and risk of 90-day major complications and 2-year PJI were observed for each identified preoperative hemoglobin stratum. RESULTS: SSLR analysis identified five male (strata, likelihood ratio [<10.4 g/dL, 12.5; 10.5 to 11.4 g/dL, 8.0; 11.5 to 12.4 g/dL, 2.4; 12.5 to 13.4 g/dL, 1.3; 13.5 to 13.9 g/dL, 0.5]) and five female (<8.9 g/dL, 10.7; 9.0 to 10.9 g/dL, 4.0; 11.0 to 11.4 g/dL, 2.0; 12.0 to 12.9 g/dL, 1.0; 13.0 to 13.4 g/dL, 0.6) preoperative hemoglobin strata associated with varying likelihoods of 90-day blood transfusion after THA. After matching in both male and female cohorts, as the calculated preoperative hemoglobin strata decreased, the relative risk of overall 90-day major complications and 2-year PJI increased incrementally (all P < 0.05). CONCLUSION: SSLR analysis established THA-specific sex-based preoperative hemoglobin strata that observe the likelihood of 90-day blood transfusion and predict the risk of 90-day medical complications and 2-year PJI. These strata are a first of their kind in THA research. While preoperatively optimizing patients, we recommend using these hemoglobin thresholds to help guide decisions on presurgery anemia optimization and to reduce the need for postoperative blood transfusion. LEVEL OF EVIDENCE: Level III.

Associations of Cognitively Active Versus Passive Sedentary Behaviors and Cognition in Older Adults.

BACKGROUND: Cognitively stimulating sedentary behavior (SB) may positively impact cognition. This study aimed to (1) describe participation across types of SB among older adults with and without cognitive impairment and (2) examine how baseline SB participation impacts cognition, longitudinally. METHODS: We used National Health and Aging Trends Study data from rounds 6 to 11 for cross-sectional and longitudinal analyses. Participants were 2244 community-dwelling older adults who were selected for the SB module in round 6. The SBs were categorized as active (eg, hobbies) and passive (eg, television). Participants were also categorized as having intact or impaired orientation, memory, and executive function based on tests of orientation, recall, and the clock-drawing test. We calculated descriptive statistics characterizing SB by cognitive status. Aim 2 involved competing risks proportional hazard models of participants with intact cognition (n = 1574) to identify associations between baseline SB and changes in cognition, moves to institutional care, and death over 6 years. RESULTS: Participants (40% ≥ 80 years, 55% female, 77% White non-Hispanic) averaged 8.75 (SD = 4.42) hours of daily SB, including 4.05 (SD = 2.32) hours of passive SB and 4.75 (SD = 3.13) hours of active SB. Active SB >3 hours per day was associated with a lower risk of impaired orientation (subdistribution hazard models = 0.60; P = .048) and memory (subdistribution hazard models = 0.62; P = .02). Baseline participation in passive SB did not impact the risk of having a change in cognition during rounds 7 to 11. CONCLUSION: Cognitive decline was lower among older adults who participated in more active SB. Thus, type of SB should be considered in examining the impact on cognition.

A Droplet Digital Polymerase Chain Reaction-Based Tool to Aid in Melanoma Diagnosis.

CONTEXT.­: Detecting copy number variations (CNVs) at certain loci can aid in the diagnosis of histologically ambiguous melanocytic neoplasms. Droplet digital polymerase chain reaction (ddPCR) is a rapid, automated, and inexpensive method for CNV detection in other cancers, but not yet melanoma. OBJECTIVE.­: To evaluate the performance of a 4-gene ddPCR panel that simultaneously tests for ras responsive binding element protein 1 (RREB1) gain; cyclin-dependent kinase inhibitor 2A (CDKN2A) loss; MYC proto-oncogene, bHLH transcription factor (MYC) gain; and MYB proto-oncogene, transcription factor (MYB) loss in melanocytic neoplasms. DESIGN.­: One hundred sixty-four formalin-fixed, paraffin-embedded skin samples were used to develop the assay, of which 65 were used to evaluate its performance. Chromosomal microarray analysis (CMA) data were used as the gold standard. RESULTS.­: ddPCR demonstrated high concordance with CMA in detecting RREB1 gain (sensitivity, 86.7%; specificity, 88.9%), CDKN2A loss (sensitivity, 80%; specificity, 100%), MYC gain (sensitivity, 70%; specificity, 100%), and MYB loss (sensitivity, 71.4%; specificity, 100%). When one CNV was required to designate the test as positive, the 4-gene ddPCR panel distinguished nevi from melanomas with a sensitivity of 78.4% and a specificity of 71.4%. For reference, CMA had a sensitivity of 86.2% and a specificity of 78.6%. Our data also revealed interesting relationships with histology, namely (1) a positive correlation between RREB1 ddPCR copy number and degree of tumor progression; (2) a statistically significant correlation between MYC gain and nodular growth; and (3) a statistically significant correlation between MYB loss and a sheetlike pattern of growth. CONCLUSIONS.­: With further validation, ddPCR may aid both in our understanding of melanomagenesis and in the diagnosis of challenging melanocytic neoplasms.

One-pot Golden Gate Assembly of an avian infectious bronchitis virus reverse genetics system.

Avian infectious bronchitis is an acute respiratory disease of poultry of particular concern for global food security. Investigation of infectious bronchitis virus (IBV), the causative agent of avian infectious bronchitis, via reverse genetics enables deeper understanding of virus biology and a rapid response to emerging variants. Classic methods of reverse genetics for IBV can be time consuming, rely on recombination for the introduction of mutations, and, depending on the system, can be subject to genome instability and unreliable success rates. In this study, we have applied data-optimized Golden Gate Assembly design to create a rapidly executable, flexible, and faithful reverse genetics system for IBV. The IBV genome was divided into 12 fragments at high-fidelity fusion site breakpoints. All fragments were synthetically produced and propagated in E. coli plasmids, amenable to standard molecular biology techniques for DNA manipulation. The assembly can be carried out in a single reaction, with the products used directly in subsequent viral rescue steps. We demonstrate the use of this system for generation of point mutants and gene replacements. This Golden Gate Assembly-based reverse genetics system will enable rapid response to emerging variants of IBV, particularly important to vaccine development for controlling spread within poultry populations.

Improved quantitative parameter estimation for prostate T2 relaxometry using convolutional neural networks.

OBJECTIVE: Quantitative parameter mapping conventionally relies on curve fitting techniques to estimate parameters from magnetic resonance image series. This study compares conventional curve fitting techniques to methods using neural networks (NN) for measuring T2 in the prostate. MATERIALS AND METHODS: Large physics-based synthetic datasets simulating T2 mapping acquisitions were generated for training NNs and for quantitative performance comparisons. Four combinations of different NN architectures and training corpora were implemented and compared with four different curve fitting strategies. All methods were compared quantitatively using synthetic data with known ground truth, and further compared on in vivo test data, with and without noise augmentation, to evaluate feasibility and noise robustness. RESULTS: In the evaluation on synthetic data, a convolutional neural network (CNN), trained in a supervised fashion using synthetic data generated from naturalistic images, showed the highest overall accuracy and precision amongst the methods. On in vivo data, this best performing method produced low-noise T2 maps and showed the least deterioration with increasing input noise levels. DISCUSSION: This study showed that a CNN, trained with synthetic data in a supervised manner, may provide superior T2 estimation performance compared to conventional curve fitting, especially in low signal-to-noise regions.

Influence of Training Background on Elbow Arthroplasty Case Numbers: An Analysis of the American Board of Orthopaedic Surgery Part II Oral Examination Case List Database.

INTRODUCTION: This study aimed to evaluate the influence of training background on the frequency and indications of elbow arthroplasty performed by early-career surgeons. METHODS: A review of the American Board of Orthopaedic Surgery Part II Oral Examination Case List database from 2010 to 2021 was completed. The number of cases performed by surgeons from each individual training background were calculated and compared with the total number of surgeons who completed each fellowship during the study period. RESULTS: Hand surgeons performed the most elbow arthroplasty cases (132, 44%), but a higher percentage of shoulder/elbow surgeons performed elbow arthroplasty in comparison (15% vs. 7%). The mean number of TEA cases performed by shoulder/elbow surgeons was significantly higher than in other subspecialties (P < 0.01). However, when comparing only surgeons who performed elbow arthroplasty during the board collection period, there was no significant difference between training backgrounds (P = 0.20). DISCUSSION: While hand surgeons performed the most elbow arthroplasty cases, a higher percentage of shoulder/elbow surgeons performed elbow arthroplasty during the study period. The high prevalence of distal humerus fracture as an indication for arthroplasty reflected a shift in indications and was not related to training background.

Validation and Implementation of a Somatic-Only Tumor Exome for Routine Clinical Application.

Next-generation sequencing-based genomic testing is standard of care for tumor workflows. However, its application across different institutions continues to be challenging given the diversity of needs and resource availability among different institutions globally. Moreover, the use of a variety of different panels, including those from a few individual genes to those involving hundreds of genes, results in a relatively skewed distribution of care for patients. It is imperative to obtain a higher level of standardization without having to be restricted to specific kits or requiring repeated validations, which are generally expensive. We show the validation and clinical implementation of the DH-CancerSeq assay, a tumor-only whole-exome-based sequencing assay with integrated informatics, while providing similar input requirements, sensitivity, and specificity to a previously validated targeted gene panel and maintaining similar turnaround times for patient care.