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Introduction: Pediatric-onset Crohn's disease (CD) has a more severe phenotype than adult-onset, and nearly one-third of pediatric CD patients will require surgical therapy. There is limited data on patient/disease characteristics that are associated with earlier surgical management., Methods: All pediatric CD patients (<22 yrs) who underwent ileocolectomy from 2005 to 2021 were included. Unadjusted analyses were performed with Pearson chi-squared tests for categorical dependent variables, and t-tests, or analysis of variance, for numerical dependent variables., Results: One hundred thirty-five pediatric CD patients underwent ileocolectomy. The median time to surgery was 3.75 yrs. Patients treated with early surgery (<3.75 yrs from diagnosis) were older at diagnosis (16.5 versus 11.6 yrs, P < 0.001) yet had surgery at a younger age (16.8 versus 18.9 yrs, P < 0.001). They also were prescribed fewer CD medications (2.0 versus 4.0, P < 0.001), were less likely to have trialed multiple biologics (25.6% versus 54.2%, P = 0.001), had a shorter time from diagnosis to biologic (0.3 versus 3.5 yrs, P < 0.001), and had a shorter interval from biologic to surgery (0.4 versus 2.5 yrs, P < 0.001). Abscess formation was a more common indication for early surgery (39.4% versus 14.7%, P = 0.002), whereas failure to thrive/refractory pain was more common for later surgery (27.3% versus 55.9%, P = 0.001)., Conclusions: Surgical therapy remains an important component of the overall management of pediatric CD. In our cohort, earlier surgical management was associated with earlier use of biologics, a shorter duration between biologic and surgery, and decreased number of overall medications and biologic agents prior to surgery, suggesting a severe disease phenotype refractory to medical management., (Published by Elsevier Inc.)

Hypertrophic cardiomyopathy (HCM) afflicts humans, cats, pigs, and rhesus macaques. Disease sequelae include congestive heart failure, thromboembolism, and sudden cardiac death (SCD). Sarcomeric mutations explain some human and cat cases, however, the molecular basis in rhesus macaques remains unknown. RNA-Seq of the LV tissues of five HCM-affected and seven healthy control rhesus macaques was employed for differential transcriptomic analyses. DNA from 15 severely HCM-affected and 21 healthy geriatric rhesus macaques were selected for whole-genome sequencing. A genome-wide association study (GWAS) of disease status and SCD outcome was performed. 614 down- and 1,065 upregulated differentially expressed genes (DEGs) were identified between groups. The top DEG (MAFF) was overexpressed in affected animals (log2FoldChange = 4.71; P Adjusted -value = 1.14E-133). Channelopathy-associated enriched terms were identified in ~ 57% of downregulated DEGs providing transcriptomic evidence of hypertrophic and arrhythmic disease processes. For GWAS, no putative variant withstood segregation. Polygenic modeling analysis resulted in poor prediction power and burden testing could not explain HCM by an association of multiple variants in any gene. Neither single nor compound genetic variant(s), or identified polygenic profile, suggest complex genotype-phenotype interactions in rhesus macaques. Brought forth is an established dataset of robustly phenotyped rhesus macaques as an open-access resource for future cardiovascular disease genetic studies., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data., Methods: We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs. combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development., Results: A trend towards increased treatment failure among HLA DQA1*05 positive participants was not significant (HR 1.58, 95% CI 0.95-2.62; p=0.08). After stratification by HLA DQA1*05 and by methotrexate vs. placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05 positive patients on placebo (HR 0.31, 95% CI 0.13-0.70; p=0.005).A trend toward increased ADA development among HLA DQA1*05 positive participants was not significant (odds ratio [OR] 1.96, 95% CI 0.90-4.31, p=0.09). After further stratification, HLA DQA1*05 negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05 positive patients on placebo (OR 0.12, 95% CI 0.03-0.55; p=0.008)., Conclusions: In a randomized trial of children with CD initiating anti-TNF, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification., (Copyright © 2024 by The American College of Gastroenterology.)

Background: Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab)., Methods: We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization., Results: Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14)., Conclusions: LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The No Surprises Act (NSA) went into effect on January 1, 2022. This federal law is designed to minimize surprise bills for emergency care, out of network (OON) care, and care for uninsured or self-pay individuals. To achieve these goals, the NSA relies heavily on physicians providing cost estimates to patients prior to administering care. Because healthcare is often price-opaque, this study was conducted to assess physician and patient attitudes toward price transparency in plastic surgery and aesthetic/self-pay medicine., Methods: Two cohorts of providers received a survey asking whether and how their practice offers pricing information prior to a consultation and their views regarding the NSA. Patients who had previously used an online price estimator tool also received a survey regarding their experience and accuracy of estimates received online., Results: Most surveyed providers do not share the costs of their services online, whereas patients had a positive experience when receiving estimates of medical services before consultation. Although many providers cited the inaccuracy of price estimator tools as a reason not to incorporate them into their website, most patients reported that their final cost of service was close to (or even less than) the estimate received online prior to the consultation., Conclusions: This study suggests that price transparency is a patient satisfier. Therefore, plastic surgeons should exercise price transparency to be compliant with federal law and to gain a competitive advantage in the market, as the decision to implement price transparency can be mutually beneficial to patients and providers., Competing Interests: The senior author has equity interest in KP Innovations LLC. The other authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Diagnosing paediatric Crohn's disease (CD) based on histology can present challenges. We evaluate the histological spectrum of treatment-naïve biopsies from children with CD and assess these findings' diagnostic and predictive value., Methods: Three cohorts were identified: (1) 137 patients with CD, (2) 116 patients with ulcerative colitis (UC) and (3) 50 patients without inflammatory bowel disease. Biopsies from the gastrointestinal (GI) tract were re-examined for signs of active and chronic inflammation, including lymphocyte-pattern oesophagitis, focal enhancing gastritis and indicators of chronicity. Additionally, granulomas and microgranulomas (defined as clusters of 4-9 epithelioid histiocytes) were evaluated., Results: Lymphocyte-pattern oesophagitis was observed in 15% of patients (n=20). Moderate-to-severe diffuse gastritis was noted in 50.4% of patients (n=68), while focal enhancing gastritis was identified in 11.1% (n=15). In terminal ileal biopsies, 46.1% exhibited activity and 5.3% showed features of chronicity. Active colitis was present in 73% of patients (n=100), with chronic colitis seen in 11.7% (n=16). Granulomas and microgranulomas were observed in 31.4% (43/137) and 48.9% (67/137) of patients, respectively. Notably, 30.7% (42/137) of patients with microgranulomas were without granulomas. Previously undetected microgranulomas were found in 20 of 27 cases. 2.5% of patients with UC and none of the control cohort showed microgranulomas. Lymphocyte-pattern oesophagitis was associated with an increased need for anti-tumor necrosis factor (TNF) therapy (p=0.007)., Conclusions: GI microgranulomas, often overlooked, are specific to CD in the proper clinical context. Oesophageal lymphocytosis may predict a need for more aggressive treatment. The study brings to light under-recognised aspects of CD's histological diagnosis, including the oversight of microgranulomas, the high prevalence of diffuse gastritis and low prevalence of focal enhancing gastritis, the frequent absence of terminal ileitis and the infrequent occurrence of chronic colitis., Competing Interests: Competing interests: VD is the editor-in-chief of the Journal of Clinical Pathology. However, he was not involved in the adjudication process., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive HCM (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. The objective of this study was to explore the 6-, 24-, and 48-hour (h) pharmacodynamic effects of the cardiac myosin inhibitor, CK-586, in six purpose-bred cats with naturally occurring oHCM. A blinded, randomized, five-treatment group, crossover preclinical trial was conducted to assess the pharmacodynamic effects of CK-586 in this oHCM model. Dose assessments and select echocardiographic variables were assessed five times over a 48-h period. Treatment with oral CK-586 safely ameliorated LVOTO in oHCM cats. CK-586 treatment dose-dependently eliminated obstruction (reduced LVOTOmaxPG), increased measures of systolic chamber size (LVIDs Sx), and decreased select measures of heart function (LV FS% and LV EF%) in the absence of impact on heart rate. At all tested doses, a single oral CK-586 dose resulted in improved or resolved LVOTO with well-tolerated, dose-dependent, reductions in LV systolic function. The results from this study pave the way for the potential use of CK-586 in both the veterinary and human clinical setting., (© 2024. The Author(s).)

Dilated cardiomyopathy (DCM) is characterized by decreased systolic function and dilation of one or both ventricles, often leading to heart failure or sudden death. Two 10-month-old sibling Nova Scotia Duck Tolling Retrievers (NSDTR) died acutely with evidence of dilated cardiomyopathy with myocardial fibrosis. Association analysis using two cases and 35 controls identified three candidate regions homozygous in the two cases. Whole genome sequencing identified a frameshift deletion in the LMNA gene (NC&#95;049228.1:g.41688530del, NP&#95;001274080:p.(Asp576ThrfsTer124)). Three retrospectively identified NSDTRs with sudden death before 2 years of age and severe myocardial fibrosis were also homozygous for the deletion. One 5 year old with sudden death and myocardial fibrosis was heterozygous for the deletion. This variant was not identified in 722 dogs of other breeds, nor was it identified to be homozygous in 784 NSDTR. LMNA codes for lamin A/C proteins, which are type V intermediate filaments that provide structural support to the nuclear membrane. In humans, LMNA variants can cause DCM with sudden death as well as diseases of striated muscles, lipodystrophy, neuropathies, and accelerated aging disorders. This frameshift deletion is predicted to affect processing of prelamin A into lamin A. Pedigree analysis in the NSDTR and functional evaluation of heterozygotes is consistent with a predominantly recessive mode of inheritance and possibly low penetrance in heterozygotes in contrast to people, where most pathogenic LMNA variants are dominantly inherited., (© 2023. The Author(s).)

Feline HCM is the most common cardiovascular disease in cats, leading to devastating outcomes, including congestive heart failure (CHF), arterial thromboembolism (ATE), and sudden death. Evidence demonstrating long-term survival benefit with currently available therapies is lacking. Therefore, it is imperative to explore intricate genetic and molecular pathways that drive HCM pathophysiology to inspire the development of novel therapeutics. Several clinical trials exploring new drug therapies are currently underway, including those investigating small molecule inhibitors and rapamycin. This article outlines the key work performed using cellular and animal models that has led to and continues to guide the development of new innovative therapeutic strategies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) remains the single most common cardiomyopathy in cats, with a staggering prevalence as high as 15%. To date, little to no direct therapeutical intervention for HCM exists for veterinary patients. A previous study aimed to evaluate the effects of delayed-release (DR) rapamycin dosing in a client-owned population of subclinical, non-obstructive, HCM-affected cats and reported that the drug was well tolerated and resulted in beneficial LV remodeling. However, the precise effects of rapamycin in the hypertrophied myocardium remain unknown. Using a feline research colony with naturally occurring hereditary HCM (n = 9), we embarked on the first-ever pilot study to examine the tissue-, urine-, and plasma-level proteomic and tissue-level transcriptomic effects of an intermittent low dose (0.15 mg/kg) and high dose (0.30 mg/kg) of DR oral rapamycin once weekly. Rapamycin remained safe and well tolerated in cats receiving both doses for eight weeks. Following repeated weekly dosing, transcriptomic differences between the low- and high-dose groups support dose-responsive suppressive effects on myocardial hypertrophy and stimulatory effects on autophagy. Differences in the myocardial proteome between treated and control cats suggest potential anti-coagulant/-thrombotic, cellular remodeling, and metabolic effects of the drug. The results of this study closely recapitulate what is observed in the human literature, and the use of rapamycin in the clinical setting as the first therapeutic agent with disease-modifying effects on HCM remains promising. The results of this study establish the need for future validation efforts that investigate the fine-scale relationship between rapamycin treatment and the most compelling gene expression and protein abundance differences reported here.

Objective: Feline hypertrophic cardiomyopathy (HCM) remains a disease with little therapeutic advancement. Rapamycin modulates the mTOR pathway, preventing and reversing cardiac hypertrophy in rodent disease models. Its use in human renal allograft patients is associated with reduced cardiac wall thickness. We sought to evaluate the effects of once-weekly delayed-release (DR) rapamycin over 6 months on echocardiographic, biochemical, and biomarker responses in cats with subclinical, nonobstructive HCM., Animals: 43 client-owned cats with subclinical HCM., Methods: Cats enrolled in this double-blinded, multicentered, randomized, and placebo-controlled clinical trial were allocated to low- or high-dose DR rapamycin or placebo. Cats underwent physical examination, quality-of-life assessment, blood pressure, hematology, biochemistry, total T4, urinalysis, N-terminal pro-B-type natriuretic peptide, and cardiac troponin I at baseline and days 60, 120, and 180. Fructosamine was analyzed at screening and day 180. Echocardiograms were performed at all time points excluding day 120. Outcome variables were compared using a repeated measures ANCOVA., Results: No demographic, echocardiographic, or clinicopathologic values were significantly different between study groups at baseline, confirming successful randomization. At day 180, the primary study outcome variable, maximum LV myocardial wall thickness at any location, was significantly lower in the low-dose DR rapamycin group compared to placebo (P = .01). Oral DR rapamycin was well tolerated with no significant differences in adverse events between groups., Clinical Relevance: Results demonstrate that DR rapamycin was well tolerated and may prevent or delay progressive LV hypertrophy in cats with subclinical HCM. Additional studies are warranted to confirm and further characterize these results.

Background & Aims: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy., Methods: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected., Results: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs., Conclusions: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile., Clinicaltrials: gov, Number: NCT02772965., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

We sought to establish a large animal model of inherited hypertrophic cardiomyopathy (HCM) with sufficient disease severity and early penetrance for identification of novel therapeutic strategies. HCM is the most common inherited cardiac disorder affecting 1 in 250-500 people, yet few therapies for its treatment or prevention are available. A research colony of purpose-bred cats carrying the A31P mutation in MYBPC3 was founded using sperm from a single heterozygous male cat. Cardiac function in four generations was assessed by periodic echocardiography and measurement of blood biomarkers. Results showed that HCM penetrance was age-dependent, and that penetrance occurred earlier and was more severe in successive generations, especially in homozygotes. Homozygosity was also associated with progression from preclinical to clinical disease. A31P homozygous cats represent a heritable model of HCM with early disease penetrance and a severe phenotype necessary for interventional studies aimed at altering disease progression. The occurrence of a more severe phenotype in later generations of cats, and the occasional occurrence of HCM in wildtype cats suggests the presence of at least one gene modifier or a second causal variant in this research colony that exacerbates the HCM phenotype when inherited in combination with the A31P mutation., (© 2023. The Author(s).)

Background: Biologic medications are recommended for treatment of moderately-to-severely active Crohn disease (CD) or ulcerative colitis (UC) in children. However, many patients require sequential biologic treatment because of nonresponse or loss of response to the initial biologic., Methods: We analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation., Results: Of 17,649 patients with IBD [CD: 12,410 (70%); UC: 5239 (30%)], 7585 (43%) were treated with a biologic agent before age 18 (CD: 50%; UC: 25%). Biologic treatment was more likely for CD than UC (odds ratio, 3.0; 95% CI: 2.8-3.2; P < 0.0001). First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab). Probability of remaining on the first biologic was significantly higher in CD than UC ( P < 0.0001). First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%). In univariate analysis, factors associated with discontinuation of first and/or second biologics in CD include colonic-only disease, corticosteroid use, upper gastrointestinal tract involvement, and clinical and biochemical markers of severe disease. Biologic durability improved with later induction date., Conclusions: Treatment with biologic medications is common in pediatric IBD. Patients with CD are more likely to receive biologics, receive biologics earlier in disease course, and remain on the first biologic longer than patients with UC. Multiple factors may predict biologic durability in children with IBD., Competing Interests: R.B.C. received financial support for research in Janssen Biotech and received consultancy fees from Janssen Biotech and Janssen Research and Development. A.S.P. received lecture fee(s) from Janssen Biotech, AbbVie, and Abbott Nutrition and received consultancy fees from QOL. N.C. is an employee of Takeda Pharmaceuticals U.S.A., Inc., and owns stock or stock options. T.L. was an employee of Takeda Pharmaceuticals U.S.A., Inc., at the time the study was conducted. S.S. is in the Speaker’s Bureau for AbbVie, Inc. The remaining authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: We sought to evaluate the safety and effectiveness of fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (CDI) in pediatric immunocompromised (IC) patients., Methods: This is a multicenter retrospective cohort study of pediatric participants who underwent FMT between March 2013 and April 2020 with 12-week follow-up. Pediatric patients were included if they met the definition of IC and were treated with FMT for an indication of recurrent CDI. We excluded patients over 18 years of age, those with incomplete records, insufficient follow-up, or not meeting study definition of IC. We also excluded those treated for Clostridioides difficile recurrence without meeting the study definition and those with inflammatory bowel disease without another immunocompromising condition., Results: Of 59 pediatric patients identified at 9 centers, there were 42 who met inclusion and no exclusion criteria. Included patients had a median age of 6.7 years. Etiology of IC included: solid organ transplantation (18, 43%), malignancy (12, 28%), primary immunodeficiency (10, 24%), or other chronic conditions (2, 5%). Success rate was 79% after first FMT and 86% after 1 or more FMT. There were no statistically significant differences in patient characteristics or procedural components when patients with a failed FMT were compared to those with a successful FMT. There were 15 total serious adverse events (SAEs) in 13 out of 42 (31%) patients that occurred during the follow-up period; 4 (9.5%) of which were likely treatment-related. There were no deaths or infections with multidrug resistant organisms during follow-up and all patients with a SAE fully recovered., Conclusions: The success rate of FMT for recurrent CDI in this pediatric IC cohort is high and mirrors data for IC adults and immunocompetent children. FMT-related SAEs do occur (9.5%) and highlight the need for careful consideration of risk and benefit., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Cats with hypertrophic cardiomyopathy (HCM) are at risk of cardiogenic arterial thromboembolism (CATE). Neutrophil extracellular traps (NETs) may be a potential biomarker and therapeutic target for cardiomyopathy in cats., Hypothesis/objectives: Characterize NETs in cats with HCM or CATE. We hypothesized that circulating NETs assessed in the form of cell-free DNA (cfDNA) and citrullinated histone H3 (citH3) are increased in cats with HCM and CATE and associated with reported predisposing factors for thrombus formation., Animals: Eighty-five cats including client-owned cats with HCM and CATE and staff- and student-owned clinically healthy cats without HCM., Methods: After echocardiographic evaluations, NETs were measured as cfDNA and citH3., Results: Cats with CATE had significant increases in cfDNA (11.2 ng/μL; interquartile range [IQR], 8.1 to 29.6) compared to those without HCM (8.2 ng/μL; IQR, 5.7 to 11.7 μL; P = .01) and were responsible for 75% to 83% of cases with cfDNA fragments sized 100 to 2000 base pairs. Citrullinated histone 3, detected in 52% of cats with HCM (31.1 ng/mL; IQR, 16.9 to 29.8), was significantly lower than in those with CATE (48.2 ng/mL; IQR, 34.2 to 60.2; P = .007). The citH3 concentrations correlated significantly with reported risk factors of CATE, such as left atrial auricular velocity., Conclusions and Clinical Importance: Neutrophil extracellualr traps, especially citH3, are increased in cats with HCM and CATE. They may serve as a novel therapeutic target and biomarker of thrombosis in cats with HCM., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Introduction/objectives: To evaluate regurgitant fraction (RF) using Simpson's method of discs to estimate total stroke volume (RF SMOD&#95;TSV ) and using Motion-mode to estimate total stroke volume (RF M-modeTSV ) in dogs with subclinical myxomatous mitral valve disease (MMVD). We also sought to evaluate the effects of pimobendan on RF, and to determine the reproducibility of RF SMOD&#95;TSV and RF M-modeTSV ., Animals, Materials, and Methods: Echocardiography was performed on 57 dogs with MMVD (30 stage B1 and 27 stage B2). Ten dogs received pimobendan for 7-10 days and had a second echocardiogram. Nine dogs underwent six repeated echocardiographic examinations by two operators on three nonconsecutive days within one week for reproducibility analysis., Results: Both RF SMOD&#95;TSV and RF M-modeTSV exhibited a curvilinear relationship with left atrium-to-aortic root ratio. Both RF SMOD&#95;TSV and RF M-modeTSV varied considerably within stage B1 (minimum-maximum: -9.1%-58.2% and -35.7%-66.2%, respectively) and B2 (13.6%-76.2% and 20.1%-85.7%, respectively). Method comparison showed RF SMOD&#95;TSV and RF M-modeTSV were not interchangeable with proportional bias. Pimobendan significantly reduced RF SMOD&#95;TSV (-32.0% ± 23.3%) and RF M-modeTSV (-19.2% ± 10.9%) within the same dog and relative to controls. Good inter-day and between-operator reproducibility was observed for RF SMOD&#95;TSV and RF M-modeTSV based on intraclass correlation coefficients 0.86-0.90 and 0.83-0.90, respectively. Reproducibility coefficients were 19.6%-24.1% and 24.1%-27.0%, respectively., Conclusions: Use of RF using the total stroke volume method to aid the assessment of dogs with subclinical MMVD might be of clinical value. However, further study is warranted. Based on response to pimobendan and reproducibility analysis, RF SMOD&#95;TSV might be a more reliable technique to quantify RF., (Copyright © 2022 Elsevier B.V. All rights reserved.)

While breast cancer is a common disease with many available treatment options, many patients still have limited responses, especially those with metastatic breast cancer. Surgery of the primary tumor or metastatic sites is often not part of the treatment regimen for patients with metastatic breast cancer. Cryoablation is a relatively non-invasive procedure that is being investigated for patients with breast cancer. Patients with metastatic breast cancer who are not surgical candidates may derive benefit from cryoablation through the abscopal effect. In this case report, we present a patient with stage IV breast cancer who was treated with cryoablation of the primary breast tumor and showed evidence of an abscopal effect in regional and distant metastases., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease in humans and cats and lacks efficacious pharmacologic interventions in the preclinical phase of disease. LV outflow tract obstruction (LVOTO) is commonly observed in HCM-affected patients and is a primary driver of heart failure symptoms and reduced quality of life. Novel small-molecule cardiac myosin inhibitors target actin-myosin interactions to alleviate overactive protein interactions. A prospective, randomized, controlled cross-over study was performed to evaluate pharmacodynamic effects of two doses (0.3 and 1 mg/kg) of a next-in-class cardiac myosin inhibitor, aficamten (CK-3773274, CK-274), on cardiac function in cats with the A31P MYBPC3 mutation and oHCM. Dose-dependent reductions in LV systolic function, LVOT pressure gradient, and isovolumetric relaxation times compared to baseline were observed. Promising beneficial effects of reduced systolic function warrant further studies of this next-in-class therapeutic to evaluate the benefit of long-term administration in this patient population., (© 2022. The Author(s).)

Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiac disease in cats and lacks efficacious preclinical pharmacologic intervention, prompting investigation of novel therapies. Genetic mutations encoding sarcomeric proteins are implicated in the development of HCM and small molecule myosin inhibitors are an emerging class of therapeutics designed to target the interaction of actin and myosin to alleviate the detrimental effects of inappropriate contractile protein interactions. The purpose of this study was to characterize the pharmacodynamic effects of a single oral dose of the novel cardiac myosin inhibitor aficamten (CK-274) on cardiac function in purpose bred cats with naturally occurring A31P MYBPC3 mutation and a clinical diagnosis of HCM with left ventricular outflow tract obstruction (LVOTO). Five purpose bred cats were treated with aficamten (2 mg/kg) or vehicle and echocardiographic evaluations were performed at 0, 6, 24, and 48 h post-dosing. High dose aficamten (2 mg/kg) reduced left ventricular fractional shortening (LVFS%) by increasing the LV systolic internal dimension (LVIDs) and reduced isovolumic relaxation time (IVRT) compared with baseline without significant adverse effects. The marked reduction in systolic function and reduced IVRT coupled with an increased heart rate in treated cats, suggest a lower dose may be optimal. Further studies to determine optimal dosing of aficamten are indicated., (© 2022 The Authors. Journal of Veterinary Pharmacology and Therapeutics published by John Wiley & Sons Ltd.)

Purpose: The aim of this study was to explore potential correlation of the MR imaging features and clinical characteristics with formation of perianal abscess in children with Crohn's perianal fistulas (CPF)., Methods: From 2010 to 2020, pediatric patients with CPF diagnosis on their first pelvic MRI were identified retrospectively. All patients were divided into two groups based on the presence or absence of perianal abscess. Baseline clinical and MRI characteristics were recorded for each patient. All the statistical calculations were performed using R (version 3.6.3)., Results: A total of 60 patients [F:M 17:43, median age 14 years (IQR 10-15), ranging 3-18 years] were included in this study. Forty-four abscesses were identified in 36/60 children (mean volume 3 ± 8.6 ml, median 0.3 ml). In 24/60 patients with perianal disease, no abscess was detected on the MRI. Ten patients (28%) showed perianal abscess on pelvic MRI at the initial diagnosis. The rate of active disease on colonoscopy (visible ulcerations/aphthous ulcers) was similar in both groups (95% vs. 94%). With regards to disease location, the majority of patients (40/60, 66.6%) in both groups had ileocolonic CD. All patients without abscess had a single perianal fistula ( n  = 24; 3 simple and 21 complex fistulae), however, patients with perianal abscess tended to have >1 fistulous tracts ( n  = 50 fistulas; all complex, 27 single, 10 double and 1 triple). Intersphincteric fistula was the most common fistula type in both groups (79% and 66%, p  = 0.1). The total length of fistula (3.8 ± 1.7 vs. 2.8 ± 0.8 cm, p  = 0.006) and presence of multiple external openings ( n  = 25 vs. 7, p  = 0.019) were significantly higher in patients with abscesses, and fistula length >3.3 cm showed 80% specificity and 83% PPV for the presence of perianal abscess. Fistulas were symptomatic (pain, bleeding or drainage) at similar rates in both groups (68% and 70%, p  = 0.1)., Conclusion: Pediatric patients with CPF who develop perianal abscess have a distinct imaging phenotype defined by longer fistula length (>3.3 cm), multiple skin openings and multiple fistulous tracts (≥2) on MRI. Patients who have these features but does not have an abscess on imaging may merit more aggressive treatment (and close monitoring) to prevent the development of an abscess., Competing Interests: Author SH was employed by company Takeda Pharmaceuticals International Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Takeda Pharmaceuticals International Co. Takeda was involved in reviewing the final draft and the decision to submit this study for publication., (© 2022 Tabari, Kaplan, Huh, Moran and Gee.)

Background: Pimobendan might have favorable effects on renal function but this has not been well-studied in dogs with myxomatous mitral valve disease (MMVD)., Objectives: Determine the effects of standard-dose (SD&#95;pimo) and high-dose pimobendan (HD&#95;pimo) on glomerular filtration rate (GFR) and cardiac size and function in dogs with preclinical MMVD., Animals: Thirty nonazotemic dogs with stage B2 MMVD., Methods: Prospective, randomized, double-blinded, placebo-controlled clinical study. Dogs had an echocardiographic examination, assessment of GFR (iohexol clearance), N-terminal probrain natriuretic peptide (NT-proBNP), and quality of life (QOL) score at baseline and 7 to 10 days after placebo (n = 6), SD&#95;pimo 0.2 to 0.3 mg/kg q12 (n = 12), or HD&#95;pimo 0.5 to 0.6 mg/kg q12h (n = 12)., Results: No significant differences in GFR or QOL scores were detected between groups (P ≥ .07). After HD&#95;pimo, the mean [SD] percent change of NT&#95;proBNP (-46.1 [20.2]%), left atrial volume (LAV; -27.1 [16.9]%), left ventricular end-diastolic volume (EDV; -21.8 [15.0]%), and end-systolic volume (ESV; -55.0 [20.7]%) were significantly different (P ≤ .004) from placebo (0.5 [19.9]%, 1.3 [15.6]%, -0.2 [8.2]%, -7.3 [35.6]%, respectively) but not the percent change after SD&#95;pimo (-36.6 [16.1]%, -22.7 [14.9]%, -16.7 [12.5]%, -41.6 [14.8]%, respectively; P > .05). After SD&#95;pimo, percent change of NT&#95;proBNP, LAV, EDV, and ESV were significantly different from placebo (P < .05)., Conclusions and Clinical Importance: Results suggest that pimobendan (SD&#95;pimo or HD&#95;pimo) might not affect renal function in nonazotemic dogs with stage B2 MMVD. High-dose pimobendan did not demonstrate advantages over SD&#95;pimo within the constraints of our study., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

A two-week-old female llama cria was brought to the UC Davis Large Animal Hospital for evaluation of a cardiac murmur and suspected syncopal episodes. A grade IV/VI left basilar continuous murmur was present on cardiac auscultation. Echocardiography revealed a left-to-right shunting patent ductus arteriosus (PDA), mild left ventricular enlargement, scant pericardial effusion, and a suspected persistent left cranial vena cava. The PDA was successfully closed with an Amplatz canine duct occluder. Mild mitral regurgitation was present on echocardiography performed 7 d following PDA occlusion. No syncopal episodes were observed in hospital prior to or following PDA occlusion. At approximately 1 mo following PDA closure, a grade I/VI left apical systolic murmur was present and the cria's body condition was improved. Key clinical message: Patent ductus arteriosus closure is achievable in New World camelids using interventional cardiology which provides a minimally invasive treatment option for valuable or companion animals. Since interventional cardiac catheterization is commonly performed in small animal species, veterinary cardiologists are well-equipped to apply these skills to camelids., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Background: Children with inflammatory bowel disease [IBD] are disproportionally affected by recurrent Clostridioides difficile infection [rCDI]. Although faecal microbiota transplantation [FMT] has been used with good efficacy in adults with IBD, little is known about outcomes associated with FMT in paediatric IBD., Methods: We performed a retrospective review of FMT at 20 paediatric centres in the USA from March 2012 to March 2020. Children with and without IBD were compared with determined differences in the efficacy of FMT for rCDI. In addition, children with IBD with and without a successful outcome were compared with determined predictors of success. Safety data and IBD-specific outcomes were obtained., Results: A total of 396 paediatric patients, including 148 with IBD, were included. Children with IBD were no less likely to have a successful first FMT then the non-IBD affected cohort [76% vs 81%, p = 0.17]. Among children with IBD, patients were more likely to have a successful FMT if they received FMT with fresh stool [p = 0.03], were without diarrhoea prior to FMT [p = 0.03], or had a shorter time from rCDI diagnosis until FMT [p = 0.04]. Children with a failed FMT were more likely to have clinically active IBD post-FMT [p = 0.002] and 19 [13%] patients had an IBD-related hospitalisation in the 3-month follow-up., Conclusions: Based on the findings from this large US multicentre cohort, the efficacy of FMT for the treatment of rCDI did not differ in children with IBD. Failed FMT among children with IBD was possibly related to the presence of clinically active IBD., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Evidence about specific carbohydrate diet (SCD) for inflammatory bowel disease (IBD) is limited. We conducted 54 single-subject, double-crossover N-of-1 trials comparing SCD with a modified SCD (MSCD) and comparing each with the participant's baseline, usual diet (UD)., Methods: Across 19 sites, we recruited patients aged 7-18 years with IBD and active inflammation. Following a 2-week baseline (UD), patients were randomized to 1 of 2 sequences of 4 alternating 8-week SCD and MSCD periods. Outcomes included fecal calprotectin and patient-reported symptoms. We report posterior probabilities from Bayesian models comparing diets., Results: Twenty-one (39%) participants completed the trial, 9 (17%) completed a single crossover, and 24 (44%) withdrew. Withdrawal or early completion occurred commonly (lack of response [n = 11], adverse events [n = 11], and not desiring to continue [n = 6]). SCD and MSCD performed similarly for most individuals. On average, there was <1% probability of a clinically meaningful difference in IBD symptoms between SCD and MSCD. The average treatment difference was -0.3 (95% credible interval -1.2, 0.75). There was no significant difference in the ratio of fecal calprotectin geometric means comparing SCD and MSCD (0.77, 95% credible interval 0.51, 1.10). Some individuals had improvement in symptoms and fecal calprotectin compared with their UD, whereas others did not., Discussion: SCD and MSCD did not consistently improve symptoms or inflammation, although some individuals may have benefited. However, there are inherent difficulties in examining dietary changes that complicate study design and ultimately conclusions regarding effectiveness., (Copyright © 2022 by The American College of Gastroenterology.)

Introduction: Granulomas are a pathologic hallmark of Crohn disease (CD) although they are found in only a subset of patients. Well-formed granulomas are associated with an aggressive phenotype although it is unknown if microgranulomas confer a similar phenotype. This study sought to define the incidence of microgranulomas in pediatric CD and compare the clinical course with cases with granulomas and those without granulomatous inflammation., Methods: We performed a single-center, retrospective study of pediatric CD patients who had at least 3 years of follow-up. initial diagnostic biopsies were systematically re-examined by a gastrointestinal pathologist. A priori definitions of granuloma (10+ histiocytes) and microgranuloma (4-9 histiocytes) were used. Disease outcomes of hospitalization, development of complicated disease behavior, perianal disease, and the use of anti-tumor necrosis factor (anti-TNF) therapy were assessed by Kaplan-Meier survival plots., Results: This study included 138 subjects with an average follow-up of 4.6 years. Granulomas were seen in 38 of 138 subjects (27.5%) and an additional 38 subjects (27.5%) had at least 1 microgranuloma (in the absence of granulomas). Escalation to anti-TNF therapy was higher in CD with granulomas (P  = 0.001) and microgranulomas (P  = 0.0001) compared with those without granulomatous inflammation., Conclusions: A significant subset of pediatric CD patients have microgranulomas (in the absence of well-defined granulomas). Children with CD who have microgranulomas are escalated to anti-TNF therapy more frequently than those without granulomatous inflammation (and at a similar rate to those with granulomas). Pathologists should have a low threshold to report microgranulomas as they may help to predict disease behavior., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Lymphedema is defined as a dysfunction of the lymphatic system producing an accumulation of lymphatic fluid in the surrounding tissue, as well as edema and fibrosis. A total of 250 million people worldwide are affected by this condition. Greater than 99% of these cases are related to a secondary cause. As there is a lack of curative therapy, the goal involves early diagnosis, in order to prevent the progression of the disease. Additionally, early diagnosis can aid in decreasing the demand for more complex surgical procedures. Currently, there is an impressive breadth of diagnostic tests available for these patients. We aimed to review the available literature in relation to the utilization of imaging biomarkers for the early diagnosis and treatment response in lymphedema.

Background: Due to duty hour regulations, patient safety and inadequate operative time simulation have become a necessary part of surgical education and training in residency. Currently, there is no formal adoption of simulators for the use of surgical education or assessment in hand surgery. This literature review analyzes that the simulation techniques established thus far in hand surgery., Methods: A comprehensive literature search was performed on PubMed. Search results were filtered by title and abstract to isolate articles that were relevant to simulation in hand surgery. Articles that were nonspecific to the hand, non-English and cadaveric were excluded. Additional articles were identified through references from the initial search., Results: A total of 1192 articles were yielded from the initial query. After the application of the inclusion criteria, this was narrowed down to 28 articles. Another 8 additional articles were excluded as they did not pertain to the hand although the simulators could be adapted for hand surgery. A total of 20 articles were included in this study., Conclusions: Surgical simulation is a growing and essential field of surgical education. Simulators in hand surgery are limited and require further research and validation. Like other surgical subspecialties, hand surgery may benefit from the adoption of an official simulation curriculum for the assessment of residents and enhancement of technical skills., (© 2021. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Introduction: With the increasing number of breast cancer survivors and reconstruction operations, persistent pain following breast cancer surgery (PPBCT) and its management is becoming a challenge for plastic surgeons. To date, most studies compared the difference in the level of PPBCT in reconstruction versus nonreconstruction groups. We systematically reviewed the literature to assess the impact of implant-based reconstruction on PPBCT levels., Materials and Methods: PubMed, Embase, CINAHL, and Scopus databases were searched for relevant articles. We used five search strategies: (persistent pain after breast cancer surgery AND reconstruction), (chronic postsurgical pain AND breast reconstruction), (Breast Implantation [MeSH Terms] AND "Chronic Pain" [MeSH Terms]), (breast reconstruction AND chronic pain), and (postmastectomy pain syndrome AND breast reconstruction)., Results: A total of 2281 articles were detected. After scanning for the title and abstract, full-text articles were reviewed to identify the eligible articles. Eleven articles were included in the final review, with seven of these reporting no increased chance of PPBCT following reconstruction with implants, whereas two articles described lower chances of PPBCT following implant-based reconstruction., Conclusion: We discovered that implant-based reconstruction does not increase the risk of PPBCT in comparison to other surgical techniques or mastectomy alone. This relationship may facilitate doctors and their patients in the decision-making of the appropriate reconstruction technique to use. In addition, our results should prompt plastic surgeons to prescribe the same dosage and frequency of analgesics to patients undergoing implant reconstruction as they would to their patients not undergoing reconstruction., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2021 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

BACKGROUND Existing literature has detailed occurrences of retroperitoneal yolk sac tumors (YSTs) as the result of metastasis from a primary gonadal site. However, primary retroperitoneal YSTs are extremely rare, thus remaining a challenge to diagnose and treat. We present a complex case of a large primary retroperitoneal YST in a man treated with neoadjuvant chemotherapy followed by surgical resection. CASE REPORT A 31-year-old man presented with a chief symptom of severe lower abdominal pain. Diagnostic imaging revealed a large, rapidly progressing neoplasm in the retroperitoneal region, initially thought to be a sarcoma. However, the pathological results from further biopsies found the mass to be a retroperitoneal YST, which was tethered to a large portion of the small bowel. A testicular ultrasound was used to confirm that the mass was a primary tumor with no origins in the gonads. The tumor progressed to involve several fistulas connected to the small intestine and anterior abdominal wall. The patient was treated with 3 cycles of bleomycin, etoposide, and cisplatin, followed by surgical excision of the residual mass. The patient retained normal gastrointestinal functions, and subsequent imaging revealed no evidence of recurrence 2.5 years following resection. CONCLUSIONS Owing to the rarity of extragonadal primary YSTs, diagnostic and treatment standards have not yet been sufficiently explored. Our case demonstrates that a combination of chemotherapy and surgical resection should be considered for select patients with primary YST in the retroperitoneal region.

Objectives: Endoscopic mucosal improvement is the gold standard for assessing treatment efficacy in clinical trials of Crohn's disease. Current endoscopic indices are not routinely used in clinical practice. The lack of endoscopic information in large clinical registries limits their use for research. A quick, easy, and accurate method is needed for assessing mucosal improvement for clinicians in real-world practice. We developed and tested a novel simplified endoscopic mucosal assessment for Crohn's disease (SEMA-CD)., Methods: We developed a 5-point scale for ranking endoscopic severity of ileum and colon based on Simple Endoscopic Score for Crohn's disease (SES-CD). Central readers were trained to perform SES-CD and SEMA-CD. Pediatric patients with Crohn's disease undergoing colonoscopy were enrolled. Video recordings of colonoscopies were de-identified and randomly assigned to blinded central readers. The SES-CD and SEMA-CD were scored for each video. The SES-CD was considered the validated standard for comparison. Correlation was assessed with Spearman rho, inter- and intrarater reliability with kappa statistics., Results: Fifty-seven colonoscopies were read a total of 212 times. Correlation between SEMA-CD and SES-CD was strong (rho = 0.98, P < 0.0001). Inter-rater reliability for SEMA-CD was 0.80, and intrarater reliability was 0.83. Central readers rated SEMA-CD as easier than SES-CD., Conclusion: The SEMA-CD accurately and reproducibly correlates with the standard SES-CD. Central readers viewed SEMA-CD as easier than SES-CD. Use of SEMA-CD in practice should enable collecting mucosal improvement information in large populations of patients. This will improve the quality of research that can be conducted in clinical registries. External validation is needed., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A 10-year-old female spayed mixed breed dog was evaluated for diarrhea and vomiting. Diagnostic imaging demonstrated the presence of an intracardiac mass. A modified Seldinger technique was used to access the right jugular vein, and an endomyocardial biopsy forceps was introduced through a sheath to obtain several biopsies. Histopathology and immunohistochemistry demonstrated a paraganglioma. The dog underwent 1 fraction of radiotherapy and l-asparaginase chemotherapy and was discharged. The dog developed a pulmonary thromboembolism 2 days after radiotherapy and chemotherapy, and the owner elected humane euthanasia. Although long-term assessment of treatment response was unable to be performed, this novel diagnostic option could be considered for similar cases due to success in obtaining a histopathologic diagnosis, which is essential in developing a disease-specific treatment plan. This report also describes the use of radiotherapy for primary treatment of an intracardiac neoplasm, which can be a consideration in the future., (© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Objectives: Experimental studies have shown that vitamin D has an immunomodulatory effect on the innate and adaptive immune systems. Associations between vitamin D deficiency and development or progression of inflammatory bowel diseases (IBDs) are reported, but a cause-and-effect relationship between pretreatment 25 hydroxyvitamin D [25(OH)D] levels and response to anti-tumor necrosis factor-α (anti-TNF) therapy is not established., Methods: This retrospective study evaluated pediatric IBD patients who had 25(OH)D levels drawn within 3 months of initiating infliximab and/or adalimumab treatment. Demographic features, Paris classification, baseline 25(OH)D levels, disease activity, and laboratory results before and after 3 months of anti-TNF therapy were collected. The interaction between vitamin D insufficiency at induction and lack of response to anti-TNF therapy at 3 months was determined., Results: Of the 383 patients, 76 met inclusion criteria. Sixty-five patients (85.5%) had Crohn disease (CD) and 11 (14.5%) had ulcerative colitis. Seven patients had 25(OH)D levels obtained during both infliximab and adalimumab induction; hence 83 subjects were evaluated (infliximab: 70 patients, adalimumab: 13 patients). 25(OH)D <30 ng/mL was found in 55 of 83 (66.3%) subjects. There were no differences in gender, IBD type, disease activity scores between vitamin D-sufficient and vitamin D-insufficient groups. In CD, proximal gastrointestinal tract inflammation was associated with vitamin D insufficiency (P = 0.019), but other Paris classification parameters and laboratory results were similar in 2 groups. Early termination of anti-TNF therapy was significantly higher in patients who had vitamin D insufficiency (14.5% vs 0%, P = 0.034)., Conclusions: Vitamin D insufficiency before anti-TNF treatment may result in poor response to induction therapy., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

The cell wall is the primary interface between plant cells and their immediate environment and must balance multiple functionalities, including the regulation of growth, the entry of beneficial microbes, and protection against pathogens. Here, we demonstrate how API, a SCAR2 protein component of the SCAR/WAVE complex, controls the root cell wall architecture important for pathogenic oomycete and symbiotic bacterial interactions in legumes. A mutation in API results in root resistance to the pathogen Phytophthora palmivora and colonization defects by symbiotic rhizobia. Although api mutant plants do not exhibit significant overall growth and development defects, their root cells display delayed actin and endomembrane trafficking dynamics and selectively secrete less of the cell wall polysaccharide xyloglucan. Changes associated with a loss of API establish a cell wall architecture with altered biochemical properties that hinder P. palmivora infection progress. Thus, developmental stage-dependent modifications of the cell wall, driven by SCAR/WAVE, are important in balancing cell wall developmental functions and microbial invasion., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Hypothyroidism is associated with a wide array of medical, neurological, and psychiatric symptoms. Severe hypothyroidism may present as myxedema coma, a medical emergency. In addition, patients may present with myxedema psychosis, a psychiatric emergency manifested as hyperactive encephalopathy, hallucinations, delusions, and suicidal ideation. In rare instances, patients may present with symptoms of mania with psychosis. We present the case of a 26-year-old woman with no known psychiatric history who presented with gradual onset of altered mental status, distractibility, decreased need for sleep, pressured speech, and religious and paranoid delusions. Her medical history was significant for a surgically absent thyroid gland and nonadherence to thyroid hormone. The patient was found to have a severely elevated level of thyroid-stimulating hormone, low level of triiodothyronine, and undetectable thyroxine. Thyroid ultrasound demonstrated a surgically absent thyroid gland. The patient's metabolic panel and random serum cortisol level were normal. Rapid plasma reagin was nonreactive, and toxin screening was negative. It was concluded that severe hypothyroidism was the cause of the patient's mania with psychotic features, given her thyroid hormone levels and lack of history of a psychiatric or substance use disorder. Thyroid hormone monitoring and treatment of hypothyroidism is necessary in all patients who have undergone surgical excision of the thyroid gland. All patients presenting with a first episode mania should be screened for thyroid dysfunction. The preferred treatment includes an atypical antipsychotic and thyroid replacement therapy. Rapid resolution of symptoms can occur with combined levothyroxine and liothyronine. Correction of hypothyroidism improves response to antipsychotics.

Soft materials often exhibit a distinctive power-law viscoelastic response arising from broad distribution of time-scales present in their complex internal structure. A promising tool to accurately describe the rheological behaviour of soft materials is fractional calculus. However, its use in the scientific community remains limited due to the unusual notation and non-trivial properties of fractional operators. This review aims to provide a clear and accessible description of fractional viscoelastic models for a broad audience and to demonstrate the ability of these models to deliver a unified approach for the characterisation of power-law materials. The use of a consistent framework for the analysis of rheological data would help classify the empirical behaviours of soft and biological materials, and better understand their response.

Introduction: A surge in Food and Drug Administration (FDA) consumer complaints identified concerns that legume-rich, grain-free diets were associated with nutritionally-mediated dilated cardiomyopathy (DCM). Golden retrievers represent the most reported breed affected by this condition and previous studies documented the disease is responsive to dietary change and taurine supplementation. Although dietary findings across cases are compelling, prospective studies with control groups are lacking. The role of diet in developing taurine deficiency and echocardiographic changes consistent with DCM in healthy dogs is unknown., Objectives: We hypothesized that golden retrievers eating non-traditional diets are at a higher risk of having taurine deficiency and nutritionally-mediated DCM compared with those eating traditional commercial diets. We aimed to compare taurine concentrations and echocardiographic indices of systolic function between golden retrievers in each diet group and elucidate associations between diet and these variables. Additionally, we aimed to generate breed-specific reference intervals for whole blood and plasma taurine concentrations., Animals: 86 golden retrievers., Methods: Golden retrievers eating traditional or non-traditional diets were evaluated and diet history, taurine concentrations and echocardiographic data were collected. Dietary features, taurine concentrations and echocardiographic findings were compared between diet groups. Relative risks were calculated for the likelihood of echocardiographic abnormalities and taurine deficiency in each diet group. Breed-specific reference intervals were constructed for taurine concentrations in dogs from the traditional diet group., Results: Golden retrievers eating non-traditional diets had significantly lower taurine concentrations and more frequent systolic dysfunction. Breed specific reference intervals are higher than previously reported across breeds., Conclusions: Non-traditional diets, which were typically grain-free and contained legumes in this study, were significantly associated with and have increased relative risk for the identification of taurine deficiency and echocardiographic abnormalities consistent with nutritionally-mediated DCM. These findings were identifiable in the absence of clinical signs and support the findings of multiple previous studies and the ongoing FDA investigation., Competing Interests: A.J. Fascetti is the Scientific Director of and J. Yu is employed by the Amino Acid Laboratory at the University of California, Davis that provides amino acid analysis on a fee for service basis. This did not influence the collection or interpretation of results in this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Advancing the understanding of inflammatory bowel disease (IBD) pathogenesis has been facilitated by mechanistic studies that require human intestinal tissue. Enrolling pediatric subjects into these studies improves our knowledge of IBD in this underserved population. Given the additional research protections granted to children, institutional review boards (IRBs) must weigh the benefit of obtaining research biopsies against perceived risks. Although obtaining clinical biopsies from children is generally considered safe, there are only limited data on the safety of obtaining research biopsies in children. 1-6 ., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Fecal microbiota transplantation (FMT) is commonly used to treat Clostridium difficile infection (CDI). CDI is an increasing cause of diarrheal illness in pediatric patients, but the effects of FMT have not been well studied in children. We performed a multi-center retrospective cohort study of pediatric and young adult patients to evaluate the efficacy, safety, and factors associated with a successful FMT for the treatment of CDI., Methods: We performed a retrospective study of 372 patients, 11 months to 23 years old, who underwent FMT at 18 pediatric centers, from February 1, 2004, to February 28, 2017; 2-month outcome data were available from 335 patients. Successful FMT was defined as no recurrence of CDI in the 2 months following FMT. We performed stepwise logistic regression to identify factors associated with successful FMT., Results: Of 335 patients who underwent FMT and were followed for 2 months or more, 271 (81%) had a successful outcome following a single FMT and 86.6% had a successful outcome following a first or repeated FMT. Patients who received FMT with fresh donor stool (odds ratio [OR], 2.66; 95% CI, 1.39-5.08), underwent FMT via colonoscopy (OR, 2.41; 95% CI, 1.26-4.61), did not have a feeding tube (OR, 2.08; 95% CI, 1.05-4.11), or had 1 less episode of CDI before FMT (OR, 1.20; 95% CI, 1.04-1.39) had increased odds for successful FMT. Seventeen patients (4.7%) had a severe adverse event during the 3-month follow-up period, including 10 hospitalizations., Conclusions: Based on the findings from a large multi-center retrospective cohort, FMT is effective and safe for the treatment of CDI in children and young adults. Further studies are required to optimize the timing and method of FMT for pediatric patients-factors associated with success differ from those of adult patients., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: MR enterography (MRE) is the primary modality for evaluating small bowel disease in pediatric Crohn's patients. Standard clinical practice includes imaging patients at diagnosis and during symptomatic recurrence. The role for MRE in surveillance of asymptomatic Crohn's patients has not yet been established., Purpose: To determine whether MRE imaging features are associated with clinical recurrence., Study Type: Retrospective., Populations: Pediatric Crohn's patients who underwent MRE while asymptomatic, defined by pediatric gastroenterologists using a physician global assessment; 35 MREs were identified., Field Strength/sequence: 1.5T including T 2 -weighted single-shot fast spin echo, balanced steady-state free precession, diffusion-weighted, and contrast-enhanced multiphase T 1 -weighted gradient recalled echo sequences., Assessment: MREs were reviewed by three radiologists independently for mural thickening, T 2 -weighted hyperintensity, diffusion restriction, hyperenhancement, vasa recta engorgement, and overall assessment of disease activity. Two pediatric gastroenterologists reviewed patient medical records for 6 months following MRE to evaluate for recurrence, defined as Crohn's-related treatment escalation, surgery, or hospitalization., Statistical Tests: Fisher's exact test, Wald chi-square test, and model selection by Akaike information criterion minimization were used to assess statistical significance of MRE imaging features., Results: Of 35 MREs identified, seven cases demonstrated clinical recurrence at 6 months (20%); 28 cases remained in remission (80%). Imaging features of active disease were present in 86% of patients with recurrence compared to 29% of patients in remission (P = 0.01). Wall thickening, T 2 -weighted hyperintensity, hyperenhancement, and diffusion restriction were significantly associated with recurrence. Multivariate regression analysis determined diffusion restriction to be the best predictor of recurrence within 6 months (P = 0.001, area under the curve 0.786)., Data Conclusion: MRE performed on young asymptomatic Crohn's patients can identify patients who have a high probability of developing clinical recurrence in a 6-month period, indicating a potential role for surveillance imaging to assess for subclinical active disease., Level of Evidence: 3 Technical Efficacy Stage 5 J. Magn. Reson. Imaging 2019;50:1955-1963., (© 2019 International Society for Magnetic Resonance in Medicine.)

Background: With the increased focus on the neck and chin in the era of selfies and social media, neck contouring continues to be an in-demand procedure. Full correction of the neck typically requires both submental and postauricular incisions, but the postauricular incisions can be unsightly and painful. This article introduces a viable alternative for the patient., Methods: A case series of appropriate candidates undergoing a novel neck lift technique (the single incision minimally invasive neck lift) is described. Participants include men and women with an age range of 30-70. The surgical technique incorporates shifting of the typical submental incision used in a full neck lift to a cervicomental incision, and when accompanied by wide undermining, the postauricular incisions are avoided entirely., Results: Among the 20 patients in this case study, photographs show that it is possible to achieve results commonly associated with a full neck lift but without the postauricular incisions typically associated with a full neck lift., Conclusions: The single incision minimally invasive neck lift allows the surgeon to offer an effective procedure for appropriate candidates who want to treat excess fat, a sagging platysma muscle and loose, misplaced skin in the submental region without postauricular incisions typically utilized in a traditional full neck lift.

Objective: This study aims to identify program-specific critical factors in a student's path to general surgery and how different factors contribute to our high rate of matriculation., Design: Semi-structured interviews were conducted focusing on critical factors in student's decision processes to pursue general surgery. Three investigators independently evaluated the transcripts and identified recurring themes based on phenomenological qualitative methods until saturation was achieved. Inter-rater reliability was determined., Setting: The study took place at Tulane University School of Medicine, an academic medical center in New Orleans, Louisiana., Participants: Current fourth-year students from our medical school, applying into general surgery, were interviewed for the study., Results: Twelve of 21 students were interviewed. The most common factor cited was the positive effect of clinically based anatomy and of having surgeons in anatomy (81%). Other factors mentioned included interest before medical school, clerkship experience, and mentor interactions; Kappa was 0.76 or higher for each theme., Conclusions: A clinically focused anatomy course led by surgeons at our institution has a significant impact on a general surgery career choice. With the constant evolution of the medical field, understanding what guides students toward a career in general surgery will better assist medical education planners in providing resources that will positively impact future classes., (Copyright © 2018 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

[This corrects the article DOI: 10.1371/journal.pone.0209112.].

Introduction: Golden retrievers are over-represented in cases of taurine-deficient dilated cardiomyopathy and recently a surge in cases has prompted further investigation., Objective: To describe the clinical, dietary, and echocardiographic features in golden retrievers diagnosed with taurine deficiency and dilated cardiomyopathy, and to determine specific dietary associations. A second aim was to determine the whole blood taurine concentrations in a representative sample of healthy golden retrievers., Animals: Twenty-four client-owned golden retrievers with documented taurine deficiency and dilated cardiomyopathy and 52 healthy client-owned golden retrievers., Methods: In this multicenter prospective observational study, baseline and follow-up echocardiographic data, complete diet and medical histories, and whole blood, plasma, or serum taurine concentrations were obtained. Baseline and follow-up echocardiographic data were compared. Associations were evaluated between specific diets and taurine deficiency or congestive heart failure. The prevalence of low whole blood taurine concentrations in the healthy golden retrievers was calculated., Results: Twenty-three of 24 dogs diagnosed with taurine deficiency and dilated cardiomyopathy were fed diets that were either grain-free, legume-rich, or a combination of these factors. None of these diets were feeding trial tested using Association of American Feed Control Officials (AAFCO) procedures. Twenty-three of 24 dogs had significant improvement in their echocardiographic parameters and normalization of taurine concentrations following diet change and taurine supplementation. Nine of 11 dogs diagnosed with congestive heart failure (CHF) had resolution of their congestion at follow-up with five no longer requiring diuretic therapy and four tolerating diuretic dose reduction by >50%., Conclusions: Certain diets and diet characteristics were associated with the development of taurine deficiency. Taurine deficiency and dilated cardiomyopathy in golden retrievers is likely multifactorial, including a combination of dietary, metabolic, and genetic factors., Competing Interests: A.J. Fascetti is the Scientific Director of the Amino Acid Laboratory at the University of California, Davis that provides amino acid analysis on a fee for service basis. This did not lead to any conflict of interest or influence the collection or interpretation of results in this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: C-reactive protein (CRP) is a serum marker that is used to measure disease activity in Crohn's disease (CD). However, a subset of CD patients have normal CRP during flares. In rheumatoid arthritis and lupus, genetic variants can restrict CRP elevations during flares. This study sought to determine if common CRP genetic variants affect CRP values during active CD., Methods: Subjects with CD who participated in the Partners HealthCare BioBank were genotyped for 5 common CRP genetic variants (rs2794520, rs3122012, rs3093077, rs2808635, and rs1800947). Medical records were reviewed to determine disease activity and the highest CRP value during active CD. CRP values during active infection or malignancy at the time of the test were excluded. CRP values were compared by genotype using the Mann-Whitney test., Results: The study included 199 subjects with active CD (21 to 86 years of age). Subjects with the rs2794520 TT genotype had a lower CRP than subjects with the CC genotype (58.3 mg/L vs 28.4 mg/L, P = 0.008). Subjects with the rs1800947 CG genotype had a lower CRP than those with the CC genotype (54.3 mg/L vs 22.4 mg/L, P < 0.0001); 41.6% of TT subjects had a normal CRP compared with 24.1% of CT subjects and 16.5% of CC subjects (P = 0.041)., Conclusions: This study demonstrates that rs2794520 and rs1800947 are associated with a restriction of CRP elevations during active CD. While CRP is typically a reliable biomarker in CD, there is a subset of CD patients with a genetically determined restriction of CRP in whom other disease markers should be utilized., (© 2018 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Sotalol is a commonly used antiarrhythmic drug that may alter ventricular function., Objective: To determine the effect of sotalol on echocardiographic indices of ventricular systolic function in dogs with ventricular arrhythmias., Animals: Thirty-five client-owned dogs with ventricular arrhythmias., Methods: Dogs with ventricular arrhythmias (n = 27) had an echocardiogram and 5-minute ECG performed at baseline and 2-4 hours post-sotalol (2-2.5 mg/kg PO once). Eight additional dogs underwent the same protocol but did not receive sotalol (within-day variability controls). Left ventricular (LV) internal dimension at end-systole normalized to bodyweight (LVIDs&#95;N), LV ejection fraction (LV EF), LV shortening area, LV fractional shortening, tricuspid annular plane systolic excursion (TAPSE), and right ventricular systolic myocardial velocity were evaluated as indices of systolic function., Results: All indices except TAPSE had mild decreases in systolic function post-sotalol (all P ≤ .0007) compared with baseline but only the percent change in LVIDs&#95;N and LV EF were significantly (P ≤ .0079) different from the percent change of the same indices in control dogs. Sinus heart rate, ventricular premature complexes/5-minutes, and arrhythmia grade also were decreased post-sotalol (all P ≤ .01) compared with baseline when assessed by a 5-minutes ECG. No dog experienced an adverse event post-sotalol, including dogs with systolic dysfunction or atrial enlargement., Conclusions and Clinical Importance: A single dose of sotalol may cause a mild decrease in LV systolic function in dogs with ventricular arrhythmias. Sotalol appears to be well tolerated, even in dogs with atrial enlargement or systolic dysfunction., (Copyright © 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background and Aims: Mesalamine is commonly used to treat ulcerative colitis (UC). Although mesalamine acts topically, in vitro data suggest that intracellular transport is required for its beneficial effect. Genetic variants in mucosal transport proteins may affect this uptake, but the clinical relevance of these variants has not been studied. The aim of this study was to determine whether variants in genes involved in cellular transport affect the response to mesalamine in UC., Methods: Subjects with UC from a 6-week clinical trial using multiple doses of mesalamine were genotyped using a genome-wide array that included common exome variants. Analysis focused on cellular transport gene variants with a minor allele frequency >5%. Mesalamine response was defined as improvement in Week 6 Physician's Global Assessment (PGA) and non-response as a lack of improvement in Week 6 PGA. Quality control thresholds included an individual genotyping rate of >90%, SNP genotyping rate of >98%, and exclusion for subjects with cryptic relatedness. All included variants met Hardy-Weinberg equilibrium (p>0.001)., Results: 457 adults with UC were included with 280 responders and 177 non-responders. There were no common variants in transporter genes that were associated with response to mesalamine. The genetic risk score of responders was similar to that of non-responders (p = 0.18). Genome-wide variants demonstrating a trend towards mesalamine response included ST8SIA5 (p = 1x10-5)., Conclusions: Common transporter gene variants did not affect response to mesalamine in adult UC. The response to mesalamine may be due to rare genetic events or environmental factors such as the intestinal microbiome.

Background: The teratogenic effects of immunomodulatory and certain antimicrobial therapies are described in small rodents and humans. While the described teratogenic effects in small rodents have been extrapolated to make conclusions about its use in the pregnant dam, teratogenic effects of prednisone and doxycycline have not yet been reported in the dog. Here we report and describe midline defects observed in a litter of golden retriever puppies exposed to mid-gestational immunosuppressive and antimicrobial therapy., Case Presentation: Twenty-one days into gestation, the dam of a litter of eight golden retriever puppies was administered prednisone, doxycycline, and tramadol as treatment for immune-mediated polyarthritis. The individuals in the litter were subsequently diagnosed with a variety of midline defects and congenital cardiac defects. This case series describes the variety of identified defects and presents a descriptive account of complex congenital abnormalities that are likely secondary to teratogenic effects of one or more drugs administered during gestation. The available puppies, dam, and grand dam underwent thorough physical examination, complete echocardiogram, and where indicated, advanced imaging with various surgical corrections when possible. Numerous midline congenital defects and congenital heart disease were identified in the puppies evaluated. Ultimately 5 of 8 puppies born to the dam were presented for thorough evaluation. The midline defects include: gastroschisis (1), peritoneopericardial diaphragmatic hernias (4, PPDH), umbilical hernia (4), unilateral cryptorchidism (1 of 4 males), cleft palate (1), renal agenesis (1), renal abnormalities (1), sternal and vertebral abnormalities (3), remnant liver lobe (1) and malformations consistent with ductal plate malformations with congenital hepatic fibrosis (1). The congenital cardiac defects include: ventricular septal defect (4, VSD) and subaortic stenosis (4, SAS). The presence of greater than one congenital defect was noted in all 5 of the dogs evaluated. Surgical correction was necessary for PPDH in 4 puppies. Medical intervention was recommended for congenital cardiac disease in 1 puppy., Conclusion: This case report is the first to describe midline defects in dogs that have been exposed to immunomodulatory therapy during gestation. A causative relationship between mid-gestational immunomodulatory exposure and midline defects cannot be proven, however, this case supports a clear association and provides case-based evidence to support its avoidance when possible.