Evaluation of Explanted CorMatrix Intracardiac Patches in Children With Congenital Heart Disease

Animal data demonstrate that intracardiac patches of decellularized porcine small intestine submucosa (CorMatrix; CorMatrix Cardiovascular, Inc, Atlanta, GA) become repopulated with native cells, suggesting the possibility of a substrate for regenerative tissue in humans. We report the only prospective series to date of explanted CorMatrix patches placed in infants with congenital heart disease

Malignant risk of indeterminate pediatric thyroid nodules—An institutional experience

BackgroundFew studies focus on pediatric thyroid nodules categorized under indeterminate diagnostic categories. The current study was conducted to assess the risk of malignancy of indeterminate pediatric thyroid nodules.MethodsA search of the institutional electronic pathology database from 01/2011 to 09/2018 was performed to identify pediatric (<21 years old) thyroid nodules that were interpreted as follicular lesion of undetermined significance (FLUS), suspicious for follicular neoplasm (SFN), or suspicious for malignancy (SFM) and subsequently managed with surgery, repeat fine‐needle aspiration (FNA), or ≥ 6 months of clinical/imaging monitoring. Results of follow‐up (F/U) surgical resections and repeat FNA/Afirma tests, and clinical and radiologic data were collected.ResultsWe identified 46 cases from 42 patients (11‐20 years old, 33 females and 9 males), including 30 FLUS, 10 SFN, and 6 SFM. Twenty‐five FLUS, ten SFN, and six SFM cases underwent surgery. The histology revealed carcinomas in 36% of FLUS, 20% of SFN, and 100% of SFM categories; follicular adenomas in 32% of FLUS and 80% of SFN categories; and benign nodules in 32% of FLUS category. All five nonsurgically treated FLUS cases were considered benign based on the findings of repeat FNA/Afirma tests (n = 3, 3‐22 months F/U) or clinical/radiologic exams (n = 2, 8‐12 months F/U).ConclusionsBased on a limited study cohort, malignancy was identified in 36%, 20%, and 100% of surgically managed pediatric thyroid nodules categorized as FLUS, SFN, and SFM, respectively; suggesting a markedly higher malignant rate than the implied malignant risk for FLUS and SFM categories in adults.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151306/1/dc24266.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151306/2/dc24266_am.pd

Compound heterozygosity for loss‐of‐function FARSB variants in a patient with classic features of recessive aminoacyl‐tRNA synthetase‐related disease

Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in phenotypically diverse dominant and recessive human diseases. The charging of tRNAPHE with phenylalanine is performed by a tetrameric enzyme that contains two alpha (FARSA) and two beta (FARSB) subunits. To date, mutations in the genes encoding these subunits (FARSA and FARSB) have not been implicated in any human disease. Here, we describe a patient with a severe, lethal, multisystem, developmental phenotype who was compound heterozygous for FARSB variants: p.Thr256Met and p.His496Lysfs*14. Expression studies using fibroblasts isolated from the proband revealed a severe depletion of both FARSB and FARSA protein levels. These data indicate that the FARSB variants destabilize total phenylalanyl‐tRNA synthetase levels, thus causing a loss‐of‐function effect. Importantly, our patient shows strong phenotypic overlap with patients that have recessive diseases associated with other ARS loci; these observations strongly support the pathogenicity of the identified FARSB variants and are consistent with the essential function of phenylalanyl‐tRNA synthetase in human cells. In sum, our clinical, genetic, and functional analyses revealed the first FARSB variants associated with a human disease phenotype and expand the locus heterogeneity of ARS‐related human disease.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144241/1/humu23424_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144241/2/humu23424.pd

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Single nucleotide polymorphism array and cytogenetic analyses of ovarian teratomas in children

Teratomas are the most common tumors in the ovary during childhood. Previous studies suggested that they may be derived from germ cells at any developmental stage from premeiotic oogonia through meiotic oocytes to post‐meiotic ova. The majority of mature teratomas reveal normal karyotypes and immature teratomas show higher frequency of chromosomal abnormalities. We analyzed fresh tissue samples from 25 primary ovarian teratomas and three extraovarian deposits using whole genome single nucleotide polymorphism (SNP) array and karyotype. SNP array detected five patterns of copy neutral loss of heterozygosity (CN‐LOH): failure of meiosis I (type I) in 12 tumors, failure of meiosis II (type II) in six tumors, endoreduplication of a haploid ovum (type III) in two tumors, premeiotic error (type IV) in four tumors, and both meiotic I and meiotic II errors in one tumor (type V). Three tumors with type I error had a single chromosome showing meiotic II error, and two tumors with type II error had a single chromosome showing premature sister‐chromatid separation in meiosis I. Lack of recombination in multiple chromosomes in meiosis I were common, chromosomes 17, 7, 8, 21, and 22 were most commonly involved. Abnormal karyotypes were observed in four teratomas including +3, del(3q), +7, +8, +12, and i(18q). The extraovarian deposits revealed the same CN‐LOH pattern as the primary teratoma. In summary, SNP array reveals the origin of ovarian teratoma and we propose a new mechanism that consecutive meiotic I and II errors occur frequently in ovarian teratomas.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167503/1/gcc22934_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167503/2/gcc22934.pd

Diagnosis and categorization of malignant effusions: A 6‐year review from a single academic institution

BackgroundCytologic detection of malignant cells in pleural, peritoneal, or pericardial effusion most likely indicates advanced stage of malignant disease. There are a few studies updating the categorization of malignant effusions.MethodsThe electronic pathology database was searched to identify consecutive cases of malignant effusion during a 6‐year period. Patient age and gender, origins of known malignancy, and cytologic diagnoses were recorded and summarized.ResultsA total of 1059 specimens included 561 (53%) pleural, 441 (41.6%) peritoneal, and 57 (5.4%) pericardial fluids. Most of the pleural (516, 92.0%), peritoneal (418, 94.8%), and pericardial (53, 93.0%) specimens were derived from patients with a single known malignancy. More common origins involving pleural fluid were lung (152, 27.1%) followed by breast (103, 18.4%) and gastrointestinal tract (76, 13.5%). The most common etiology for women and men was breast (102, 30.8%) and lung (67, 36.2%), respectively. More common origins involving peritoneal fluid were gastrointestinal (158, 35.8%) and gynecologic (156, 35.4%) tracts, and breast (46, 10.4%). The most common etiology for women and men was Mullerian (156, 55.5%) and gastrointestinal tract (94, 68.6%), respectively. Most common origins involving the pericardial fluid were breast (20, 37.7%) and lung (17, 29.8%). Breast and lung were the most common etiology for women (20, 57.1%) and men (8, 44.4%), respectively.ConclusionsBreast and lung remain to be the most common origin of both malignant pleural and pericardial effusion for women and men, respectively. The most common origin involving peritoneal effusion is Mullerian for women and gastrointestinal tract for men.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167109/1/dc24433.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167109/2/dc24433_am.pd

Performance of Afirma genomic sequencing classifier vs gene expression classifier in Bethesda category III thyroid nodules: An institutional experience

BackgroundAfirma gene expression classifier (GEC) is an adjunct to thyroid fine needle aspiration shown to improve pre‐operative risk assessment and reduce unnecessary surgery of indeterminate thyroid nodules. Genomic sequencing classifier (GSC) is a newer version aiming to improve specificity and positive predictive value (PPV) of Afirma testing. There are limited studies comparing GSC vs GEC. This study was undertaken to compare these classifiers in terms of diagnostic performance and effect on clinical management of indeterminate thyroid nodules.MethodsThe study cohort consisted of patients with thyroid nodules that had a recurrent cytologic diagnosis of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) and were tested by either GEC or GSC. Patient demographics, nodule size, and clinical follow‐up were recorded. Benign call rate (BCR) of Afirma testing, rate of subsequent surgery (RSS), rate of histology‐confirmed malignancy (RHM), as well as diagnostic sensitivity, specificity, PPV, negative predicative value (NPV), and accuracy were calculated and compared between GSC and GEC cohorts.ResultsAmong 264 AUS/FLUS thyroid nodules, 127 and 137 were tested with GEC and GSC, respectively. Compared to GEC, GSC demonstrated increased BCR (77.3% vs 52%), decreased RSS (31.4% vs 51.2%), greater RHM (29% vs 9.8%) associated with a suspicious Afirma result, as well as improved specificity (82.8% vs 54.5%), PPV (29% vs 9.8%), and diagnostic accuracy (83.9% vs 56.7%), while maintaining high sensitivity and NPV.ConclusionAfirma GSC substantially improved BCR, RSS, RHM, and diagnostic performance, enhancing appropriate triage and thereby helped avoid unnecessary surgery in AUS/FLUS thyroid nodules.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168473/1/dc24765.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168473/2/dc24765_am.pd

Using Human Induced Pluripotent Stem Cell Derived Organoids to Identify New Pathologies in Patients with PDX1 Mutations

BACKGROUND AIMS: Two patients with homozygous mutations in PDX1 presented with pancreatic agenesis, chronic diarrhea and poor weight gain, the causes of which were not identified through routine clinical testing. We aim to perform a deep analysis of the stomach and intestine using organoids derived from induced pluripotent stem cells from PDX1 patients. METHODS: Gastric fundic, antral and duodenal organoids were generated using iPSC lines from a PDX1 patient and an isogenic iPSC line where the PDX1 point mutation was corrected. RESULTS: Patient-derived PDX1 antral organoids exhibited an intestinal phenotype, while intestinal organoids underwent gastric metaplasia with significant reduction in enteroendocrine cells. This prompted a re-examination of gastric and intestinal biopsies from both PDX1 patients, which recapitulated the organoid phenotypes. Moreover, antral biopsies also demonstrated increased parietal cells and lacked G-cells suggesting loss of antral identity. All organoid pathologies were reversed upon CRISPR-mediated correction of the mutation. CONCLUSION: These patients will now be monitored for the progression of metaplasia and gastrointestinal complications that might be related to the reduced gastric and intestinal endocrine cells. This study demonstrates the utility of organoids in diagnosing uncovered pathologies