High-depth next-generation sequencing panel testing in the evaluation of arteriovenous malformations.

Arteriovenous malformations (AVMs) are vascular lesions in which an overgrowth of blood vessels of varying sizes develops with one or more direct connections between the arterial and venous circulation. We performed a retrospective review of a cohort of 54 patients with AVMs referred to our clinical genomic laboratory for high-depth next-generation sequencing (NGS) panel of Disorders of Somatic Mosaicism (DoSM). Thirty-seven of 54 patients were female (68.5%). Among the 54 cases, 37 (68.5%) cases had pathogenic and/or likely pathogenic (P/LP) variants identified, two cases (3.7%) had variants of uncertain clinical significance, and the remaining 15 cases (27.8%) had negative results. MAP2K1 variants were found in 12 cases, followed by eight cases with KRAS variants and seven with TEK variants, and the remainder being identified in several other genes on the panel. Among the 37 positive cases, 32 cases had somatic alterations only; the remaining five cases had at least one germline P/LP variant, including four cases with PTEN and one with RASA1. Of note, two cases had the unexpected co-existence of two P/LP variants. In summary, this study illustrated the molecular diagnostic yield (68.5%) of this cohort of patients with a clinical indication of AVMs by our high-depth DoSM NGS panel.

The effects of preconception and early gestation SARS-CoV-2 infection on pregnancy outcomes and placental pathology.

OBJECTIVE: To evaluate if peri-pregnancy timing of a PCR+ test for SARS-CoV-2 RNA affects pregnancy outcomes and placental pathology. METHODS: This is a retrospective cohort study conducted in a tertiary center. Pregnancy outcomes and placental pathology were compiled for women who tested positive for SARS-CoV-2 RNA from a nasopharyngeal swab assessed by RT-PCR. The population comprised four groups that were PCR+ preconception (T0) or in the 1st (T1), 2nd (T2), or 3rd (T3) trimester of pregnancy. A fifth, control group (TC) tested PCR- for SARS-CoV-2 before delivery. RESULTS: Seventy-one pregnancies were studied. The T0 group exhibited lower gestational ages at delivery, had infants with the lowest birth weights, the highest rate of pregnancy loss before 20 weeks. Features of maternal vascular malperfusion and accelerated villous maturation were prominent findings in the histopathology of placentas from women PCR+ for SARS-CoV-2 RNA, especially in the T0 and the T1 groups. CONCLUSION: Women at highest risk for pregnancy complications are those who test PCR+ for viral RNA preconception or during first trimester of pregnancy.

HLA-B evolutionary divergence is associated with outcomes after SARS-CoV-2 infection.

We examined the correlation between class I HLA evolutionary divergence (HED), a surrogate for the capacity to present different peptides, and the outcomes of 234 adult inpatients with confirmed SARS-CoV-2 infection. Genomic DNA was extracted from peripheral blood and genotyped by next-generation sequencing (NGS). HED scores for HLA class I (HLA-A, -B, and -C) genotypes were calculated using Grantham's distance. Higher HED scores for HLA-B, but not HLA-A or -C, are significantly associated with a decreased probability of poor outcomes including ICU admission, mechanical ventilation, and death (OR = 0.93; P = 0.04) in the univariate analysis. In the multivariate analysis, increased HLA-B HED score, younger age, and no comorbidity were independently associated with favorable outcomes (P = 0.02, P = 0.01, and P = 0.05, respectively). This finding is consistent with the notion that broader peptide repertoires presented by class I HLA may be beneficial in infection control.

Comprehensive molecular profiling of pancreatic ductal adenocarcinoma in FNA, biopsy, and resection specimens.

BACKGROUND: Molecular testing to identify molecular alterations in pancreatic ductal adenocarcinoma (PDAC) has been increasingly requested because of potential therapeutic implications. In this study, we compared the performance of PDAC fine-needle aspiration (FNA), fine-needle biopsy (FNB), and resection specimens for comprehensive molecular analysis. METHODS: A next-generation sequencing-based Oncomine Comprehensive Assay (OCA) was used to analyze molecular alterations in FNA, FNB, or resection specimens. We examined adequacy and success rates for completion of molecular testing and catalogued molecular alterations in these specimen types. RESULTS: The cohort included 23 FNA, 20 FNB, and 27 resection cases. Gene mutation or amplification analysis was successful in 18 (78%) FNA and 16 (80%) FNB specimens, whereas gene fusion assessment succeeded in 12 (52%) FNA and 12 (60%) FNB samples. All 27 (100%) resection specimens were adequate for complete OCA. There were significant differences in success rates for mutation and amplification analysis between resection and FNA or FNB specimens (P < .01) but not between FNA and FNB samples (P > .05). Manual microdissection was less likely to be performed for FNA specimens than FNB or resection specimens (P < .01). KRAS mutation was the most common mutation identified (90%), followed by mutations in TP53 (64%), CDKN2A (25%), and SMAD4 (15%) genes. CONCLUSIONS: Our study demonstrated similar success rates for comprehensive molecular analysis using FNA and FNB specimens of PDAC, suggesting that FNA material could serve as an alternative source for comprehensive molecular testing. The molecular alterations identified in these specimens may have potential diagnostic and therapeutic implications.

Risk factors for severe COVID-19 differ by age for hospitalized adults.

Risk stratification for hospitalized adults with COVID-19 is essential to inform decisions about individual patients and allocation of resources. So far, risk models for severe COVID outcomes have included age but have not been optimized to best serve the needs of either older or younger adults. Models also need to be updated to reflect improvements in COVID-19 treatments. This retrospective study analyzed data from 6906 hospitalized adults with COVID-19 from a community health system across five states in the western United States. Risk models were developed to predict mechanical ventilation illness or death across one to 56 days of hospitalization, using clinical data available within the first hour after either admission with COVID-19 or a first positive SARS-CoV-2 test. For the seven-day interval, models for age ≥ 18 and < 50 years reached AUROC 0.81 (95% CI 0.71-0.91) and models for age ≥ 50 years reached AUROC 0.82 (95% CI 0.77-0.86). Models revealed differences in the statistical significance and relative predictive value of risk factors between older and younger patients including age, BMI, vital signs, and laboratory results. In addition, for hospitalized patients, sex and chronic comorbidities had lower predictive value than vital signs and laboratory results.

Angiotensin-Converting Enzyme (ACE) Inhibitors May Moderate COVID-19 Hyperinflammatory Response: An Observational Study with Deep Immunophenotyping.

Background: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARB), the most commonly prescribed antihypertensive medications, counter renin-angiotensin-aldosterone system (RAAS) activation via induction of angiotensin-converting enzyme 2 (ACE2) expression. Considering that ACE2 is the functional receptor for SARS-CoV-2 entry into host cells, the association of ACEi and ARB with COVID-19 outcomes needs thorough evaluation. Methods: We conducted retrospective analyses using both unmatched and propensity score (PS)-matched cohorts on electronic health records (EHRs) to assess the impact of RAAS inhibitors on the risk of receiving invasive mechanical ventilation (IMV) and 30-day mortality among hospitalized COVID-19 patients. Additionally, we investigated the immune cell gene expression profiles of hospitalized COVID-19 patients with prior use of antihypertensive treatments from an observational prospective cohort. Results: The retrospective analysis revealed that there was no increased risk associated with either ACEi or ARB use. In fact, the use of ACEi showed decreased risk for mortality. Survival analyses using PS-matched cohorts suggested no significant relationship between RAAS inhibitors with a hospital stay and in-hospital mortality compared to non-RAAS medications and patients not on antihypertensive medications. From the analysis of gene expression profiles, we observed a noticeable up-regulation in the expression of 1L1R2 (an anti-inflammatory receptor) and RETN (an immunosuppressive marker) genes in monocytes among prior users of ACE inhibitors. Conclusion: Overall, the findings do not support the discontinuation of ACEi or ARB treatment and suggest that ACEi may moderate the COVID-19 hyperinflammatory response.

Measuring the Efficacy of Pathology Career Recruitment Strategies in US Medical Students.

CONTEXT.­: Multiple articles and surveys in the literature suggest that medical students find a career in pathology undesirable and believe it is disproportionately focused primarily on the autopsy. OBJECTIVE.­: To measure the effect of applied interventions on medical student attitudes about the field of pathology. DESIGN.­: This prospective study involving medical students from first through fourth year was conducted as a pilot study in 2 medical schools in the United States. A 2-part anonymous survey regarding interest in pathology as a career and familiarity with the specialty using a 10-point scale was given to first- and second-year medical students before and after they listened to a 10-minute pathology career presentation. The same survey was given to third- and fourth-year medical students before and after a 4-week pathology elective. RESULTS.­: A total of 121 and 83 students responded to the survey before and after the intervention, respectively. Of the 121 students who responded to the survey before the intervention, 106 (87.6%) had not spent significant time in a pathology laboratory before the intervention. The majority of responses in interest in career, job responsibilities, and features of pathologists before and after the intervention demonstrated a statistically significant difference (P < .001). We compared survey scores of presentation versus 4-week rotation groups before and after the intervention. Students who experienced the presentation did not differ from students who experienced the rotation in the majority of questions related to interest in career, job responsibilities, and features of pathologists. CONCLUSIONS.­: Our study suggests that pathology exposure strategies can have a beneficial effect on student perceptions of the field and consideration of a career in pathology. Overall, the presentation intervention seemed to have the greatest effect on the first- and second-year students.

Effect of bowel preparation volume in inpatient colonoscopy. Results of a prospective, randomized, comparative pilot study.

BACKGROUND: Inpatient status has been shown to be a predictor of poor bowel preparation for colonoscopy; however, the optimal bowel preparation regimen for hospitalized patients is unknown. Our aim was to compare the efficacy of bowel preparation volume size in hospitalized patients undergoing inpatient colonoscopy. METHODS: This prospective, single blinded (endoscopist), randomized controlled trial was conducted as a pilot study at a tertiary referral medical center. Hospitalized patients undergoing inpatient colonoscopy were assigned randomly to receive a high, medium, or low-volume preparation. Data collection included colon preparation quality, based on the Boston Bowel Preparation Scale, and a questionnaire given to all subjects evaluating the ability to completely finish bowel preparation and adverse effects (unpleasant taste, nausea, and vomiting). RESULTS: Twenty-five colonoscopies were performed in 25 subjects. Patients who received low-volume preparation averaged a higher mean total BBPS (7.4, SD 1.62), in comparison to patients who received high-volume (7.0, SD 1.41) and medium-volume prep (6.9, SD 1.55), P = 0.77. When evaluating taste a higher score meant worse taste. The low-volume group scored unpleasant taste as 0.6 (0.74), while the high-volume group gave unpleasant taste a score of 2.2 (0.97) and the medium-volume group gave a score of 2.1 (1.36), P < 0.01. CONCLUSION: In this pilot study we found that low-volume colon preparation may be preferred in the inpatient setting due its better rate of tolerability and comparable bowel cleanliness when compared to larger volume preparation, although we cannot overreach any definitive conclusion. Further more robust studies are required to confirm these findings. TRIAL REGISTRATION: The Affect of Low-Volume Bowel Preparation for Hospitalized Patients Colonoscopies. TRIAL REGISTRATION: NCT01978509 (terminated). Retrospectively registered on November 07, 2013.

Response to multiple rapid swallows shows impaired inhibitory pathways in distal esophageal spasm patients with and without concomitant esophagogastric junction outflow obstruction.

Distal esophageal spasm (DES) is a motility disorder characterized by premature contraction of the esophageal body during single swallows. It is thought to be due to impairment of esophageal inhibitory pathways, but studies to support this are limited. The normal response to multiple rapid swallows (MRS) is deglutitive inhibition of the esophageal body during the MRS sequence. Our aim was to compare the response to MRS in DES patients and healthy control subjects. Response to MRS during HRM was evaluated in 19 DES patients (8 with and 11 without concomitant esophagogastric junction outflow obstruction [EGJOO]) and 24 asymptomatic healthy controls. Patients with prior gastroesophageal surgery, peroral endoscopic myotomy, pneumatic dilation, esophageal botulinum toxin injection within 6 months of HRM, opioid medication use, and esophageal stricture were excluded. Response to MRS was evaluated for complete versus impaired inhibition (esophageal body contractility with distal contractile integral [DCI] > 100 mmHg-sec-cm during MRS), presence of post-MRS contraction augmentation (DCI post MRS greater than single swallow mean DCI), and integrated relaxation pressure (IRP). Impaired deglutitive inhibition during MRS was significantly more frequent in DES compared to controls (89% vs. 0%, P < 0.001), and frequency was similar for DES with versus without concomitant EGJOO (100% vs. 82%, P = 0.48). The proportion of subjects with augmentation post MRS was similar for both groups (37% vs. 38%, P = 1.00), but mean DCI post MRS was higher in DES than controls (3360.0 vs. 1238.9, P = 0.009). IRP was lower during MRS compared to single swallows in all patients, and IRP during MRS was normal in 5 of 8 patients with DES and EGJOO. Our study suggests that impaired deglutitive inhibition during MRS is present in the majority of patients with DES regardless of whether they have concomitant EGJOO, and future studies should explore the usefulness of incorporating response to MRS in the diagnosis of DES.

Removal of a Large Stone in the Upper Thoracic Esophagus.

Ingestion of a foreign body is a common occurrence. Flexible endoscopy is most commonly used for treatment, but certain large foreign bodies are more easily retrieved with rigid endoscopy. We present a technically challenging case of intentional ingestion of a large stone that required retrieval from the upper thoracic esophagus using rigid endoscopy. This case highlights the importance of alternative methods to manage large foreign bodies and of collaboration of medical subspecialties.

Eosinophilic esophagitis: imaging features with endoscopic and pathologic correlation.

OBJECTIVE: We aim to review the imaging features of eosinophilic esophagitis on fluoroscopy and present how they can correlate with endoscopic and pathologic findings. RESULTS: Eosinophilic esophagitis is a chronic immune-mediated disease that results in esophageal dysfunction. Upper esophagogastroduodenoscopy is high yield and required for biopsies to demonstrate the hallmark histologic findings of eosinophil-predominant inflammation. While esophagogastroduodenoscopy is currently mandatory for diagnosis, imaging findings can provide valuable information regarding the structural and functional properties of the esophagus. In addition, fluoroscopic studies may be very helpful in the setting of subtle findings and to evaluate fibrotic remodeling changes. CONCLUSION: Radiologic examinations are a valuable tool in the assessment of eosinophilic esophagitis and can highlight changes of fibrostenotic disease, as overall narrowing can be more conspicuous fluoroscopically than endoscopically. As the disease increases in prevalence, it is critical that physicians recognize this condition and facilitate diagnosis and treatment.