The impact of confined placental mosaicism on prenatal cell-free DNA screening: Insights from a monocentric study of 99 cases.

INTRODUCTION: Confined placental mosaicism (CPM) is thought to be one of the main sources of false-positive prenatal cell-free DNA (cfDNA) screening results, but extensive and systematic studies to prove this statement are limited. We evaluate the contribution of CPM to false-positive prenatal cfDNA screening results in the largest cohort published to date. METHOD: We systematically offered postnatal analysis on placenta and umbilical cord to women who had a negative amniocentesis following a positive prenatal cfDNA screening result. A standardized protocol was used in which (when available) biopsies were taken at five locations in the placenta and umbilical cord. RESULTS: We analyzed a series of 99 placentas. CPM could be confirmed in 32.3 % of cases (32/99). CPM was detected across all subtypes of chromosomal aberrations (common and rare autosomal trisomies, sex chromosome abnormalities, copy number variations and autosomal monosomies). A lower detection rate was present in umbilical cord biopsies in comparison with placental biopsies. When comparing different sections of the placenta, no clear difference could be observed with regard to the probability of CPM being present nor to the grade of mosaicism. DISCUSSION: We confirm an important role for CPM in explaining false-positive prenatal cfDNA screening results. Placental regional differences are common. Given its limited clinical relevance, we do however not advocate placental studies in a diagnostic setting.

Primary Arthroscopic Repair for Massive Rotator Cuff Tears Results in Good Shoulder Function, Low Pain, and Satisfactory Outcomes at 2-Year Minimum Follow-Up.

PURPOSE: To evaluate outcomes of patients who underwent primary arthroscopic repair for massive rotator cuff tears (MRCTs). METHODS: Patients with MRCTs (full-thickness tear of 2 or more tendons or full-thickness tear ≥5 cm) who underwent arthroscopic repair with a minimum follow-up of 2 years were retrospectively reviewed (n = 51). All patients had preoperative magnetic resonance imaging used to characterize pattern of tear, degree of fatty degeneration (Goutallier classification), and degree of rotator cuff arthropathy (Hamada classification). Outcomes were determined by American Shoulder and Elbow Surgeons (ASES) scores and Penn Shoulder Scores (PSS). RESULTS: A total of 51 patients with a minimum 2.3-year follow-up (mean, 5.4 years; range, 2.3-9.7 years) were included in this study. Mean ASES score was 46.1 ± 7.8 (95% CI, 43.9-48.3) for pain and 39.4 ± 12.1 (95% CI, 36.0-42.8) for function. Total ASES score averaged 85.5 ± 18.4 (95% CI, 80.4-90.7). PSS had a mean pain score of 26.8 ± 4.4 (95% CI, 25.4-28.1), a mean satisfaction score of 7.9 ± 2.9 (95% CI, 7.0-8.2), and a mean function score of 48.5 ± 13.5 (95% CI, 44.7-52.3). Total PSS averaged 83.2 ± 19.6 (95% CI, 77.7-87.7). No correlation was found between Goutallier grade and ASES/PSS scores or between Hamada grade and ASES/PSS scores. Three patients underwent reoperation after primary arthroscopic repair of an MRCT (5.9%). CONCLUSIONS: Patients with MRCTs who undergo primary arthroscopic repair have postoperative outcome scores indicative of good shoulder function, low pain, and high satisfaction. The rate of reoperation for individuals who underwent primary arthroscopic repair with MRCTs was low at 6%. LEVEL OF EVIDENCE: Level IV, retrospective case series.

The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

Abnormal fetal ultrasound leading to the diagnosis of ADNP syndrome.

ADNP syndrome, also known as the Helsmoortel-Van der Aa syndrome (HVDAS), is a neurodevelopmental disorder characterized by hypotonia, developmental delay, and intellectual disability. Diagnosis is typically made postnatally, and little is known about prenatal presentation of the disorder. We report a child who presented with intrauterine growth restriction, proportionate microcephaly, and an abnormal skull shape on fetal ultrasound. Whole exome sequencing performed on amniotic fluid cells showed a de novo pathogenic variant in the ADNP gene, corresponding to a diagnosis of ADNP syndrome.

Lung Cancer Screening Among Mammography Patients: Knowledge, Eligibility, Participation, and Interest.

OBJECTIVE: To determine lung cancer screening eligibility, knowledge, and interest and to quantify the effect of the expanded 2021 lung cancer screening eligibility criteria among women presenting for screening mammography, a group with demonstrable interest in cancer screening. METHODS: A single-page survey was distributed to patients presenting for screening mammography, from January-March 2020 and June 2020-January 2021, at 2 academic medical centers on the East and West Coasts. The population served by the East Coast institution has greater poverty, greater ethnic/racial diversity, and lower education levels. Survey questions included age, smoking history, lung cancer screening knowledge, participation, and interest. Lung cancer screening eligibility was determined for both 2013 and 2021 USPSTF guidelines. Descriptive statistics were calculated, and data were compared between groups using the Chi-square test, Mann-Whitney nonparametric test, and the 2-sample t test. RESULTS: 5512 surveys were completed; 33% (1824) of women reported a history of smoking-30% (1656) former smokers and 3% (156) current smokers. Among women with a smoking history, 7% (127/1824) were eligible for lung cancer screening using 2013% and 11% (207/1824) using the 2021 USPSTF criteria. Interest in lung cancer screening was high (73%; 151/207) among eligible women using 2021 USPSTF criteria, but only 42% (87/207) had heard of lung cancer screening and only 28% (57/207) had received prior LDCT screening. CONCLUSION: Eligible screening mammography patients reported high levels of interest in lung cancer screening but low levels of knowledge and participation. Linking mammography and LDCT appointments may improve lung cancer screening participation.

Harnessing Technology: Using an iPad to Enhance Radiology Medical Student Education.

RATIONALE AND OBJECTIVES: Our goal was to determine whether use of the iPad would increase the students' radiologic knowledge, aid in their interpretation of imaging exams, and increase learner satisfaction. MATERIAL AND METHODS: iPads were pre-populated with ten image data sets, which included plain film, ultrasound, and CT of the head, chest, abdomen, and pelvis. The students, working in small groups, were charged with identifying the salient imaging findings, formulating a differential diagnosis, and choosing the most appropriate imaging modality, if further work-up was necessary. After the student group problem-solved for an hour, a faculty facilitator joined the group and reviewed the cases with them in an interactive fashion. Pre- and post- intervention tests were administered, and statistical analysis was performed. RESULTS: Student satisfaction surveys were administered to 125 students in the first 2 years of the study. These scores rated their assessment of the iPad exercise and ranged from 4.6 to 4.9 out of 5. The knowledge evaluation group included 219 students, 110 in the study group and 109 in the control group, in the latter 3 years of the study. The average improvement from the initial to the second test was 1.04 points among the control group and 2.32 among the study group, which was statistically significant (p = 0.0001). CONCLUSION: We demonstrate increased learner satisfaction, as well as improved knowledge acquisition and interpretive skills of third year medical students engaged in hands-on learning using iPads.

Correction: Genomic and Clinical Effects Associated with a Relaxation Response Mind-Body Intervention in Patients with Irritable Bowel Syndrome and Inflammatory Bowel Disease.

[This corrects the article DOI: 10.1371/journal.pone.0123861.].

Evaluation of Qualitative Magnetic Resonance Imaging Features for Diagnosis of Chronic Pancreatitis.

OBJECTIVES: The purpose of this study was to determine qualitative pancreatic magnetic resonance imaging (MRI) features that must be present to predict abnormal pancreatic secretory function in patients evaluated for chronic pancreatitis (CP). METHODS: The MRIs of study subjects were reviewed by 2 abdominal radiologists; qualitative parenchyma and ductal features were recorded. Endoscopic pancreatic function test (ePFT) results (reference standard) were classified as normal (peak pancreatic fluid bicarbonate [HCO3-] ≥75 meq/L) or abnormal (<75). Abnormal ePFT was further classified as mild/moderate (74-65) and marked deficiency (<65). Statistical analysis was performed to assess the association between MRI features and abnormal ePFT. RESULTS: The study cohort was composed of 93 subjects, mean age 49 years (range, 18-78 years), 65% females. Univariate analysis identified 9 qualitative MRI features significantly (P < 0.05) associated with abnormal pancreatic secretory function. Number of MRI features increases as peak pancreatic fluid [HCO3-] decreases (Pearson r = -0.629; P = 0.001). Receiver operating characteristic curve analysis determined that a threshold of 6 or more associated MRI features 64% sensitive and 94% specific for marked bicarbonate deficiency. CONCLUSIONS: Qualitative MRI parenchymal and ductal features are associated with CP. Presence of 6 or more features results in a higher specificity for the diagnosis of CP in advanced disease.

Genomic and clinical effects associated with a relaxation response mind-body intervention in patients with irritable bowel syndrome and inflammatory bowel disease.

INTRODUCTION: Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD) can profoundly affect quality of life and are influenced by stress and resiliency. The impact of mind-body interventions (MBIs) on IBS and IBD patients has not previously been examined. METHODS: Nineteen IBS and 29 IBD patients were enrolled in a 9-week relaxation response based mind-body group intervention (RR-MBI), focusing on elicitation of the RR and cognitive skill building. Symptom questionnaires and inflammatory markers were assessed pre- and post-intervention, and at short-term follow-up. Peripheral blood transcriptome analysis was performed to identify genomic correlates of the RR-MBI. RESULTS: Pain Catastrophizing Scale scores improved significantly post-intervention for IBD and at short-term follow-up for IBS and IBD. Trait Anxiety scores, IBS Quality of Life, IBS Symptom Severity Index, and IBD Questionnaire scores improved significantly post-intervention and at short-term follow-up for IBS and IBD, respectively. RR-MBI altered expression of more genes in IBD (1059 genes) than in IBS (119 genes). In IBD, reduced expression of RR-MBI response genes was most significantly linked to inflammatory response, cell growth, proliferation, and oxidative stress-related pathways. In IBS, cell cycle regulation and DNA damage related gene sets were significantly upregulated after RR-MBI. Interactive network analysis of RR-affected pathways identified TNF, AKT and NF-κB as top focus molecules in IBS, while in IBD kinases (e.g. MAPK, P38 MAPK), inflammation (e.g. VEGF-C, NF-κB) and cell cycle and proliferation (e.g. UBC, APP) related genes emerged as top focus molecules. CONCLUSIONS: In this uncontrolled pilot study, participation in an RR-MBI was associated with improvements in disease-specific measures, trait anxiety, and pain catastrophizing in IBS and IBD patients. Moreover, observed gene expression changes suggest that NF-κB is a target focus molecule in both IBS and IBD-and that its regulation may contribute to counteracting the harmful effects of stress in both diseases. Larger, controlled studies are needed to confirm this preliminary finding. TRIAL REGISTRATION: ClinicalTrials.Gov NCT02136745.

Can non-contrast-enhanced CT (NECT) triage patients suspected of having non-traumatic acute aortic syndromes (AAS)?

This work was conducted to determine whether non-contrast-enhanced CT (NECT) of patients with suspected acute aortic syndrome (AAS) can identify patients with a very low likelihood of a positive diagnosis. In the derivation phase, patients who received both NECT and contrast-enhanced CT angiography (CTA) for suspected AAS were identified. Two readers blinded to CTA results analyzed NECTs from AAS positive and negative cases, recording maximal aortic diameters and qualitative findings of aortic disease. Logistic regression analysis was performed to identify independent positive predictors for AAS; those predictors were then used to create a decision rule. For the validation phase, NECTs from patients evaluated for AAS at a second institution were reviewed by two independent readers who recorded the presence of decision rule predictors while blinded to CTA results. In the derivation phase, 34 CTA positive and 83 CTA negative cases were reviewed. Measurements of aortic diameter alone achieved mean sensitivity and specificity of 82 % and of 83 %, respectively. Logistic regression identified aortic diameter, displaced calcifications, high attenuation aortic wall and abnormal aortic contour as independent predictors of AAS. The decision rule incorporating these findings achieved higher mean sensitivity (93 %), negative predictive value (96 %), and moderate reader agreement (kappa = 0.59). For the validation phase, application of the decision rule to 35 AAS positive and 45 AAS negative cases at the second institution yielded sensitivity of 100 % and specificity of 74 % for both readers. NECT can identify patients with a very low likelihood of AAS and potentially mitigate the urgency of performing CTA.

A quality improvement project significantly increased the vaccination rate for immunosuppressed patients with IBD.

BACKGROUND: Immunosuppressed patients with inflammatory bowel disease (IBD) are at risk for vaccine preventable illnesses. Our aim was to develop a quality improvement intervention to measure and improve the proportion of immunosuppressed IBD patients receiving recommended vaccinations. METHODS: Using a Plan-Do-Study-Act quality improvement model, a process was developed to improve the proportion of patients with immunosuppressed IBD receiving recommended vaccinations. A 1-page vaccine questionnaire was developed and distributed to consecutive patients being seen in the IBD clinic during influenza season. If recommended vaccines were due, patients were offered and given vaccines by a nurse at that visit. After a period of observation, a second Plan-Do-Study-Act was performed and processes were improved. Data were collected and analyzed using simple descriptive statistics, Pearson's chi-square, and analysis of means. RESULTS: Over a 10-week period, 184 patients were included in the intervention. Eighty-four of these patients (46%) were receiving immunosuppressant medications. Of these 84 patients, 45 (54%) had received an influenza vaccination in the previous year and 26 (31%) had received a pneumococcal vaccination within the previous 5 years. After the quality improvement intervention, the rate increased to 81% for influenza (P < 0.001) and 54% for pneumococcal vaccination (P < 0.001). An analysis of means confirms a significant change from the overall mean before and after the intervention. CONCLUSIONS: The vaccination rate for a high-risk IBD population was significantly improved using a quality improvement intervention. A similar approach can be taken for other processes associated with improved quality of care.

Acute aortic syndromes: a second look at dual-phase CT.

OBJECTIVE: The purpose of this article is to assess the diagnostic performance of the unenhanced and contrast-enhanced phases separately in patients imaged with CT for suspected acute aortic syndromes. MATERIALS AND METHODS: All adults (n = 2868) presenting to our emergency department from January 1, 2006, through August 1, 2010, who underwent unenhanced and contrast-enhanced CT of the chest and abdomen for suspected acute aortic syndrome were retrospectively identified. Forty-five patients with acute aortic syndrome and 45 healthy control subjects comprised the study population (55 women; mean age, 61 ± 16 years). Unenhanced followed by contrast-enhanced CT angiography (CTA) images were reviewed. Contrast-enhanced CTA examinations of case patients and control subjects with isolated intramural hematoma were reviewed. Radiation exposure was estimated by CT dose-length product. RESULTS: Forty-five patients had one or more CT findings of acute aortic syndrome: aortic dissection (n = 32), intramural hematoma (n = 27), aortic rupture (n = 10), impending rupture (n = 4), and penetrating atherosclerotic ulcer (n = 2). Unenhanced CT was 89% (40/45) sensitive and 100% (45/45) specific for acute aortic syndrome. Unenhanced CT was 94% (17/18) and 71% (10/14) sensitive for type A and type B dissection, respectively (p = 0.142). Contrast-enhanced CTA was 100% (8/8) sensitive for isolated intramural hematoma. Mean radiation effective dose was 43 ± 20 mSv. CONCLUSION: Unenhanced CT performed well in detection of acute aortic syndrome treated surgically, although its performance does not support its use in place of contrast-enhanced CTA. Unenhanced CT may be a reasonable first examination for rapid triage when IV contrast is contraindicated. Contrast-enhanced CTA was highly sensitive for intramural hematoma, suggesting that unenhanced imaging may not always be needed. Acute aortic syndrome imaging protocols should be optimized to reduce radiation dose.

Cigarette smoking impairs pancreatic duct cell bicarbonate secretion.

OBJECTIVE: To compare pancreatic duct cell function in smokers (current and past) and never smokers by measurement of secretin-stimulated peak bicarbonate concentration ([HCO3-]) in endoscopic collected pancreatic fluid (PF). METHODS: This retrospective study was cross-sectional in design, recording demographic information (age, gender, etc.), smoking status (former, current, never), alcohol intake, clinical data (imaging, endoscopy), and laboratory results (peak PF [HCO3-]) from subjects evaluated for pancreatic disease at a tertiary pancreas center. Univariate and multivariate statistical analysis (SAS Version 9.2, Cary, NC, USA) was performed to assess the relationship between cigarette smoking and secretin-stimulated pancreatic fluid bicarbonate concentration. RESULTS: A total of 131 subjects underwent pancreatic fluid collection (endoscopic pancreatic function test, ePFT) for bicarbonate analysis: 25.2% (33 out of 131) past smokers, 31.3% (41 out of 131) current smokers, and 43.5% (57 out of 131) were never smokers. Measures of Association: The mean peak PF [HCO3-] in never smokers (81.3 ± 18.5 mEq/L) was statistically higher (indicating better duct cell function) when compared to past smokers (66.8 ± 24.7 mEq/L, P=0.005) and current smokers (70.0 ± 20.2 mEq/L, P=0.005). However, the mean peak [HCO3-] in past smokers was not statistically different from that in current smokers (P=0.575), and therefore, the two smoking groups were combined to form a single "smokers cohort". When compared to the never smokers, the smokers cohort was older (P=0.037) and had a greater proportion of subjects with definite chronic pancreatitis imaging (P=0.010), alcohol consumption ≥20 g/day (P=0.012), and abnormal peak PF [HCO3-] (P<0.001). Risk-Based Estimates: Cigarette smoking (risk ratio, RR: 2.2, 95% CI: 1.3-3.5; P<0.001), diagnosis of definite chronic pancreatitis imaging (RR: 2.2, 95% CI: 1.6-3.2; P<0.001) and alcohol consumption ≥20 g/day (RR: 1.6, 95% CI: 1.1-2.4; P=0.033) were all associated with low mean peak PF [HCO3-] (indicating duct cell secretory dysfunction). Multivariate Analysis: Smoking (odds ratio, OR: 3.8, 95% CI: 1.6-9.1; P=0.003) and definite chronic pancreatitis imaging (OR: 5.7, 95% CI: 2.2-14.8; P<0.001) were determined to be independent predictors of low peak PF [HCO3-], controlling for age, gender, and alcohol intake. Furthermore there was no interaction between smoking status and alcohol intake in predicting duct cell dysfunction (P=0.571). CONCLUSION: Measurement of pancreatic fluid bicarbonate in smokers reveals that cigarette smoking (past and current) is an independent risk factor for pancreatic duct cell secretory dysfunction (low PF [HCO3-]). Furthermore, the risk of duct cell dysfunction in subjects who smoked was approximately twice the risk (RR: 2.2) in never smokers. Further in depth, translational research approaches to pancreatic fluid analysis may help unravel mechanisms of cigarette smoking induced pancreatic duct cell injury.

Gallbladder torsion resulting in gangrenous cholecystitis within a parastomal hernia: findings on unenhanced CT.

Gallbladder torsion is a rare cause of acute gangrenous cholecystitis; its occurrence within an abdominal hernia has not been previously reported. We present such a case occurring within a parastomal hernia and imaged with unenhanced CT.

Differentiating neoplastic from nonneoplastic processes in the anterior extradural space.

PURPOSE: To compare neoplastic and nonneoplastic disease in the anterior extradural space (AES) with regard to the contour of the disease and the tethering of the central septum, as seen on axial magnetic resonance (MR) images. MATERIALS AND METHODS: In this institutional review board-approved HIPAA-compliant study, the data of patients who had AES disease determined at MR imaging and underwent diagnostic biopsy were studied. Two blinded observers reviewed the MR images and assigned the patients to one of two groups on the basis of the contour of AES disease: those with a centrally convex disease contour posteriorly and those whose disease contour was tethered in the midline to the posterior aspect of the vertebral body. Biopsy results served as the standard of reference. The two-tailed Fisher exact test, the Breslow-Day test, and κ statistics were used to compare groups. The sensitivity, specificity, and accuracy of the midline tethered contour of AES disease for the detection of neoplasm were calculated. RESULTS: The data of 32 patients (16 men, 16 women; mean age, 68 years) were studied. Seventeen patients had malignant epidural disease. Fifteen patients had nonneoplastic epidural disease: Six patients had hematomas, and nine had abscesses. A greater proportion of AES neoplasms (13 [76%] and 14 [82%] of 17 lesions for observers 1 and 2, respectively) than nonneoplastic AES lesions (four [27%] and three [20%] of 15 lesions for observers 1 and 2, respectively) demonstrated midline tethering of the central septum. For observers 1 and 2, a unilobed or bilobed appearance of AES disease had sensitivities of 76% (13 of 17 lesions) and 82% (14 of 17 lesions), respectively; specificities of 73% (11 of 15 lesions) and 80% (12 of 15 lesions), respectively; and accuracies of 75% (24 of 32 lesions) and 81% (26 of 32 lesions), respectively, for the detection of neoplasm. The mean κ value for interobserver variability was 0.62 (95% confidence interval: 0.35, 0.90). CONCLUSION: AES disease preserving the midline tethering of the central septum is more common with neoplastic disease than with infections or hematomas.

Mechanical and enzymatic thrombolysis of acute pulmonary embolus: review of the literature and cases from our institution.

Pulmonary embolism (PE) is a major cause of morbidity and mortality in the United States. Patients with massive PE have a high mortality rate, with two of every three deaths occurring in the first hour. The mainstay of treatment for PE is anticoagulation. However, when the patient is in extremis, intravenous lysis of the clot is indicated. Recently, mechanical fragmentation with or without pharmacologic thrombolysis has been shown to have a role in therapy for patients with massive PE, as well as in those patients who have a contraindication to anticoagulation. We discuss our experience with mechanical fragmentation in the treatment of PE and review the literature.