Explainable COVID-19 Detection Based on Chest X-rays Using an End-to-End RegNet Architecture.

COVID-19,which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one of the worst pandemics in recent history. The identification of patients suspected to be infected with COVID-19 is becoming crucial to reduce its spread. We aimed to validate and test a deep learning model to detect COVID-19 based on chest X-rays. The recent deep convolutional neural network (CNN) RegNetX032 was adapted for detecting COVID-19 from chest X-ray (CXR) images using polymerase chain reaction (RT-PCR) as a reference. The model was customized and trained on five datasets containing more than 15,000 CXR images (including 4148COVID-19-positive cases) and then tested on 321 images (150 COVID-19-positive) from Montfort Hospital. Twenty percent of the data from the five datasets were used as validation data for hyperparameter optimization. Each CXR image was processed by the model to detect COVID-19. Multi-binary classifications were proposed, such as: COVID-19 vs. normal, COVID-19 + pneumonia vs. normal, and pneumonia vs. normal. The performance results were based on the area under the curve (AUC), sensitivity, and specificity. In addition, an explainability model was developed that demonstrated the high performance and high generalization degree of the proposed model in detecting and highlighting the signs of the disease. The fine-tuned RegNetX032 model achieved an overall accuracy score of 96.0%, with an AUC score of 99.1%. The model showed a superior sensitivity of 98.0% in detecting signs from CXR images of COVID-19 patients, and a specificity of 93.0% in detecting healthy CXR images. A second scenario compared COVID-19 + pneumonia vs. normal (healthy X-ray) patients. The model achieved an overall score of 99.1% (AUC) with a sensitivity of 96.0% and specificity of 93.0% on the Montfort dataset. For the validation set, the model achieved an average accuracy of 98.6%, an AUC score of 98.0%, a sensitivity of 98.0%, and a specificity of 96.0% for detection (COVID-19 patients vs. healthy patients). The second scenario compared COVID-19 + pneumonia vs. normal patients. The model achieved an overall score of 98.8% (AUC) with a sensitivity of 97.0% and a specificity of 96.0%. This robust deep learning model demonstrated excellent performance in detecting COVID-19 from chest X-rays. This model could be used to automate the detection of COVID-19 and improve decision making for patient triage and isolation in hospital settings. This could also be used as a complementary aid for radiologists or clinicians when differentiating to make smart decisions.

Severe Antenatal Hypertrophic Cardiomyopathy Secondary to ACAD9-Related Mitochondrial Complex I Deficiency.

Introduction: Antenatal presentation of hypertrophic cardiomyopathy (HCM) is rare. We describe familial recurrence of antenatal HCM associated with intrauterine growth restriction and the diagnostic process undertaken. Methods: Two pregnancies with antenatal HCM were followed up. Biological assessment including metabolic analyses, genetic analyses, and respiratory chain study was performed. We describe the clinical course of these two pregnancies, antenatal manifestations as well as specific histopathological findings, and review the literature. Results: The assessment revealed a deficiency in complex I of the respiratory chain and two likely pathogenic variations in the ACAD9 gene. Discussion and Conclusion: Antenatal HCM is rare and a diagnosis is not always made. In pregnancies presenting with cardiomyopathy and intrauterine growth restriction, ACAD9 deficiency should be considered as one of the potential underlying diagnoses, and ACAD9 molecular testing should be included among other prenatal investigations.

Rhinologic manifestations of Burkitt Lymphoma in a pediatric population: Case series and systematic review.

INTRODUCTION: Burkitt lymphoma (BL), an aggressive form of B-cell non-Hodgkin's lymphoma, arising from the nose and paranasal sinuses is relatively rare. It can present with various symptoms leading to potential misdiagnosis and delayed treatment. BL is fatal if left untreated, while early identification and treatment can improve prognosis. OBJECTIVES: 1) To review clinical presentations and sites of involvement of six cases of pediatric BL with rhinologic manifestations and compare these with the current literature. 2) To raise awareness on the variety of presentations of BL in this particular anatomic location. METHODS: A series of six cases of pediatric (0-18 years) BL with rhinologic manifestations is presented. Age, sex, ethnicity, symptoms, imaging, staging, treatment and outcome were recorded. A systematic review of literature was also conducted using PRISMA guidelines. The search strategy used keywords related to rhinologic manifestations of BL (nasal cavity, nasopharynx, paranasal sinus etc.; Burkitt etc.) and included studies published in English and French describing patients 0-18 years of age. RESULTS: 42 patients were included (six from case series and 36 from current literature). Most common presenting symptoms were: nasal obstruction (29%), facial swelling (24%), headache (21%) and proptosis (19%). Most frequent sites of presentation were: nasopharynx (40%), maxilla (40%) and sphenoid (33%). More than half (60%) had systemic involvement, of which the most common locations were: kidney (19%), pancreas (17%) and liver (17%). Mortality from BL in children from this study population was correlated with a longer duration of symptoms prior to presentation, as well as a misdiagnosis preceding the final diagnosis of BL. CONCLUSIONS: This study brings understanding to the numerous presentations of the same aggressive disease, promotes high clinical suspicion when evaluating common otolaryngologic symptoms and can guide healthcare providers in diagnosing pediatric BL with rhinologic manifestations.

Recessive mutation in CD2AP causes focal segmental glomerulosclerosis in humans and mice.

Although sequence variants in CD2-associated protein (CD2AP) have been identified in patients with focal segmental glomerulosclerosis (FSGS), definitive proof of causality in human disease is meager. By whole-exome sequencing, we identified a homozygous frame-shift mutation in CD2AP (p.S198fs) in three siblings born of consanguineous parents who developed childhood-onset FSGS and end stage renal disease. When the same frameshift mutation was introduced in mice by gene editing, the mice developed FSGS and kidney failure. These results provide conclusive evidence that homozygous mutation of CD2AP causes FSGS in humans.

Renal tubular dysgenesis and microcolon, a novel association. Report of three cases.

Renal tubular dysgenesis (RTD) is a developmental abnormality of the nephron characterized by fetal anuria, oligohydramnios, and severe postnatal hypotension. Genetic forms have an autosomal recessive inheritance and are caused by mutations in genes encoding key components of the renin-angiotensin pathway. We report three patients from two unrelated families with RTD due to pathogenic variants of the angiotensin-converting enzyme (ACE) gene, in whom RTD was associated with microcolon. We also detail key variations of the renin-angiotensin system in one of these infants. The severe intestinal developmental abnormality culminating in microcolon and early terminal ileum perforation/necrotizing enterocolitis is a novel finding not previously associated with RTD, which points to a role of the renin-angiotensin system in gut development.

Guidelines from the Canadian Association of Pathologists for establishing a telepathology service for anatomic pathology using whole-slide imaging.

The use of telepathology for clinical applications in Canada has steadily become more attractive over the last 10 years, driven largely by its potential to provide rapid pathology consulting services throughout the country regardless of the location of a particular institution. Based on this trend, the president of the Canadian Association of Pathologists asked a working group consisting of pathologists, technologists, and healthcare administrators from across Canada to oversee the development of guidelines to provide Canadian pathologists with basic information on how to implement and use this technology. The guidelines were systematically developed, based on available medical literature and the clinical experience of early adopters of telepathology in Canada. While there are many different modalities and applications of telepathology, this document focuses specifically on whole-slide imaging as applied to intraoperative pathology consultation (frozen section), primary diagnosis, expert or second opinions and quality assurance activities. Applications such as hematopathology, microbiology, tumour boards, education, research and technical and/or standard-related issues are not covered.

Inflammatory myofibroblastic tumor of the aortic valves causing sudden cardiac death: a case report and review of the literature.

Cardiac inflammatory myofibroblastic tumor (IMT) is a rare entity affecting predominantly infants, children, and young adults. Although most tumors have a benign clinical course after complete surgical resection, some have significant clinical effects. We report the case of a 9-year-old girl who had sudden cardiac death as a result of occlusion of the left circumflex coronary artery. A review of 57 cases of cardiac IMTs reported in the literature in terms of epidemiology, clinical presentation, histologic and immunohistologic features, and outcome is presented. Recognition of this rare abnormality is important in order to initiate prompt surgical intervention.

Dextranomer hyaluronic acid copolymer effects on gastroesophageal junction.

OBJECTIVE: The outcomes of fundoplication for gastroesophageal reflux disease are suboptimal in many children, and alternatives are clearly needed. Dextranomer hyaluronic acid (DxHA) copolymer, an agent with proven efficacy in vesicoureteral reflux, was studied with respect to its effects on the gastroesophageal junction (GEJ). METHODS: Twelve New Zealand white rabbits underwent measurement of lower esophageal sphincter pressure followed by laparotomy and injection into the muscular layer of the GEJ (controls, 1.0 mL saline; low-dose DxHA [0.5 mL]; high-dose DxHA [1.0 mL]). After a 12-week survival period, the animals underwent manometry, sacrifice, and necropsy. Organs were examined histologically by pathologists blinded to the injection delivered. RESULTS: All animals survived. Weight gain was equal in the 3 groups. There was no significant difference in mean lower esophageal sphincter pressure from baseline in any group (control 2.3 mmHg [95% confidence interval, CI -3.3 to 7.9]; low-dose group 3.2 mmHg [95% CI -0.8 to 7.2]; high-dose group -4.0 mmHg [95% CI -18.95 to 10.95]). Histologically, DxHA injection produced an intramural implant, with a foreign body giant cell reaction, and fibroblastic infiltration with collagen deposition. High-dose injection did not consistently result in a qualitative increase in the magnitude of the reaction. There was no mucosal injury or luminal stenosis. CONCLUSIONS: In this first study evaluating the effects of DxHA injection at the GEJ, a histologic bulking effect was observed without obvious functional complications. The agent may have a role in the treatment of gastroesophageal reflux disease.

ARHGDIA: a novel gene implicated in nephrotic syndrome.

BACKGROUND: Congenital nephrotic syndrome arises from a defect in the glomerular filtration barrier that permits the unrestricted passage of protein across the barrier, resulting in proteinuria, hypoalbuminaemia, and severe oedema. While most cases are due to mutations in one of five genes, in up to 15% of cases, a genetic cause is not identified. We investigated two sisters with a presumed recessive form of congenital nephrotic syndrome. METHODS AND RESULTS: Whole exome sequencing identified five genes with diallelic mutations that were shared by the sisters, and Sanger sequencing revealed that ARHGDIA that encodes Rho GDP (guanosine diphosphate) dissociation inhibitor α (RhoGDIα, OMIM 601925) was the most likely candidate. Mice with targeted inactivation of ARHGDIA are known to develop severe proteinuria and nephrotic syndrome, therefore this gene was pursued in functional studies. The sisters harbour a homozygous in-frame deletion that is predicted to remove a highly conserved aspartic acid residue within the interface where the protein, RhoGDIα, interacts with the Rho family of small GTPases (c.553_555del(p.Asp185del)). Rho-GTPases are critical regulators of the actin cytoskeleton and when bound to RhoGDIα, they are sequestered in an inactive, cytosolic pool. In the mouse kidney, RhoGDIα was highly expressed in podocytes, a critical cell within the glomerular filtration barrier. When transfected in HEK293T cells, the mutant RhoGDIα was unable to bind to the Rho-GTPases, RhoA, Rac1, and Cdc42, unlike the wild-type construct. When RhoGDIα was knocked down in podocytes, RhoA, Rac1, and Cdc42 were hyperactivated and podocyte motility was impaired. The proband's fibroblasts demonstrated mislocalisation of RhoGDIα to the nucleus, hyperactivation of the three Rho-GTPases, and impaired cell motility, suggesting that the in-frame deletion leads to a loss of function. CONCLUSIONS: Mutations in ARHGDIA need to be considered in the aetiology of heritable forms of nephrotic syndrome.

Neonatal hypoxic-ischemic injury: sonography and dynamic color Doppler sonography perfusion of the brain and abdomen with pathologic correlation.

OBJECTIVE: The purpose of this article is to describe the role of cerebral and abdominal sonography with color Doppler sonography, including assessment of multiorgan tissue perfusion, in neonates with hypoxic-ischemic injury. CONCLUSION: Bedside sonography and color Doppler sonography of the brain and abdominal organs can provide reliable and comprehensive information in asphyxiated neonates with hypoxic-ischemic injury. This article, which includes pathologic correlation, illustrates the major sonographic findings in this critical population.

Gangrenous appendicitis in children: a prospective evaluation of definition, bacteriology, histopathology, and outcomes.

INTRODUCTION: The definition and treatment of gangrenous appendicitis are not agreed upon. We performed a prospective study in children to evaluate an objective definition of gangrenous appendicitis, as well as associated bacteriology, histopathology, and outcomes. METHODS: Five staff pediatric surgeons prospectively enrolled patients in the study at the time of appendectomy if the following five criteria were met: gray or black discoloration of the appendiceal wall; absence of fecalith outside the appendix; absence of visible hole in the appendix; absence of gross purulence or fibrinous exudate remote from the appendix; and absence of intraoperative appendiceal leak. Peritoneal fluid was cultured, and a standard histopathologic review was undertaken. Persistence of fever (>37.5°C) and ileus was documented daily. Patients were continued postoperatively on ampicillin, gentamicin, and metronidazole until they tolerated diet, manifested a 24-h afebrile period, and had a normal leukocyte count. Hospital stay, readmissions, and infectious complications were recorded. The study took place over a 12-mo period. RESULTS: Thirty-eight patients were enrolled, representing 17% of all patients with appendicitis treated during the year. Average age was 10.8 ± 3.5 y. Peritoneal cultures were positive in 53% of cases. Gangrene was documented histologically in 61% of specimens. Hospital stay was 3.2 ± 1.1 d. There were no postoperative infectious complications or readmissions related to the disease. Neither culture results nor histologic gangrene had a statistically significant effect on hospital stay. CONCLUSIONS: An objective definition of gangrenous appendicitis is reproducible and has good histopathologic association. Recovery from gangrenous appendicitis is not influenced by culture or pathology results, and postoperative complications are rare. Limiting postoperative antibiotics to 24 h in gangrenous appendicitis may significantly decrease the cost of treatment without increasing morbidity.

Prognostic impact of high ABC transporter activity in 111 adult acute myeloid leukemia patients with normal cytogenetics when compared to FLT3, NPM1, CEBPA and BAALC.

ATP-binding cassette transporter (and specially P-glycoprotein) activity is a well known prognostic factor in acute myeloid leukemia, but when compared to other molecular markers its prognostic value has not been well studied. Here we study relationships between this activity, fms-like tyro-sine kinase 3(FLT3/ITD), nucleophosmin(NPM1), CAAT-enhancer binding protein alpha(CEBPα), and brain and acute leukemia cytoplasmic protein (BAALC), in 111 patients with normal cytogenetics who underwent the same treatment, and evaluate its prognostic impact. Independent factors for survival were age (P=0.0126), ATP-binding cassette transporter activity (P=0.018) and duplications in the fms-like tyrosine kinase 3 (P=0.0273). In the 66 patients without fms-like tyrosine kinase 3 duplication and without nucleophosmin mutation, independent prognostic factors for complete remission achievement and survival were age and ATP-binding cassette transporter activity. In conclusion, ATP-binding cassette transporter activity remains an independent prognostic factor, and could assist treatment decisions in patients with no nucleophosmin mutation and no fms-like tyrosine kinase 3 duplication.

Multicentric castleman disease in a child with primary immunodeficiency.

Multicentric Castleman disease is a rare lymphoproliferative disorder mostly seen in adults with HIV. It presents with fever and systemic symptoms and is extremely uncommon in children. We describe a novel case of multicentric Castleman disease associated with primary immunodeficiency (common variable immunodeficiency) and discuss pathophysiologic mechanisms and recent advances in understanding this disease.

High level of apoptosis and low AKT activation in mass screening as opposed to standard neuroblastoma.

AIMS: Neuroblastoma is a paediatric solid tumour with a poor outcome except in children <1 year old. Based on catecholamine urinary excretion, mass screening (MS) programmes have been organized but failed to decrease the mortality of this tumour. To test the hypotheses of a spontaneous maturation/differentiation or regression, the levels of poly (ADP-ribose) polymerase (PARP)-1, an early apoptosis marker, of PhosphoAKT, a major apoptosis inhibitor, and of maturation/differentiation were compared in standard and in MS neuroblastomas. METHODS AND RESULTS: We performed a case-control study of 55 primary tumours and 21 metastases of MS neuroblastomas. Matched controls were standard unscreened neuroblastomas and were paired according to age, stage, and MYCN amplification. The tumours were included in tissue microarrays. Immunohistochemical staining was performed using antibodies against, AKT, phosphoAKT, TRKB and PARP-1. The expression of PARP-1 and that of phosphoAKT were significantly higher in standard than in MS neuroblastomas independently of age and stage of the tumour. PhosphoAKT and PARP-1 expression was significantly correlated in both tumours. CONCLUSIONS: These data suggest that the better prognosis of patients with MS neuroblastomas compared with classical neuroblastomas was secondary to spontaneous tumour regression mediated by higher levels of apoptosis associated with low activation of AKT.

Cryptogenic organizing pneumonia after rituximab therapy for presumed post-kidney transplant lymphoproliferative disease.

Cryptogenic organizing pneumonia (COP, formerly bronchiolitis obliterans organizing pneumonia) is rare in children. We describe an 11-year-old girl with Epstein-Barr virus (EBV) reactivation/presumed post-transplant lymphoproliferative disease (PTLD) 15 months after undergoing a deceased donor kidney transplantation. Treatment with reduced immunosuppression, ganciclovir, and cytomegalovirus immunoglobulin was complicated by severe graft rejection, prompting therapy with methylprednisolone, anti-thymocyte globulin and four weekly doses of rituximab (total 1500 mg/m(2)). Tacrolimus- and prednisone-based anti-rejection prophylaxis was complemented with low-dose sirolimus. When the lactate dehydrogenase and uric acid levels rose 10 weeks after the first rituximab infusion and bilateral pulmonary nodules were detected by computerized tomography, recurrence of PTLD was suspected. Open lung biopsy of the clinically asymptomatic patient identified the nodules as COP, characterized by abundant CD3(+) T-cells, few B-cells, and the absence of EBV, cytomegalovirus, or adenovirus antigens. With normalization of the peripheral B-cell count, EB viremia reappeared and persisted, despite minimal immunosuppression. Four years later, the patient was diagnosed with classical Hodgkin lymphoma-type PTLD with multiple pulmonary and abdominal nodes. This first report of rituximab-associated, pediatric COP highlights the risk of pulmonary complications after treatment with B-cell depleting agents in solid organ transplant recipients, and the importance of a histopathologic diagnosis and vigilant follow-up of such lesions.

Current trends in nontuberculous mycobacteria infections in Canadian children: A pediatric investigators collaborative network on infections in Canada (PICNIC) study.

BACKGROUND: Nontuberculous mycobacteria (NTM) infections appear to be increasing in number and severity in developed countries worldwide. Surgical excision has been considered the standard treatment for NTM lymphadenitis, but the use of medical therapy seems to be increasing. OBJECTIVE: To determine the disease characteristics as well as the current therapeutic management of NTM infections in Canadian children. METHODS: Cases of definite or probable NTM infections were identified prospectively in children up to 18 years of age seen in 10 Canadian paediatric tertiary care centres from September 2005 to August 2006. Clinical, microbiological and pathological data were collected. RESULTS: A total of 60 cases were identified. Data were complete for 45 patients, including 34 cases of lymphadenitis, four cases of skin and soft tissue infection, and seven cases of pulmonary NTM infection. Seventy-nine per cent of children (27 of 34) with lymphadenitis had an unsuccessful course of antibiotics before diagnosis. Sixty-eight per cent of purified protein derivative tests (15 of 22) were positive. NTM was detected in 76% of samples (29 of 38), of which 62% were Mycobacterium avium complex. All patients with lymphadenitis underwent surgical therapy and most patients (74%) also received antimicrobials. CONCLUSIONS: Current trends indicate that the majority of the study centres are using medical therapy with variable regimen and duration as an adjunct to surgical excision in the treatment of NTM lymphadenitis. Larger numbers and longer follow-up times are needed to better evaluate the efficacy of medical therapy and outcome of disease. A randomized controlled study comparing surgical therapy alone and chemotherapy for NTM lymphadenitis is required.

Spindle epithelial tumor with thymus-like elements of the thyroid: a multi-institutional case series and review of the literature.

BACKGROUND/PURPOSE: Spindle epithelial tumor with thymus-like elements (SETTLE) is a rare tumor of the thyroid observed in children and adolescents. We present a case series of 3 patients with SETTLE, focusing on the clinical and pathologic features of this rare tumor. METHODS: Three male patients presented at ages 4.5, 6.5, and 7 years with a right thyroid mass. All were treated by standard hemithyroidectomy. None had evidence of distant metastases at presentation. The diagnosis of SETTLE was confirmed at the time of the initial operation in 2 of the 3 patients. RESULTS: All patients had uneventful postoperative courses. Two patients remain disease-free 4 and 7 years postresection, respectively. One patient presented 10 years after resection with shortness of breath and hemoptysis secondary to multiple bilateral parenchymal lung metastases. This patient received chemotherapy against the epithelial components of the tumor with a 25% response based on imaging studies. CONCLUSION: Spindle epithelial tumor with thymus-like elements is rare tumor that should be suspected if spindle elements are observed in the resected thyroid specimen. Because these patients may present with delayed metastases, follow-up is recommended. However, chemotherapy against specific tumor elements is only marginally effective.