A Large Postmortem Database of COVID-19 Patients Can Inform Disease Research and Public Policy Decision Making.

CONTEXT.­: Autopsies performed on COVID-19 patients have provided critical information about SARS-CoV-2's tropism, mechanisms of tissue injury, and the spectrum of disease. OBJECTIVE.­: To provide an updated database of postmortem disease in COVID-19 patients, assess relationships among clinical and pathologic variables, evaluate the accuracy of death certification, and correlate disease variables to causes of death. DESIGN.­: The 272 postmortem examinations reported in this paper were submitted by 14 pathologists from 9 medical or forensic institutions across the United States. The study spans the eras of the 3 principal COVID-19 strains and incorporates surveyed demographic, clinical, and postmortem data from decedents infected with SARS-CoV-2, including primary and contributing causes of death. It is the largest database of its kind to date. RESULTS.­: Demographics of the decedents reported here correspond well to national statistics. Primary causes of death as determined by autopsy and official death certificates were significantly correlated. When specifically cited disease conditions found at autopsy were correlated with COVID-19 versus non-COVID-19 death, only lung findings characteristic of SARS-CoV-2 infection or the absence of lung findings were significantly associated. CONCLUSIONS.­: Changes in hospitalization and disease likely stem from longer lifespans after COVID-19 diagnosis and alteration in treatment approaches. Although Omicron variants preferentially replicate in the upper airways, autopsied patients who died of COVID-19 in that time period showed the same lung damage as earlier decedents. Most importantly, findings suggest that there are still unelucidated risk factors for death from COVID-19 including possibly genetic susceptibility.

FIP1L1-PDGFRA Clonal Hypereosinophilic Syndrome With Eosinophilic Myocarditis and Intracardiac Thrombus.

A 45-year-old man from El Salvador with no past medical history presented with cough and chest pain. Investigations revealed 60% peripheral eosinophilia (absolute count 12.3 K/uL). Cardiac imaging was consistent with myocarditis with intracardiac thrombus formation. Endomyocardial biopsy confirmed eosinophilic infiltration of the myocardium, and bone marrow biopsy showed hypercellular marrow with 28% eosinophils. Cytogenetics/fluorescence in situ hybridization (FISH) confirmed positive FIP1L1-PDGFRA rearrangement. The patient was treated for FIP1L1-PDGFRA clonal hypereosinophilic syndrome with associated eosinophilic myocarditis and intracardiac thrombus. The treatment regimen consisted of a steroid taper, imatinib, and anticoagulation. Treatment was followed by normalization of the eosinophil count. At two-year follow-up, the patient was without recurrence of eosinophilia on maintenance imatinib and indefinite anticoagulation with warfarin.

Inflammatory Myofibroblastic Tumor of the Orbit in a 5-Month-Old Infant.

Inflammatory myofibroblastic tumors are mesenchymal neoplasms composed of spindle cells and inflammatory infiltrate. The authors describe a 5-month-old infant with orbital inflammatory myofibroblastic tumor, the youngest patient currently reported in the literature. The histo-pathology, orbital apex location, and patient's age led to a chemotherapy-driven treatment using crizotinib with near-complete resolution of the tumor. [J Pediatr Ophthalmol Strabismus. 2022;59(2):e25-e28.].

The Use of Sunitinib as Maintenance Therapy in a Pediatric Patient With a Poorly Differentiated Thymic Carcinoma.

BACKGROUND: Thymic carcinomas are rare aggressive mediastinal tumors with a median survival of 2 years. OBSERVATION: We present a pediatric patient who was diagnosed with metastatic thymic carcinoma and showed continuous improvement of his primary mass and lung metastases with a regimen of cisplatin/docetaxel followed by long-term maintenance therapy with sunitinib for over 5 years. CONCLUSIONS: This report demonstrates a long-term positive treatment effect using chemotherapy followed by sunitinib in an advanced thymic carcinoma. We are not aware of other reports of pediatric patients with metastatic thymic carcinoma treated with sunitinib maintenance who maintained a durable response for this prolonged period of time.

Pulmonary hypoplasia correlates with the length of anhydramnios in patients with early pregnancy renal anhydramnios (EPRA).

BACKGROUND: Early pregnancy renal anhydramanios (EPRA) occurs when the fetus is anuric before 22 weeks gestational age (GA) and is considered universally lethal. Serial amnioinfusions have successfully ameliorated the lethal pulmonary hypoplasia associated with EPRA and have resulted in cases of neonatal survival, peritoneal dialysis, and renal transplant. OBJECTIVE: We sought to evaluate the lung pathology of untreated fetuses and neonates that had EPRA. STUDY DESIGN: This is a retrospective case series of all fetuses and neonates diagnosed with isolated EPRA that underwent autopsy at a single tertiary care center between 1987 and 2018. Autopsy data were correlated with ultrasound findings and GA at delivery. Fetal weights, lung weights, and lung developmental stage were recorded. RESULTS: Nineteen cases met criteria for analysis and ranged from 16 to 38 weeks GA at termination or birth. The observed-to-expected (O/E) lung-to-body-weight ratio was significantly associated with GA (r = -0.51, p = 0.03), such that as GA increased the O/E ratio decreased. When limited to patients >22 weeks, this relationship strengthened (r = -0.75, p = 0.01). Importantly, overall O/E body weight had no relationship with GA. CONCLUSION: This study shows that the degree of pulmonary hypoplasia in EPRA increases with the length of anhydramnios. This suggests that amnioinfusions are likely to be of most benefit the soonest they can feasibly be initiated.

Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy.

Importance: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus that has no proven effective treatment. Although rare cases of PML have occurred with other anti-CD20 therapies, there had been no prior cases associated with ocrelizumab. Objective: To report the first ever case of PML occurring with ocrelizumab monotherapy in a patient with progressive multiple sclerosis without prior immunomodulation. Design, Setting, and Participant: This case was reported from an academic medical center. The patient had multiple sclerosis while receiving ocrelizumab monotherapy. Exposures: Ocrelizumab monotherapy. Results: A 78-year-old man with progressive multiple sclerosis treated with ocrelizumab monotherapy for 2 years presented with 2 weeks of progressive visual disturbance and confusion. Examination demonstrated a right homonymous hemianopia, and magnetic resonance imaging revealed an enlarging nonenhancing left parietal lesion without mass effect. Cerebrospinal fluid revealed 1000 copies/mL of JC virus, confirming the diagnosis of PML. Blood work on diagnosis revealed grade 2 lymphopenia, with absolute lymphocyte count of 710/µL, CD4 of 294/µL (reference range, 325-1251/µL), CD8 of 85/µL (reference range, 90-775/µL), CD19 of 1/µL, preserved CD4/CD8 ratio (3.45), and negative HIV serology. Retrospective absolute lymphocyte count revealed intermittent grade 1 lymphopenia that preceded ocrelizumab (absolute lymphocyte count range, 800-1200/µL). The patient's symptoms progressed over weeks to involve bilateral visual loss, right-sided facial droop, and dysphasia. Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated. The patient nevertheless declined rapidly and ultimately died. PML was confirmed at autopsy. Conclusions and Relevance: In this case report, PML occurrence was likely a result of the immunomodulatory function of ocrelizumab as well as age-related immunosenescence. This case report emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections such as elderly patients.

A Postmortem Portrait of the Coronavirus Disease 2019 (COVID-19) Pandemic: A Large Multi-institutional Autopsy Survey Study.

CONTEXT.­: This study represents the largest compilation to date of clinical and postmortem data from decedents with coronavirus disease 2019 (COVID-19). It will augment previously published small series of autopsy case reports, refine clinicopathologic considerations, and improve the accuracy of future vital statistical reporting. OBJECTIVE.­: To accurately reflect the preexisting diseases and pathologic conditions of decedents with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection through autopsy. DESIGN.­: Comprehensive data from 135 autopsy evaluations of COVID-19-positive decedents is presented, including histologic assessment. Postmortem examinations were performed by 36 pathologists at 19 medical centers or forensic institutions in the United States and Brazil. Data from each autopsy were collected through the online submission of multiple-choice and open-ended survey responses. RESULTS.­: Patients dying of or with COVID-19 had an average of 8.89 pathologic conditions documented at autopsy, spanning a combination of prior chronic disease and acute conditions acquired during hospitalization. Virtually all decedents were cited as having more than 1 preexisting condition, encompassing an average of 2.88 such diseases each. Clinical conditions during terminal hospitalization were cited 395 times for the 135 autopsied decedents and predominantly encompassed acute failure of multiple organ systems and/or impaired coagulation. Myocarditis was rarely cited. CONCLUSIONS.­: Cause-of-death statements in both autopsy reports and death certificates may not encompass the severity or spectrum of comorbid conditions in those dying of or with COVID-19. If supported by additional research, this finding may have implications for public health decisions and reporting moving forward through the pandemic.

The P2RX7B splice variant modulates osteosarcoma cell behaviour and metastatic properties.

Background: Osteosarcoma (OS) is the most common type of primary bone cancer affecting children and adolescents. OS has a high propensity to spread meaning the disease is often incurable and fatal. There have been no improvements in survival rates for decades. This highlights an urgent need for the development of novel therapeutic strategies. Here, we report in vitro and in vivo data that demonstrates the role of purinergic signalling, specifically, the B isoform of the purinergic receptor P2RX7 (P2RX7B), in OS progression and metastasis. Methods: TE85 and MNNG-HOS OS cells were transfected with P2RX7B. These cell lines were then characterised and assessed for proliferation, cell adhesion, migration and invasion in vitro. We used these cells to perform both paratibial and tail vein injected mouse studies where the primary tumour, bone and lungs were analysed. We used RNA-seq to identify responsive pathways relating to P2RX7B. Results: Our data shows that P2RX7B expression confers a survival advantage in TE85 + P2RX7B and MNNG-HOS + P2RX7B human OS cell lines in vitro that is minimised following treatment with A740003, a specific P2RX7 antagonist. P2RX7B expression reduced cell adhesion and P2RX7B activation promoted invasion and migration in vitro, demonstrating a metastatic phenotype. Using an in vivo OS xenograft model, MNNG-HOS + P2RX7B tumours exhibited cancer-associated ectopic bone formation that was abrogated with A740003 treatment. A pro-metastatic phenotype was further demonstrated in vivo as expression of P2RX7B in primary tumour cells increased the propensity of tumour cells to metastasise to the lungs. RNA-seq identified a novel gene axis, FN1/LOX/PDGFB/IGFBP3/BMP4, downregulated in response to A740003 treatment. Conclusion: Our data illustrates a role for P2RX7B in OS tumour growth, progression and metastasis. We show that P2RX7B is a future therapeutic target in human OS.

Evaluation of Concordance Between Original Death Certifications and an Expert Panel Process in the Determination of Sudden Unexplained Death in Childhood.

Importance: The true incidence of sudden unexplained death in childhood (SUDC), already the fifth leading category of death among toddlers by current US Centers for Disease Control and Prevention estimates, is potentially veiled by the varied certification processes by medicolegal investigative offices across the United States. Objective: To evaluate the frequency of SUDC incidence, understand its epidemiology, and assess the consistency of death certification among medical examiner and coroner offices in the US death investigation system. Design, Setting, and Participants: In this case series, 2 of 13 forensic pathologists (FPs) conducted masked reviews of 100 cases enrolled in the SUDC Registry and Research Collaborative (SUDCRRC). Children who died aged 11 months to 18 years from 36 US states, Canada, and the United Kingdom had been posthumously enrolled in the SUDCRRC by family members from 2014 to 2017. Comprehensive data from medicolegal investigative offices, clinical offices, and family members were reviewed. Data analysis was conducted from December 2014 to June 2020. Main Outcomes and Measures: Certified cause of death (COD) characterized as explained (accidental or natural) or unexplained, as determined by SUDCRRC masked review process. Results: In this study of 100 cases of SUDC (mean [SD] age, 32.1 [31.8] months; 58 [58.0%] boys; 82 [82.0%] White children; 92 [92.0%] from the United States), the original pathologist certified 43 cases (43.0%) as explained COD and 57 (57.0%) as unexplained COD. The SUDCRRC review process led to the following certifications: 16 (16.0%) were explained, 7 (7.0%) were undetermined because of insufficient data, and 77 (77.0%) were unexplained. Experts disagreed with the original COD in 40 cases (40.0%). These data suggest that SUDC incidence is higher than the current Centers for Disease Control and Prevention estimate (ie, 392 deaths in 2018). Conclusions and Relevance: To our knowledge, this is the first comprehensive masked forensic pathology review process of sudden unexpected pediatric deaths, and it suggests that SUDC may often go unrecognized in US death investigations. Some unexpected pediatric deaths may be erroneously attributed to a natural or accidental COD, negatively affecting surveillance, research, public health funding, and medical care of surviving family members. To further address the challenges of accurate and consistent death certification in SUDC, future studies are warranted.

COVID-19 in recent heart transplant recipients: Clinicopathologic features and early outcomes.

BACKGROUND: The impact of COVID-19 on heart transplant (HTx) recipients remains unclear, particularly in the early post-transplant period. METHODS: We share novel insights from our experience in five HTx patients with COVID-19 (three within 2 months post-transplant) from our institution at the epicenter of the pandemic. RESULTS: All five exhibited moderate (requiring hospitalization, n = 3) or severe (requiring ICU and/or mechanical ventilation, n = 2) illness. Both cases with severe illness were transplanted approximately 6 weeks before presentation and acquired COVID-19 through community spread. All five patients were on immunosuppressive therapy with mycophenolate mofetil (MMF) and tacrolimus, and three that were transplanted within the prior 2 months were additionally on prednisone. The two cases with severe illness had profound lymphopenia with markedly elevated C-reactive protein, procalcitonin, and ferritin. All had bilateral ground-glass opacities on chest imaging. MMF was discontinued in all five, and both severe cases received convalescent plasma. All three recent transplants underwent routine endomyocardial biopsies, revealing mild (n = 1) or no acute cellular rejection (n = 2), and no visible viral particles on electron microscopy. Within 30 days of admission, the two cases with severe illness remain hospitalized but have clinically improved, while the other three have been discharged. CONCLUSIONS: COVID-19 appears to negatively impact outcomes early after heart transplantation.

Comparison of Cooled and Uncooled IR Sensors by Means of Signal-to-Noise Ratio for NDT Diagnostics of Aerospace Grade Composites.

This work aims to address the effectiveness and challenges of non-destructive testing (NDT) by active infrared thermography (IRT) for the inspection of aerospace-grade composite samples and seeks to compare uncooled and cooled thermal cameras using the signal-to-noise ratio (SNR) as a performance parameter. It focuses on locating impact damages and optimising the results using several signal processing techniques. The work successfully compares both types of cameras using seven different SNR definitions, to understand if a lower-resolution uncooled IR camera can achieve an acceptable NDT standard. Due to most uncooled cameras being small, lightweight, and cheap, they are more accessible to use on an unmanned aerial vehicle (UAV). The concept of using a UAV for NDT on a composite wing is explored, and the UAV is also tracked using a localisation system to observe the exact movement in millimetres and how it affects the thermal data. It was observed that an NDT UAV can access difficult areas and, therefore, can be suggested for significant reduction of time and cost.

Case Report: Acute Hepatitis E in a Pediatric Traveler Presenting with Features of Autoimmune Hepatitis: A Diagnostic and Therapeutic Challenge.

Hepatitis E virus (HEV) is globally the most common cause of acute viral hepatitis. In industrialized countries, HEV infection can be seen in travelers returning from hyperendemic countries or in individuals at risk for autochthonous infection due to zoonotic exposure. Hepatitis E virus infection is often unrecognized and at times misdiagnosed because of nonspecific findings that can overlap with other causes of hepatitis, including autoimmune hepatitis (AIH). Although most cases of acute HEV infection resolve spontaneously and do not require treatment, life-threatening acute liver failure may occur in some cases. We discuss the case of an 8-year-old boy returning from Bangladesh with progressive acute liver injury and a clinical profile suggestive of AIH, who showed a favorable response to corticosteroid treatment before the diagnosis of an acute HEV infection could be established.

Congenital Rhabdomyosarcoma Presenting as a Neck Mass at Birth.

Rhabdomyosarcoma is a malignant tumor of the soft tissues which preferentially affects the pediatric population. Neonatal rhabdomyosarcoma is rare, and much of the published literature concerning this entity consists of isolated case reports and small case series. Recent work involving the classification of rhabdomyosarcoma has helped to delineate prognostic information based on gene rearrangements. Here, we present a case of congenital rhabdomyosarcoma seen in utero which manifested as a neck mass at birth and was found to harbor a favorable gene fusion.