De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca2+ regulation.

Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 "trios" (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10-4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C Both RYR2 mutations are pathogenic (P = 1.7 × 10-7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10-7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.

Age-related histopathological findings in temporal arteries.

AIMS: Giant cell arteritis (GCA) is a systemic vasculitis affecting medium and large arteries in patients aged over 50 years. Involvement of temporal arteries (TA) can lead to complications such as blindness and stroke. While the diagnostic gold standard is temporal artery biopsy (TAB), comorbidities and age-related changes can make interpretation of such specimens difficult. This study aims to establish a baseline of TA changes in subjects without GCA to facilitate the interpretation of TAB. METHODS AND RESULTS: Bilateral TA specimens were collected from 100 consecutive eligible postmortem examinations. Subjects were divided into four age groups and specimens semiquantitatively evaluated for eccentric intimal fibroplasia, disruption and calcification of the internal elastic lamina (IEL), medial attenuation and degree of lymphocytic inflammation of the peri-adventitia, adventitia, media and intima. The individual scores of intimal fibroplasia, IEL disruption and medial attenuation were added to yield a 'combined score (CS)'. Seventy-eight 78 decedents were included in the final analysis following exclusion of 22 individuals for either lack of clinical information or inability to collect TA tissue. A total of 128 temporal artery specimens (50 bilateral from individual decedents, 28 unilateral) were available for examination. Intimal proliferation, IEL loss, IEL calcification and CS increased with age in a statistically significant fashion. Comparison of the oldest age group with the others showed statistically significant differences, although this was not uniformly preserved in comparison between the three youngest groups. CONCLUSION: Senescent arterial changes and healed GCA exhibit histological similarity and such changes increase proportionally with age. The CS demonstrates significant association with age overall and represents a potential avenue for development to 'normalise' TA biopsies from older individuals.

COVID-19-Associated Nonocclusive Fibrin Microthrombi in the Heart.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, coronavirus disease 2019 (COVID-19), is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of individuals with COVID-19 undergoing postmortem evaluation is provided, with 4 aims: (1) describe the pathological spectrum of the myocardium; (2) compare with an alternate viral illness; (3) investigate angiotensin-converting enzyme 2 expression; and (4) provide the first description of the cardiac findings in patients with cleared infection. METHODS: Study cases were identified from institutional files and included COVID-19 (n=15: 12 active, 3 cleared), influenza A/B (n=6), and nonvirally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An angiotensin-converting enzyme 2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction. RESULTS: Male sex was more common in the COVID-19 group (P=0.05). Nonocclusive fibrin microthrombi (without ischemic injury) were identified in 16 cases (12 COVID-19, 2 influenza, and 2 controls) and were more common in the active COVID-19 cohort (P=0.006). Four active COVID-19 cases showed focal myocarditis, whereas 1 case of cleared COVID-19 showed extensive disease. Arteriolar angiotensin-converting enzyme 2 endothelial expression was lower in COVID-19 cases than in controls (P=0.004). Angiotensin-converting enzyme 2 myocardial expression did not differ by disease category, sex, age, or number of patient comorbidities (P=0.69, P=1.00, P=0.46, P=0.65, respectively). SARS-CoV-2 immunohistochemistry showed nonspecific staining, whereas ultrastructural examination and droplet digital polymerase chain reaction were negative for viral presence. Four patients (26.7%) with COVID-19 had underlying cardiac amyloidosis. Cases with cleared infection had variable presentations. CONCLUSIONS: This detailed histopathologic, immunohistochemical, ultrastructural, and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of patients with active and cleared COVID-19 but is usually limited in extent. Histological features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease.

Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.

AIMS: Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement including elevated serum troponin levels and acute heart failure with reduced ejection fraction. The cardiac pathological changes in these patients with COVID-19 have yet to be well described. METHODS AND RESULTS: In an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists. The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry. Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement. Lymphocytic myocarditis was present in 3 (14%) of the cases. In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant. Increased interstitial macrophage infiltration was present in 18 (86%) of the cases. A mild pericarditis was present in four cases. Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases. There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified. CONCLUSIONS: In SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases. Other forms of myocardial injury are also present in these patients. The macrophage infiltration may reflect underlying diseases rather than COVID-19.

Sudden Unexpected Death in MELAS Syndrome Due to Diabetic Ketoacidosis.

We present a case report of a 25 year-old man with MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndrome, who died suddenly and unexpectedly from diabetic ketoacidosis. This case report illustrates why it is important for medical examiners to be familiar with the clinical and autopsy features of MELAS syndrome and to be aware of the common complications, which may lead to sudden unexpected death.

Formalin pigment artifact deposition in autopsy tissue: predisposing factors, patterns of distribution and methods for removal.

Formalin pigment deposition is a known artifact of autopsy histology, often anecdotally associated with decomposition of bodies. However, there is minimal data within the forensic literature demonstrating an association between formalin pigment deposition and length of postmortem interval. Furthermore, there is minimal data concerning other predisposing factors and patterns of distribution of formalin pigment deposition. In this study, we compare the amount and patterns of formalin deposition on histology slides from three categories of death: 1) decomposed bodies, 2) critically ill at time of death, and 3) sudden cardiac death. We also compare the effectiveness of two relatively simple histology laboratory methods to remove formalin pigment deposition from histology slides. Amongst the three categories of death, formalin deposition was highest in the decomposed category, second highest in the critically ill category, and lowest in the sudden cardiac death category. The organs most severely affected by formalin deposition were liver/spleen/pancreas and kidneys, and the organs least affected were brain and lung. Formalin pigment deposition correlated with length of postmortem interval. Histologic patterns of formalin deposition included the endothelial lining of vessels, perinuclear compartment of neurons and myocytes, and the basal epithelial compartment of renal tubular epithelial cells. The alcoholic ammonium hydroxide method (AAH) was slightly more effective than the alkylphenol ethoxylate (APE) method for removing formalin pigment, though both methods were effective. Because formalin pigment is strongly refractile under polarized light, a polarization filter can also be useful for distinguishing formalin pigment from other pigments.

Open staged repair of splenic and extensive superior mesenteric artery aneurysms.

A 31-year-old man with a history of multiple strokes of unknown etiology presented with multiple asymptomatic visceral artery aneurysms including a 3.3-cm bilobed splenic artery aneurysm and a 3.1-cm fusiform superior mesenteric artery aneurysm. He had no family history of aneurysms, and there was no evidence of collagen disease. He underwent open splenic artery aneurysm resection without splenectomy and had an uneventful recovery. Seven months later, he had open repair of his 14.6-cm-long fusiform superior mesenteric artery aneurysm with a 15-cm-long collagen-coated polyester interposition graft with multiple visceral branch reimplantations into the graft. The postoperative course was uneventful, and computed tomography confirmed patent graft and side branches. Two years later, the patient remained free of abdominal symptoms, although he suffered another episode of a mild stroke.

The characteristics of all-terrain vehicle (ATV)-related deaths: A forensic autopsy data-based study.

Using forensic autopsy-based data from a regional medical examiner office in the midwestern U.S. with a mixed small urban-rural population, we describe the characteristics of all-terrain vehicle (ATV)-related deaths occurring between 2000 and 2018. During this period, there were 25 ATV-related deaths. There was a strong male predominance with 22 male and 3 female decedents. The average age at death was 35 years, with a range from 10 to 82 years, and a bimodal age distribution with one peak at 10-19 years old, and a second peak at 60-69 years old. The most common cause of death was blunt trauma (n = 22), with the remainder being torso compression (n = 1), drowning (n = 1) and hypothermia (n = 1). Of the 22 blunt trauma deaths, 15 were due to head trauma. The most common mechanism of accident was roll-over (n = 11), followed by striking a stationary object (n = 6). Of the stationary objects struck, the most common was cable wire fencing accounting for 3 of the 6. A survival period following discovery of the body was present in 11 of the 25 deaths. Postmortem toxicology was positive for ethanol in 7 deaths and tramadol in 1 death.

Long-term depression-like plasticity of the blink reflex for the treatment of blepharospasm.

Our previous work showed a beneficial therapeutic effect on blepharospasm using slow repetitive transcranial magnetic stimulation, which produces a long-term depression (LTD)-like effect. High-frequency supraorbital electrical stimulation, asynchronous with the R2 component of the blink reflex, can also induce LTD-like effects on the blink reflex circuit in healthy subjects. Patients with blepharospasm have reduced inhibition of their blink recovery curves; therefore, a LTD-like intervention might normalize the blink reflex recovery (BRR) and have a favorable therapeutic effect. This is a randomized, sham-controlled, observer-blinded prospective study. In 14 blepharospasm patients, we evaluated the effects of high-frequency supraorbital stimulation on three separate treatment days. We applied 28 trains of nine stimuli, 400 Hz, either before or after the R2 or used sham stimulation. The primary outcome was the blink rate, number of spasms rated by a blinded physician and patient rating before, immediately after and 1 hour after stimulation while resting, reading, and talking; secondary outcome was the BRR. Stimulation "before" and "after" the R2 both showed a similar improvement as sham stimulation in physician rating, but patients felt significantly better with the before condition. Improvement in recovery of the blink reflex was noted only in the before condition. Clinical symptoms differed in the three baseline conditions (resting, reading, and talking). Stimulation before R2 increased inhibition in trigeminal blink reflex circuits in blepharospasm toward normal values and produced subjective, but not objective, improvement. Inhibition of the blink reflex pathway by itself appeared to be insufficient for a useful therapeutic effect.

Sudden cardiac death in the young: A consensus statement on recommended practices for cardiac examination by pathologists from the Society for Cardiovascular Pathology.

Sudden cardiac death is, by definition, an unexpected, untimely death caused by a cardiac condition in a person with known or unknown heart disease. This major international public health problem accounts for approximately 15-20% of all deaths. Typically more common in older adults with acquired heart disease, SCD also can occur in the young where the cause is more likely to be a genetically transmitted process. As these inherited disease processes can affect multiple family members, it is critical that these deaths are appropriately and thoroughly investigated. Across the United States, SCD cases in those less than 40 years of age will often fall under medical examiner/coroner jurisdiction resulting in scene investigation, review of available medical records and a complete autopsy including toxicological and histological studies. To date, there have not been consistent or uniform guidelines for cardiac examination in these cases. In addition, many medical examiner/coroner offices are understaffed and/or underfunded, both of which may hamper specialized examinations or studies (e.g., molecular testing). Use of such guidelines by pathologists in cases of SCD in decedents aged 1-39 years of age could result in life-saving medical intervention for other family members. These recommendations also may provide support for underfunded offices to argue for the significance of this specialized testing. As cardiac examinations in the setting of SCD in the young fall under ME/C jurisdiction, this consensus paper has been developed with members of the Society of Cardiovascular Pathology working with cardiovascular pathology-trained, practicing forensic pathologists.

Extracorporeal membrane oxygenation in the forensic setting: A series of 19 forensic cases.

Extracorporeal membrane oxygenation (ECMO) employs vascular cannulation and a gas exchange circuit to provide support to patients with severely compromised cardiopulmonary function. ECMO is often the last intervention taken before death and thus presents a unique challenge to medical examiners. This study describes the characteristics of decedents on ECMO at the time of death, including clinical indications, types of circuit configurations, causes and manners of death, gross findings at autopsy, and therapeutic complications. Files of a regional medical examiner office within an academic medical center were searched for the period between 2013 and 2019. Nineteen cases were identified with a median age of 36 years. The circumstances surrounding the initial presentation included: sudden death, trauma, substance abuse, homicide, therapeutic complication, work-related injury, drowning, and hypothermia. The underlying causes of death included injury-related, as well as respiratory and cardiac-related natural diseases. The time spent on ECMO varied from less than 1 h to 10 months. Complications encountered due to ECMO included cannulation site bleeding, pneumohemopericardium, retroperitoneal hematoma, limb ischemia, clotting, and cannula dislodgement. The patient population likely to receive ECMO has significant overlap with death circumstances likely to be reported to the medical examiner. As ECMO therapy has become increasingly available, it is of importance for medical examiners and death investigators to be familiar with the procedure as well as its limitations. Familiarity with ECMO and its sequelae allows for the proper documentation of postmortem findings and fosters an informed determination of the cause and manner of death.

Real-World Evidence of Transcutaneous Afferent Patterned Stimulation for Essential Tremor.

Background: Transcutaneous afferent patterned stimulation (TAPS) is a prescription, wrist-worn device-delivered, non-invasive neuromodulation therapy for treatment of hand tremor in patients with essential tremor (ET). This retrospective post-market surveillance study evaluated real-world effectiveness of TAPS from patients using therapy on-demand for at least 90 days between August 2019 through June 2021. Methods: Demographics were summarized from TAPS prescriptions received from the patient's healthcare provider. Therapy usage and effectiveness were analyzed from device logs, which included tremor measurements from onboard motion sensors. Tremor history and patient-reported outcomes were assessed from a voluntary survey. Results: A total of 321 patients (average age 71 years, 32% female) met the criteria for this analysis, 216 of whom had tremor measurements available for analysis and 69 of whom completed the survey. Total usage period ranged from 90 to 663 days, with 28% of patients using the device for over one year. Patients used therapy 5.4 ± 4.5 (mean ± 1 standard deviation) times per week. TAPS reduced tremor power by 71% (geometric mean) across all sessions, with 59% of patients experiencing >50% tremor reduction after their sessions. Eighty-four percent (84%) of patients who returned the voluntary survey reported improvement in at least one of eating, drinking, or writing, and 65% of patients reported improvement in quality of life. Self-reported device-related safety complaints were consistent with adverse events in prior clinical trials. Discussion: Real-world evidence is consistent with prior clinical trials and confirms TAPS provides safe and effective tremor control for many patients with ET. Future work assessing multi-year safety and effectiveness would be valuable to extend these data.

Nonskeletal injuries related to cardiopulmonary resuscitation: An autopsy study.

The current standard technique for cardiopulmonary resuscitation (CPR), initially described in the early 1960s, has quickly become the expected response for all persons found without a pulse or respiration. Despite the potentially lifesaving properties of external cardiac massage, the mainstay of resuscitation, it consists of repeated blunt force trauma to the chest, which can lead to extensive traumatic skeletal and nonskeletal injuries. Numerous autopsy-based studies have documented the incidence and patterns of rib and sternal fractures associated with attempted CPR, but there is relatively little data on the incidence and severity of nonskeletal CPR-related injuries. We reviewed reports from 1878 autopsies performed between September 2017 and December 2019 (inclusive), for documentation of CPR-related injuries. Among these cases, there were 93 cases with resuscitation-related nonskeletal injuries. The most common type of injury identified were visceral contusions, documented in 57.0% of cases. These contusions predominantly involved the heart, lungs, neck soft tissue, and surrounding structures. Resuscitation-related lacerations were seen in 17.2% of the cases, most predominantly involving the pericardium, heart, and liver. Statistical analysis of the data demonstrated that lacerations were more likely to be seen in females and with associated sternal fractures. Additionally, hemothoraces were present in 34.4% of cases and hemopericardium was seen in 8.6% of cases. This study provides additional documentation of the range, severity, and incidence of various types of resuscitation-related visceral injuries to better assist autopsy pathologists in distinguishing these injuries from other antecedent traumatic injuries.

Unmasking Hydroxychloroquine Cardiotoxicity in a Patient With Heart Failure and Chronotropic Incompetence.

Chronic use of hydroxychloroquine can result in cardiomyopathy and conduction disturbances. Here, we describe a case of hydroxychloroquine cardiotoxicity in a patient with heart failure with preserved ejection fraction and severe chronotropic incompetence. (Level of Difficulty: Intermediate.).

The Spectrum of Histopathologic Findings in Lungs of Patients With Fatal Coronavirus Disease 2019 (COVID-19) Infection.

CONTEXT.­: Respiratory failure appears to be the ultimate mechanism of death in most patients with severe coronavirus disease 2019 (COVID-19) infection. Studies of postmortem COVID-19 lungs largely report diffuse alveolar damage and capillary fibrin thrombi, but we have also observed other patterns. OBJECTIVE.­: To report demographic and radiographic features along with macroscopic, microscopic, and microbiologic postmortem lung findings in patients with COVID-19 infections. DESIGN.­: Patients with confirmed COVID-19 infection and postmortem examination (March 2020-May 2020) were included. Clinical findings were abstracted from medical records. Lungs were microscopically reviewed independently by 4 thoracic pathologists. Imaging studies were reviewed by a thoracic radiologist. RESULTS.­: Eight patients (7 men, 87.5%; median age, 79 years; range, 69-96 years) died within a median of 17 days (range, 6-100 days) from onset of symptoms. The median lung weight was 1220 g (range, 960-1760 g); consolidations were found in 5 patients (62.5%) and gross thromboemboli were noted in 1 patient (12.5%). Histologically, all patients had acute bronchopneumonia; 6 patients (75%) also had diffuse alveolar damage. Two patients (25%) had aspiration pneumonia in addition. Thromboemboli, usually scattered and rare, were identified in 5 patients (62.5%) in small vessels and in 2 of these patients also in pulmonary arteries. Four patients (50%) had perivascular chronic inflammation. Postmortem bacterial lung cultures were positive in 4 patients (50%). Imaging studies (available in 4 patients) were typical (n = 2, 50%), indeterminate (n = 1, 25%), or negative (n = 1, 25%) for COVID-19 infection. CONCLUSIONS.­: Our study shows that patients infected with COVID-19 not only have diffuse alveolar damage but also commonly have acute bronchopneumonia and aspiration pneumonia. These findings are important for management of these patients.

Smartwatch inertial sensors continuously monitor real-world motor fluctuations in Parkinson's disease.

Longitudinal, remote monitoring of motor symptoms in Parkinson's disease (PD) could enable more precise treatment decisions. We developed the Motor fluctuations Monitor for Parkinson's Disease (MM4PD), an ambulatory monitoring system that used smartwatch inertial sensors to continuously track fluctuations in resting tremor and dyskinesia. We designed and validated MM4PD in 343 participants with PD, including a longitudinal study of up to 6 months in a 225-subject cohort. MM4PD measurements correlated to clinical evaluations of tremor severity (ρ = 0.80) and mapped to expert ratings of dyskinesia presence (P < 0.001) during in-clinic tasks. MM4PD captured symptom changes in response to treatment that matched the clinician's expectations in 94% of evaluated subjects. In the remaining 6% of cases, symptom data from MM4PD identified opportunities to make improvements in pharmacologic strategy. These results demonstrate the promise of MM4PD as a tool to support patient-clinician communication, medication titration, and clinical trial design.

Acute Kidney Injury in Severe COVID-19 Has Similarities to Sepsis-Associated Kidney Injury: A Multi-Omics Study.

OBJECTIVE: To compare coronavirus disease 2019 (COVID-19) acute kidney injury (AKI) to sepsis-AKI (S-AKI). The morphology and transcriptomic and proteomic characteristics of autopsy kidneys were analyzed. PATIENTS AND METHODS: Individuals 18 years of age and older who died from COVID-19 and had an autopsy performed at Mayo Clinic between April 2020 to October 2020 were included. Morphological evaluation of the kidneys of 17 individuals with COVID-19 was performed. In a subset of seven COVID-19 cases with postmortem interval of less than or equal to 20 hours, ultrastructural and molecular characteristics (targeted transcriptome and proteomics analyses of tubulointerstitium) were evaluated. Molecular characteristics were compared with archived cases of S-AKI and nonsepsis causes of AKI. RESULTS: The spectrum of COVID-19 renal pathology included macrophage-dominant microvascular inflammation (glomerulitis and peritubular capillaritis), vascular dysfunction (peritubular capillary congestion and endothelial injury), and tubular injury with ultrastructural evidence of mitochondrial damage. Investigation of the spatial architecture using a novel imaging mass cytometry revealed enrichment of CD3+CD4+ T cells in close proximity to antigen-presenting cells, and macrophage-enriched glomerular and interstitial infiltrates, suggesting an innate and adaptive immune tissue response. Coronavirus disease 2019 AKI and S-AKI, as compared to nonseptic AKI, had an enrichment of transcriptional pathways involved in inflammation (apoptosis, autophagy, major histocompatibility complex class I and II, and type 1 T helper cell differentiation). Proteomic pathway analysis showed that COVID-19 AKI and to a lesser extent S-AKI were enriched in necroptosis and sirtuin-signaling pathways, both involved in regulatory response to inflammation. Upregulation of the ceramide-signaling pathway and downregulation of oxidative phosphorylation in COVID-19 AKI were noted. CONCLUSION: This data highlights the similarities between S-AKI and COVID-19 AKI and suggests that mitochondrial dysfunction may play a pivotal role in COVID-19 AKI. This data may allow the development of novel diagnostic and therapeutic targets.

Thoracic aortic dissection associated with involvement by small lymphocytic lymphoma/chronic lymphocytic leukemia: a possible underappreciated risk factor?

We report a case of a 77-year-old man with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) thought to be in remission who developed an acute type A thoracic aortic dissection despite no known risk factors for aortic dissection. Surgical pathology evaluation of the aorta specimen removed at surgery showed direct lymphocytic infiltration of the aortic adventitia and media in the region of the aortic dissection. The potential causative role and pathophysiologic mechanisms of SLL/CLL in aortic dissection are discussed.