Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling.

Low blood flow through the fetal left heart is often conjectured as an etiology for hypoplastic left heart syndrome (HLHS). To investigate if a decrease in left heart flow results in growth failure, we generate left ventricular inflow obstruction (LVIO) in mid-gestation fetal lambs by implanting coils in their left atrium using an ultrasound-guided percutaneous technique. Significant LVIO recapitulates important clinical features of HLHS: decreased antegrade aortic valve flow, compensatory retrograde perfusion of the brain and ascending aorta (AAo) from the arterial duct, severe left heart hypoplasia, a non-apex forming LV, and a thickened endocardial layer. The hypoplastic AAo have miRNA-gene pairs annotating to cell proliferation that are inversely differentially expressed by bulk RNA-seq. Single-nucleus RNA-seq of the hypoplastic LV myocardium shows an increase in fibroblasts with a reciprocal decrease in cardiomyocyte nuclei proportions. Fibroblasts, cardiomyocytes and endothelial cells from hypoplastic myocardium have increased expression of extracellular matrix component or fibrosis genes with dysregulated fibroblast growth factor signaling. Hence, a severe sustained ( ~ 1/3 gestation) reduction in fetal left heart flow is sufficient to cause left heart hypoplasia. This is accompanied by changes in cellular composition and gene expression consistent with a pro-fibrotic environment and aberrant induction of mesenchymal programs.

Fatal Pediatric Streptococcal Infection: A Clinico-Pathological Study.

PURPOSE AND CONTEXT: Streptococcal Infection (SI) is an important cause of pediatric death in children, yet limited reports exist on autopsy findings in fatal SI cases. METHOD: Case records (1997-2019) of SI with no pre-existing risk factors were reviewed and selected. Their clinical and pathological findings in the autopsy reports were analyzed. RESULTS: In our cohort of 38 cases based on bacterial culture results, SI was most commonly caused by Streptococcus pneumoniae (SPn; 45%) and Streptococcus pyogenes (SPy; 37%). 92% of decedents had some prodromal symptoms prior to terminal presentation. The clinical course was often rapid, with 89% found unresponsive, suddenly collapsing, or dying within 24 hours of hospital admission. 64% of deaths were attributed to sepsis, more frequently diagnosed in the SPy group than in the SPn group (71% vs 48%). Pneumonia was found in both SPn and SPy groups, whereas meningitis was exclusively associated with SPn. CONCLUSION: Our study shows fatal SI is most commonly caused by either SPn or SPy, both of which are frequently associated with prodromal symptoms, rapid terminal clinical course, and evidence of sepsis. Postmortem diagnosis of sepsis is challenging and should be correlated with clinical features, bacterial culture results, and autopsy findings.

Paediatric dilated cardiomyopathy with and without endocardial fibroelastosis - a pathological analysis of 89 explants.

Heart failure due to dilated cardiomyopathy is a major indication for paediatric cardiac transplantation. Endocardial fibroelastosis is a recognised pathological finding of unknown prognostic significance in paediatric dilated cardiomyopathy. To evaluate the nature of the association between left ventricular endocardial fibroelastosis and paediatric dilated cardiomyopathy, we reviewed surgical pathology reports of dilated cardiomyopathy explants (1986-2016) in order to characterise the pathological findings and to compare and contrast their frequency among four age groups: less than 1 year; 1-5 years; 6-10 years; and greater than 11 years. The 89 explants (47 males and 42 females) were all characterised by increased weight and left ventricular chamber dilatation without increased wall thickness. Ninety-five per cent of the specimens in the two youngest subsets had left ventricular endocardial fibroelastosis. Compared to the oldest age group, recipients aged 1-5 years had a 6-fold increase and those younger than 1 year a 19-fold increase in the odds of observing left ventricular endocardial fibroelastosis. Explants with and without endocardial fibroelastosis were otherwise phenotypically similar. In paediatric dilated cardiomyopathy endocardial fibroelastosis is a very common pathological finding, especially in infants and young children. We propose that the descriptive, clinico-pathological designation "Dilated Cardiomyopathy with Endocardial Fibroelastosis" should be adopted to facilitate future investigation into the potential prognostic/therapeutic significance of left ventricular endocardial fibroelastosis.

Mixed-reality view of cardiac specimens: a new approach to understanding complex intracardiac congenital lesions.

Digital reality is an emerging platform for three-dimensional representation of medical imaging data. In this technical innovation paper, the authors evaluated the accuracy and utility of mixed-reality technology in the morphological evaluation of complex congenital heart disease. The authors converted CT datasets of 12 heart specimens with different subtypes of double-outlet right ventricle to stereoscopic images and interrogated them using a mixed-reality system. The morphological features identified on the stereoscopic models were compared with findings at macroscopic examination of the actual heart specimens. The results showed that the mixed-reality system provided highly accurate stereoscopic display of spatially complex congenital cardiac lesions, with interactive features that might enhance 3-D understanding of morphology. Additionally, the authors found that high-resolution digital reproduction of cardiac specimens using clinical CT scanners is feasible for preservation and educational purposes.

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal ß-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and ß-catenin. A pharmacological activator of the WNT/ß-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and ß-catenin, and evidence for targeted activation of the WNT/ß-catenin pathway as a potential treatment for this disease.

Sudden Unexpected Death in Neonates: A Clinico-pathological Study.

Clinico-pathological studies that focus on sudden unexpected death (SUD) in the neonatal period are rare. The objective of this study was to elucidate the frequency and pathological spectrum of anatomical causes of death (CODs), found in the setting of sudden unexpected death in neonates (SUD-N), and to correlate the COD with premortem circumstantial information. We conducted a detailed review of all autopsy reports on SUD-N cases at our institution from 1997 to 2015. Analyzed clinical data included obstetrical history, postpartum/neonatal medical course, and circumstances surrounding death. Evaluated autopsy data included growth parameters, pathological findings, ancillary test results, and COD. Data from decedents in which a COD was established (COD-E) were statistically compared with that from decedents in which the COD was undetermined (COD-U). Of 104 neonates (M: 49; F: 55) who fulfilled our inclusion criteria, a COD was established at autopsy in 46 cases (44%). Infections, congenital abnormalities, and inborn errors of metabolism were the most common CODs. Single variables statistically more likely to be found in COD-E neonates were clinical history of prodromal illness, witnessed loss of vital signs, and evidence of physiological stress in the thymus or the liver. A prodrome was statistically more common in the COD-E group, but the absence of a prodrome does not reliably exclude COD-E cases, since over 50% of these patients were asymptomatic prior to their demise. In COD-U neonates, the statistically significant factors were death during sleep, death during sleep while "bed"-sharing, "heavy" lungs, and petechial hemorrhages on the epicardium or pleura. Given the frequency and wide spectrum of underlying pathologies in COD-E neonates, referral of SUD-N cases to pathologists with specialized pediatric autopsy expertise is recommended.

Improving Autopsy Report Turnaround Times by Implementing Lean Management Principles.

The autopsy is an integral part of the service of a large academic pathology department. Timely reporting is central to providing good service and is beneficial for many stakeholders, including the families, the clinical team, the hospital, and the wider community. The current study aimed to improve hospital-consented autopsy reporting times (turnaround time, TAT) by using lean principles modified for a healthcare setting, with an aim of signing out 90% of autopsies in 90 days. An audit of current and historical TATs was performed, and a working group incorporating administrative, technical, and professional staff constructed a value stream map documenting the steps involved in constructing an autopsy report. Two areas of delay were noted: examination of the microscopy and time taken to sign-out the report after the weekly autopsy conference. Several measures were implemented to address these delays, including visual tracking using a whiteboard and individualized tracking sheets, weekly whiteboard huddles, and timelier scheduling of clinicopathologic conference rounds. All measures resulted in an improvement of TATs. In the 30 months prior to the institution of lean, 37% of autopsies (53/144) were signed out in 90 days, with a wide variation in reporting times. In the 30 months following the institution of lean, this improved to 74% (136/185) ( P < .0001, Fisher exact test), with a marked reduction in variability. Further, the time from autopsy to presentation at weekly clinicopathological rounds was also reduced (median: 73 days prior to lean; 63 days post-lean). The application of lean principles to autopsy sign-out workflow can significantly improve TATs and reduce variability, without changing staffing levels or significantly altering scheduling structure.

Histopathologic Analysis in Sudden Infant and Child Deaths: A Practical Approach.

The forensic pathologist responsible for sudden unexpected death (SUD) investigation in the pediatric setting faces many challenges. It usually takes many years to obtain reasonable experience and exposure to the wide variety of diseases that may present as SUD in a pediatric context, and to appreciate the differences in the etiology and clinical context between the pediatric and adult SUD setting. In pediatric SUD, it is necessary to conduct a systematic, pediatric-focused autopsy investigation including extensive histopathological assessment and ancillary testing. Postmortem histologic findings in the context of SUD in the pediatric population are often subtle and distinctly different from those seen in the adult population. The pathologist must have an understanding of both developmental and pathological processes in order to correctly interpret the findings during a pediatric autopsy. A system-based, histopathology-focused review of common entities, normal variants, and incidental findings that can prove challenging will be discussed. For the forensic pathologist tasked with pediatric SUD autopsies, development of a strong collaborative relationship with a pediatric pathologist and/or neuropathologist to assist with histopathological analysis is strongly endorsed.

Histological validation of cardiovascular magnetic resonance T1 mapping markers of myocardial fibrosis in paediatric heart transplant recipients.

BACKGROUND: Adverse fibrotic remodeling is detrimental to myocardial health and a reliable method for monitoring the development of fibrotic remodeling may be desirable during the follow-up of patients after heart transplantation (HTx). Quantification of diffuse myocardial fibrosis with cardiovascular magnetic resonance (CMR) has been increasingly applied and validated histologically in adult patients with heart disease. However, comparisons of CMR findings with histological fibrosis burden in children are lacking. This study aimed to compare native T1 times and extracellular volume fraction (ECV) derived from CMR with the degree of collagen on endomyocardial biopsy (EmBx), and to investigate the association between myocardial fibrosis and clinical as well as functional markers in children after HTx. METHODS: EmBx and CMR were performed on the same day. All specimens were stained with picrosirius red. The collagen volume fraction (CVF) was calculated as ratio of stained collagen area to total myocardial area on EmBx. Native T1 values and ECV were measured by CMR on a mid-ventricular short axis slice, using a modified look-locker inversion recovery approach. RESULTS: Twenty patients (9.9 ± 6.2 years of age; 9 girls) after HTx were prospectively enrolled, at a median of 1.3 years (0.02-12.6 years) post HTx, and compared to 24 controls (13.9 ± 2.6 years of age; 12 girls). The mean histological CVF was 10.0 ± 3.4%. Septal native T1 times and ECV were higher in HTx patients compared to controls (1008 ± 32 ms vs 979 ± 24 ms, p < 0.005 and 0.30 ± 0.03 vs 0.22 ± 0.03, p < 0.0001, respectively). CVF showed a moderate correlation with native T1 (r = 0.53, p < 0.05) as well as ECV (r = 0.46, p < 0.05). Native T1 time, but not ECV and CVF, correlated with ischemia time (r = 0.46, p < 0.05). CONCLUSIONS: CMR-derived fibrosis markers correlate with histological degree of fibrosis on EmBx in children after HTx. Further, native T1 times are associated with longer ischemia times.

Value of postmortem thoracic CT over radiography in imaging of pediatric rib fractures.

BACKGROUND: Studies have reported that thoracic CT may provide greater sensitivity compared with radiography in detection of pediatric rib fractures and fracture healing. The additional sensitivity afforded by thoracic CT may have medicolegal implications where abuse is suspected. OBJECTIVE: To determine the additional value of postmortem thoracic CT compared with radiography in detecting pediatric rib fractures, and fracture healing, using autopsy findings as a gold standard. MATERIALS AND METHODS: We retrospectively reviewed 56 coroner's cases with postmortem radiography and CT thoracic survey. All studies underwent primary interpretation by one or two radiologists. The study radiologist independently reviewed all images from 13 patients with positive findings on radiography, CT or autopsy. Sensitivity and specificity between observers and imaging modalities were compared. RESULTS: Primary interpretation: Fractures were recognized on radiography in 5/12 patients who had fractures found at autopsy, and on CT in 8/12 patients. In total, 29% (24/83) of fractures were reported on radiography, and 51% (52/101) of fractures were reported on CT. Study radiologist: Fractures were recognized on radiography in 7/12 patients who had fractures found at autopsy, and on CT in 11/12 patients. In total, 46% (38/83) of fractures were reported on radiography, and 85% (86/101) of fractures were reported on CT. CONCLUSION: Postmortem thoracic CT provides greater sensitivity than radiography in detecting pediatric rib fractures, most notably in anterior and posterior fractures. However, the degree of improvement in sensitivity provided by CT might depend on observer experience.

Presence of periorbital and conjunctival petechial hemorrhages in accidental pediatric drowning.

The pathological findings of drowning are variable and non-specific. Petechial hemorrhages involving the periorbital region and the conjunctiva have been described in many causes of death, but are thought to be exceedingly uncommon in cases of drowning. However, such studies have not specifically addressed the pediatric population. The current study retrospectively examined 79 cases of accidental pediatric drowning for the presence of periorbital/conjunctival hemorrhages and analyzed factors that may have affected their presence. Ten victims had periorbital/conjunctival petechial hemorrhages (13%), with five having periorbital petechiae, three having conjunctival petechiae, and two having both periorbital and conjunctival petechiae. The age and gender of the victim, site of drowning, resuscitation history and the presence of other pathological findings were not significantly associated with the presence of periorbital/conjunctival petechiae. However, as the interval between the drowning episode and autopsy increased, the incidence of periorbital/conjunctival petechiae decreased (28% for <24h; 7% for >24h). The presence of periorbital/conjunctival hemorrhages in a significant proportion of pediatric drowning victims confirms that the pathologist must add this finding to the spectrum of changes seen in pediatric drowning.

Does hyperthyroidism increase risk of death due to the ingestion of ecstasy?

Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is a psychoactive amphetamine derivative widely used for recreational purposes. Deaths caused by acute drug intoxication with MDMA are rare but can often involve a severe hyperthermic episode. The factors underlying the increased risk of some ecstasy users to a fatal drug reaction are not known. We present a case report of a 24-year-old woman who developed fatal hyperthermia with multi-organ complications following MDMA use and was found at autopsy to have diffuse thyroid hyperplasia (Graves' disease). An antemortem blood MDMA concentration of 0.68 mg/L was measured in a sample obtained on admission to hospital. Although a cause and effect cannot be established, as the thyroid hormone is a major regulator of thermogenesis, we suggest that hyperthyroidism predisposed the subject to ecstasy-induced hyperthermia and that a pre-existing defect affecting temperature status could be one factor in explaining some ecstasy intoxication deaths.

Pediatric drowning: a 20-year review of autopsied cases: III. Bathtub drownings.

Bathtub drownings are a significant cause of mortality in the pediatric population. Infants and preambulatory children are disproportionately affected, and several studies have suggested that preventative campaigns have been ineffective in the prevention of such deaths. To obtain a better understanding of the factors associated with bathtub drownings, a retrospective review of autopsy records over a 20-year period (1984-2003) was performed. Eighteen consecutive cases of bathtub drownings were identified in 8 males and 10 females (ratio, 0.8; P = 0.6374). The age ranged from 6 months to 70 months (mean, 17 months; median, 11 months), and most cases occurred in infants aged 12 months or less (72%). Males tended to be older than females (mean, 23 months versus 11 months; P = 0.1889). Associated factors included inadequate adult supervision (89%), cobathing (39%), the use of infant bath seats (17%), and coexistent medical disorders predisposing the infant or child to the drowning episode (17%). The pathologic findings included a frothy exudate (28%), pleural effusion (28%), and increased lung weight (61%). All toxicologic samples submitted for analysis were negative. The present study highlights the factors associated with bathtub drownings and may aid in the prevention of such deaths in the pediatric population.

Pediatric drowning: a 20-year review of autopsied cases: II. Pathologic features.

The pathologic findings in autopsies of drowning victims are nonspecific and vary from case to case. However, most reported pathologic series of drowning cases exclude children and do not take into consideration the unique circumstances surrounding bathtub drownings. In addition, the effect of resuscitation on the autopsy findings has not been studied in children. A retrospective review of autopsy records of non-bathtub drownings from a 20-year period (1984-2003) was performed and 63 cases were identified in 45 males and 18 females (age range 9 months to 17 years). The incidence of frothy exudate, pleural effusion, and increased lung weight was 43%, 36%, and 80%, respectively. The incidence of frothy exudate and the combination of all 3 factors was significantly higher in cases with no resuscitation compared with those cases with attempted resuscitation with or without delayed death. As the interval between the drowning episode and autopsy increased, the incidence of frothy exudate decreased significantly. There was no relationship between these findings and the age and sex of the decedent. Other clinical conditions or occult pathologic findings that may have contributed to death were found in 8 cases (13%). The findings highlight the need for thorough clinicopathologic correlation in cases of drowning to accurately interpret the pathologic findings.

Pediatric drowning: a 20-year review of autopsied cases: I. Demographic features.

Drowning is a significant cause of childhood mortality in the developed world. Males and preschool-aged children are overrepresented in most series of pediatric drowning. To obtain a better understanding of age- and gender-related factors, a retrospective review of autopsy records over a 20-year period (1984-2003) for cases of drowning (exclusive of bathtub drownings) was performed. Sixty-three consecutive cases of drowning were identified in 45 males and 18 females (ratio 2.5; P = 0.0007). The ages ranged from 9 months to 17 years, and most cases occurred in the 0- to 4-year age group (57%). Boys tended to be older than girls (5 years 9 months versus 4 years 4 months; P = 0.2133). Sites of drowning were open water (48%) and pools (44%), with children drowning in open water being significantly older than those drowning in pools (6 years 6 months versus 4 years 6 months; P = 0.0462). Most boys drowned in open water (53%), whereas most girls drowned in pools (50%). Resuscitation was attempted after the drowning episode in 84% of cases, with children aged 4 years or less having significantly higher rates than older children (P = 0.0346). The present study highlights differences in the pattern of drowning according to age and sex and may aid in developing targeted educational and preventative campaigns.

Fatal child abuse-maltreatment syndrome. A retrospective study in Ontario, Canada, 1990-1995.

Child death due to repeated episodes of physical assault or neglect has been termed the child abuse-maltreatment syndrome (CAMS). We characterized the injuries in a series of fatally abused or maltreated child to delineate objective diagnostic criteria for the CAMS for use by clinicians and pathologists. All deaths (age <17 years) investigated by the Office of the Chief Coroner for Ontario, Canada during the time period 1990-1995 were reviewed. Cases of CAMS were defined as death due to lethal recent injury or malnutrition in the presence of significant old (healing or healed) injuries indicative of repeated episode of inflicted trauma. The nature and frequency of the various injuries was determined. The frequency of the shaken baby syndrome, and the types and frequency of ano-genital injuries were also studied. Twenty-one cases of fatal CAMS were found in the study period. Most cases had significant recent head injury with intra-cranial hemorrhage (71%). Other significant recent injuries commonly observed included blunt injuries of the skin and soft tissues (67%), blunt abdominal trauma with visceral injuries (14%), and fractures (18%). Eight cases (38%) fulfilled accepted criteria for the shaken baby syndrome. Many children with fatal head injuries had evidence of older head trauma (38% of all cases). A significant minority of cases had evidence of malnutrition due to neglect (10%) or ongoing ano-genital injuries (10%). Most cases of child homicides due to repeated episodes of abuse or maltreatment involve head trauma including shaken baby syndrome. Fractures of long bone and ribs, the classical markers of child abuse, were relatively infrequent compared with head injury. A proportion of cases had ano-genital injuries due to repeated sexual abuse or punitive maltreatment. All clinicians and pathologists must recognize the wide spectrum of injuries in child abuse to ultimate protect the victim or other children in an at-risk situation.