A map of signaling responses in the human airway epithelium.

Receptor-mediated signaling plays a central role in tissue regeneration, and it is dysregulated in disease. Here, we build a signaling-response map for a model regenerative human tissue: the airway epithelium. We analyzed the effect of 17 receptor-mediated signaling pathways on organotypic cultures to determine changes in abundance and phenotype of epithelial cell types. This map recapitulates the gamut of known airway epithelial signaling responses to these pathways. It defines convergent states induced by multiple ligands and diverse, ligand-specific responses in basal cell and secretory cell metaplasia. We show that loss of canonical differentiation induced by multiple pathways is associated with cell-cycle arrest, but that arrest is not sufficient to block differentiation. Using the signaling-response map, we show that a TGFB1-mediated response underlies specific aberrant cells found in multiple lung diseases and identify interferon responses in COVID-19 patient samples. Thus, we offer a framework enabling systematic evaluation of tissue signaling responses. A record of this paper's transparent peer review process is included in the supplemental information.

Postmortem survey of haemoglobin A1c, non-alcoholic steatohepatitis and liver fibrosis within a general population.

AIMS: Non-alcoholic steatohepatitis (NASH), fatty liver disease and fibrosis are associated with diabetes mellitus and obesity. Previous autopsy series have reported prevalence of fatty liver disease to be 11%-24%. Recent studies, using imaging and serology, suggest a prevalence of 20%-35%, NASH of 5% and advanced fibrosis of 2%-3%. We examined the prevalence of NASH and liver fibrosis in a general autopsy population. METHODS: A cross-sectional study of consecutive, adult, medicolegal autopsies over a 1-year period was conducted. Liver sections were scored for fibrosis, inflammation and steatosis using a modified NASH scoring system. Stepwise logistic regression was used to identify associations between NASH or moderate/severe fibrosis and several clinicopathological parameters, including postmortem haemoglobin A1c (HbA1c). RESULTS: Of 376 cases, 86 (22.9%) were classified as NASH. Prevalence of diabetes mellitus, body mass index (BMI) and postmortem HbA1c were significantly higher in NASH cases (39.5%, 32.3 kg/m2 and 6.88%) than non-NASH cases (12.1%, 27.0 kg/m2 and 5.73%). Decedents with moderate/severe fibrosis (6.9%) had higher prevalence of diabetes, BMI and HbA1c (50%, 31.4 kg/m2 and 6.7%) compared with those with no/mild fibrosis (16%, 28 kg/m2 and 5.9%). HbA1c ≥7% was found to be an independent predictor of NASH (OR 5.11, 95% CI 2.61 to 9.98) and advanced fibrosis (OR 3.94, 95% CI 1.63 to 9.53). CONCLUSIONS: NASH and advanced fibrosis were higher in our general adult autopsy population compared with previously published estimates. This is a large series with histological evaluation showing that HbA1c >7.0% is independently associated with NASH and advanced fibrosis.

The value of the defence postmortem examination in England and Wales.

The defence or second postmortem examination is instructed by the defence legal team, per defendant, following an initial postmortem examination performed by a Home Office registered forensic pathologist. The obscure origin of this practice has allowed it to proceed as a matter of routine in English and Welsh culture, in stark contrast to international jurisdictions. The Chief Coroner's Guidance (2019) describes a change in perspective from the Home Office Circular 30 (1999) in which a presumed right to request a second postmortem examination is replaced by a process of heavy scrutiny, favouring a paper-based desktop review of the evidence. The reasons for supporting this seismic change in practice are numerous, from the limited evidential value attained to undue distress experienced by the decedent's family. Whilst it remains imperative for accused persons to examine and test the evidence, this can often be objectively and robustly enacted without a second invasive examination. Any paradigm shift takes time, and may be met with resistance, particularly when the culture is established at all levels of the legal system in which it exists. We discuss the reasons why this shift in practice is necessary to best serve both the defendant and the decedent.

Challenges to recruitment and retention of Black forensic pathologists.

BACKGROUND: Informal estimates place the number of practicing Black forensic pathologists (BFPs) in the United States (US) at somewhere between 35 and 45 which is less than 10% the estimated total of 600. The legacy of medical and institutional racism means that BFPs in the US encounter particular challenges to training and career development that their White peers do not have to contend with. METHODS: A survey developed on SurveyMonkey in English, was distributed through social media networks and by direct email to known BFPs. Their responses to questions about the challenges they faced in training and as qualified specialists and factors that eased or facilitated their progress were collected and analyzed. FINDINGS: BFPs report challenges to recruitment and retention that are like those faced by Black peers in other medical specialties. INTERPRETATION: While personal determination is an essential ingredient to career success as a BFP, there are certain structural barriers that must be eliminated to increase the total number of BFPs. The pipeline that produces BFPs must be nurtured, reimagined, and reinvigorated.

The Postmortem Interpretation of Cardiac Genetic Variants of Unknown Significance in Sudden Death in the Young: A Case Report and Review of the Literature.

Sudden cardiac death (SCD) in adolescents and young adults is a major traumatic event for families and communities. In these cases, it is not uncommon to have a negative autopsy with structurally and histologically normal heart. Such SCD cases are generally attributed to channelopathies, which include long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Our understanding of the causes for SCDs has changed significantly with the advancements in molecular and genetic studies, where many mutations are now known to be associated with certain channelopathies. Postmortem analysis provides great value in informing decision-making with regard to screening tests and prophylactic measures that should be taken to prevent sudden death in first degree relatives of the decedent. As this is a rapidly advancing field, our ability to identify genetic mutations has surpassed our ability to interpret them. This led to a unique challenge in genetic testing called variants of unknown significance (VUS). VUSs present a diagnostic dilemma and uncertainty for clinicians and patients with regard to next steps. Caution should be exercised when interpreting VUSs since misinterpretation can result in mismanagement of patients and their families. A case of a young adult man with drowning as his proximate cause of death is presented in circumstances where cardiac genetic testing was indicated and undertaken. Eight VUSs in genes implicated in inheritable cardiac dysfunction were identified and the interpretation of VUSs in this scenario is discussed.

The Adult Pancreas in Trauma and Disease.

The spectrum of traumatic and natural disease that can affect the adult pancreas is multiple and varied. Some entities are more commonly encountered in routine forensic pathology practice and the forensic pathologist needs to be very familiar with their pathological features and development from a pathophysiological perspective. However, many of the conditions are extremely rare and may never be encountered in the professional lifetimes of an individual pathologist. Still, forensic pathologists need to be aware of them in case they are one day faced with these entities as possible diagnoses to be established at postmortem examination. This can be the result of clinical concerns raised in life, potential natural disease explanations for unexpected biochemical results, and sudden, unexpected or otherwise unexplained deaths where criminal concern about the exogenous administration of a substance must be considered. Acad Forensic Pathol. 2018 8(2): 192-218.

Fatal Mitragynine-Associated Toxicity in Canada: A Case Report and Review of the Literature.

Mitragynine is amongst the more than 40 natural indole alkaloids derived from the Mitragyna speciosa, or kratom tree, also referred to as ketum. The compound is unique in that it exhibits dose-dependent clinical outcomes with stimulant effects at lower doses but sedative effects at higher concentrations. It is indigenous to Southeast Asia, where the local population has had extensive experiences utilizing the substance for its medicinal as well as recreational effects. Mitragynine is advertised as an herbal remedy and is readily accessible via the Internet, resulting in its expansive distribution throughout the world. The addictive potential of this substance is quickly becoming recognized and mitragynine has been implicated in multidrug toxicity deaths. We present a case of the first reported mitragynine-associated fatality in Canada where an independently fatal mitragynine concentration was detected in the postmortem femoral venous blood and the source drug was likely obtained as a powder from Indonesia. Acad Forensic Pathol. 2018 8(2): 340-346.

Analysis of the Medical Assistance in Dying Cases in Ontario: Understanding the Patient Demographics of Case Uptake in Ontario since the Royal Assent and Amendments of Bill C-14 in Canada.

On June 17, 2016, the Canadian government legalized medical assistance in dying (MAID) across the country by giving Royal Assent to Bill C-14. This Act made amendments to the Criminal Code and other Acts relating to MAID, allowing physicians and nurse practitioners to offer clinician-administered and self-administered MAID in conjunction with pharmacists being able to dispense the necessary medications. The eligibility criteria for MAID indicates that the individual 1) must be a recipient of publicly funded health services in Canada, 2) be at least 18 years of age, 3) be capable of health-related decision-making, and 4) has a grievous and irremediable medical condition. Because this is a new practice in Canadian health care, there are no published Canadian statistics on MAID cases to date, and this paper constitutes the first analysis of MAID cases in both the province of Ontario and Canada. Internationally, there are only a few jurisdictions with similar legislation already in place (US, the Netherlands, Belgium, Luxembourg, Switzerland, Columbia, Japan, and the United Kingdom). The published statistics on MAID cases from these jurisdictions were reviewed and used to establish the current global practices and demographics of MAID and will provide useful comparisons for Canada. This analysis will 1) outline the Canadian legislative approach to MAID, 2) provide an understanding of which patient populations in Ontario are using MAID and under what circumstances, and 3) determine if patterns exist between the internationally published MAID patient demographics and the Canadian MAID data. Selected patient demographics of the first 100 MAID cases in Ontario were reviewed and analyzed using anonymized data obtained from the Office of the Chief Coroner for Ontario so that an insight into the provision of MAID in Ontario could be obtained. Demographic factors such as age, sex, the primary medical diagnosis that prompted the request for MAID, the patient rationale for making a MAID request, the place where MAID was administered, the nature of MAID drug regimen used, and the status/specialty of medical personnel who administered the MAID drug regimen were analyzed. The analysis revealed that the majority of the first 100 MAID recipients were older adults (only 5.2% of patients were aged 35-54 years, with no younger adults between ages 18-34 years) who were afflicted with cancer (64%) and had opted for clinician-administered MAID (99%) that had been delivered in either a hospital (38.8%) or private residence (44.9%). Although the cohort was small, these Ontario MAID demographics reflect similar observations as those published internationally, but further analysis of both larger and annual case uptake in both Ontario and Canada will be conducted as the number of cases increases.

Rickets: Historical, Epidemiological, Pathophysiological, and Pathological Perspectives.

Rickets was a common metabolic disease of bone a century ago in Europe, North America, and East Asia (mainly due to vitamin D deficiency) but was largely eradicated in growing children by use of cod liver oil and the introduction of vitamin D fortification of milk in the 1930s in the United States. Vitamin D deficiency (VDD) remains the most common form of metabolic bone disease that is entirely preventable and treatable. Historically, rickets has appeared in sporadic epidemics and, despite the introduction of numerous preventive strategies, VDD has remained a global health problem amongst children. Moreover, developed countries such as Canada, Australia, the United Kingdom, and the United States have not been exempt from this. The radiological and histological features of rickets are both distinctive and characteristic and they reflect the underlying pathophysiological issue of decreased mineralization of bone as a result of VDD. The radiological features include 1) metaphyseal cupping and fraying, 2) poor mineralization of epiphyseal centers, 3) irregular and widened epiphyseal plates, 4) increased distance between the end of shaft and epiphyseal center, 5) cortical spurs at right angles to the metaphysis, 6) coarse trabeculation, and 7) periosteal reactions. Fractures may also be evident. The histological features of rickets reflect the failure of cartilage to mineralize and undergo resorption. This results in 1) disordered proliferation of chondrocytes in the hypertrophic zone secondary to a lack of apoptosis, 2) loss of the columnar arrangement of chondrocytes that results in thickening and disorganization of the hypertrophic zone, 3) tongue-like projections of cartilage that extend into the spongiosa, 4) irregularity of the limit between the proliferative and hypertrophic zones, and 5) penetration of blood vessels into the hypertrophic zone. The case of a premature 3-month-old female infant, born in the winter months in the arctic region of Canada who died from a lobar pneumonia with an incidental finding of radiological and pathological evidence of rickets, is presented. The case is used to review the entity of rickets from historical, pathophysiological, radiological, and histological perspectives.

Fatal Entrapment of the Basilar Artery in a Longitudinal Fracture of the Clivus Due to Head Injury: A Case Report and Review of the Literature.

Infarction of the posterior cerebral artery circulation arising from entrapment of the basilar artery in a fracture of the clivus has been reported in the medical literature, predominantly in the radiology and emergency medicine journals. Review of the medical literature on the topic revealed 14 published cases of entrapment of the basilar and/or vertebral artery within a longitudinal fracture of the clivus. These were all reported between 1964 and 2016 and postmortem examination had been conducted on seven cases. To date, no case of entrapment of the basilar and/or vertebral artery in a fracture of the clivus has been reported in the forensic pathology literature, and the published literature on the entity is reviewed.

Are There Hallmarks of Child Abuse? I. Osseous Injuries.

Fractures are commonly found in cases regarded as child abuse. The most commonly encountered fractures are to the ribs and the metaphyses. This paper examines the specificity of the classical metaphyseal lesion (CML) and rib fractures as hallmarks of child abuse. Recently, vitamin D deficiency (rickets) has been proposed as an alternative cause for the appearances typically described in CML. The literature in this area is examined. Rib fractures have also been highly associated with child abuse, particularly posterior rib fractures. As well as metabolic bone disease, resuscitation has been examined as a cause of rib fractures in young children. The current literature remains strongly supportive of rib fractures and metaphyseal fractures being indicators of child abuse.

Are There Hallmarks of Child Abuse? II. Non-Osseous Injuries.

Certain conditions have been considered hallmarks of child abuse. Such pathognomonic conditions have led to an inevitable diagnosis of inflicted injury. Forensic pathologists are faced with complex analyses and decisions related to what is and what is not child abuse. In this review, we examine the literature on the specificity of five conditions that have been linked to inflicted injury to varying degrees of certainty. The conditions examined include tears of the labial frena (frenula), cigarette burns, pulmonary hemorrhage and intraalveolar hemosiderin-laden macrophages as markers of upper airway obstruction, intraabdominal injuries, and anogenital injuries and postmortem changes. Analysis of the literature indicates that frena tears are not uniquely an inflicted injury. Cigarette burns are highly indicative of child abuse, though isolated cigarette burns may be accidental. Pulmonary hemorrhage is seen more commonly in cases with a history suggestive of upper airway obstruction, but is not diagnostic in an individual case. Hemosiderin-laden macrophages may be seen in cases with inflicted injuries and in natural deaths. Abdominal injuries may be seen in accidents and from resuscitation, though panreatico-duodenal complex injuries in children under five years of age are not reported to be seen in falls or resuscitation. The understanding of anogenital injuries is increasing, but misunderstanding of postmortem changes has led to miscarriages of justice.

Fatal foreign-body granulomatous pulmonary embolization due to microcrystalline cellulose in a patient receiving total parenteral nutrition: all crystals are not what they seem.

Pulmonary foreign-body granulomatous embolization has been described secondary to crystal precipitation in total parenteral nutrition (TPN) as well as when pharmaceutical tablets are crushed and injected intravenously. Extensive granulomatous embolization may cause pulmonary hypertension and death due to acute cor pulmonale. We report the case of a 34-year old woman who had been receiving TPN post-operatively secondary to complications of a paraesophageal hernia repair. During and following receiving TPN, she experienced episodes of hypoxia, tachycardia, fever, and hypotension. Computed tomography scans of the thorax showed centrilobular nodules, tree-in-bud and ground-glass opacities, as well as findings of pulmonary hypertension. Following an episode of hypoxia she was found unresponsive and died despite resuscitative efforts. Microscopic examination of the lungs following post-mortem examination revealed occlusive granulomatous inflammation of the pulmonary arterial vasculature by crystalline material. The morphologic and histochemical patterns of the crystals were suggestive of microcrystalline cellulose, a finding that was confirmed by energy dispersive X-spectroscopy and infrared spectroscopy. Ancillary tests did not support that the crystalline material was the result of TPN precipitation. Foreign-body granulomatous embolization leading to acute core pulmonale may occur as a complication of both intravenous injection of oral medications as well as of TPN crystallization. The source of crystalline material may be difficult to discern based solely on morphological assessment or by histochemical staining. Ancillary studies such as energy dispersive X-spectroscopy or infrared spectroscopy should be performed to definitively discern the two entities.