Nodding syndrome is unlikely to be an autoimmune reaction to leiomodin-1 after infection by Onchocerca volvulus.

Nodding syndrome is a neurological disease of children in northern Uganda. Infection with the nematode parasite Onchocerca volvulus has been epidemiologically implicated as the cause of the disease. It has been proposed that an autoantibody directed against the human protein leiomodin-1 cross reacts with a tropomyosin-like nematode protein, thus suggesting that nodding syndrome is an autoimmune brain disease due to extra-cerebral parasitism. This hypothesis is dependent on constitutive neuronal expression of leiomodin-1. We tested this hypothesis by studying the distribution of leiomodin-1 in the normal human brain and other human tissues using immunohistochemistry. We found that immunostaining for leiomodin-1 follows a smooth muscle cell specific pattern. In the brain, it is confined to the smooth muscle cells of cerebral blood vessels and is not generally present in neurons or glia. However, immunoreactivity was identified in human Purkinje cell membrane and the body wall of C. elegans (as a proxy for Onchocerca volvulus) but only when immunostained with an antibody recognizing the N-terminal of leiomodin-1. Homology between leiomodin-1 and tropomodulin, specifically at the N-terminus, could explain why leiomodin-1 antibody cross reactivity between human Purkinje cells and C. elegans. However, we cannot provide proof confirming that the immunoreactivity in the membranes of Purkinje cells is specifically caused by the expression of tropomodulin. To overcome this limitation, further investigations using additional immunohistochemical and biochemical studies are required to corroborate our findings and provide more comprehensive evidence. Nevertheless, our findings do not support to the autoimmunity hypothesis involving Onchocerca volvulus and leiomodin-1. To gain a more comprehensive understanding of the cause and pathogenesis of NS, it is essential to explore alternative hypotheses.

SARS-CoV-2 infection dysregulates the expression of clinically relevant drug metabolizing enzymes in Vero E6 cells and membrane transporters in human lung tissues.

SARS-CoV-2-mediated interactions with drug metabolizing enzymes and membrane transporters (DMETs) in different tissues, especially lung, the main affected organ may limit the clinical efficacy and safety profile of promising COVID-19 drugs. Herein, we investigated whether SARS-CoV-2 infection could dysregulate the expression of 25 clinically relevant DMETs in Vero E6 cells and postmortem lung tissues from COVID-19 patients. Also, we assessed the role of 2 inflammatory and 4 regulatory proteins in modulating the dysregulation of DMETs in human lung tissues. We showed for the first time that SARS-CoV-2 infection dysregulates CYP3A4 and UGT1A1 at the mRNA level, as well as P-gp and MRP1 at the protein level, in Vero E6 cells and postmortem human lung tissues, respectively. We observed that at the cellular level, DMETs could potentially be dysregulated by SARS-CoV-2-associated inflammatory response and lung injury. We uncovered the pulmonary cellular localization of CYP1A2, CYP2C8, CYP2C9, and CYP2D6, as well as ENT1 and ENT2 in human lung tissues, and observed that the presence of inflammatory cells is the major driving force for the discrepancy in the localization of DMETs between COVID-19 and control human lung tissues. Because alveolar epithelial cells and lymphocytes are both sites of SARS-CoV-2 infection and localization of DMETs, we recommend further investigation of the pulmonary pharmacokinetic profile of current COVID-19 drug dosing regimen to improve clinical outcomes.

The spectrum of disease and tau pathology of nodding syndrome in Uganda.

Nodding syndrome is an enigmatic recurrent epidemic neurologic disease that affects children in East Africa. The illness begins with vertical nodding of the head and can progress to grand mal seizures and death after several years. The most recent outbreak of nodding syndrome occurred in northern Uganda. We now describe the clinicopathologic spectrum of nodding syndrome in northern Uganda. The neuropathologic findings of 16 children or young adults with fatal nodding syndrome were correlated with the onset, duration and progression of their neurological illness. The affected individuals ranged in age from 14 to 25 years at the time of death with a duration of illness ranging from 6-15 years. All 16 cases had chronic seizures. In 10 cases, detailed clinical histories were available and showed that three individuals had a clinical course that was predominantly characterized by epilepsy, whereas the other seven individuals had progressive cognitive, behavioural and motor decline, in addition to epilepsy. The main neuropathologic findings included: tau pathology (16/16 cases), cerebellar degeneration (11/16 cases) and white matter degeneration (7/16 cases). The tau pathology was characterized by filamentous tau-positive deposits in the form of neurofibrillary tangles, pre-tangles and dot-like grains and threads in the neuropil. All cases showed some degree of tau pathology in the neocortex and in the locus coeruleus with frequent involvement of the substantia nigra and tegmental nuclei and lesser involvement of other grey matter sites, but there was a lack of glial tau pathology. The tau pathology in the neocortex showed a multifocal superficial laminar pattern. We conclude that nodding syndrome is a clinicopathological entity associated consistently with tau pathology, but our observations did not establish the cause of the disease, or an explanation for the tau pathology.

Preclinical evaluation of a SARS-CoV-2 mRNA vaccine PTX-COVID19-B.

Safe and effective vaccines are needed to end the COVID-19 pandemic. Here, we report the preclinical development of a lipid nanoparticle­formulated SARS-CoV-2 mRNA vaccine, PTX-COVID19-B. PTX-COVID19-B was chosen among three candidates after the initial mouse vaccination results showed that it elicited the strongest neutralizing antibody response against SARS-CoV-2. Further tests in mice and hamsters indicated that PTX-COVID19-B induced robust humoral and cellular immune responses and completely protected the vaccinated animals from SARS-CoV-2 infection in the lung. Studies in hamsters also showed that PTX-COVID19-B protected the upper respiratory tract from SARS-CoV-2 infection. Mouse immune sera elicited by PTX-COVID19-B vaccination were able to neutralize SARS-CoV-2 variants of concern, including the Alpha, Beta, Gamma, and Delta lineages. No adverse effects were induced by PTX-COVID19-B in either mice or hamsters. Based on these results, PTX-COVID19-B was authorized by Health Canada to enter clinical trials in December 2020 with a phase 2 clinical trial ongoing.

Death by fecaloma.

A 59-year-old man with a history of cerebral palsy and dextroscoliosis died in a group home. He required supplemental oxygen and had no bowel movement for weeks prior to death. At autopsy, the abdomen was markedly distended and there were flexion contractures of the legs. Postmortem computed tomography revealed a dilated digestive tract and fecal loading in the sigmoid and rectum, marked upwardly displaced diaphragm and scoliosis. On internal examination, the diaphragm was displaced rostrally and the rectosigmoid colon contained 2.5 kg of fecaloma with two rectal fecaliths. Severe scoliosis with marked reduction in volume of thoracic cavity was present. Microscopic examination revealed chronic aspiration pneumonia and chronic pulmonary hypertension. Overall, four factors led to respiratory failure: fecaloma; cerebral palsy; scoliosis; and chronic aspiration pneumonia. Based on clinicopathological correlation, the cause of death was determined to be a combination of these factors, and the key acute factor was the fecaloma.

Postmortem radiologic and pathologic findings in COVID-19: The Toronto experience with pre-hospitalization deaths in the community.

Over a year after the initial emergence of the disease, the COVID-19 pandemic continues to strain healthcare systems worldwide. The value of feedback and connection between clinical care, public health, and death investigation systems has never been more clear. To this end, knowledge of the radiologic and histopathologic features of fatal COVID-19 is critical for those working with the living and the dead. Most of the medical descriptions of COVID-19 are either focused on clinical in vivo medical imaging or autopsies performed following an intensive course of treatment over days to weeks prior to death, rather than deaths in the community prior to hospitalization. Here we report the postmortem computed tomography (PMCT) and lung histopathology in five fatal cases of COVID-19 that were subject to medicolegal death investigation. All individuals died in the community without medical treatment, or after a brief terminal admission to hospital. In these cases, the main PMCT findings included: diffuse lung changes including ground glass-type opacifications, a "crazy paving" appearance, variable areas of more dense consolidation, and relatively few areas of spared/less involved lung parenchyma. The unifying histopathology was diffuse alveolar damage in various stages of cellular evolution. In all cases, the pattern of PMCT and the lung histopathology corroborated the diagnosis of COVID-19. We propose the routine use of PMCT as a potential screening tool for the identification of COVID-19 related fatalities in the medicolegal setting where a paucity of historical information may not otherwise permit the identification of this disease prior to autopsy.

Autopsy-reported cause of death in a population-based cohort of sudden unexpected death in epilepsy.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a diagnosis of exclusion; the definition includes individuals with epilepsy who die suddenly without an identifiable toxicological or anatomical cause of death. Limited data suggest underidentification of SUDEP as the cause of death on death certificates. Here, we evaluate the autopsy-reported cause of death in a population-based cohort of SUDEP cases. METHODS: Case summaries of forensic autopsies conducted in Ontario, Canada between January 2014 and June 2016 were retrospectively screened using a language processing script for decedents with a history of epilepsy or seizures. After manual review for potential SUDEP cases, two neurologists independently examined the autopsy reports and classified deaths by Nashef criteria. Demographic characteristics and consideration by the forensic pathologist of the role of epilepsy, seizure, and SUDEP in death were summarized. RESULTS: One hundred and eight Definite, 34 Definite Plus, and 22 Possible SUDEP cases were identified. Seventy-five percent of Definite/Definite Plus SUDEP cases identified by the neurologists were attributed to SUDEP, epilepsy, or seizure disorder in the autopsy report. There was a significant association between the proportion of cases listed in the autopsy report as SUDEP, epilepsy, or seizure disorder and neurologists' SUDEP classification (86% of Definite, 38% of Definite Plus, 0% of Possible). Age was significantly associated with SUDEP classification; Definite cases were younger than Definite Plus, which were younger than Possible SUDEP cases. SIGNIFICANCE: Most SUDEP cases identified by neurologists were classified concordantly by forensic pathologists in Ontario, Canada; however, concordance decreased with increased case complexity. Although the role of epilepsy/seizures was considered in most Definite/Definite Plus cases, this study highlights the need for autopsy report review of potential SUDEP cases in research studies and assessments of the public health burden of SUDEP. The relationship between age and SUDEP classification has important public health implications; SUDEP incidence may be underappreciated in older adults.

Fatal pneumococcal septicemia in a girl with visceral heterotaxy and polysplenia: a case report.

We report an unusual case of a 15-month old previously healthy girl who died of pneumococcal septicemia in the background of visceral heterotaxy with polysplenia. Heterotaxy can also present with asplenia whereas polysplenia cases usually present with functional asplenia. Of particular note, this girl received the 13-valent pneumococcal conjugate vaccine as recommended by the Centers for Disease Control and Prevention in the routine pediatric immunization schedule used in the USA and Canada. Unfortunately, although the strain causing death (serotype 22F) is not contained in Prevnar 13®, it is in the 23-valent pneumococcal polysaccharide vaccine (e.g. Pneumovax 23®), currently suggested only for immunocompromised children age 2 with either functional or anatomic asplenia. This syndrome has the potential of being diagnosed prenatally. The intent of our case report is to raise awareness of the syndrome, highlight that heterotaxy patients with polysplenia are at danger for infections with encapsulated organism, such as pneumococcus, meningococcus, and Haemophilus influenza amongst others due to functional asplenia, recommend the 23-valent pneumococcal polysaccharide vaccine for these children before age two for the outlined reasons, and illustrate that with early diagnosis of the heterotaxy syndrome, and early diagnosis and treatment of septic complications, the morbidity or death of young children with heterotaxy syndrome can likely be reduced or prevented.

Nodding syndrome in Uganda is a tauopathy.

Nodding syndrome is an epidemic neurologic disorder of unknown cause that affects children in the subsistence-farming communities of East Africa. We report the neuropathologic findings in five fatal cases (13-18 years of age at death) of nodding syndrome from the Acholi people in northern Uganda. Neuropathologic examination revealed tau-immunoreactive neuronal neurofibrillary tangles, pre-tangles, neuropil threads, and dot-like lesions involving the cerebral cortex, subcortical nuclei and brainstem. There was preferential involvement of the frontal and temporal lobes in a patchy distribution, mostly involving the crests of gyri and the superficial cortical lamina. The mesencephalopontine tegmental nuclei, substantia nigra, and locus coeruleus revealed globose neurofibrillary tangles and threads. We conclude that nodding syndrome is a tauopathy and may represent a newly recognized neurodegenerative disease.

Drowning in epilepsy: A population-based case series.

OBJECTIVES: The risk of drowning is reported to be 15-19 times greater in people with epilepsy compared to the general population. Despite this disproportionate burden, there is limited data about the circumstances surrounding drowning deaths in people with epilepsy. This population-based case series characterizes drowning deaths in people with epilepsy. METHODS: Postmortem data from coroner-ordered autopsies conducted in Ontario between 2014 and 2016 were screened for cases of drowning in people with a history of seizures. Demographic information, epilepsy characteristics, and circumstances surrounding death were extracted from post mortem reports. The incidence of drowning in people with epilepsy was calculated using government estimates of the Ontario population and the number of people with epilepsy. RESULTS: Twenty-five people with epilepsy drowned during the three-year study period, giving an estimated incidence of 1.5 per 10,000 epilepsy person-years (95% CI: 0.98, 2.23). Decedents were mostly young (mean age 36 years) and without physical or developmental disability. Approximately one-third had psychiatric comorbidities. Epilepsy severity ranged from well-controlled to drug refractory. Only 3 people had alcohol or illicit drugs detected on toxicological analysis. Forty-four percent of deaths were the result of an unwitnessed drowning in a bathtub. CONCLUSIONS: This population-based case series confirms people with epilepsy drown at a rate nearly ten times greater than the general population (1.5 per 10,000 epilepsy person-years compared to the estimated provincial average of 0.13 per 10,000). Drowning deaths in people with epilepsy most often occur in the bathtub. These deaths are only rarely associated with intoxication. People with epilepsy should receive counseling on the increased risk of drowning, including information regarding the significant risk associated with bathtub use, the potential protective roles of anti-epileptic drug (AED) adherence and supervision when in or around water, and the fact that all people with epilepsy remain at an increased risk of drowning regardless of their apparent seizure control.

Incidence of sudden unexpected death in epilepsy in children is similar to adults.

OBJECTIVE: To determine the incidence of sudden unexpected death in epilepsy (SUDEP) in children in Ontario, Canada. METHODS: Cases of suspected pediatric SUDEP occurring between January 1, 2014, and December 31, 2015, in Ontario, Canada, were eligible for inclusion. Potential cases were identified through 3 sources: a national pediatrician surveillance program, child neurologist report, and screening of provincial forensic autopsies. Cases were classified as definite, definite plus, probable, possible, and near/near plus according to criteria described by Nashef et al. (Epilepsia 2012). Overall crude pediatric SUDEP incidence and the incidence of definite or probable pediatric SUDEP were calculated using estimates of the prevalence of pediatric epilepsy in Canada drawn from government survey data and the number of children living in Ontario. Capture-recapture analysis was used to estimate the number of missing cases and determine an adjusted definite/probable SUDEP incidence. RESULTS: Seventeen cases of pediatric SUDEP resulted in an overall incidence of 1.17 (95% confidence interval 0.68-1.88) per 1,000 pediatric epilepsy person-years. The definite/probable incidence, including definite (n = 11), definite plus (n = 2), or probable (n = 3) SUDEP cases, was 1.11 (0.63-1.79). Capture-recapture analysis indicated an estimated 21 (16-39) definite/probable SUDEP cases occurred during the study period, giving an adjusted incidence of definite/probable SUDEP of 1.45 (0.90-2.22) per 1,000 pediatric epilepsy person-years. CONCLUSION: SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

The pathology of torture.

Detainees may be subjected to torture and extra-judicial execution by State actors and terrorists. But, the pathology of torture has not been well-described. This is due to the lack of autopsies performed on victims of torture, mostly due to the disposal of the bodies of the victims by their torturers. On this basis, the cause of death of detainees subjected to torture is often a matter of speculation or remains obscure. This paper provides an overview of the pathology of torture based on the authour's experience with the autopsies of torture victims. At autopsy, many different types of inflicted injuries may be observed, often ranging in severity. However, three recurrent patterns of trauma that are the hallmarks of torture were recognized by the authour: (1) blunt impact trauma characterized by bruises, patterned injuries, and internal injuries; (2) electrical and thermal injuries; and (3) injuries from stress positions that occur from prolonged suspension. The most under-recognized form of fatal torture are the complications of stress positions related to suspension of the victim's body by the upper, or lower extremities. For example, prolonged suspension by reverse hanging (suspension of the victim's body by the wrists or forearms with the arms extended backward at the shoulder joint) can cause over-stretching and necrosis of the muscles of the shoulder, resulting in fatal myoglobinuric renal failure. It is essential that autopsies be performed on all detainees who die in custody, to determine if torture played a role in death. Furthermore, the true nature of the injuries sustained often remains obscure unless a musculocutaneous dissection is performed. Specifically, dissection of the back, limbs and the soles of the feet, as well as the shoulders and knees is essential to determine if specific forms of torture have been applied. This is especially true for fatal complications of stress positions. Seeking the truth about the medical consequences of fatal torture will raise awareness about torture-related injuries, assist in rehabilitation of torture survivors, and strengthen forensic humanitarian action.

Fatal acute retropharyngeal hemorrhage in neurofibromatosis type 1.

We report the sudden death of a woman with neurofibromatosis type 1 (NF1). The decedent developed acute respiratory distress and died rapidly despite an emergent cricothyroidotomy. An autopsy with postmortem CT scan was performed to determine the cause of the fatal respiratory collapse and to determine if death was related to neurofibromatosis. Postmortem examination revealed the classical external hallmarks of neurofibromatosis, including innumerable cutaneous neurofibromas. In addition, there was a massive retropharyngeal hematoma with fatal extrinsic compression of the airway. On macroscopic examination A localized 3 cm diameter tumor nodule was found in the soft tissues of the neck. Histologic examination of the nodule revealed a neurofibroma. In addition, histologic sections of the hematoma and surrounding soft tissues revealed plexiform neurofibroma with infiltration of the walls of small blood vessels and of the right vertebral artery. The fatal retropharyngeal hemorrhage was caused by diffuse infiltration of the blood vessels of the neck by plexiform neurofibroma. We concluded that the underlying cause of death was NF1. This case underscores the protean nature of neurofibroma, particularly when diffuse interstitial hemorrhage is present. Infiltration of soft tissues by neurofibroma may only be detectable on histologic examination.

Intra-Abdominal Hemorrhage Complicating Electrothermal Arterial Injury During Pelvic Surgery: A Case Report.

Iatrogenic vascular injury is a potentially serious complication of surgical procedures. Here we report a case of delayed fatal intra-abdominal hemorrhage because of electrocautery injury of a right external iliac artery. The decedent, a 31-year-old woman, died suddenly on postoperative day 1 after a laparoscopic staging operation for an ovarian tumor. Her past medical history included a recent diagnosis of a microinvasive carcinoma in the background of a mucinous cystic neoplasm of the right ovary. Postmortem examination revealed a young woman with evidence of emergency intervention, recent laparoscopic pelvic surgery, and pale hypostasis limited to the back surfaces of the body. The internal examination confirmed the postmortem computed tomography findings of a large amount of blood in the pelvic and abdominal cavities and evidence of recent surgical intervention. The soft tissues around the aorta and major pelvic vessels showed electrocautery change and marked perivascular hemorrhage preferentially surrounding the right external iliac artery. Histological examination of the vascular bundle showed an electrocautery injury of the arterial wall: transmural necrosis, acute inflammation, and hemorrhage. In this report, we offer an approach to a postmortem examination in postoperative deaths with emphasis on deaths due to iatrogenic vascular injuries and discuss the rationale for determining the manner of death.

A mimic of sexually-motivated homicide: insect stings and heat exhaustion in a forest.

We report the case a woman who was found dead in a forest. The body was nude and the position of the body suggested a sexually motivated homicide. We concluded that death was not related to homicide, but was related to the conjunction of environmental factors, including insect stings, and acute psychosis. A medicolegal death investigation with postmortem examination was undertaken to determine cause of death. At the scene, the body was supine with legs spread apart and the knees flexed, exposing the external genitalia. There were multiple apparent bruises on the body and neck. At autopsy, based on macroscopic and microscopic examination, the apparent bruises were found to be hemorrhagic insect bites. No significant injuries were present and no semen was found. Death appeared to be related to heat exhaustion and innumerable insect stings. Investigation of the medical history revealed longstanding schizoaffective disorder with episodic psychotic decompensations. In the past, during an acute psychotic episode the decedent removed her clothing and ran wildly in a forest, until she was rescued in a state of exhaustion and marked agitation, and taken to hospital for treatment. We concluded that the same circumstances had been repeated but with a fatal outcome. This case is an example of a mimic of sexually-motivated homicide and is a reminder to forensic pathologists to avoid tunnel vision. We need to be skeptical of the allure of common sense based on first impressions of the scene and the body. Forensic pathologists must be unafraid to scientifically explore improbable, but true, alternate explanations.

Clinical Examination and Reporting of a Victim of Torture.

Torture is the most inhuman form of punishment. Forensic practitioners should be aware of the common forms of torture, their presentation, and the after effects. Forensic practitioners should examine victims and issue an impartial report to serve mankind in accordance with the United Nations organization. Clinical forensic medicine is the application of medical knowledge for the assessment of injuries in living persons for the purposes of administering justice. Unfortunately, the forensic examination of living individuals is a comparatively neglected field of forensic practice in some countries. In this article, common presentations of torture in the clinical forensic medicine setting are discussed, with special attention to physical forms of torture, common presentations, after effects of torture, and recognizing the difficulties encountered by refugee claims of torture victims. We also describe how to examine and report a victim of torture in clinical forensic medicine. It is a known fact that some of the refugee claimants who come before the refugee claim board have been subjected to torture. They are walking reminders of the worst ways people can treat to fellow human beings. It is sad to see some doctors still participate or collaborate with perpetrators and at the same time there are some reported cases of physicians being imprisoned due to reporting of torture victims in certain countries.

The Dead Detainee: The Autopsy in Cases of Torture.

The fatal maltreatment of people that are detained against their will, such as political prisoners and suspected terrorists, can occur in unstable countries. The death of such detainees is often controversial and debated in the media, legal tribunals, and communities. Therefore, there is a need for nonpartisan information about the cause of death of prisoners due to the implications that the data may have about a conclusion that human rights were abused. Autopsies are the only scientific way to prove the cause of death of detainees and to ascertain the truth behind how injuries may have occurred. On this basis, all forensic pathologists ought to be able to interpret the basic injury patterns commonly encountered in torture. The injuries are similar to those found in child abuse, but also include trauma from suspension and "homicide by heart attack" during interrogation. This paper will review the postmortem findings in cases of torture.

The West Kingston/Tivoli Gardens Incursion in Kingston, Jamaica.

On May 24, 2010, 800 soldiers and 370 police officers stormed into Tivoli Gardens, an impoverished district in the capital of Jamaica. Their aim was to restore state authority in this part of Kingston and to arrest Christopher "Dudus" Coke, who was wanted for extradition to the United States on drug and arms trafficking charges. The incursion was the culmination of nine months of national political turmoil. The first aim was achieved, but the second was not, and only at great cost. Around 70 civilians and three members of the security forces were killed. The authors constituted a small group of international forensic pathologists who, at the request of the Public Defender and over a four-week period from mid-June, observed the autopsies of the civilians. This paper describes some of the outcomes of this work, set within the evaluation of the incursion by the Commission of Enquiry. The Enquiry concluded there was evidence of at least 15 extrajudicial killings and was highly critical of many other aspects of the operation and its aftermath.

Forensic Legacy of the Khmer Rouge: The Cambodian Genocide.

The people of Cambodia were subjected to widespread forced migration and labor, disease, starvation, torture, murder, and indeed, genocide over a period of four years during the control of the country by Pol Pot and the Khmer Rouge in the 1970s. While the country awaits some form of justice from the hybrid tribunal hearing cases against a few of the perpetrators of these crimes, it has undertaken to memorialize the dead in visible monuments in order that the people remember and never allow it to happen again. This paper outlines the few forensic investigations which have been undertaken on the remains of the deceased from this period in Cambodia's history. The current status of the legal proceedings and the current death investigation system in Cambodia are also presented. There is a wealth of objective forensic information that can be gathered from analyzing the remains that have been disturbed and placed in monuments (stupas), and also in the undisturbed graves across the country. This information cannot only assist in any legal proceedings, but can aide in training medicolegal experts in Cambodia for the future good of the country and its rule of law.