The effects of the (fentanyl-fueled) drug overdose epidemic on medicolegal death investigation in the United States.

The evolving opioid epidemic in the United States, fueled by illicit fentanyl, has greatly increased deaths from illicit drug use. These nonnatural deaths require formal death investigation. The National Association of Medical Examiners states in its Forensic Autopsy Performance Standards that autopsy remains a necessary component for proper investigation of suspected acute overdose deaths. If a death investigation office lacks adequate resources to investigate all deaths under its jurisdiction while meeting expected standards, then that office may be forced to consider altering its protocols for investigation by changing the types of deaths investigated or the extent of its investigations. Drug death investigations take longer to complete because novel illicit drugs and mixtures of drugs complicate toxicological analyses, prolonging a family's wait for completion of a death certificate and autopsy report. Public health agencies must also wait for results, but some agencies have developed mechanisms for rapid notification of preliminary results to allow timely deployment of public health resources. The increased deaths have strained the resources of medicolegal death investigation systems throughout the United States. Given the significant workforce shortage of forensic pathologists, newly trained forensic pathologists are too few to meet the demand. Nevertheless, forensic pathologists (and all pathologists) must make time to present their work and themselves to medical students and pathology trainees to encourage an understanding of the importance of quality medicolegal death investigation and autopsy pathology and to provide a model that can encourage interest in a career in forensic pathology.

Postmortem Study of Cause of Death Among Children Hospitalized With Respiratory Illness in Kenya.

BACKGROUND: In resource-limited settings, acute respiratory infections continue to be the leading cause of death in young children. We conducted postmortem investigations in children <5 years hospitalized with a clinical diagnosis of respiratory disease at Kenya's largest referral hospital. METHODS: We collected respiratory and other tissues postmortem to examine pathologic processes using histology, molecular and immunohistochemistry assays. Nasopharyngeal, trachea, bronchi and lung specimens were tested using 21-target respiratory pathogen real-time reverse transcription polymerase chain reaction assays deployed on Taqman Array Cards. Expert panels reviewed all findings to determine causes of death and associated pathogens. RESULTS: From 2014 to 2015, we investigated 64 pediatric deaths (median age 7 months). Pneumonia was determined as cause of death in 70% (42/52) of cases where death was associated with an infectious disease process. The main etiologies of pneumonia deaths were respiratory syncytial virus (RSV) (n = 7, 19%), Pneumocystis jirovecii (n = 7, 19%), influenza A (n = 5, 14%) and Streptococcus pneumoniae (n = 5, 14%)-10% of cases had multi-pathogen involvement. Among the other 10 deaths associated with a nonpneumonia infectious process, 4 did not have an etiology assigned, the others were associated with miliary tuberculosis (2), cerebral thrombosis due to HIV (1), Enterobacteriaceae (1), rotavirus (1), and 1 case of respiratory infection with severe hypokalemia associated with RSV. CONCLUSIONS: In spite of well-established vaccination programs in Kenya, some deaths were still vaccine preventable. Accelerated development of RSV monoclonal antibodies and vaccines, introduction of seasonal influenza vaccination, and maintenance or improved uptake of existing vaccines can contribute to further reductions in childhood mortality.

Position Paper: Recommendations for the Investigation, Diagnosis, and Certification of Deaths Related to Opioid and Other Drugs.

The National Association of Medical Examiners convened an expert panel to update the association's evidence-based recommendations for investigating and certifying deaths associated with opioids and other misused substances to improve death certificate and mortality data for public health surveillance. The recommendations are as follows:1. Autopsy provides the best information on a decedent's medical condition for optimal interpretation of toxicology results, circumstances surrounding death, medical history, and scene findings. The panel considers autopsy an essential component of investigating apparent overdose deaths.2. Scene investigation includes reconciling prescription information and medication counts. Investigators should note drug paraphernalia or other evidence of using intoxicating substances.3. Retain blood, urine, and vitreous humor whenever available. Blood from the iliofemoral vein is preferable to blood from more central sites.4. A toxicological panel should be comprehensive, including potent depressant, stimulant, and antidepressant medications. Detecting novel substances present in the community may require special testing.5. When death is attributed to a drug or combination of drugs (as cause or contributing factor), the certifier should list the drugs by generic name in the autopsy report and death certificate.6. The best classification for manner of death in an overdose without any apparent intent of self-harm is "accident."

Comparison of Minimally Invasive Tissue Sampling With Conventional Autopsy to Detect Pulmonary Pathology Among Respiratory Deaths in a Resource-Limited Setting.

OBJECTIVES: We compared minimally invasive tissue sampling (MITS) with conventional autopsy (CA) in detection of respiratory pathology/pathogens among Kenyan children younger than 5 years who were hospitalized with respiratory disease and died during hospitalization. METHODS: Pulmonary MITS guided by anatomic landmarks was followed by CA. Lung tissues were triaged for histology and molecular testing using TaqMan Array Cards (TACs). MITS and CA results were compared for adequacy and concordance. RESULTS: Adequate pulmonary tissue was obtained by MITS from 54 (84%) of 64 respiratory deaths. Comparing MITS to CA, full histologic diagnostic concordance was present in 23 (36%) cases and partial concordance in 19 (30%), an overall 66% concordance rate. Pathogen detection using TACs had full concordance in 27 (42%) and partial concordance in 24 (38%) cases investigated, an overall 80% concordance rate. CONCLUSIONS: MITS is a viable alternative to CA in respiratory deaths in resource-limited settings, especially if combined with ancillary tests to optimize diagnostic accuracy.

Determining the Cause of Death Among Children Hospitalized With Respiratory Illness in Kenya: Protocol for Pediatric Respiratory Etiology Surveillance Study (PRESS).

BACKGROUND: In sub-Saharan Africa, where the burden of respiratory disease-related deaths is the highest, information on the cause of death remains inadequate because of poor access to health care and limited availability of diagnostic tools. Postmortem examination can aid in the ascertainment of causes of death. This manuscript describes the study protocol for the Pediatric Respiratory Etiology Surveillance Study (PRESS). OBJECTIVE: This study protocol aims to identify causes and etiologies associated with respiratory disease-related deaths among children (age 1-59 months) with respiratory illness admitted to the Kenyatta National Hospital (KNH), the largest public hospital in Kenya, through postmortem examination coupled with innovative approaches to laboratory investigation. METHODS: We prospectively followed children hospitalized with respiratory illness until the end of clinical care or death. In case of death, parents or guardians were offered grief counseling, and postmortem examination was offered. Lung tissue specimens were collected using minimally invasive tissue sampling and conventional autopsy where other tissues were collected. Tissues were tested using histopathology, immunohistochemistry, and multipathogen molecular-based assays to identify pathogens. For each case, clinical and laboratory data were reviewed by a team of pathologists, clinicians, laboratorians, and epidemiologists to assign a cause of and etiology associated with death. RESULTS: We have enrolled pediatric cases of respiratory illness hospitalized at the KNH at the time of this submission; of those, 14.8% (140/945) died while in the hospital. Both analysis and interpretation of laboratory results and writing up of findings are expected in 2019-2020. CONCLUSIONS: Postmortem studies can help identify major pathogens contributing to respiratory-associated deaths in children. This information is needed to develop evidence-based prevention and treatment policies that target important causes of pediatric respiratory mortality and assist with the prioritization of local resources. Furthermore, PRESS can provide insights into the interpretation of results using multipathogen testing platforms in resource-limited settings. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/10854.

Islet Interleukin-1ß Immunoreactivity Is an Early Feature of Cystic Fibrosis That May Contribute to ß-Cell Failure.

OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), increasing patient morbidity and mortality. Poor understanding of CFRD pathogenesis limits the development of targeted therapies to treat and/or prevent the disease. The aim of this study was to evaluate islet pathology, specifically, inflammation, amyloid deposition, and endocrine cell composition in subjects with CF with diabetes and with CF without diabetes. RESEARCH DESIGN AND METHODS: A retrospective analysis of archived pancreas tissue collected at autopsy was conducted using pancreas tissue from subjects with CF and diabetes (CFRD) (n = 18) and CF without diabetes (CF-no DM) (n = 17). Two cohorts of control non-CF subjects were identified, each matched to CFRD and CF-no DM subjects for age, sex, and BMI (non-CF older, n = 20, and non-CF younger, n = 20), respectively. Immunohistochemistry was performed to assess interleukin-1ß (IL-1ß) and islet hormone (insulin, glucagon, somatostatin, and pancreatic polypeptide) immunoreactivity; histochemistry was performed to quantify amyloid deposition. RESULTS: Islet IL-1ß immunoreactivity was substantially increased in both CFRD and CF-no DM subjects compared with non-CF subjects and was common in young subjects with CF (≤10 years of age). In contrast, islet amyloid deposition was increased only in CFRD subjects. We also observe abnormal islet hormone immunoreactivity, characterized by increased glucagon immunoreactivity, in CF-no DM and CFRD subjects compared with non-CF subjects. CONCLUSIONS: These findings reveal novel molecular pathways and therapeutic targets underlying islet pathology in CF subjects and may be important in developing new approaches to treat CFRD.

Acute Liver Failure Due to Echovirus 9 Associated With Persistent B-Cell Depletion From Rituximab.

We describe a case of fatal acute liver failure due to echovirus 9 in the setting of persistent B-cell depletion and hypogammaglobulinemia 3 years after rituximab therapy. Metagenomic next-generation sequencing further specified the etiologic agent. Early recognition may provide an opportunity for interventions including intravenous immunoglobulin and liver transplantation.

Placental Imaging: Normal Appearance with Review of Pathologic Findings.

The placenta plays a crucial role throughout pregnancy, and its importance may be overlooked during routine antenatal imaging evaluation. Detailed systematic assessment of the placenta at ultrasonography (US), the standard imaging examination during pregnancy, is important. Familiarity with the normal and abnormal imaging appearance of the placenta along with the multimodality and methodical approach for evaluation of its related abnormalities is necessary, so that radiologists can alert clinicians regarding appropriate prompt management decisions. This will potentially decrease fetal and maternal morbidity and mortality. This article reviews early placental formation and the expected imaging appearance of the placenta during pregnancy, as well as variations in its morphology. It also discusses various placental diseases and their potential clinical consequences. Placental pathologic conditions include abnormalities of placental size, cord insertion, placental and cord location, and placental adherence. Other conditions such as bleeding in and around the placenta, as well as trophoblastic and nontrophoblastic tumors of the placenta, are also discussed. US with Doppler imaging is the initial imaging modality of choice for placental evaluation. Magnetic resonance (MR) imaging is reserved for equivocal cases or when additional information is needed. Computed tomography (CT) has a limited role in evaluation of placental abnormalities because of the ionizing radiation exposure and the relatively limited assessment of the placenta; however, CT can provide important information in specific circumstances, particularly evaluation of trauma and staging of choriocarcinoma. This article also addresses recent techniques and updates in placental imaging, including elastography, diffusion-weighted MR imaging, and blood oxygen level-dependent (BOLD) MR imaging. These advanced imaging techniques may provide additional information in evaluation of abnormal placental adherence and new insights into placental pathophysiology in selected patients. Online supplemental material is available for this article. ©RSNA, 2017.

Human Type 1 Diabetes Is Characterized by an Early, Marked, Sustained, and Islet-Selective Loss of Sympathetic Nerves.

In humans, the glucagon response to moderate-to-marked insulin-induced hypoglycemia (IIH) is largely mediated by the autonomic nervous system. Because this glucagon response is impaired early in type 1 diabetes, we sought to determine if these patients, like animal models of autoimmune diabetes, have an early and severe loss of islet sympathetic nerves. We also tested whether this nerve loss is a permanent feature of type 1 diabetes, is islet-selective, and is not seen in type 2 diabetes. To do so, we quantified pancreatic islet and exocrine sympathetic nerve fiber area from autopsy samples of patients with type 1 or 2 diabetes and control subjects without diabetes. Our central finding is that patients with either very recent onset (<2 weeks) or long duration (>10 years) of type 1 diabetes have a severe loss of islet sympathetic nerves (Δ = -88% and Δ = -79%, respectively). In contrast, patients with type 2 diabetes lose no islet sympathetic nerves. There is no loss of exocrine sympathetic nerves in either type 1 or type 2 diabetes. We conclude that patients with type 1, but not type 2, diabetes have an early, marked, sustained, and islet-selective loss of sympathetic nerves, one that may impair their glucagon response to IIH.

Macrocyclic and Other Non-Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue: Preliminary Results From 9 Patients With Normal Renal Function.

OBJECTIVE: The purpose of this study was to determine whether gadolinium (Gd) is deposited in brain and bone tissues in patients receiving only non-Group 1 agents, either macrocyclic or linear protein interacting Gd-based contrast agents, with normal renal function. Group 1 agents are linear agents most associated with nephrogenic systemic fibrosis that the US Federal Drug Administration has defined as contraindicated in patients at risk for this disease. MATERIALS AND METHODS: This study was institutional review board approved and Health Insurance Portability and Accountability Act compliant for retrospective review of records and also had signed autopsy consent authorizing use of decedent's tissue in research studies. Tissue samples were collected from 9 decedents undergoing autopsy who had contrast-enhanced magnetic resonance imaging (MRI) with only single agent exposure to a non-Group 1 Gd-based contrast agent. Decedents with only noncontrast MRI or no MRI served as controls. Multiple brain areas, including globus pallidus and dentate nucleus, as well as bone and skin, were sampled and analyzed for Gd using inductively coupled plasma mass spectrometry. Gadolinium levels were compared between groups of decedents using the Mann-Whitney test and between brain and bone tissues of the same cases using the Wilcoxon signed-rank test. RESULTS: Of the 9 decedents, 5 received gadoteridol (ProHance; Bracco Diagnostics, Princeton, NJ), 2 received gadobutrol (Gadovist; Bayer Healthcare, Whippany, NJ), and 1 each had gadobenate (MultiHance; Bracco Diagnostics) and gadoxetate (Eovist; Bayer Healthcare). Gadolinium was found with all agents in all brain areas sampled with highest levels in globus pallidus and dentate. Bone levels measured 23 times higher (median) than brain levels (P = 0.008 for bone vs globus pallidus) and showed a significant correlation (r = 0.81, P = 0.022). In controls, Gd levels in the brain were at or below limits of measurement and were significantly lower compared with study cases (P = 0.005 for globus pallidus). CONCLUSION: Gadolinium deposition in normal brain and bone tissue occurs with macrocyclic and linear protein interacting agents in patients with normal renal function. Deposition of Gd in cortical bone occurs at much higher levels compared with brain tissue and shows a notable correlation between the two. Thus, the bone may serve as a surrogate to estimate brain deposition if brain Gd were to become a useful clinical or research marker.

Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans.

OBJECTIVE: To use quantitative magnetic resonance imaging (MRI) to test whether mediobasal hypothalamic (MBH) gliosis is associated with obesity and insulin resistance in humans. METHODS: Sixty-seven participants underwent a fasting blood draw and MRI. Cases with radiologic evidence of MBH gliosis (N = 22) were identified as the upper tertile of left MBH T2 relaxation time and were compared to controls (N = 23) from the lowest tertile. In a separate postmortem study, brain slices (N = 10) through the MBH were imaged by MRI and stained for glial fibrillary acidic protein (GFAP). RESULTS: In all participants, longer T2 relaxation time in the left MBH was associated with higher BMI (P = 0.01). Compared with controls, cases had longer T2 relaxation times in the right MBH (P < 0.05), as well as higher BMI (P < 0.05), fasting insulin concentrations (P < 0.01), and HOMA-IR values (P < 0.01), adjusted for sex and age. Elevations in insulin and HOMA-IR were also independent of BMI. In the postmortem study, GFAP staining intensity was positively associated with MBH T2 relaxation time (P < 0.05), validating an MRI-based method for the detection of MBH gliosis in humans. CONCLUSIONS: These findings link hypothalamic gliosis to insulin resistance in humans and suggest that the link is independent of the level of adiposity.

Regional Isolation Drives Bacterial Diversification within Cystic Fibrosis Lungs.

Bacterial lineages that chronically infect cystic fibrosis (CF) patients genetically diversify during infection. However, the mechanisms driving diversification are unknown. By dissecting ten CF lung pairs and studying ∼12,000 regional isolates, we were able to investigate whether clonally related Pseudomonas aeruginosa inhabiting different lung regions evolve independently and differ functionally. Phylogenetic analysis of genome sequences showed that regional isolation of P. aeruginosa drives divergent evolution. We investigated the consequences of regional evolution by studying isolates from mildly and severely diseased lung regions and found evolved differences in bacterial nutritional requirements, host defense and antibiotic resistance, and virulence due to hyperactivity of the type 3 secretion system. These findings suggest that bacterial intermixing is limited in CF lungs and that regional selective pressures may markedly differ. The findings also may explain how specialized bacterial variants arise during infection and raise the possibility that pathogen diversification occurs in other chronic infections characterized by spatially heterogeneous conditions.

Human Islets Have Fewer Blood Vessels than Mouse Islets and the Density of Islet Vascular Structures Is Increased in Type 2 Diabetes.

Human and rodent islets differ substantially in several features, including architecture, cell composition, gene expression and some aspects of insulin secretion. Mouse pancreatic islets are highly vascularized with interactions between islet endothelial and endocrine cells being important for islet cell differentiation and function. To determine whether human islets have a similar high degree of vascularization and whether this is altered with diabetes, we examined the vascularization of islets from normal human subjects, subjects with type 2 diabetes (T2D), and normal mice. Using an integrated morphometry approach to quantify intra-islet capillary density in human and mouse pancreatic sections, we found that human islets have five-fold fewer vessels per islet area than mouse islets. Islets in pancreatic sections from T2D subjects showed capillary thickening, some capillary fragmentation and had increased vessel density as compared with non-diabetic controls. These changes in islet vasculature in T2D islets appeared to be associated with amyloid deposition, which was noted in islets from 8/9 T2D subjects (and occupied 14% ± 4% of islet area), especially around the intra-islet capillaries. The physiological implications of the differences in the angioarchitecture of mouse and human islets are not known. Islet vascular changes in T2D may exacerbate ß cell/islet dysfunction and ß cell loss.

Providers' beliefs about expressing condolences to the family of a deceased patient: a qualitative and quantitative analysis.

BACKGROUND: Most providers do not receive training in expressing condolences to bereaved families, and most health care institutions do not have policies in place encouraging expression of condolences. Physicians may fail to meet the expectations of bereaved families. OBJECTIVE: Our aim was to describe providers' beliefs and practices regarding expressing condolences to families of patients who have died. METHODS: A confidential online survey was conducted. Subjects were all physicians, nurse practitioners, and physician assistants on the active and adjunct medical staff at the University of Washington Medical Center (UWMC). Using the responses to the survey questions, we measured the nature and frequency of practices surrounding condolences; qualitative analysis using grounded theory was performed for open-ended questions. RESULTS: Four hundred ninety-seven of 1063 providers (47%) responded to the survey. Of 432 respondents who provide direct patient care, 375 answered the question, "Excluding condolences offered when notifying someone of a death, how often do you express your condolences to the family after the death of [a patient]?" Two hundred eight of the 375 (55%) responded "always" or "often." Providers who only provide inpatient care were significantly less likely to express condolences than those who provide some or only outpatient care, p=0.029. In multinomial regression models, the only factor significantly associated with the likelihood of expressing condolences was number of years in practice. Providers in practice for 20 or more years were more likely to write letters than less experienced providers (p<0.05). Qualitative data suggested that respondents want institutional support for expressing condolences. CONCLUSIONS: A small majority of providers at an academic medical center usually expressed condolences to the families of patients who died. Hospitalists and less experienced providers may be less likely to express condolences and interventions should target these physicians.

Pulmonary effects of i.v. injection of crushed oral tablets: "excipient lung disease".

OBJECTIVE: When crushed oral tablets are injected i.v., their filler material (excipient) can induce a potentially fatal foreign-body reaction in pulmonary arterioles, presenting as dyspnea and pulmonary hypertension with centrilobular nodules on CT. We will describe the imaging and pathologic features of "excipient lung disease." CONCLUSION: The radiologist has a critical role in recognizing and reporting excipient lung disease because the referring clinician may be unaware of the patient's i.v. drug abuse.