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Introduction: The coronavirus disease of 2019 (COVID-19) pandemic has resulted in a great deal of morbidity and mortality worldwide. Since most deaths related to COVID-19 are currently considered natural, and they tend to occur following a clinically recognized illness, many medical examiner/coroner offices within the United States do not take jurisdiction over the majority of COVID-19 deaths. Methods: In this review, we present the experience of a medium-sized medical examiner's office affiliated with an academic medical school institution, over the first 15 months of the COVID-19 pandemic. Results: Compared to a 15-month period that immediately preceded the pandemic, our office experienced a significant increase in the total number of reported deaths, scene investigations, full autopsies, natural deaths, accidents, homicides, and drug-related deaths, but a decrease in the number of suicides. Overall, our office performed 5 autopsies during the study period where COVID-19 was considered the primary cause of death, 4 cases where COVID-19 was considered a contributory cause of death, and 28 cases where COVID-19 testing was positive, but COVID-19 was not contributory to death. Discussion: The COVID-19 pandemic was accompanied by a sizeable increase in work volume within our academic medical examiner's office. Although this increased workload was not related to a large number of COVID-19-related deaths investigated by the office, there were numerous areas of increased workload that were likely secondarily related to the conditions associated with the pandemic.

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A 2-year professional master of health science program at the University of Toronto provides a unique integrated educational program to train allied health science personnel to practice as physician extenders and health care professionals in two high-demand clinical laboratory disciplines, Pathologists' Assistant (PA) and Clinical Embryologist (CE). This report describes an integrated graduate program developed and delivered in a research-intensive laboratory medicine department. The core courses in fundamental biomedical science and in general medical laboratory function and operations formed the foundation on which the requisite clinical skills required to practice as a PA or CE were subsequently delivered as comprehensive CE and PA specialty courses and practicums. Students acquired research skills through courses that teach research methods, critical analysis of research articles, and biostatistics for clinical research scientists. A capstone research project provided students the opportunity to design a research project relevant to the CE or PA fields, perform and analyze the findings, and present the project as an oral abstract and a written scientific article. Students learn to face the clinical challenges by focusing on critical analysis of evidence-based professional practice. The PA field received a 5-year accreditation. CE and PA students presented their clinical research at national and international meetings, with some receiving awards, and published scientific articles. All graduates found meaningful employment in their respective fields, and initial employer response has been favorable.

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Heritable mutations in BRCA1 associate with increased risk of high-grade serous tubo-ovarian cancer. Nongenetic risk factors associated with this cancer, which arises from fallopian tube epithelial (FTE) cells, suggests a role for repetitive ovulation wherein FTE cells are exposed to inflammatory signaling molecules within follicular fluid. We previously reported increased NFκB and EGFR signaling in BRCA1-deficient primary FTE cells, with follicular fluid exposure further increasing abundance of interferon-stimulated gene (ISG) transcripts, including the ubiquitin-like protein ISG15 and other ISGylation pathway members. Both NFκB and type I interferon signaling are upregulated by stimulation of cGAS-STING or MDA5 and RIGI pattern recognition receptors. Since some pattern recognition receptors and their signal transduction pathway members are ISGylated, we tested the impact of ISG15 and ISGylation on interferon regulatory factor 3 (IRF3) and NFκB signaling through cGAS-STING or RIGI and MDA5 activation. Expression of ISG15 or UBA7, the E1-like ISG15-activating enzyme, in immortalized FTE cells was disrupted by CRISPR gene editing. Activation of IRF3 by RIGI or MDA5 but not cGAS-STING was attenuated by loss of either ISG15 or UBA7 and this was reflected by a similar effect on NFκB activation and downstream targets. Loss of ISGylation decreased levels of both MDA5 and RIGI, with knockdown of RIGI but not MDA5, decreasing IRF3 and NFκB activation in parental cells. These finding indicate that ISGylation enhances the ability of dsRNA to activate cytokine release and proinflammatory signaling. Further work to explore ISGylation as a target for prevention of high-grade serous tubo-ovarian cancer in BRCA1 mutation carriers is warranted.

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BACKGROUND: Proximal row carpectomy (PRC) is a mainstay of wrist arthritis treatment; however, it is traditionally contraindicated in patients with an affected capitate. The use of soft tissue interposition grafts to resurface the radiocapitate articulation has been previously described to allow for PRC in these patients. In the current study, we reviewed our outcomes using knee meniscus allograft interposition to resurface the radiocapitate articulation in patients who would have otherwise been contraindicated for PRC. METHODS: A retrospective study of patients who underwent PRC with or without meniscus interposition arthroplasty was performed from 2011 to 2022. Patient demographics (age, sex, occupation, hand dominance, etc) were collected. Improvement in pain was the primary outcome. Wrist range of motion and reconstructive failure requiring fusion were the secondary outcomes. RESULTS: We identified a total of 83 patients and 43 met the inclusion criteria. Fifteen patients (35%) underwent PRC with meniscus interposition arthroplasty, and 28 patients (65%) underwent PRC alone. Patients with and without meniscus interposition arthroplasty had documented improvement in pain postoperatively (93% vs 95%, P > .05) at a median follow-up time of 11 (range, 3-38 months) and 9 months (range, 3-64 months), respectively. Postoperative wrist range of motion (flexion: +9 vs -4, P > .05, extension: +12 vs -4, P = .10) trended toward increase in patients undergoing meniscus interposition arthroplasty compared with PRC alone. CONCLUSIONS: Our short- to mid-term outcomes in patients with end-stage wrist arthritis affecting the capitate who undergo PRC and meniscus interposition arthroplasty are comparable with those receiving PRC alone.

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Radiocarpal fracture translocations are uncommon injuries without well-defined treatment. This case report presents a patient with this injury that was treated with repair of the volar and dorsal structures and dynamic external fixation. Eight weeks after the procedure, the external fixation device was unlocked to allow wrist flexion and extension only. Twelve weeks after the procedure, the external fixation device was removed completely to allow full wrist range of motion. Six months after surgery, the patient had no reported pain or dysfunction, and no recurrence of radiocarpal translation. Treatment with repair of both volar and dorsal structures and dynamic external fixation was effective for this historically challenging injury to manage.

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OBJECTIVE: The previous laboratory and clinical experience of the authors had demonstrated that application of controlled subatmospheric pressure directly to injured soft tissue can result in increased survival of compromised tissues. Mechanical tissue resuscitation (MTR) is a new concept evolving from these discoveries. The authors' recent studies have demonstrated that traumatic brain injury tissue can also be salvaged. The aim of this study was to examine the effects of MTR application to injuries from intracerebral hemorrhages (ICHs) in a swine model. METHODS: The ICHs in swine were simulated by infusion of autologous artery blood into the right frontal lobe. A specially designed silicone manifold device was introduced directly into the hematoma. Continuous negative pressure at -50 mm Hg was applied through this device. T2- and T2*-weighted MRI, histological H&E staining, and immunostaining were examined. RESULTS: After 1 week of treatment, MTR significantly decreased gross hematoma volume by more than 60%, from 472.62 ± 230.19 mm3 in the nontreated group to 171.25 ± 75.38 mm3 in the MTR-treated group (p < 0.05). Total hypointense volumes measured on T2*-weighted MR images decreased from 791.99 ± 360.47 mm3 in the nontreated group to 371.16 ± 105.75 mm3 in the MTR-treated group (p < 0.05). The hyperintense area on the T2-weighted MR image decreased significantly from 2656.23 ± 426.26 mm3 in the nontreated group to 1816.66 ± 525.26 mm3 in the MTR-treated group (p < 0.05). When ICHs were treated with MTR for 2 weeks, the gross hematomas were reduced by 94%, from 112.23 ± 66.21 mm3 in the nontreated group to 6.12 ± 10.99 mm3 in the MTR-treated group (p = 0.003). MTR significantly decreased the total necrotic tissue volume in H&E staining from 120.42 ± 48.35 mm3 in the nontreated group to 60.94 ± 38.99 mm3 in the MTR-treated group (p < 0.05). The total hypointense volumes on T2*-weighted MR images were significantly reduced, from 385.54 ± 93.85 mm3 in the nontreated group to 220.54 ± 104.28 mm3 in the MTR-treated group (p < 0.05), while their mean T2 hyperintense volume decreased significantly from 2192.83 ± 728.27 mm3 in the nontreated group to 1366.97 ± 463.36 mm3 in the MTR-treated group (p < 0.05). Histology revealed that the capillary diameter in the reactive tissue rim adjacent to the hematoma increased in both the 1- and 2-week MTR-treated groups. Both von Willebrand factor and CD31 signals were detectable in endothelial cells within the hematoma cavity of both MTR-treated groups. CONCLUSIONS: This study demonstrates that local continuous application of controlled subatmospheric pressure to an ICH can safely remove more than half of a clot in 1 week and more than 90% in 2 weeks.

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Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate T cell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit systemic inflammation in the absence of widespread immune expression of the GLP-1R remains uncertain. Here, we show that GLP-1R activation attenuates the induction of plasma tumor necrosis factor alpha (TNF-α) by multiple Toll-like receptor agonists. These actions are not mediated by hematopoietic or endothelial GLP-1Rs but require central neuronal GLP-1Rs. In a cecal slurry model of polymicrobial sepsis, GLP-1RAs similarly require neuronal GLP-1Rs to attenuate detrimental responses associated with sepsis, including sickness, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation leads to reduced TNF-α via α1-adrenergic, δ-opioid, and κ-opioid receptor signaling. These data extend emerging concepts of brain-immune networks and posit a new gut-brain GLP-1R axis for suppression of peripheral inflammation.

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Clinical embryologists are responsible for the handling, evaluation, and care of human gametes and preimplantation embryos within the context of an assisted reproductive technology laboratory. They are integral members of a team of professionals who provide care for fertility patients. Despite the increasing recognition of clinical embryologists as professionals, training requirements, continuing professional development, and appropriate credentialing have lagged in several countries. In many cases, individuals enter the profession with training limited to technical aspects provided by individual laboratory directors through an apprenticeship model. In this article, we present the rationale for rigorous formal training in clinical embryology, introduce CanEMB competencies for practicing professional clinical embryologists that are founded on CanMEDs role principles, and present a nascent Masters of Health Sciences degree program in Laboratory Medicine with a specialization in clinical embryology. This 2-year program has unique features including a Clinical Embryology Skills Development Laboratory, research capstone project, and 200-hour placement within a practicing assisted reproductive technology laboratory. Importantly, this program is delivered through a university-based Department of Laboratory Medicine and Pathobiology in partnership with a Department of Obstetrics and Gynecology. Thus, this program represents a formal acceptance of clinical embryology as a clinical laboratory science. It can be adopted elsewhere to provide a relevant, robust education that will meet current and future needs of the profession.

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ABSTRACT: Railroad-related fatalities in the United States are increasing. A paucity of literature exists regarding the medicolegal death investigation of railroad-related deaths. We report on a subset of deaths in western Michigan, propose protocols for investigating train-related deaths, and propose a stepwise approach for the medicolegal investigation of railroad-related fatalities. Fourteen railroad-related fatalities from 2015 to 2019 were reviewed. Each case was analyzed for demographics, investigative components, train variables, and death certification. The average age was 32 years. Nine decedents involved pedestrians versus trains, and 5 involved motor vehicles versus trains. Male victims were more common, and 50% of the cases were associated with mental illness or recent stressors. Accident was the most common manner of death. With the exception of basic weather conditions, the remaining investigative variables were rarely reported. Image and audio recordings were taken in 3 cases, but railroad companies refused to allow the recordings to be viewed by the medical examiner. We conclude that in addition to a thorough medicolegal death scene investigation and postmortem examination, audio/video recordings are crucial components of death certification in railroad-related fatalities and advocate that medical examiners/coroners be given the legal right to view and retain them.

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Objective: Given variability in how practices manage patients on antithrombotic medications, we undertook this study to understand the current practice of antithrombotic management for patients undergoing percutaneous breast and axillary procedures. Methods: A 20-item survey with multiple-choice and write-in options was emailed to 2094 active North American members of the Society of Breast Imaging (SBI) in March 2021. Data were collected anonymously and analyzed quantitatively, with free-text responses categorized by themes. Results: Three-hundred twenty-six of 2094 members (15.6%) completed the survey. Eighty-seven percent (274/313) reported having a policy for managing antithrombotic medications. Fifty-nine percent (185/312) reported routinely withholding medications before biopsy, more commonly in the Northeast and South (P = 0.08). Withholding of medications did not vary by lesion location (182/308, 59%, breast vs 181/308, 58.7%, axillary; P = 0.81). Respondents were statistically more likely to withhold medications if using a vacuum-assisted device for all classes of antithrombotic medications (P < 0.001). Up to 50.2% (100/199) on warfarin and 33.6% (66/196) on direct oral anticoagulants had medications withheld more stringently than guidelines suggest. Conclusion: Based on a survey of SBI members, breast imaging practices vary widely in antithrombotic management for image-guided breast and axillary procedures. Of the 60% who withhold antithrombotic medications, a minority comply with recommended withhold guidelines, placing at least some patients at potential risk for thrombotic events. Breast imaging radiologists should weigh the risks and benefits of withholding these medications, and if they elect to withhold should closely follow evidence-based guidelines to minimize the risks of this practice.

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Upregulation of ERBB2 and activating mutations in downstream KRAS/BRAF and PIK3CA are found in several ovarian cancer histotypes. ERBB2 enhances signaling by the ERBB family of EGF receptors, and contains docking positions for proteins that transduce signaling through multiple pathways. We identified the adaptor protein ventricular zone-expressed pleckstrin homology domain-containing protein 1 (VEPH1) as a potential interacting partner of ERBB2 in a screen of proteins co-immunoprecipitated with VEPH1. In this study, we confirm a VEPH1 - ERBB2 interaction by co-immunoprecipitation and biotin proximity labelling and show that VEPH1 interacts with the juxtamembrane-kinase domain of ERBB2. In SKOV3 ovarian cancer cells, which bear a PIK3CA mutation and ERBB2 overexpression, ectopic VEPH1 expression enhanced EGF activation of ERK1/2, and mTORC2 activation of AKT. In contrast, in ES2 ovarian cancer cells, which bear a BRAFV600E mutation with VEPH1 amplification but low ERBB2 expression, loss of VEPH1 expression enabled further activation of ERK1/2 by EGF and enhanced EGF activation of AKT. VEPH1 expression in SKOV3 cells enhanced EGF-induced cell migration consistent with increased Snail2 and decreased E-cadherin levels. In comparison, loss of VEPH1 expression in ES2 cells led to decreased cell motility independent of EGF treatment despite higher levels of N-cadherin and Snail2. Importantly, we found that loss of VEPH1 expression rendered ES2 cells less sensitive to BRAF and MEK inhibition. This study extends the range of adaptor function of VEPH1 to ERBB2, and indicates VEPH1 has differential effects on EGF signaling in ovarian cancer cells that may be influenced by driver gene mutations.

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Overactive bladder (OAB) is experienced by more than half of patients with untreated Parkinson's disease. Treatment of overactive bladder in these patients has included antimuscarinic anticholinergics, raising concerns about the possibility of exacerbating cognitive impairment or constipation. Mirabegron (Myrbetriq), a ß3-receptor agonist, provides relief of OAB without increasing cognitive impairment. While prior studies have examined the effect of mirabegron on OAB in a variety of patient populations, this study is the first controlled, prospective study investigating the effect of mirabegron on overactive bladder in patients with Parkinson's disease. By studying effective treatments for overactive bladder, this trial emphasizes the importance of antimicrobial stewardship so that lower urinary tract symptoms are not treated as lower urinary tract infections with antimicrobials and instead overactive bladder can be treated appropriately with medication. The MAESTRO study compared the effect of adding mirabegron to behavioral modification (including pelvic floor exercises) to behavior modification alone. Results from this novel study show that both the mean absolute change in the volume of micturition (objective measure) and the mean percent change increased significantly between visits two and three in the experimental group using mirabegron. Moreover, improvements in micturition in this study indicate that a larger-scale study of mirabegron with pelvic floor exercises and behavior modification is warranted.

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OBJECTIVE: Our aim was to determine if the time interval between bowel resection and initiation of adjuvant chemotherapy impacts survival in advanced ovarian cancers. METHODS: This was a retrospective cohort study using data from two cancer centers, Princess Margaret Cancer Centre in Toronto, Ontario, Canada and Samsung Comprehensive Cancer Center in Seoul, South Korea. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV ovarian cancer that underwent large bowel resection during primary cytoreductive surgery (PCS) were included. RESULTS: Ninety-one women were eligible of which the majority (90.1%) were diagnosed with high-grade serous cancer. The median interval from PCS to chemotherapy for all patients was 21 days (7-86 days). Patients were stratified into 3 groups: 1) Interval ≤14 days, 32 (35.2%) patients; 2) Interval between 15-28 days, 27 (29.6%) patients; and 3) Interval between 29-90 days, 32 (35.2%) patients. Surgical procedures and postoperative outcomes were similar between groups. Multivariate analysis indicated that PCS to chemotherapy interval of 2-4 weeks, younger age, and completion of 4 or more adjuvant chemotherapy cycles were independent prognostic factors of favorable overall survival. CONCLUSION: Initiation of adjuvant chemotherapy between 2 to 4 weeks after PCS with bowel resection may improve survival outcomes in women with advanced ovarian cancer by maximizing the benefit of PCS plus adjuvant chemotherapy.

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BACKGROUND: Patients treated with neoadjuvant chemotherapy (NACT) for advanced high-grade serous ovarian carcinoma (HGSC) have a higher rate and shorter time to platinum-resistant recurrence compared to patients treated with primary cytoreductive surgery (PCS) and adjuvant chemotherapy. The purpose of this study is to determine the impact of NACT on somatic mutation status in platinum-sensitive and resistant HGSC. Patients with advanced HGSC who had a documented response to platinum-based NACT, a banked blood sample, and a banked tumor sample before and after NACT were identified. Whole exome and/or targeted deep sequencing was performed in matched normal and pre/post-NACT tumor samples from 3 platinum-resistant and 2 platinum-sensitive patients to identify somatic non-synonymous mutations at each time point. RESULTS: When comparing exonic non-synonymous mutations in pre-NACT and post-NACT samples from the same patient, an average of 41% (1-68%) of genes were mutated at both time points. There were no trends detected in the mutational burden following exposure to NACT in platinum-resistant vs. platinum-sensitive cases. The majority of mutated genes were unique to each case. We identified several genes that were commonly mutated in pre-NACT samples specific to platinum-resistant (CSPG4, SLC35G5, TUBA3D) or sensitive (CYP2D6, NUTM1, DNAH5) cases. Four mutated genes emerged exclusively in the platinum-resistant cases (ADGRV1, MUC17, MUC20, PAK2) following NACT. CONCLUSIONS: Patients with advanced HGSC present with significant intra-tumor heterogeneity. NACT significantly impacts the somatic mutation status irrespective of the time to recurrence. The mutated genes detected in chemo-naive pre-NACT tumor samples from either resistant or sensitive cases could potentially have a role in the prediction of chemotherapy response in patients scheduled to receive NACT; larger studies are required to further validate these genes.

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The extraction of mineral calcium from bone by decalcification is a critical step in the preparation of histological samples for light microscopy. This study assessed the time required for complete decalcification and the resultant histomorphological preservation of bone histomorphology by three decalcification agents: 7% hydrochloric acid (HCl), 5% nitric acid, and 10% ethylenediaminetetraacetic acid (EDTA). The goal of this study was to identify which decalcification agent provides the optimal combination of expedient processing and quality histological outcomes of cranial fracture samples. HCl provided the most rapid decalcification ( X ¯  = 3.57 days), nitric acid followed closely ( X ¯  = 10.35 days), while EDTA took significantly longer on average ( X ¯  = 78.97 days) but encompassed a broader range of times. Decalcification agent, sample thickness, sample width, and decedent age are significant predictors of decalcification time. Sample visualization quality, measured for tissues, cells, and nuclei on a five-point Likert scale, was highest for samples decalcified in 10% EDTA, second highest using 5% nitric acid, and lowest for 7% HCl. The quality difference between EDTA and nitric acid was not highly significant for any of the three features. For basic assessments of bone histomorphology, the study results indicate 5% nitric acid is suitable for the decalcification of adult specimens and samples thicker than 3 mm. EDTA is a suitable agent for thin samples of the cranial vault (<3 mm) from infants and young children less than three years old, decalcifying samples in a timeframe comparable to nitric acid while providing the best quality and clarity of samples.

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OBJECTIVES: Low-grade serous ovarian cancer (LGSC) is a relatively chemo-resistant disease with limited effective treatment options for patients with recurrence. Secondary cytoreductive surgery (SCS) is commonly offered at recurrence, although any benefit this has on survival is not fully determined. This review evaluates the impact of SCS, including residual disease, on progression-free survival (PFS) and overall survival (OS) in recurrent LGSC. METHODS: A comprehensive search of Medline ALL, Embase Classic + Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science was conducted to obtain studies evaluating optimal or complete SCS versus suboptimal SCS and the amount of residual disease in recurrent LGSC. Meta-analysis was performed and PFS and OS outcomes were calculated. RESULTS: 1Of 5296 studies screened, 350 progressed to full-text review, with 9 ultimately selected for inclusion in the systematic review. Two studies met criteria for meta-analysis of PFS and of OS. The presence of visible residual disease at the conclusion of SCS negatively impacted PFS (HR = 3.51, 95% CI = 1.72-7.14), whereas SCS with no residual disease significantly improved OS (HR = 0.4, 95% CI = 0.23-0.7) in patients with recurrent LGSC. Diffuse and extensive disease distribution was inversely linked to survival. In addition, SCS as an initial treatment for recurrent LGSC was associated with superior survival in comparison to chemotherapy. A short platinum-free interval was not associated with worse survival in this cohort. CONCLUSIONS: Complete SCS, and to a lesser extent optimal SCS, are associated with improved PFS and OS in patients with recurrent LGSC. SCS may be a better initial treatment strategy than systemic chemotherapy for recurrent disease. Patients with recurrent LGSC should be evaluated for the role of SCS based on disease distribution and functional status, irrespective of the platinum-free interval. Prospective studies are needed to further study the role of SCS in patients with recurrent LGSC.

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BACKGROUND: Investigate the impact of interval cytoreductive surgery (ICS) on progression in an orthotopic mouse model of ovarian cancer and the impact of chemotherapy delivered at various timelines following surgery. METHODS: Luciferase-expressing ID8 murine ovarian cancer cells were implanted intra-bursally and IP to C57BL/7 mice. Once disease was established by bioluminescence, 2 cycles of neoadjuvant cisplatin were administered, and animals received either ICS (removal of the injected bursa/primary tumor) or anesthesia alone. Postsurgical chemotherapy was administered on the same day as the intervention (ICS/anesthesia), or on day 7 or day 28 following the intervention. Progression was quantified serially with in vivo bioluminescence imaging. Volume of ascitic fluid volume collected at necropsy was measured. RESULTS: Animals were matched for tumor burden at stratification. There was no accelerated growth of residual tumor after interval cytoreduction compared to controls. Animals who received chemotherapy on postoperative day (POD) 7 had better disease control compared to standard-of-care POD 28. Animals who underwent surgery had less ascites at necropsy compared to those who had anesthesia alone. CONCLUSIONS: In this animal model, surgical wounding with suboptimal cytoreduction after neoadjuvant chemotherapy did not cause accelerated expansion of residual disease. Surgical wounding appears to impair cisplatin activity when given at time of surgery.

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A "plated bullet" has a thin layer of electroplated metal covering the lead core of the projectile. In certain situations, this thin layer of electroplated metal can fracture upon discharge of the firearm. When such fracturing occurs, vaporous lead can escape through the fracture lines of the spinning projectile, resulting in a spiral-shaped deposition of dark residue surrounding a central bullet defect. The spiral-shaped pattern is referred to as "comet-tailing," or the "vortex effect." In this report, three homicide cases with associated comet-tailing are presented. Police, death investigators, and forensic pathologists should be aware of this unique finding.

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