Alpert Medical School - Brown University

Racism has not only contributed to disparities in healthcare outcomes, but has also negatively impacted the recruitment, retention, and promotion of historically excluded groups in academic medicine. The 2022 Society for Academic Emergency Medicine (SAEM) consensus conference, "Diversity, Equity, and Inclusion: Developing a Research Agenda for Addressing Racism in Emergency Medicine," convened a diverse group of researchers, healthcare providers , educators, administrative leaders, and healthcare providers to help address the impact of racism in three domains in academic emergency medicine: clinical research, education and training, and academic leadership. The main goals of the consensus process were to identify current knowledge gaps and create a research agenda within each domain using an iterative consensus-building methodology. 90 SAEM members representing faculty and trainees participated in breakout groups in each domain to generate consensus recommendations for priority research. For clinical research, 3 research gaps with 6 questions (N) were identified: remedies for bias and systematic racism (3), biases and heuristics in clinical care (2), and racism in study design (1). For education and training, 3 research gaps with 7 questions were identified: curriculum and assessment (2), recruitment (1), and learning environment (4). For academic leadership, 3 research gaps with 5 questions were identified: understanding the current DEI landscape and culture (1), analyzing programs that improve DEI and identifying factors that lead to improved diversity (3), and quantifying the value of professional stewardship activities (1). This article reports the results of the consensus conference with the goal of influencing emergency care research, education, and policy, and facilitating collaborations, grant funding, and publications in these domains.

In animal models, human bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EV) have been found to have beneficial effects in cardiovascular disease, but only when administered via intramyocardial injection. The biodistribution of either intravenous or intramyocardial injection of MSC-EV in the presence of myocardial injury is uncharacterized at this time. We hypothesized that intramyocardial injection will ensure delivery of MSC-EV to the ischemic myocardium, while intravenous injection will not. Human bone marrow mesenchymal stem cells were cultured and the MSC-EV were isolated and characterized. The MSC-EVs were then labeled with DiD lipid dye. FVB mice with normal cardiac function underwent left coronary artery ligation followed by either peri-infarct intramyocardial or tail vein injection of 3*106 or 2*109 particles of DiD-labeled MSC-EV or a DiD-saline control. The heart, lungs, liver, spleen and kidneys were harvested 2 h post-injection and were submitted for fluorescent molecular tomography imaging. Myocardial uptake of MSC-EV was only visualized after intramyocardial injection of 2*109 MSC-EV particles (p = 0.01) compared to control, and there were no differences in cardiac fluorescence after tail vein injection of MSC-EV (p = 0.5). There was no significantly detectable MSC-EV uptake in other organs after intramyocardial injection. After tail vein injection of 2*109 particles of MSC-EV, the liver (p = 0.02) and spleen (p = 0.04) appeared to have diffuse MSC-EV uptake compared to controls. Even in the presence of myocardial injury, only intramyocardial but not intravenous administration resulted in detectable levels of MSC-EV in the ischemic myocardium. This study confirms the role for intramyocardial injection in maximal and effective delivery of MSC-EV. Our ongoing studies aimed at developing bioengineered MSC-EV for targeted delivery to the heart may render MSC-EV clinically applicable for cardiovascular disease.

Objectives Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is hallmarked by age-dependent accumulation of microangiopathy with antiplatelet medications commonly used for stroke prevention though without known therapeutic benefit. Our objective was to identify whether antiplatelet therapy impacted the incidence of acute ischemic stroke (AIS) or intracerebral hemorrhage (ICH) in those with reported CADASIL.Materials and methodsOwing to the rarity of the disease, we performed a retrospective study of anonymized data from the international TriNetX Research Network (Oct 2015 through January 2021). Individuals had an ICD-10 code (I67.850) for CADASIL. The primary outcome was incidence of validated ICD-10 codes for AIS (I63) and ICH (I61) linked with unique hospital admission encounters. The primary exposure was use of an antiplatelet medication for at least 1 month prior to the primary outcome. Age-adjusted logistic regression was used for likelihood ratios.ResultsWe identified 455 individuals: 36% female, 40 (8.8%) antiplatelet exposed. Those with antiplatelet use were older (antiplatelet: 61±12 years vs. unexposed: 57±14 years, p = 0.034) with similar rates of AIS [antiplatelet: 23%(9/40) vs. unexposed: 14%(60/415); p=0.18] and ICH [antiplatelet: 3%(1/40) vs. unexposed: 5%(19/415); p = 0.54) and without significant impact on age-adjusted AIS likelihood (OR 1.62, 95%CI 0.73–3.60, p=0.23). Sample size precluded ICH regression analyses.Conclusions Our data suggests that antiplatelet use did not significantly impact incidence of AIS or ICH within a group of individuals with suspected CADASIL This study highlights the need for further understanding of the pathophysiology of CADASIL to lead to disease modifying treatments.

This is a descriptive study of 21 cases of serial sexual murder by children and adolescents spanning nearly the past century and a half. No earlier cases worldwide were identified. Each of these youth committed two or more sexual homicides prior to age 18. Their psychopathological, psychosocial, crime scene behaviors, and offender–victim relationship characteristics are presented. Additionally, the role of sexual sadism and its measurement using the SADSEX‐SH rating scale is addressed. Nearly all of the sample had conduct disorder, a paraphilic disorder, and sadistic fantasies, and two‐thirds had sexual sadism disorder. Family dysfunction, serious school problems, and average or above IQ levels were typical. Their modus operandi generally reflected predatory behavior and direct contact methods of killing were most common. Two case reports are provided to illustrate the breadth and complexity of these offenders. Juvenile Serial Sexual Homicide is an extremely rare but persistent phenomenon. Prognostic implications and future research directions are discussed.

Objectives: The ways in which children understand dying and death remain poorly understood; most studies have been carried out with samples other than persons with an illness. The objective of this study was to understand the process by which children directly involved with life-limiting conditions understand dying and death. Methods: This qualitative study obtained interview data from N = 44 5-18-year-old children in the USA, Haiti, and Uganda who were pediatric palliative care patients or siblings of patients. Of these, 32 were children with a serious condition and 12 were siblings of a child with a serious condition. Interviews were recorded, transcribed, verified, and analyzed using grounded theory methodology. Results: Loss of normalcy and of relationships emerged as central themes described by both ill children and siblings. Resilience, altruism, and spirituality had a bidirectional relationship with loss, being strategies to manage both losses and anticipated death, but also being affected by losses. Resiliency and spirituality, but not altruism, had a bidirectional relationship with anticipating death. Themes were consistent across the 3 samples, although the beliefs and behaviors expressing them varied by country. Significance of results: This study partially fills an identified gap in research knowledge about ways in which children in 3 nations understand dying and death. While children often lack an adult vocabulary to express thoughts about dying and death, results show that they are thinking about these topics. A proactive approach to address issues is warranted, and the data identify themes of concern to children.

The objective of this multicenter retrospective study was to examine the incidence, patient characteristics, pathology, and outcomes associated with Epstein-Barr virus (EBV)-related CNS lymphoma (CNSL) in older patients. Among 309 CNSL patients aged ≥60, 11.7% had EBV + tumors of which 72.2% were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD). Younger age, SOT or autoimmune disease, and immunosuppressive treatment correlated highly with EBV-positivity. EBV + tumors were associated with absent C-MYC and BCL6 expression. EBV + PTLD was more likely to be associated with the absence of CD5 expression. EBV + non-PTLD had better median OS (not reached) compared to EBV + PTLD (10.8 months) and EBV-negative patients (43 months). Multivariable Cox regression analysis showed that age, performance status, and PTLD were negative predictors of OS. EBV status and immunosuppressive treatment were not correlated with OS. Our findings merit further investigation of EBV + PCNSL tumors and EBV-directed therapies.

Background: Prior systematic reviews have compared the efficacy of intravenous tenecteplase and alteplase in acute ischemic stroke, assigning their relative complications as a secondary objective. The objective of the present study is to determine whether the risk of treatment complications differs between patients treated with either agent. Methods: We performed a systematic review including interventional studies and prospective and retrospective, observational studies enrolling adult patients treated with intravenous tenecteplase for ischemic stroke (both comparative and noncomparative with alteplase). We searched MEDLINE, Embase, the Cochrane Library, Web of Science, and the www. Clinicaltrials: gov registry from inception through June 3, 2022. The primary outcome was symptomatic intracranial hemorrhage, and secondary outcomes included any intracranial hemorrhage, angioedema, gastrointestinal hemorrhage, other extracranial hemorrhage, and mortality. We performed random effects meta-analyses where appropriate. Evidence was synthesized as relative risks, comparing risks in patients exposed to tenecteplase versus alteplase and absolute risks in patients treated with tenecteplase. Results: Of 2226 records identified, 25 full-text articles (reporting 26 studies of 7913 patients) were included. Sixteen studies included alteplase as a comparator, and 10 were noncomparative. The relative risk of symptomatic intracranial hemorrhage in patients treated with tenecteplase compared with alteplase in the 16 comparative studies was 0.89 ([95% CI, 0.65-1.23]; I2=0%). Among patients treated with low dose (<0.2 mg/kg; 4 studies), medium dose (0.2-0.39 mg/kg; 13 studies), and high dose (≥0.4 mg/kg; 3 studies) tenecteplase, the RRs of symptomatic intracranial hemorrhage were 0.78 ([95% CI, 0.22-2.82]; I2=0%), 0.77 ([95% CI, 0.53-1.14]; I2=0%), and 2.31 ([95% CI, 0.69-7.75]; I2=40%), respectively. The pooled risk of symptomatic intracranial hemorrhage in tenecteplase-treated patients, including comparative and noncomparative studies, was 0.99% ([95% CI, 0%-3.49%]; I2=0%, 7 studies), 1.69% ([95% CI, 1.14%-2.32%]; I2=1%, 23 studies), and 4.19% ([95% CI, 1.92%-7.11%]; I2=52%, 5 studies) within the low-, medium-, and high-dose groups. The risks of any intracranial hemorrhage, mortality, and other studied outcomes were comparable between the 2 agents. Conclusions: Across medium- and low-dose tiers, the risks of complications were generally comparable between those treated with tenecteplase versus alteplase for acute ischemic stroke.

Background: Respiratory syncytial virus (RSV) is shown to cause substantial morbidity, hospitalization, and mortality in infants and older adults. Population-level modelling of RSV would allow for estimation of the full burden of disease and the potential epidemiological impact of novel prophylactics. Methods: We model the epidemiology of RSV in the US across all ages using a deterministic compartmental transmission model. Population-level symptomatic RSV acute respiratory tract infection (ARI) cases were projected across different natural history scenarios, both with and without vaccination of older adults aged ≥ 60. Impact of vaccine efficacy against ARIs and infectiousness and vaccine coverage on ARI incidence were assessed. Impact on medical attendance, hospitalization, complications, death and other outcomes were also derived. Results: In the absence of a vaccine, we project 17.5-22.6 million symptomatic RSV ARI cases per year in ≥18-year-olds in the US, with 3.6-4.8 million/year occurring in ≥60-year-olds. Modelling indicates that up to 2.0 million symptomatic RSV ARI cases per year could be prevented in ≥60-year-olds with a hypothetical vaccine (70% vaccine efficacy against symptomatic ARI, and 60% vaccine coverage), and up to 0.69 million cases per year can be prevented in the non-vaccinated population, assuming 50% vaccine impact on infectiousness. Conclusions: The model provides estimated burden of RSV in the US across all age groups, with substantial burden projected specifically in older adults. Vaccination of ≥ 60 years-old population could significantly reduce the burden of disease in this population, with additional indirect effect in the < 60 years-old population due to reduced transmissibility.

Background Despite wide use of adjuvanted influenza vaccine in nursing home residents (NHR), little immunogenicity data exist for this population. Methods We collected blood from NHR (n=85) living in nursing homes participating in a cluster randomized clinical trial comparing MF59-adjuvanted trivalent inactivated influenza vaccine (aTIV) with non-adjuvanted vaccine (TIV) (parent trial, NCT02882100). NHR received either vaccine during the 2016-2017 influenza season. We assessed cellular and humoral immunity using flow cytometry and hemagglutinin inhibition (HAI), anti-neuraminidase (ELLA), and microneutralization assays. Results Both vaccines were similarly immunogenic and induced antigen-specific antibodies and T cells, but aTIV specifically induced significantly larger D28 titers against A/H3N2 neuraminidase than TIV. Conclusions NHRs respond immunologically to TIV and aTIV. From these data, the larger aTIV-induced anti-neuraminidase response at D28 may help explain the increased clinical protection observed in the parent clinical trial for aTIV over TIV in NHR during the A/H3N2-dominant 2016-2017 influenza season. Additionally, a decline back to pre-vaccination titers at 6 months after vaccination emphasizes the importance of annual vaccination against influenza.

Chronic pain is common in people living with HIV (PLWH), causes substantial disability and is associated with limitations in daily activities. Opioids are commonly prescribed for pain treatment among PLWH, but evidence of sustained efficacy is mixed. There is little information available on how PLWH who have chronic pain use multimodal strategies in pain management. The current cross-sectional study examined background characteristics, self-reported pain, and the use of other pain treatments among 187 PLWH with chronic pain and depressive symptoms who were and were not prescribed opioids. Approximately 20.9% of participants reported using prescription opioids at the time of the study interview. These individuals were significantly more likely to report having engaged in physical therapy or stretching, strengthening or aerobic exercises in the previous 3 months, recent benzodiazepine use, and receiving disability payments. There were no significant differences in pain characteristics (pain-related interference, average pain severity, and worst pain severity) between the two groups. Those not prescribed opioids were more likely to report better concurrent physical functioning and general health, and fewer physical role limitations, but higher depression symptom severity. Our findings suggest that many PLWH with chronic pain and depressive symptoms express high levels of pain with deficits in physical function or quality of life despite their use of opioids. The high rate of co-use of opioids and benzodiazepines (30.8%) is a concern because it may increase risk of overdose. An integrated care approach that includes a variety of effective non-pharmacologic treatment strategies such as physical therapy may be beneficial in reducing the reliance on opioids for pain management.

Background: Patients with carpal tunnel syndrome (CTS) may also have cervical radiculopathy (CR) or vice versa, potentially requiring carpal tunnel release (CTR) and anterior cervical discectomy and fusion (ACDF). This study evaluates whether there is an increased risk of complications following CTR or ACDF in patients with concurrent CTS and CR (CTS-CR) compared with those with only CTS or CR. Methods: A multipayer database was used to identify patients with CTS-CR. From this cohort, patients who underwent CTR and/or ACDF were identified. Patients with CTS-CR undergoing surgery were compared with those undergoing surgery with only CTS or CR. Multivariable logistic regression was used to compare matched populations to assess postoperative complications and risk of undergoing both procedures. Results: A total of 110 379 patients with CTS-CR were identified. Carpal tunnel release was performed in 21 152 patients (19.2%) with CTS-CR, from which 835 (0.76%) underwent ACDF. Anterior cervical discectomy and fusion was performed in 6960 patients (6.31%) with CTS-CR followed by CTR in 1098 patients (0.99%). Patients with CTS-CR were at greater risk of reoperation and complex regional pain syndrome following CTR. In ACDF, patients with CTS-CR were at greater risk of reoperation. Obesity and tobacco use were significant risk factors in patients with CTS-CR who underwent both CTR and ACDF rather than a single surgery. Conclusions: Examination of more than 100 000 patients with CTS-CR found a greater likelihood of reoperation and perioperative complications following surgery than those without concurrent diagnoses. Obesity and smoking increased the risk for patients undergoing both procedures. Patients presenting with CTS-CR are high risk and should be counseled on risk of complication and reoperation and optimized to reduce risk of undergoing both CTR and ACDF.

Young adults may benefit from civic engagement as a health promotion tool, as civic engagement is generally associated with positive well-being. However, more information is needed to examine civic engagement among lesser-educated young adults who are least likely to civically engage, and more likely to demonstrate mental health needs. We surveyed noncollege young adults (N = 621) to measure their civic engagement, meaning, civic efficacy, well-being, and sociodemographic factors. Using an a priori model, direct, indirect, and full effects path analyses were conducted across men and women, and then the entire sample. The full effects model best fit the data with mediation by civic efficacy and meaning (χ2 (2) = 0.59, p = 0.74; comparative fit index = 1.0; root mean square error of approximation = 0.00, 90% confidence interval [0.00-0.06]; R2 = 0.42). Types of engagement (civic, electoral, activism, and online) demonstrated differing relationships with well-being. Stakeholders should resource young adults with civic skills and coping strategies to address the many challenges that civic experiences often elicit.

Background: Newly diagnosed multiple myeloma patients have many available treatment options. While lenalidomide, bortezomib, and dexamethasone (RVD) is the preferred initial treatment for many patients, several other agents may provide similar efficacy with less toxicity and improved ease of administration. Methods: We evaluated the safety and efficacy of the all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. Results: The study was stopped prior to planned enrollment due to slow recruitment, with 12 patients available for final analysis. The overall response rate was 58.3% with 2 patients achieving a very good partial response (16.7%) and 5 patients achieving a partial response (41.7%). Median progression-free survival was 16 months, and median overall survival was 43 months. There were no episodes of grade 3 or greater peripheral neuropathy. Grade 3 or greater dermatologic toxicity was experienced in 50% of patients. Conclusion: Although limited enrollment prevented full efficacy evaluation, our data do not support further study of metronomic cyclophosphamide in combination with ixazomib and dexamethasone in the treatment of newly diagnosed multiple myeloma. The activity of this regimen in the relapsed/refractory setting requires further study (ClinicalTrials.gov Identifier: NCT02412228).

Objective: To identify characteristics of malpractice litigations involving skull deformity in infants (craniosynostosis and deformational plagiocephaly). Design: Retrospective review of all lawsuits with jury verdicts or settlements involving infant skull deformity as the primary diagnosis using the Westlaw Legal Database. Setting: United States. Patients, participants: Plaintiffs with skull deformity as the primary diagnosis. Main outcome measures: Litigation outcome and indemnity payment amount. Results: From 1990 to 2019, 9 cases involving infant skull deformity met our inclusion/exclusion criteria. Among these cases, 8 (88.9%) cases resulted in indemnity payments to plaintiffs, totaling $30,430,000. Failure to diagnose (n = 4, 44.4%) and surgical negligence (n = 3, 33.3%) were the most common reasons for litigations. Conclusions: There were a small number of malpractice lawsuits involving infant skull deformity over three decades. When cases go to court, physicians and hospitals have a high likelihood of judgment against them, frequently resulting in high indemnity payments.