Citations

Abstract Objective The objective was to derive a risk score that uses variables available early during the emergency department (ED) encounter to identify high‐risk geriatric patients who may benefit from delirium screening. Methods This was an observational study of older adults age ≥ 75 years who presented to an academic ED and who were screened for delirium during their ED visit. Variable selection from candidate predictors was performed through a LASSO‐penalized logistic regression. A risk score was derived from the final prediction model, and predictive accuracy characteristics were calculated with 95% confidence intervals (CIs). Results From the 967 eligible ED visits, delirium was detected in 107 (11.1%). The area under the curve for the REcognizing DElirium in Emergency Medicine (REDEEM) score was 0.901 (95% CI = 0.864–0.938). The REEDEM risk score included 10 different variables (seven based on triage information and three obtained during early history taking) with a score ranging from –3 to 66. Using an optimal cutoff of ≥11, we found a sensitivity of 84.1% (90 of 107 ED delirium patients, 95% CI = 75.5%–90.2%) and a specificity of 86.6% (745 of 860 non‐ED delirium patients, 95% CI = 84.1%–88.8%). A lower cutoff of ≥5 was found to minimize false negatives with an improved sensitivity at 91.6% (98 of 107 ED delirium patients, 95% CI = 84.2%–95.8%). Conclusion A risk stratification score was derived with the potential to augment delirium recognition in geriatric ED patients. This has the potential to assist on delirium‐targeted screening of high‐risk patients in the ED. Validation of REDEEM, however, is needed prior to implementation.

Abstract The complex and dynamic system of fluid flow through the perivascular and interstitial spaces of the CNS has new-found implications for neurological diseases. CSF movement throughout the CNS parenchyma is more dynamic than could be explained via passive diffusion mechanisms alone. Indeed, a semistructured glial-lymphatic (glymphatic) system of astrocyte-supported extracellular perivascular channels serves to directionally channel extracellular fluid, clearing metabolites and peptides to optimize neurological function. Clinical studies of the glymphatic network have to date proven challenging, with most data gleaned from rodent models and post-mortem investigations. However, increasing evidence suggests that disordered glymphatic function contributes to the pathophysiology of CNS ageing, neurodegenerative disease and CNS injuries, as well as normal pressure hydrocephalus. Unlocking such pathophysiology could provide important avenues towards novel therapeutics. We here provide a multidisciplinary overview of glymphatics and critically review accumulating evidence regarding its structure, function and hypothesized relevance to neurological disease. We highlight emerging technologies of relevance to the longitudinal evaluation of glymphatic function in health and disease. Finally, we discuss the translational opportunities and challenges of studying glymphatic science.

Abstract Background The National Institutes of Health define African Americans or Blacks, American Indians, Alaska Natives, Hispanics or Latinos, Native Hawaiians, and other Pacific Islanders as being underrepresented in medicine. A number of studies have demonstrated that improving diversity of such underrepresented demographics within the medical profession improves patient outcomes, medical education and reduces health disparities in patients from vulnerable racial or socioeconomic groups. Despite this recognition, significant underrepresentation of various racial, ethnic, and sexual identities still exists within nearly all medical specialties. Aims The purpose of this study was to a gain a greater understanding of the current state of diversity, equity, and inclusion (DEI) efforts among U.S. hematology and medical oncology fellowship training programs. We explored the perspectives of adult and pediatric fellowship program directors regarding current recruitment strategies and suggestions for improvement to help mitigate the effects of implicit and explicit bias. Here, we present an interim analysis of the data using descriptive statistics. Methods: We convened a multi-institutional collaboration of fellowship program directors, teaching faculty, and staff members of the American Society of Hematology to develop a survey examining perceptions of DEI efforts among hematology and medical oncology fellowship program directors. The survey was pilot tested in a small group of program directors representing 6 different academic programs (5 adult, 1 pediatric). The final online survey was distributed via email to 224 fellowship program directors at U.S. adult and pediatric hematology and medical oncology fellowship programs. The survey included 29 questions regarding perspectives on bias within the fellowship selection process, current DEI initiatives, and current faculty and fellow demographics. Survey respondents were asked to rate the importance of numerous factors in determining which applicants to invite utilizing a scale of 0-10, with 0 and 10 representing lowest and highest importance, respectively. To measure program director perceptions of certain applicant groups, survey respondents were asked to rate applicant demographics as being advantaged/disadvantaged based on survey options ranging from 0-5, with 0 and 5 representing very disadvantaged and very advantaged, respectively. Results: At interim analysis, 41 of 224 program directors completed the survey for an interim response rate of 21%, including 25 adult program directors and 16 pediatric program directors, with representation from university and community programs. Of the program directors surveyed, 28 (68%) reported having access to a dedicated diversity committee or DEI policies in place to improve recruitment of underrepresented applicants. In determining which applicants to invite, respondents placed highest value on the applicant's program director letter (mean score ± standard deviation: 7.44±1.93), caliber of the applicant's residency program (7.28±2.06) and letters of recommendations (7.15±2.23). Survey respondents viewed white and male applicants as representing the most advantaged demographic group, while LGBTQI, age>40, and U.S. citizen and non-citizen international medical graduates were the most disadvantaged (Table 1). Suggestions regarding improving DEI in the fellowship selection process included implementing bias training, identifying potentially disadvantaged applicants in ERAS, increasing faculty diversity, and pairing underrepresented applicants with interviewers based on applicant preference. Conclusion: While the majority of hematology and medical oncology fellowship program directors report having DEI programs or policies to improve recruitment of underrepresented applicants, perceptions of advantaged/disadvantaged groups may extend beyond demographics traditionally viewed as being underrepresented in medicine. As our survey is ongoing, we plan to reanalyze our data when the survey has been finalized with a higher response rate utilizing multivariable regression to identify themes that may further improve DEI efforts within the fellowship selection process. Figure 1 Figure 1. Disclosures LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Murphy: North American Thrombosis Foundation: Honoraria. Naik: Rigel: Research Funding. Podoltsev: Pfizer: Honoraria; Blueprint Medicines: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; PharmaEssentia: Honoraria; Bristol-Myers Squib: Honoraria; CTI BioPharma: Honoraria.

Abstract BACKGROUND Progress for gliomas is slowed in part by the paucity of mechanistic feedback during treatment with experimental therapies. Access to extracellular tumor pharmacodynamic biomarkers could provide an avenue to accelerate progress. We have initiated a program of intra-operative microdialysis to accelerate biomarker discovery and to identify candidate outcome measures for translational therapies. METHODS Intraoperative microdialysis was performed with M-dialysis 100kDA catheters and 107 variable rate pumps under an IDE. Four IDH-mutant and two IDH-WT lesions were studied intraoperatively with 3 divergently placed catheters. Microperfusate (artifical CSF+ 3% dextran) was perfused at 2uL/min and collected in 20 min increments. Paired CSF was also obtained when accessible. A parallel cohort of nude mice bearing human IDH-mutant, IDH-WT, or sham intracranial xenografts (n=6-12) underwent intratumoral microdialysis. A pilot murine study of intracranial drug delivery was performed via concurrent microdialysis during convection-enhanced delivery (CED) of saline or the IDH-inhibitor AG120. RESULTS Microdialysate from IDH-mutant intracranial xenografts revealed >100 differentially abundant metabolites compared to sham or IDH-WT tumors, including D2-HG (21x) and MTA(18x), p< 10^-5. The most significantly abundant metabolite was DMA (4x, p< 10^-10). 15-1000uM D2HG was recovered from intra-operative human IDH-mutant tumors and 1-2uM from normal brain adjacent to IDH-WT gliomas and < 1uM in all IDH-WT samples. Forty metabolites differentiated enhancing tumor from adjacent brain in 3/3 paired human samples including upregulated Aminoacyl-tRNA biosynthesis and downregulated purine metabolism. Serial aliquots of microdialysate during saline CED yielded steady D2-HG levels whereas CED with AG120 yielded undetectable D2-HG within 6 hours. CONCLUSION The extracellular metabolic landscape of glioma is diverse, dynamic and reflects tumor biology and response to therapy. Collectively, these studies suggest that intra-tumoral drug testing should be feasible with realistic expectation of gaining metabolic feedback within a short timeframe. Leveraging this paradigm can provide opportunities to accelerate therapeutic translation for gliomas.

AbstractIntroductionEarly detection of cognitive decline in older adults is a public health priority. Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA), a multisite study, is validating cognition, emotion, motor, and sensory modules of the National Institutes of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in the aging spectrum from cognitively normal to dementia of the Alzheimer's type (DAT).MethodsParticipants 65 to 85 years old, in demographic groups racially proportional to the general US population, are recruited in one of three groups to validate the NIHTB: cognitively normal, amnestic mild cognitive impairment (aMCI), or mild DAT. Additional special emphasis cohorts include (1) Blacks in the three clinical groups; (2) Spanish‐speakers in the three clinical groups; (3) cognitively normal, population‐proportional, over age 85.DiscussionLongitudinal study will determine whether NIHTB can predict cognitive decline and is associated with Alzheimer's disease biomarkers. Here, we detail the methods for the ARMADA study.

Abstract Rationale Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. Objectives To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. Methods Genotypes of SERPINA1were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. Measurements and Main Results We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV1% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV1was 3.9% lower (95% confidence interval [CI], −6.55% to −1.26%) and emphysema (the percentage of lung attenuation areas <−950 HU) was 4.14% greater (95% CI, 1.44% to 6.84%) in MZ subjects. We found one gene, PGF(placental growth factor), to be differentially expressed in lung tissue from one study between MZ subjects and MM subjects. Conclusions Carriers of the AAT Z allele (those who were MZ heterozygous) with COPD had lower lung function and more emphysema than MM subjects with COPD. Taken with the subtle differences in gene expression between the two groups, our findings suggest that MZ subjects represent an endotype of COPD.

Abstract Venomous snakebite is an important cause of preventable death. The World Health Organization (WHO) set a goal to halve snakebite mortality by 2030. We used verbal autopsy and vital registration data to model the proportion of venomous animal deaths due to snakes by location, age, year, and sex, and applied these proportions to venomous animal contact mortality estimates from the Global Burden of Disease 2019 study. In 2019, 63,400 people (95% uncertainty interval 38,900–78,600) died globally from snakebites, which was equal to an age-standardized mortality rate (ASMR) of 0.8 deaths (0.5–1.0) per 100,000 and represents a 36% (2–49) decrease in ASMR since 1990. India had the greatest number of deaths in 2019, equal to an ASMR of 4.0 per 100,000 (2.3-5.0). We forecast mortality will continue to decline, but not sufficiently to meet the WHO’s goals. Improved data collection should be prioritized to help target interventions, improve burden estimation, and monitor progress.

Abstract ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Objectives: The current literature lacks evidence to guide treatment of isolated lateral meniscus tears in young patients. Accordingly, the purpose of this study was to describe our institutional experience in young patients with lateral meniscus tear with regard to i) treatment trends in meniscectomy and repair ii) long-term patient reported and radiographic outcomes, and iii) failure rates and associated patient and treatment factors. Methods: Patients <26 years of age who underwent surgery for lateral meniscus tears between 2001 and 2017. Patients with ligamentous injury or prior surgeries in the same knee were excluded. Records were reviewed to obtain patient demographics, injury characteristics, surgical details, reoperation rates, repeat imaging, and patient outcome scores. Statistical analysis compared treatment trends over time. Patient reported outcomes (PROs), imaging outcomes, and failure rates were compared by treatment modality. Failure was defined as reoperation, symptomatic osteoarthritis, or IKDC <75. Simple logistic regressions were calculated to predict failure and IKDC based on treatment, type of tear, location of tear, or amount of meniscus removed. Results: 226 knees in 217 patients were identified with average clinical follow-up of 3.2 years. Our cohort consisted of 158 male patients, and average age was 17.4 years (7-25). 138 patients (144 knees) were treated with meniscectomy (partial to complete) (64%) and 79 patients (82 knees) were treated with repair (36%). Repair rates compared to meniscectomy (any degree) increased over time with 63% of lateral meniscus tears from 2013-2017 treated with repair compared to 23% from 2001 -2004 ( P = <.0001). IKDC scores in the meniscectomy group increased from 76.3 ± 9.1 pre-operatively to 97.2 ± 3.9 post-operatively ( P = <.0001) and increased in the repair group from 71.0 ± 11.5 pre-operatively to 97.4 ± 4.1 post-operatively ( P = <.0001).The change in IKDC score was greater in repair (26.0 ± 12.3) than meniscectomy (21.1 ± 9.8) ( P = .002). Reoperation rates in meniscectomy (20%) and repair (20%) were similar ( P = .910). Pre-operative IKDC scores were lower in the repair group ( P = .001), but final IKDC scores were similar ( P = 0.695). Symptomatic OA was noted in 17 patients in the meniscectomy group (22%) and 5 patients in the repair group (11%) ( P = .121). The failure rate was similar between meniscectomy (35%) and repair (28%) ( P = .307). Regression equations evaluating treatment modality, type and location of tear, and amount of meniscus removed did not reach significance in predicting IKDC or failure. Conclusions: In this cohort of young patients with isolated lateral meniscus tears, rate of repair increased over time. IKDC scores improved more in the repair group compared to the meniscectomy patients, however IKDC scores obtained at final follow-up were similar. Rates of symptomatic OA, reoperation, and failure were similar between groups. Treatment modality, type and location of tear, and amount of meniscus removed were not predictive of final IKDC or failure.

Introduction: Omentum flap is a viable reconstructive option for complex chest wall and mediastinal reconstruction. The impact of vasoconstrictors and the laminar pattern of blood flow associated with left ventricular assist devices (LVADs) on the outcomes of reconstructions has not been thoroughly evaluated. Methods: A retrospective review of all patients who underwent chest wall or mediastinal reconstruction using pedicled omentum flaps between 2003 and 2019. Results: Forty patients (60% males) underwent chest wall or mediastinal reconstruction using a pedicled omentum flap at a mean age of 58 years. The median follow-up was 24.3 months. The most common indication was the reconstruction of anterior chest wall/sternal defects (n = 16), followed by coverage of repaired bronchopleural fistula (n = 6), osteoradionecrosis of the anterolateral chest wall (n = 5), reconstruction of anterior/lateral chest wall following oncologic resections (n = 5), coverage of replaced infected LVAD (n = 4), and coverage of exposed/replaced aortic root vascular grafts (n = 4). Vasoconstrictors were used in 26 patients (65%). Eight flaps had partial necrosis, and none of the flaps had complete necrosis. There was no difference in flap complication rates in patients who received vasoconstrictors during the case compared to those who did not ( P = 1.0). Thirteen (33%) flaps were skin grafted at a median of 13 days with 100% skin graft viability. Abdominal incisional hernia developed in 8 patients. In patients with LVADs, the omentum remained viable during the follow-up period. Conclusion: The ability of the omentum to easily reach various regions in the chest and the low failure rate make this flap a reliable reconstructive method.