Quantifying Efficacy of Video Interventions about Adverse Events in Medical Student Education.

OBJECTIVES: The coronavirus disease 2019 pandemic catalyzed a rapid shift toward remote learning in medicine. This study hypothesized that using videos on adverse events and patient safety event reporting systems could enhance education and motivation among healthcare professionals, leading to improved performance on quizzes compared with those exposed to standard, in-person lectures. METHODS: Participants were randomly assigned to a group both watching the video and attending an in-person lecture or a group that received only the in-person lecture in this study performed in 2022. Surveys gathered demographic information, tested knowledge, and identified barriers to reporting adverse events. RESULTS: A total of 83 unique participants responded to the survey out of the 130 students enrolled (64%; 83/130). Among the students completing all of the surveys, the group who watched the Osmosis video had a higher average quiz score (6.46/7) than the lecture group (6.31/7) following the first intervention. Only 25% of respondents agreed or strongly agreed that they knew what to include in a patient safety report and only 10% agreed or strongly agreed that they knew how to access the reporting system. CONCLUSIONS: This study suggests virtual preclass video learning can be a beneficial tool to complement traditional lecture-based learning in medical education. Further research is needed to determine the efficacy of long-term video interventions in adverse events.

Dynamic Changes in Circulating Tumor Fraction as a Predictor of Real-World Clinical Outcomes in Solid Tumor Malignancy Patients Treated with Immunotherapy.

INTRODUCTION: A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort. METHODS: This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior to the start of ICI initiation and an on-treatment blood sample 15-180 days post ICI initiation. TF was calculated via an ensemble algorithm that utilizes TF estimates derived from variants and copy number information. Patients with molecular response (MR) were defined as patients with a ≥ 50% decrease in TF between tests. In the subset of patients with rw-imaging data between 2 and 18 weeks of ICI initiation, the predictive value of MR in addition to rw-imaging was compared to a model of rw-imaging alone. RESULTS: The evaluable cohort (N = 86) was composed of 14 solid cancer types. Patients received either ICI monotherapy (38.4%, N = 33) or ICI in combination with chemotherapy (61.6%, N = 53). Patients with MR had significantly longer rw-overall survival (rwOS) (hazard ratio (HR) 0.4, P = 0.004) and rw-progression free survival (rwPFS) (HR 0.4, P = 0.005) than patients with molecular non-response (nMR). Similar results were seen in the ICI monotherapy subcohort; HR 0.2, P = 0.02 for rwOS and HR 0.2, P = 0.01 for rwPFS. In the subset of patients with matched rw-imaging data (N = 51), a model incorporating both MR and rw-imaging was superior in predicting rwOS than rw-imaging alone (P = 0.02). CONCLUSIONS: xM used for TRM is a novel serial quantitative TF algorithm that can be used clinically to evaluate ICI therapy efficacy.

Intranasal Dexmedetomidine Use in Pediatric Patients for Anxiolysis in the Emergency Department.

OBJECTIVES: In recent years, dexmedetomidine has gained traction as a treatment for anxiolysis in the emergency department (ED). When used with an atomizer, it may also be given intranasally for anxiolysis. The primary objective was to determine the level of ED provider satisfaction and comfort with intranasal (IN) dexmedetomidine for anxiolysis in pediatric patients with behavioral agitation and/or acute psychosis. The secondary objectives included determining safety, rates of therapy failure, and ED length of stay compared with oral midazolam. The efficacy of IN dexmedetomidine versus oral midazolam in patients with autism spectrum disorder (ASD) was also evaluated. METHODS: This was a single-center, prospective study in a pediatric ED from March 1 to December 31, 2021. Patients were included in the study if the ED provider requested IN dexmedetomidine anxiolysis and completed a postadministration survey. Safety and efficacy outcomes were assessed by chart review and compared with patients who received oral midazolam during the same study period. Efficacy was defined as the rate of treatment failure, as the need for procedural termination, progression to procedural sedation, or the requirement of additional medications for anxiolysis. RESULTS: Sixty-two patients received IN dexmedetomidine {median dose [interquartile range (IQR)] of 3.05 [2.04-4.00] µg/kg/dose} compared with 58 who received oral midazolam [median (IQR) dose of 0.29 (0.25-0.48) mg/kg/dose). Providers reported high comfort and satisfaction scores, with median (IQR) scores of 90 (75-100) and 88 (60-100) of 100. Twenty-nine percent of patients experienced treatment failure, most commonly because of the need for additional medications. Those who received IN dexmedetomidine had a longer ED length of stay (6.0 vs 4.4 hours, P = 0.010). Among the patients with ASD, those who received IN dexmedetomidine had a lower rate of treatment failure compared with oral midazolam (21.2% vs 66.7%, P = 0.039). CONCLUSIONS: This study demonstrates that IN dexmedetomidine has high levels of provider comfort and satisfaction, moderately high success rate, and a promising safety profile. In addition, IN dexmedetomidine may be superior to oral midazolam in patients with ASD for anxiolysis, but additional studies are needed.

Clinical Outcomes of Oral Zinc Therapy in Hepatic Encephalopathy Treatment.

BACKGROUND: Additional therapies for hepatic encephalopathy (HE) treatment are warranted. There are data evaluating the use of zinc for HE; however, clinical outcomes, specifically in the United States, are unknown. OBJECTIVE: To compare 30-day and 1-year all-cause readmission rates in patients with cirrhosis complicated by HE on lactulose and rifaximin to those on lactulose, rifaximin, and zinc. METHODS: This retrospective study included patients admitted with documented cirrhosis and home medications of lactulose and rifaximin, with or without zinc. Patients were stratified into 2 groups: those receiving lactulose and rifaximin for HE (control) and those receiving lactulose, rifaximin, and zinc for HE (treatment). The primary outcomes were 30-day and 1-year all-cause readmission rates. RESULTS: One-hundred fifty-seven patients were included (102 in control group, 55 in treatment group). Regarding 30-day and 1-year all-cause readmission rates, there was no difference between the control and treatment groups. CONCLUSION AND RELEVANCE: This is the first study conducted in the United States evaluating zinc for HE treatment. Zinc did not impact 30-day or 1-year all-cause readmission rates. Further studies are warranted to evaluate the potential benefit of zinc for HE, possibly in correlation with Model for End-stage Liver Disease-Sodium (MELD-Na) scores.

Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue.

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking. Methods: A subset of research volunteers from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure homocysteine and related metabolites in the current pilot study. Genetic expression profiles of inflammatory markers were evaluated using the Human Neuroinflammation NanoString panel. Further analyses included an evaluation of plasma homocysteine effects on amyloid beta, tau, ionized calcium-binding adaptor molecule 1, and glial fibrillary acidic protein immunohistochemistry in the frontal and occipital cortices. Analytes and other study outcomes were evaluated in relation to ante mortem HHcy status: We identified 13 persons with normal ante mortem plasma homocysteine levels (<14 µmol/L) and 18 who had high plasma homocysteine levels (≥14 µmol/L). Results: Participants with HHcy demonstrated increased levels of several plasma homocysteine cycle metabolites such as total cysteine, S-adenosyl-homocysteine, cystathionine, and choline. Inflammatory gene expression profiles showed a general downregulation in the setting of elevated plasma homocysteine. HHcy was associated with more and longer microglial processes, but smaller and fewer astrocytes, especially in participants of older age at death. HHcy in older participants was also associated with occipital cortex microhemorrhages and increased severity of atherosclerosis throughout the cerebral vasculature. Conclusions: Increased plasma homocysteine and older age were associated with the downregulation of inflammatory gene expression markers in association with significant glial and vascular pathology changes. Impaired immune function is a plausible mechanism by which HHcy increases cerebrovascular damage leading to impaired cognitive function.

Cell sorting microbeads as novel contrast agent for magnetic resonance imaging.

The success of several cell-based therapies and prevalent use of magnetic resonance imaging (MRI) in the clinic has fueled the development of contrast agents for specific cell tracking applications. Safe and efficient labeling of non-phagocytic cell types such as T cells nonetheless remains challenging. We developed a one-stop shop approach where the T cell sorting agent also labels the cells which can subsequently be depicted using non-invasive MRI. We compared the MR signal effects of magnetic-assisted cell sorting microbeads (CD25) to the current preclinical gold standard, ferumoxytol. We investigated in vitro labeling efficiency of regulatory T cells (Tregs) with MRI and histopathologic confirmation. Thereafter, Tregs and T cells were labeled with CD25 microbeads in vitro and delivered via intravenous injection. Liver MRIs pre- and 24 h post-injection were performed to determine in vivo tracking feasibility. We show that CD25 microbeads exhibit T2 signal decay properties similar to other iron oxide contrast agents. CD25 microbeads are readily internalized by Tregs and can be detected by non-invasive MRI with dose dependent T2 signal suppression. Systemically injected labeled Tregs can be detected in the liver 24 h post-injection, contrary to T cell control. Our CD25 microbead-based labeling method is an effective tool for Treg tagging, yielding detectable MR signal change in cell phantoms and in vivo. This novel cellular tracking method will be key in tracking the fate of Tregs in inflammatory pathologies and solid organ transplantation.

Adipocyte-Derived Serum Amyloid A Promotes Angiotensin II-Induced Abdominal Aortic Aneurysms in Obese C57BL/6J Mice.

BACKGROUND: Obesity increases the risk for human abdominal aortic aneurysms (AAAs) and enhances Ang II (angiotensin II)-induced AAA formation in C57BL/6J mice. Obesity is also associated with increases in perivascular fat that expresses proinflammatory markers including SAA (serum amyloid A). We previously reported that deficiency of SAA significantly reduces Ang II-induced inflammation and AAA in hyperlipidemic apoE-deficient mice. In this study. we investigated whether adipose tissue-derived SAA plays a role in Ang II-induced AAA in obese C57BL/6J mice. METHODS: The development of AAA was compared between male C57BL/6J mice (wild type), C57BL/6J mice lacking SAA1.1, SAA2.1, and SAA3 (TKO); and TKO mice harboring a doxycycline-inducible, adipocyte-specific SAA1.1 transgene (TKO-Tgfat; SAA expressed only in fat). All mice were fed an obesogenic diet and doxycycline to induce SAA transgene expression and infused with Ang II to induce AAA. RESULTS: In response to Ang II infusion, SAA expression was significantly increased in perivascular fat of obese C57BL/6J mice. Maximal luminal diameters of the abdominal aorta were determined by ultrasound before and after Ang II infusion, which indicated a significant increase in aortic luminal diameters in wild type and TKO-TGfat mice but not in TKO mice. Adipocyte-specific SAA expression was associated with MMP (matrix metalloproteinase) activity and macrophage infiltration in abdominal aortas of Ang II-infused obese mice. CONCLUSIONS: We demonstrate for the first time that SAA deficiency protects obese C57BL/6J mice from Ang II-induced AAA. SAA expression only in adipocytes is sufficient to cause AAA in obese mice infused with Ang II.

Predicting mortality in nonsurgical patients before cannulation for veno-arterial extracorporeal life support: Development and validation of the LACT-8 score.

OBJECTIVES: We sought to derive and validate a model to predict inpatient mortality after veno-arterial extracorporeal life support (VA-ECLS) based on readily available, precannulation clinical data. BACKGROUND: Refractory cardiogenic shock supported by VA-ECLS is associated with high morbidity and mortality. METHODS: VA-ECLS cases at our institution from January 2014 through July 2019 were retrospectively reviewed. Exclusion criteria were cannulation: (1) at another institution; (2) for primary surgical indication; or (3) for extracorporeal cardiopulmonary resuscitation. Multivariable logistic regression compared those with and without inpatient mortality. Multiple imputation was performed and optimism-adjusted area under the curve (oAUC) values were computed. RESULTS: VA-ECLS cases from August 2019 through November 2020 were identified as a validation cohort. In the derivation cohort (n = 135), the final model included Lactate (mmol/L), hemoglobin (g/dl; Anemia), Coma (Glasgow Coma Scale [GCS] < 8) and resusciTATEd cardiac arrest (LACTATE score; oAUC = 0.760). In the validation cohort (n = 30, LACTATE showed similar predictability [AUC = 0.710]). A simplified (LACT-8) score was derived by dichotomizing lactate (>8) and hemoglobin (<8) and summing together the number of components for each patient. LACT-8 performed similarly (derivation, oAUC = 0.724; validation, AUC = 0.725). In the derivation cohort, both scores outperformed SAVE (oAUC = 0.568) and SOFA (oAUC = 0.699) scores. A LACT-8 ≥ 3 had a specificity for mortality of 97.9% and 92.9%, in the derivation and validation cohorts, respectively. CONCLUSIONS: The LACT-8 score can predict inpatient mortality prior to before cannulation for VA-ECLS. LACT-8 can be implemented utilizing clinical data without the need for an online calculator.

Limbic-Predominant Age-Related TDP-43 Encephalopathy: Medical and Pathologic Factors Associated With Comorbid Hippocampal Sclerosis.

BACKGROUND AND OBJECTIVES: Limbic-predominant age-related Tar DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is present in ≈25% of older persons' brains and is strongly associated with cognitive impairment. Hippocampal sclerosis (HS) pathology is often comorbid with LATE-NC, but the clinical and pathologic correlates of HS in LATE-NC are not well understood. METHODS: This retrospective autopsy cohort study used data derived from the National Alzheimer's Coordinating Center Neuropathology Data Set, which included neurologic status, medical histories, and neuropathologic results. All autopsies were performed in 2014 or later. Among participants with LATE-NC, those who also had HS pathology were compared with those without HS with regard to candidate risk factors or common underlying diseases. Statistical significance was set at nominal p < 0.05 in this exploratory study. RESULTS: A total of 408 participants were included (n = 221 were LATE-NC+/HS-, n = 145 were LATE-NC+/HS+, and n = 42 were LATE-NC-/HS+). Most of the included LATE-NC+ participants were severely impaired cognitively (83.3% with dementia). Compared to HS- participants, LATE-NC+ participants with HS trended toward having worse cognitive status and scored lower on the Personal Care and Orientation domains (both p = 0.03). Among LATE-NC+ participants with Braak neurofibrillary tangle (NFT) stages 0 to IV (n = 88), HS+ participants were more impaired in the Memory and Orientation domains (both p = 0.02). There were no differences (HS+ compared with HS-) in the proportion with clinical histories of seizures, stroke, cardiac bypass procedures, diabetes, or hypertension. The HS+ group lacking TDP-43 proteinopathy (n = 42) was relatively likely to have had strokes (p = 0.03). When LATE-NC+ participants with or without HS were compared, there were no differences in Alzheimer disease neuropathologies (Thal ß-amyloid phases or Braak NFT stages) or Lewy body pathologies. However, the HS+ group was less likely to have amygdala-restricted TDP-43 proteinopathy (LATE-NC stage 1) and more likely to have neocortical TDP-43 proteinopathy (LATE-NC stage 3) (p < 0.001). LATE-NC+ brains with HS also tended to have more severe circle of Willis atherosclerosis and arteriolosclerosis pathologies. DISCUSSION: In this cohort skewed toward participants with severe dementia, LATE-NC+ HS pathology was not associated with seizures or with Alzheimer-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy and with more severe non-ß-amyloid vessel wall pathologies.

Association between WWOX/MAF variants and dementia-related neuropathologic endophenotypes.

The genetic locus containing the WWOX and MAF genes was implicated as a clinical Alzheimer's disease (AD) risk locus in two recent large meta-analytic genome wide association studies (GWAS). In a prior GWAS, we identified a variant in WWOX as a suggestive risk allele for hippocampal sclerosis. We hypothesized that the WWOX/MAF locus may be preferentially associated with non-plaque- and non-tau-related neuropathological changes (NC). Data from research participants with GWAS and autopsy measures from the National Alzheimer's Coordinating Center and the Religious Orders Study and the Rush Memory and Aging Project were meta-analyzed. Notably, no variants in the locus were significantly associated with ADNC. However, several WWOX/MAF variants had significant adjusted associations with limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC), HS, and brain arteriolosclerosis. These associations remained largely unchanged after adjustment for ADNC (operationalized with standard semiquantitative staging), suggesting that these associations are independent of ADNC. Thus, WWOX genetic variants were associated pathologically with LATE-NC, not ADNC.

Intravenous phytonadione administered orally in reducing warfarin-related coagulopathy.

INTRODUCTION: The cost of phytonadione tablets has increased markedly and is significantly higher than the intravenous formulation. The intravenous formulation given orally is a potential alternative but has not been directly evaluated in comparison to the commercially available tablet. The objective of this study was to evaluate the efficacy of phytonadione intravenous solution given orally compared to commercially available phytonadione tablets for reversal of coagulopathy related to warfarin. METHODS: We conducted a retrospective, observational study of adult patients who received phytonadione tablets and the IV formulation orally for warfarin-related coagulopathy. The international normalized ratio (INR) was measured before and after phytonadione administration. The primary outcome was INR <1.5 at 24 h after phytonadione administration. RESULTS: From January 1, 2015 to August 1, 2018 a total of 200 patients were identified. In total, 58% (n = 116) patients received IV phytonadione solution given orally and 42% (n = 84) patients received the tablets. The primary outcome of INR <1.5 at 24 h was not significantly different between groups (p = 0.321). DISCUSSION: The IV phytonadione solution given by mouth and the tablet formulation performed similarly.

Validation of the modified Bosniak classification system to risk stratify pediatric cystic renal masses: An international, multi-site study from the pediatric urologic oncology working group of the societies for pediatric urology.

BACKGROUND: Pediatric cystic renal lesions are challenging to manage as little is known about their natural course. A modified Bosniak (mBosniak) classification system has been proposed for risk stratification in pediatric patients that takes ultrasound (US) and/or computed tomogram (CT) characteristics into account. However, literature validating this system remains limited. OBJECTIVE: To determine if the mBosniak classification system correlates with pathologic diagnoses. The hypothesis is that mBosniak classification can stratify the risk of malignancy in children with renal cysts. STUDY DESIGN: Patients treated for cystic renal masses with available imaging and pathology between 2000 and 2019 from five institutions were identified. Clinical characteristics and pathology were obtained retrospectively. Characteristics from the most recent US, CT, and/or magnetic resonance imaging (MRI) were recorded. Reviewers assigned a mBosniak classification to each scan. mBosniak scores 1/2 were considered low-risk and 3/4 high-risk. These groups were compared with pathology (classified as benign, intermediate, malignant). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) were calculated to assess this categorization as a screening tool to guide surgical intervention. Agreement between imaging modalities was also explored. RESULTS: 99 patients were identified. High-risk imaging findings were correlated with malignant or intermediate pathology with a sensitivity of 88.3%, specificity of 84.6%, PPV of 89.8%, NPV of 82.5%, +LR of 5.7, and -LR of 0.14. The sensitivity for detecting malignant lesions only was 100%. There was substantial agreement between US/CT (n = 55; κ = 0.66) and moderate agreement between US/MRI (n = 20; κ = 0.52) and CT/MRI (n = 13; κ = 0.47). DISCUSSION: The mBos classification system is a useful tool in predicting the likelihood of benign vs. intermediate or malignant pathology. The relatively high sensitivity and specificity of the system for prediction of high-risk lesions makes this classification applicable to clinical decision making. In addition, all malignant lesions were accurately identified as mBosniak 4 on imaging. This study adds substantial data to the relatively small body of literature validating the mBosniak system for risk stratifying pediatric cystic renal lesions. CONCLUSIONS: Pediatric cystic renal lesions assigned mBosniak class 1/2 are mostly benign, whereas class 3/4 lesions are likely intermediate or malignant pathology. We observed that the mBosniak system correctly identified pathology appropriate for surgical management in 88% of cases and did not miss malignant pathologies. There is substantial agreement between CT and US scans concerning mBos classification.

Stratification by obesity class, rather than age, can identify a higher percent of children at risk for non-alcoholic fatty liver disease and metabolic dysfunction.

BACKGROUND: An increasing number of clinical practice guidelines recommend screening children with obesity for non-alcoholic fatty liver disease (NAFLD). However, there is limited evidence regarding what parameters should be used to initiate the screening. OBJECTIVE: The objective of this study was to determine whether obesity class rather than age group can identify a higher percent of children at risk of NAFLD as assessed by abnormal alanine aminotransferase (ALT). METHODS: This is a cross-sectional study in a regional referral clinic for evaluation of obesity. Children were stratified by age group or by obesity class, and data obtained at first visit were analysed. RESULTS: Of the 784 children, 482 were ≥10, 209 were 6 to 9 and 93 were 2 to 5 years of age. Abnormal ALT was observed in 32.1%, 46.9% and 61.0% of children with class I, II or III obesity, respectively (p < 0.001), while the risk of abnormal ALT did not differ in very young (2-5), young (6-9), or children older than 10 years. A multivariable analysis showed that class II and class III obesity were associated with 2.1-fold (1.27-3.72) and 4-fold (2.41-6.96) greater odds of abnormal ALT compared with class I obesity. African-American children had lower risk of abnormal ALT (0.27), whereas Hispanic children had higher risk (2.37). Obesity class was a better predictor of abnormal ALT than age, especially in girls. Furthermore, 66.7% of boys (p = 0.009) and 69% of girls (p < 0.001) with abnormal ALT exhibited additional signs of metabolic dysfunction. CONCLUSION: Obesity class is more strongly associated with abnormal ALT than age.

Changes in physical activity during the initial stages of the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic response limited access to many traditional forms of physical activity (PA). Purpose:To assess changes in objectively measured PAofUniversity staff during the initial stageofthe COVID-19 pandemic. METHODS: We implemented a repeated measures natural experiment design. PA data (walking distance, steps∙d#x2D;1, and Moderate#x2D;to#x2D;Vigorous PA (MVPA) time) from commercial grade triaxial accelerometers were collected from employees (N#x3D;625) of a large, public university in the southeast United States during the months of Jan#x2D;May in calendar years 2019 and 2020. RESULTS: Walking distance (6#x2D;9#x25;, p#x3C;0.001) and steps∙d#x2D;1(7#x2D;11#x25;, p#x3C;0.001) were lower during April and May 2020 compared to 2019. However, MVPA time was not significantly different among calendar years for the months of March#x2D;May. Steps∙d#x2D;1significantly decreased after WHO's worldwide pandemic declaration (10,348#xB1;171 v. 9551#xB1;156 steps∙d#x2D;1, p#x3C;0.001) and campus closure (10,100#xB1;160 v. 9,186#xB1;167 steps∙d#x2D;1, p#x3C;0.001). Conversely, steps∙d#x2D;1significantly increased after implementation of the state's "Healthy at Home" order (9,693#xB1;177 vs. 10,156#xB1;185 steps∙d#x2D;1, p#x3C;0.001). CONCLUSION: A decrease in daily steps, but not MVPA, suggests increased sedentary behavior, not reduced participation in exercise, during the early stages of the COVID#x2D;19 pandemic. Specific pandemic response policies may positively or negatively affect PA and sedentary behavior.

Temporal Sequencing of Mental Health Symptom Severity and Suicidal Ideation in Post-9/11 Men and Women Veterans Who Recently Separated from the Military.

BACKGROUND: Despite some evidence for gender differences in associations between military veterans' mental health and suicidal ideation (SI), gender-specific prospective studies are lacking. The aims of this prospective study were to: (1) examine gender differences in veterans' initial status and trajectories of mental health severity and SI status and (2) identify temporal sequencing of mental health predictors of SI. METHODS: Surveys of 1035 US veterans were administered at 3 time-points (T1, T2, T3) over a 7-year period following military separation, with an initial assessment within 2 years of military separation. RESULTS: Men reported higher baseline PTSD and alcohol misuse severity than women. No baseline gender difference in SI prevalence was detected. Baseline gender differences in mental health severity were maintained over time. For both men and women, remittance of SI was more likely from T1 to T2 than from T2 to T3 while chronic SI was more likely from T2 to T3. The strongest predictors of T3 SI were prior SI followed by alcohol misuse, depression, and PTSD severity with stronger effects for T2 predictors than T1. CONCLUSION: The maintenance of baseline gender differences throughout trajectories of mental health predictors of SI supports the need for ongoing gender-specific mental health services. Current governmental interorganizational efforts are focused on suicide prevention during the first year after military service completion. Our findings indicate a need to extend mental health screening and treatment beyond the early post-military period to reduce risk and recurrence of SI for both men and women.

Inflammatory Pathways Are Impaired in Alzheimer Disease and Differentially Associated With Apolipoprotein E Status.

Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-ε4 significantly increases AD risk, APOE-ε3 is the most common gene variant, and APOE-ε2 protects against AD. However, the underlying mechanisms of APOE-ε4 on AD risk remains unclear, with APOE-ε4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-ε3/3 (n = 9) or APOE-ε4/4 (n = 10) participants with AD pathology and APOE-ε3/3 (n = 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-ε4/4-AD individuals compared to APOE-ε3/3-AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-ε3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-ε4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.

Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer's Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n = 780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10 kb of TMEM106B, GRN, ABCC9, KCNMB2, and APOE were tested for association with HS and LATE-NC, and separately for Alzheimer's pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, TMEM106B, GRN, and APOE had significant gene-based associations with both LATE and HS, whereas ABCC9 had significant associations with HS only. In a sensitivity analysis limited to LATE-NC + cases, ABCC9 variants were again associated with HS. By contrast, the associations of TMEM106B, GRN, and APOE with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except APOE appeared to be associated with Alzheimer's-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS.

American Society of Emergency Radiology Multicenter Blunt Splenic Trauma Study: CT and Clinical Findings.

Background Treatment of blunt splenic trauma (BST) continues to evolve with improved imaging for detection of splenic vascular injuries. Purpose To report on treatments for BST from 11 trauma centers, the frequency and clinical impact of splenic vascular injuries, and factors influencing treatment. Materials and Methods Patients were retrospectively identified as having BST between January 2011 and December 2018, and clinical, imaging, and outcome data were recorded. Patient data were summarized descriptively, both overall and stratified by initial treatment received (nonoperative management [NOM], angiography, or surgery). Regression analyses were used to examine the primary outcomes of interest, which were initial treatment received and length of stay (LOS). Results This study evaluated 1373 patients (mean age, 42 years ± 18; 845 men). Initial treatments included NOM in 849 patients, interventional radiology (IR) in 240 patients, and surgery in 284 patients. Rates from CT reporting were 22% (304 of 1373) for active splenic hemorrhage (ASH) and 20% (276 of 1373) for contained vascular injury (CVI). IR management of high-grade injuries increased 15.6%, from 28.6% (eight of 28) to 44.2% (57 of 129) (2011-2012 vs 2017-2018). Patients who were treated invasively had a higher injury severity score (odds ratio [OR], 1.04; 95% CI: 1.02, 1.05; P < .001), lower temperature (OR, 0.97; 95% CI: 0.97, 1.00; P = .03), and a lower hematocrit (OR, 0.96; 95% CI: 0.93, 0.99; P = .003) and were more likely to show ASH (OR, 8.05; 95% CI: 5.35, 12.26; P < .001) or CVI (OR, 2.70; 95% CI: 1.64, 4.44; P < .001) on CT images, have spleen-only injures (OR, 2.35; 95% CI: 1.45, 3.8; P < .001), and have been administered blood product for fewer than 24 hours (OR, 2.35; 95% CI: 1.58, 3.51; P < .001) compared with those chosen for NOM, after adjusting for key demographic and clinical variables. After adjustment, factors associated with a shorter LOS were female sex (OR, 0.84; 95% CI: 0.73, 0.96; P = .009), spleen-only injury (OR, 0.72; 95% CI: 0.6, 0.86; P < .001), higher admission hematocrit (OR, 0.98; 95% CI: 0.6, 0.86; P < .001), and presence of ASH at CT (OR, 0.74; 95% CI: 0.62, 0.88; P < .001). Conclusion Contained vascular injury and active splenic hemorrhage (ASH) were frequently reported, and rates of interventional radiologic management increased during the study period. ASH was associated with a shorter length of stay, and patients with ASH had eight times the odds of undergoing invasive treatment compared with undergoing nonoperative management. © RSNA, 2021 See also the editorial by Patlas in this issue.

Mental Health and Psychosocial Functioning in Recently Separated U.S. Women Veterans: Trajectories and Bi-Directional Relationships.

Prior research on the relationship between veterans' mental health and psychosocial functioning has primarily relied on male samples. Here, we investigated prospective longitudinal relationships between mental health and psychosocial functioning in 554 female Iraq and Afghanistan War veterans who were surveyed three times between two- and seven-years following separation from service. Mixed effects modeling revealed that increasing depression and posttraumatic stress disorder (PTSD) severity predicted declines in work functioning. Increasing PTSD severity predicted declining parental functioning and worsening depression predicted a decline in relationship functioning. In turn, decreased work and intimate relationship functioning predicted increased PTSD and depression symptom severity suggesting bi-directional effects between mental health and psychosocial functioning. An examination of the effect of deployment stressors on psychosocial functioning revealed that deployment sexual harassment was the strongest predictor of decreased psychosocial functioning across all domains. Evidence for the reciprocal nature of relationships between mental health and psychosocial functioning underscore the need for treatment targeted at PTSD and depression, as well as work and relationship functioning to improve outcomes for women veterans.