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.

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.

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.

Is supplemental regional anesthesia associated with more complications and readmissions after ankle fracture surgery in the inpatient and outpatient setting?

BACKGROUND: There is concern that regional anesthesia is associated with increased risk of complications, including return to the hospital for uncontrolled pain once the regional anesthetic wears off. METHODS: Retrospective database review of patients who underwent open reduction and internal fixation of a closed ankle fracture from 2014-16 who received general anesthesia alone (GA) or general anesthesia plus regional anesthesia (RA). RESULTS: 9459 patients met inclusion criteria. Patients in the RA group had significantly longer operative duration in both inpatient (GAI=71min vs RAI=79min, p=0.002) and outpatient setting (GAO=66min vs RAI=72min, p<0.001), lower overall LOS (GA=1.7 days vs RA=1.1 days, p<0.001), and higher readmission rate for pain (RAO=4 [0.3%] vs GAO=1 [0.0%], p=0.007). CONCLUSIONS: Patients who received supplemental regional anesthesia had shorter hospital LOS, increased operative time, and increased readmission rates for rebound pain. However, the small number of patients needing readmission are not clinically significant demonstrating that regional anesthesia is safe, effective and readmission for rebound pain should not be a concern. LEVEL OF EVIDENCE: III.

High Prevalence of Moyamoya Syndrome in Appalachia.

INTRODUCTION: Moyamoya is a chronic cerebrovascular condition of unclear etiology characterized by progressive occlusion of 1 or both internal carotid arteries with neovascular collateral formation. With both an idiopathic form (moya-moya disease) and congenital condition-associated form (moyamoya syndrome), it can cause ischemic and hemorrhagic stroke. Recent findings in Kentucky have challenged traditional estimates of its incidence in US populations. Using the Kentucky Appalachian Stroke Registry (KApSR), our aim was to further characterize its incidence as a cause of stroke and to understand the patient population in Appalachia. METHODS: A retrospective review of moyamoya patients was performed using the KApSR database. Data collected included demographics, county location, risk factors, comorbidities, and health-care encounters from January 1, 2012, to December 31, 2016. RESULTS: Sixty-seven patients were identified; 36 (53.7%) resided in Appalachian counties. The cohort accounted for 125 of 6,305 stroke admissions, representing an incidence of 1,983 per 100,000 stroke admissions. Patients presented with ischemic strokes rather than hemorrhagic strokes (odds ratio 5.50, 95% CI: 2.74-11.04, p < 0.01). Eleven patients (16.4%) exhibited autoimmune disorders. Compared to the general population with autoimmune disorder prevalence of 4.5%, the presence of autoimmunity within the cohort was significantly higher (p < 0.01). Compared to non-Appalachian patients, Appalachian patients tended to present with lower frequencies of tobacco use (p = 0.08), diabetes mellitus (p = 0.13), and hypertension (p = 0.16). CONCLUSIONS: Moyamoya accounts for a substantial number of stroke admissions in Kentucky; these patients were more likely to develop an ischemic stroke rather than a hemorrhagic stroke. Autoimmune disorders were more prevalent in moyamoya patients than in the general population. The reduced frequency of traditional stroke risk factors within the Appalachian group suggests an etiology distinct to the population.

Autologous Fat Grafting Does Not Increase Risk of Oncologic Recurrence in the Reconstructed Breast.

INTRODUCTION: Autologous fat grafting (AFG) is a popular and effective method of breast reconstruction after mastectomy; however, the oncological safety of AFG remains in question. The aim of this study was to determine whether AFG increases the risk of cancer recurrence in the reconstructed breast. METHODS: A matched, case-control study was conducted from 2000 to 2017 at the senior author's institution. Inclusion was limited to female patients who underwent mastectomy and breast reconstruction with or without AFG. Data were further subdivided at the breast level. χ analyses were used to test the association between AFG status and oncologic recurrence. A Cox proportional-hazards model was constructed to assess for possible differences in time to oncologic recurrence. The probability of recurrence was determined by Kaplan-Meier analyses and confirmed with log-rank testing. RESULTS: Overall, 428 breasts met study criteria. Of those, 116 breasts (27.1%) received AFG, whereas 312 (72.9%) did not. No differences in the rates of oncologic recurrence were found between the groups (8.2% vs 9.0%, P < 1.000). Unadjusted (hazard ratio = 1.03, confidence interval = 0.41-2.60, P < 0.957) and adjusted hazard models showed no statistically significant increase in time to oncologic recurrence when comparing AFG to non-AFG. In addition, no statistical differences in disease-free survival were found (P = 0.96 by log rank test). CONCLUSION: Autologous fat grafting for breast reconstruction is oncologically safe and does not increase the likelihood of oncologic recurrence. Larger studies (eg, meta analyses) with longer follow-up are needed to further elucidate the long-term safety of AFG as a reconstructive adjunct.

Appalachian Status Is a Negative Predictor of Breast Reconstruction Following Breast Cancer Resection.

BACKGROUND: Health care disparities in Appalachia are well documented. However, no previous studies have examined possible differences in the utilization of breast reconstruction (BR) in Appalachia. This study aims to determine if a disparity in BR utilization exists in women from Appalachia Kentucky. METHODS: A retrospective, population-based cohort study was conducted from January 1, 2006, to December 31, 2015. The Kentucky Cancer Registry was queried to identify population-level data for female patients diagnosed with breast cancer and treated with mastectomy. A multivariate logistic regression model controlling for patient, disease, and treatment characteristics was constructed to predict the likelihood of BR. RESULTS: Bivariate testing showed differences (P < 0.0001) in BR utilization between Appalachian and non-Appalachian women in Kentucky (15.0% and 26.3%, respectively). Multivariate analysis showed that women from Appalachia (odds ratio, 0.54; confidence interval (95), 0.48-0.61; P < 0.0001) were less likely to undergo BR than non-Appalachian women. Interestingly, the rate of BR increased over time in both Appalachian (r = 0.115; P < 0.0001) and non-Appalachian women (r = 0.148; P < 0.0001). CONCLUSIONS: Despite the benefits of BR, women from Appalachia undergo BR at lower rates and are less likely to receive BR than non-Appalachian Kentuckians. Although the rates of BR increased over time in both populations, access to comprehensive breast cancer care remains a challenge for women from Kentucky's Appalachian region.

A breast prosthesis infection update: Two-year incidence, risk factors and management at single institution.

BACKGROUND: Infection following augmentation and prosthetic-based breast reconstruction can cause significant physical and psychological distress for patients. It may delay adjuvant therapies and compromise aesthetic outcomes. The aim of this study is to identify modifiable risk factors for infection and identify common bacterial isolates to achieve optimal outcomes for patients. METHODS: A retrospective cohort study was performed for patients undergoing implant-based breast reconstruction over a 2-year period. In each case, we documented demographics, co-morbidities, complications and antibiotic use. We reviewed treatments, infectious species cultured where applicable and all outcomes. RESULTS: A total of 292 patients met the inclusion criteria. Fifty-five patients (19%) developed an infection. Univariate analysis showed a significantly increased infection rate with longer operative times (P = 0.001) and use of tissue expanders (P = 0.001). Multiple logistic regression analysis confirmed drain use and elevated body mass index (BMI) as risk factors (odds ratio [OR] 2.427 and 1.061, respectively). After controlling for BMI, smoking status and radiation, we found an increased odd of infection with allograft use (OR 1.838) and a decreased odd with skin preparation using 2% chlorhexidine gluconate in 70% isopropyl (OR 0.554), though not statistically significant. Forty of 55 patients with infections had cultures, with 62.5% of isolates being Gram-positive species and 30% Gram-negative species. The median time to clinical infection was 25 days. Implant salvage with surgical interventions was achieved in 61.5% of patients. CONCLUSIONS: This study identified judicious use of drains and efficiency in the operating room as modifiable risk factors for infections following implant-based breast reconstruction. Prospective trials to analyse techniques for infection prevention are warranted. Implant salvage following infection is a possible end-point in the appropriate patient.

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.

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.

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.

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.

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.

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.

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.

Occurrence of Hyperbilirubinemia in Neonates Given a Short-term Course of Ceftriaxone versus Cefotaxime for Sepsis.

OBJECTIVE: Ceftriaxone and cefotaxime are appealing options for the treatment of neonatal infections. Guidelines recommend cefotaxime as the cephalosporin of choice in neonates because of ceftriaxone's potential to cause hyperbilirubinemia. Unfortunately, due to cefotaxime discontinuation, providers must choose between alternative antibiotics. Clinicians at our institution adopted a protocol allowing for the utilization of cefepime and ceftriaxone for the management of neonatal sepsis. The objective of this study was to compare the incidence of hyperbilirubinemia between ceftriaxone and cefotaxime in the treatment of neonatal infections beyond the first 14 days of life. METHODS: This was a retrospective chart review of patients receiving ceftriaxone or cefotaxime for the treatment of neonatal infections. Patients were 15 to 30 days old at the time of antimicrobial administration and received at least 1 dose of ceftriaxone or cefotaxime during hospital admission. Patient characteristics and bilirubin levels were compared between ceftriaxone and cefotaxime. RESULTS: The analysis included 88 patients. There was no statistically significant difference between groups in age, gestational age, weight, and baseline total calcium and bilirubin levels. Normal baseline bilirubin levels increased to an abnormal level after antibiotic administration in 2 patients in the cefotaxime group and 1 patient in the ceftriaxone group. The median number of doses of cefotaxime and ceftriaxone were 3 and 2, respectively. CONCLUSION: Patients who received a short-term course of ceftriaxone did not have a higher likelihood of developing hyperbilirubinemia compared with those who received a short-term course of cefotaxime during their hospital stay.

Improved survival following transarterial radioembolization of infiltrative-appearance hepatocellular carcinoma.

PURPOSE: Infiltrative-appearance hepatocellular carcinoma presents a challenge to clinicians as diagnostic criteria continue to evolve and evidence-based treatment guidelines have yet to be established. While transarterial radioembolization has shown efficacy in hepatocellular carcinoma, many studies exclude infiltrative-appearance HCC in their analysis. The purpose of this study was to describe imaging features of infiltrative-appearance hepatocellular carcinoma and evaluate effects of radioembolization on survival. METHODS: In a retrospective review, infiltrative HCC patients treated from 2008 to 2017 were identified. Patients were divided into two groups: TARE versus systemic therapy/palliative care. Demographics, dates of diagnosis/expiry, albumin, international normalized ratio (INR), sodium, alpha-fetoprotein (AFP), creatinine, Child-Pugh class, model for end-stage liver disease (MELD) score, bilirubin, radiation dose and volume were collected. Patients with bilirubin > 3 were excluded. Mann-Whitney U test and Fisher's exact test assessed differences between groups. Kaplan-Meier survival and Cox proportional hazard analyses were performed. RESULTS: Fifty-three patients were identified, 15 underwent TARE while 38 served as control. Mean age was 60, 43 patients were male. The mean overall survival was 16.2 months for the TARE group and 5.3 months for the control group (Log-rank p < 0.0001). Cox proportional regression analysis revealed significant associations between survival and albumin (HR 0.210, 0.052-0.839, p = 0.027), Child-Pugh class B (HR 0.196, 0.055-0.696, p = 0.012), sorafenib (HR 0.106, 0.031-0.360, p < 0.001), and number of affected liver lobes (HR 1.864, 1.387-2.506, p < 0.001). CONCLUSIONS: Transarterial radioembolization for infiltrative HCC improves life expectancy compared to treatment with comfort measures or systemic therapy.

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.

Trends in the Surgical Management of Lower Extremity Gustilo Type IIIB/IIIC Injuries.

BACKGROUND: Over the past 20 years, innovations in microsurgical technique have coincided with advances in orthoplastic approaches. However, no single algorithm exists to guide management of limb salvage versus amputation. As such, one would expect these procedures to be performed at equal rates given studies showing similar outcomes. Anecdotally, the observation at the authors' institution is that amputations are being performed more frequently. The purpose of this study was to determine trends in lower extremity trauma management. METHODS: A retrospective cohort study was conducted at a Level I trauma center on patients with Gustilo type IIIB/IIIC lower extremity trauma from 2005 to 2014. Overall, 148 patients were included. Patients were subdivided into amputation (n = 69) and reconstruction (n = 79) cohorts. The Spearman rank correlation coefficient was used to compare trends in amputation and reconstruction groups. Plastic surgery consultation data were analyzed using the Mann-Whitney U and chi-square tests and the Pearson correlation coefficient. RESULTS: Amputation was performed more frequently over the study period (r = 0.292; p < 0.001). Plastic surgeons were consulted in 67.5 percent of cases. A plastic surgery consultation was obtained in only 30 percent of amputation cases (p < 0.001). CONCLUSIONS: Although the data show a trend toward amputation and a shift in management of lower extremity trauma, the observed trend may be attributable in part to deviation from an orthoplastic approach to lower extremity trauma. However, lower extremity reconstruction remains a viable option in select patients, and advances in microsurgery can provide excellent outcomes in the face of severe lower extremity trauma.