Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project.

BACKGROUND: Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1ß, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals. METHODS: Our cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES. RESULTS: CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations. CONCLUSION: Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.

Increased all-cause mortality following occupational injury: a comparison of two states.

OBJECTIVES: To measure the impact of lost-time occupational injuries on all-cause mortality in Washington State and, using the same data elements and study design, to determine whether the estimated impact was similar to previous estimates for New Mexico. METHODS: We linked injuries in the Washington workers' compensation system with Social Security Administration data on earnings and mortality. We estimated Cox survival models of mortality for women and men with lost-time compared with medical-only injuries, adjusting for age, pre-injury earnings and industry. We used quantitative bias analysis to account for confounding by pre-injury smoking and obesity. RESULTS: The estimated mortality HR was 1.24 for women (95% CI 1.21 to 1.28) and 1.22 for men (95% CI 1.20 to 1.24). After adjusting for unmeasured pre-injury smoking and obesity, the estimated HR for women was 1.10, 95% simulation interval (SI) 1.00 to 1.21; for men, it was 1.15, 95% SI 1.04 to 1.27. CONCLUSIONS: All-cause mortality for Washington workers with lost-time injuries was higher than for those with medical-only injuries. Estimated HRs for Washington were consistent with those previously estimated for New Mexico, a less populous state with lower median wages and a different workers' compensation insurance mechanism. This suggests that the relationship between workplace injury and long-term mortality may be generalisable to other US states. These findings support greater efforts to enhance safety and to investigate factors that improve postinjury employment opportunities and long-term health. This association should be examined in additional locations, with different study conditions, or using additional data on pre-injury risk factors.

Association of Playing College American Football With Long-term Health Outcomes and Mortality.

Importance: Exposure to repetitive head impacts from playing American football (including impacts resulting in symptomatic concussions and subconcussive trauma) is associated with increased risk for later-life health problems, including cognitive and neuropsychiatric decline and neurodegenerative disease. Most research on long-term health consequences of playing football has focused on former professional athletes, with limited studies of former college players. Objectives: To estimate the prevalence of self-reported health conditions among former college football players compared with a sample of men in the general population as well as standardized mortality ratios (SMRs) among former college football players. Design, Setting, and Participants: This cohort study included data from 447 former University of Notre Dame (ND) football players aged 59 to 75 years who were seniors on the rosters from 1964 to 1980. A health outcomes survey was distributed to living players and next of kin of deceased players for whom contact information was available. The survey was completed from December 2018 to May 2019. Exposure: Participation in football at ND. Main Outcomes and Measures: Prevalence of health outcomes was compared between living former players who completed the survey and propensity score-matched participants in the Health and Retirement Study (HRS). Standardized mortality ratios of all causes and specific causes of death among all former players were compared with those among men in the general US population. Results: A total of 216 living players completed the health survey (median age, 67 years; IQR, 63-70 years) and were compared with 638 participants in the HRS (median age, 66 years; IQR, 63-70 years). Former players reported a higher prevalence of cognitive impairment (10 [5%] vs 8 [1%]; P = .02), headaches (22 [10%] vs 22 [4%]; P = .001), cardiovascular disease (70 [33%] vs 128 [20%]; P = .001), hypercholesterolemia (111 [52%] vs 182 [29%]; P = .001), and alcohol use (185 [86%] vs 489 [77%]; P = .02) and a lower prevalence of diabetes (24 [11%] vs 146 [23%]; P = .001). All-cause mortality (SMR, 0.54; 95% CI, 0.42-0.67) and mortality from heart (SMR, 0.64; 95% CI, 0.39-0.99), circulatory (SMR, 0.23; 95% CI, 0.03-0.83), respiratory (SMR, 0.13; 95% CI, 0.00-0.70), and digestive system (SMR, 0.13; 95% CI, 0.00-0.74) disorders; lung cancer (SMR, 0.26; 95% CI, 0.05-0.77); and violence (SMR, 0.10; 95% CI, 0.00-0.58) were significantly lower in the ND cohort than in the general population. Mortality from brain and other nervous system cancers was significantly higher in the ND cohort (SMR, 3.82; 95% CI, 1.04-9.77). Whereas point estimates were greater for all neurodegenerative causes (SMR, 1.42; 95% CI, 0.29-4.18), amyotrophic lateral sclerosis (SMR, 2.93; 95% CI, 0.36-10.59), and Parkinson disease (SMR, 2.07; 95% CI, 0.05-11.55), the difference did not reach statistical significance. Conclusions and Relevance: In this cohort study of former college football players, both positive and negative health outcomes were observed. With more than 800 000 former college players living in the US, additional research appears to be needed to provide stakeholders with guidance to maximize factors that improve health outcomes and minimize factors that may increase risk for later-life morbidity and mortality.

Association of Unmet Social Needs with Chronic Illness: A Cross-Sectional Study.

Screening for social needs during routine medical visits is increasingly common. To date, there are limited data on which social needs are most predictive of health outcomes. The aim of this study is to build a predictive model from integrated social needs screening and health data to identify individual or clusters of social needs that are predictive of chronic illnesses. Using the electronic medical record data from a Federally Qualified Health Center collected from January 2016 to December 2020, demographic, diagnosis, and social needs screening data were used to look at adjusted and unadjusted associations of individual unmet social needs with chronic illnesses (n = 2497). The least absolute shrinkage and selection operator (LASSO) model was used to identify which social need(s) were associated with overall burden of chronic illness, and individual diagnoses of hypertension, obesity, diabetes, and psychiatric illness. The LASSO model identified age, race, language, gender, insurance, transportation, and food insecurity as significant predictors of any chronic illness. Using these variables in a multivariable model, transportation (adjusted odds ratio [aOR] 1.66) was the only social need that remained significantly associated with chronic illness diagnosis. Transportation need was also significantly associated with diabetes (aOR 1.44) and psychiatric illness (aOR 1.98). Food insecurity was associated with obesity (aOR 10.21). Using LASSO models to identify significant social needs, transportation was identified as a predictor in 3 of the 5 models. Further research is warranted to evaluate if addressing patients' transportation needs has the potential to mitigate chronic disease sequelae for vulnerable adults to advance health equity.

Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts.

BACKGROUND AND OBJECTIVES: Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathologic correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH and repetitive head impact exposure and informant-reported cognitive and daily function were tested. METHODS: This imaging-pathologic correlation study included symptomatic male decedents exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathologic assessments included semiquantitative ratings of white matter rarefaction, cerebrovascular disease, hyperphosphorylated tau (p-tau) severity (CTE stage, dorsolateral frontal cortex), and ß-amyloid (Aß). Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p ≤ 0.05. RESULTS: The sample included 75 donors: 67 football players and 8 nonfootball contact sport athletes or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log TLV was associated with white matter rarefaction (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.03, 5.24; p = 0.04), arteriolosclerosis (OR 2.38, 95% CI 1.02, 5.52; p = 0.04), CTE stage (OR 2.58, 95% CI 1.17, 5.71; p = 0.02), and dorsolateral frontal p-tau severity (OR 3.03, 95% CI 1.32, 6.97; p = 0.01). There was no association with Aß. More years of football play was associated with log TLV (unstandardized ß 0.04, 95% CI 0.01, 0.06; p = 0.01). Greater log TLV correlated with higher FAQ (unstandardized ß 4.94, 95% CI 0.42, 8.57; p = 0.03) and CDS scores (unstandardized ß 15.35, 95% CI -0.27, 30.97; p = 0.05). DISCUSSION: WMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging-pathologic correlation studies are needed. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence of associations between FLAIR white matter hyperintensities and neuropathologic changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.

Mortality following workplace injury: Quantitative bias analysis.

PURPOSE: Recent studies have shown increased all-cause mortality among workers following disabling workplace injury. These studies did not account for 2 potentially important confounders, smoking and obesity. We estimated injury-related mortality accounting for these factors. METHODS: We followed workers receiving New Mexico workers' compensation benefits (1994-2000) through 2013. Using data from the Panel Study of Income Dynamics, we derived the joint distribution of smoking status and obesity for workers with and without lost-time injuries. We conducted a quantitative bias analysis (QBA) to determine the adjusted relationship of injury and mortality. RESULTS: We observed hazard ratios after adjusting for smoking and obesity of 1.13 for women (95% simulation interval (SI) 0.97 to 1.31) and 1.12 for men (95% SI 1.00 to 1.27). The estimated fully adjusted excess hazard was about half the estimates not adjusted for these factors. CONCLUSIONS: Using QBA to adjust for smoking and obesity reduced the estimated mortality hazard from lost-time injuries and widened the simulation interval. The adjusted estimate still showed more than a 10 percent increase for both women and men. The change in estimates reveals the importance of accounting for these confounders. Of course, the results depend on the methods and assumptions used.

CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy.

BACKGROUND: Neuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football. Past work has implicated early and sustained activation of microglia as a potential driver of tau pathology within the frontal cortex in CTE. However, the RHI induced signals required to recruit microglia to areas of damage and pathology are unknown. METHODS: Postmortem brain tissue was obtained from 261 individuals across multiple brain banks. Comparisons were made using cases with CTE, cases with Alzheimer's disease (AD), and cases with no neurodegenerative disease and lacked exposure to RHI (controls). Recruitment of Iba1+ cells around the CTE perivascular lesion was compared to non-lesion vessels. TMEM119 staining was used to characterize microglia or macrophage involvement. The potent chemoattractant CCL2 was analyzed using frozen tissue from the dorsolateral frontal cortex (DLFC) and the calcarine cortex. Finally, the amounts of hyperphosphorylated tau (pTau) and Aß42 were compared to CCL2 levels to examine possible mechanistic pathways. RESULTS: An increase in Iba1+ cells was found around blood vessels with perivascular tau pathology compared to non-affected vessels in individuals with RHI. TMEM119 staining revealed the majority of the Iba1+ cells were microglia. CCL2 protein levels in the DLFC were found to correlate with greater years of playing American football, the density of Iba1+ cells, the density of CD68+ cells, and increased CTE severity. When comparing across multiple brain regions, CCL2 increases were more pronounced in the DLFC than the calcarine cortex in cases with RHI but not in AD. When examining the individual contribution of pathogenic proteins to CCL2 changes, pTau correlated with CCL2, independent of age at death and Aß42 in AD and CTE. Although levels of Aß42 were not correlated with CCL2 in cases with CTE, in males in the AD group, Aß42 trended toward an inverse relationship with CCL2 suggesting possible gender associations. CONCLUSION: Overall, CCL2 is implicated in the pathways recruiting microglia and the development of pTau pathology after exposure to RHI, and may represent a future therapeutic target in CTE.

Revised Framingham Stroke Risk Profile: Association with Cognitive Status and MRI-Derived Volumetric Measures.

BACKGROUND: The Framingham Stroke Risk Profile (FSRP) was created in 1991 to estimate 10-year risk of stroke. It was revised in 2017 (rFSRP) to reflect the modern data on vascular risk factors and stroke risk. OBJECTIVE: This study examined the association between the rFSRP and cognitive and brain aging outcomes among participants from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS). METHODS: Cross-sectional rFSRP was computed at baseline for 19,309 participants (mean age = 72.84, SD = 8.48) from the NACC-UDS [9,697 (50.2%) normal cognition, 4,705 (24.4%) MCI, 4,907 (25.4%) dementia]. Multivariable linear, logistic, or ordinal regressions examined the association between the rFSRP and diagnostic status, neuropsychological test performance, CDR® Sum of Boxes, as well as total brain volume (TBV), hippocampal volume (HCV), and log-transformed white matter hyperintensities (WMH) for an MRI subset (n = 1,196). Models controlled for age, sex, education, racial identity, APOEɛ4 status, and estimated intracranial volume for MRI models. RESULTS: The mean rFSRP probability was 10.42% (min = 0.50%, max = 95.71%). Higher rFSRP scores corresponded to greater CDR Sum of Boxes (ß= 0.02, p = 0.028) and worse performance on: Trail Making Test A (ß= 0.05, p < 0.001) and B (ß= 0.057, p < 0.001), and Digit Symbol (ß= -0.058, p < 0.001). Higher rFSRP scores were associated with increased odds for a greater volume of log-transformed WMH (OR = 1.02 per quartile, p = 0.015). No associations were observed for diagnosis, episodic memory or language test scores, HCV, or TBV. CONCLUSION: These results support the rFSRP as a useful metric to facilitate clinical research on the associations between cerebrovascular disease and cognitive and brain aging.

Temporal trends in pharmacologic prophylaxis for venous thromboembolism after hip and knee replacement in older adults.

Trends in prescription for venous thromboembolism (VTE) prophylaxis following total hip (THR) and knee replacement (TKR) since the approval of direct oral anticoagulants (DOACs) and the 2012 guideline endorsement of aspirin are unknown, as are the risks of adverse events. We examined practice patterns in the prescription of prophylaxis agents and the risk of adverse events during the in-hospital period (the 'in-hospital sample') and 90 days following discharge (the 'discharge sample') among adults aged ⩾ 65 undergoing THR and TKR in community hospitals in the Institute for Health Metrics database over a 30-month period during 2011 to 2013. Eligible medications included fondaparinux, DOACs, low molecular weight heparin (LMWH), other heparin products, warfarin, and aspirin. Outcomes were validated by physician review of source documents: VTE, major hemorrhage, cardiovascular events, and death. The in-hospital and the discharge samples included 10,503 and 5722 adults from 65 hospitals nationwide, respectively (mean age 73, 74 years; 61%, 63% women). Pharmacologic prophylaxis was near universal during the in-hospital period (93%) and at discharge (99%). DOAC use increased substantially and was the prophylaxis of choice for nearly a quarter (in-hospital) and a third (discharge) of the patients. Aspirin was the sole discharge prophylactic agent for 17% and 19% of patients undergoing THR and TKR, respectively. Warfarin remained the prophylaxis agent of choice for patients aged 80 years and older. The overall risk of adverse events was low, at less than 1% for both the in-hospital and discharge outcomes. The low number of adverse events precluded statistical comparison of prophylaxis regimens.

The Association of Primary Language With Emergency General Surgery Outcomes Using a Statewide Database.

BACKGROUND: Emergency general surgery (EGS) represents a diverse set of operations performed on acutely ill patients. Those undergoing EGS are at higher likelihood of complications, readmission, and death, but the effect of primary language on EGS outcomes has not been evaluated. We aimed to evaluate the association of non-English primary language on outcomes after EGS operations. METHODS: The New Jersey Statewide Inpatient Database from 2009 to 2014 was used to evaluate cases representing 80% of the national burden of EGS. Cases were restricted to ages ≥18 y, emergency department admissions, noted to be emergent or urgent, and performed between 0 and 2 d after admission. We evaluated Spanish speakers and non-English, non-Spanish (NENS) speakers compared with English. Outcomes included in-hospital mortality, 7-d readmission, and hospital length of stay (LOS). Logistic and negative binomial regression was used, and generalized linear mixed models were used to account for hierarchy in the data. RESULTS: There were 105,171 patients included. English speakers were majority white and with private insurance; Spanish speakers were younger and with fewer comorbidities. Where differences between Spanish and NENS speakers existed, NENS were more like the English-speaking group. Adjusted results indicate that Spanish speakers had reduced LOS after appendectomy (IRR: 0.92 [0.89-0.95]) and lysis of adhesion [0.93 (0.88-0.97)]. Spanish speakers had an increased LOS after higher risk operations (IRR: 1.14 [1.10-1.20]). NENS speakers had a reduced LOS after adhesiolysis (IRR: 0.94 [0.89-0.99]). There was no difference in mortality or short-term readmission CONCLUSIONS: These data from a large database suggest that the effect of primary language on LOS after EGS depends on the type of operation. Future studies should focus on long-term outcomes and determining if the lack of association we observed is generalizable to other regions of the United States.

Correction to: Association of Primary Language with Outcomes After Operations Typically Performed to Treat Cancer: Analysis of a Statewide Database.

In the original article, there were errors in Table 1 that were not in accordance with requirements set by the Healthcare Cost and Utilization Project (HCUP) Data Use Agreement that apply to this article. Following is the corrected Table 1.

Association of Primary Language with Outcomes After Operations Typically Performed to Treat Cancer: Analysis of a Statewide Database.

BACKGROUND: Few studies have evaluated the effect of primary language on surgical outcomes, and no studies have addressed operations typically performed for cancer diagnoses. This study aimed to determine the effect of primary languages other than English on outcomes after surgical oncology operations. METHODS: This study retrospectively analyzed adults undergoing operations typically performed to treat cancer using the NJ Healthcare Cost and Utilization Project State Inpatient Database during the interval of 2009-2014. Language was grouped according to English-, Spanish-, and non-English/non-Spanish (NENS)-speaking groups. The study evaluated in-hospital mortality, 7-day readmission, and hospital length of stay (LOS). Logistic and negative binomial regression methods were applied, and generalized linear mixed models were used to account for nesting within a hospital. RESULTS: This study analyzed 37,531 cases. Non-English speakers were of lower economic status, more likely to be admitted on the weekend, and more likely to undergo higher-risk operations. The likelihood of death in the risk-adjusted multi-level models did not differ between Spanish speakers (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.41-1.10) and NENS speakers (OR, 1.16; 95% CI, 0.77-1.75). Readmission rates exhibited high inter-hospital variability (intra-class correlation, 53%). The odds of readmission among Spanish speakers in the non-hierarchical model was increased (OR, 1.50; 95% CI, 1.11-2.02), but this was ameliorated in the multilevel modeling that accounted for variability between hospitals (OR, 1.29; 95% CI, 0.93-1.80). No changes in LOS were observed. CONCLUSIONS: No independent association was observed between primary language and outcomes after operations typically performed to treat cancer in the study population. The higher proportion of weekend admissions may suggest more acute or advanced presentations for non-English speakers. Long-term outcomes may be necessary to discern an impact.

Prevalence and Risk Factors for CKD Among Brickmaking Workers in La Paz Centro, Nicaragua.

RATIONALE & OBJECTIVE: In Central America, there is a high prevalence of chronic kidney disease (CKD) of nontraditional etiology often observed among agricultural workers. Few studies have assessed CKD prevalence among workers in nonagricultural occupations, which was the objective of this investigation. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Male and female workers (n = 224) employed by artisanal brickmaking facilities in La Paz Centro, Nicaragua. PREDICTORS: Age, sex, education, smoking status, body mass index, alcohol consumption, water consumption, first-degree relative(s) with CKD, years worked, hours worked per week, job category, study visit (baseline and follow-up), and self-reported hypertension and diabetes. OUTCOMES: CKD defined as estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m2 at 2 time points 4 months apart and CKD stage. ANALYTICAL APPROACH: A linear mixed-effects model with an unstructured covariance matrix was used to evaluate the association between demographics, occupational risk factors, and eGFR at baseline. The interaction between risk factors and time with change in eGFR was also evaluated. Multivariable logistic regression models were used to evaluate predictors of CKD. RESULTS: The CKD prevalence was 12.1% (n = 27), 100% of cases were male, 30% had stage 5 CKD (eGFR < 15mL/min/1.73m2), and 22% were younger than 35 years. Proportions of participants with eGFRs < 60mL/min/1.73m2 at baseline and follow-up were 13.8% and 15.2%, respectively. Linear regression analysis demonstrated significant predictors of lower kidney function at baseline including oven work, older age, lack of education, and having an immediate family member with CKD. Predictors of CKD identified using logistic regression analysis included oven work and lack of education. LIMITATIONS: Crude job classification measures, loss to follow-up, self-reported exposures. CONCLUSIONS: The prevalence of CKD is high in this population of brick workers, suggesting that the epidemic of CKD affecting Mesoamerica is not limited to agricultural workers. These results are consistent with the hypothesis that occupational heat exposure is a risk factor for kidney disease in this region.

A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology.

BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer's disease. Clinicopathological studies are needed to elucidate and confirm this possibility. OBJECTIVE: This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer's disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP. METHODS: The sample included 82 participants from the National Alzheimer's Coordinating Center's Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. RESULTS: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP-participants (ps < 0.04). CONCLUSIONS: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer's disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

Dioxins and related environmental contaminants increase TDP-43 levels.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition that is characterized by progressive loss of motor neurons and the accumulation of aggregated TAR DNA Binding Protein-43 (TDP-43, gene: TARDBP). Increasing evidence indicates that environmental factors contribute to the risk of ALS. Dioxins, related planar polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) are environmental contaminants that activate the aryl hydrocarbon receptor (AHR), a ligand-activated, PAS family transcription factor. Recently, exposure to these toxicants was identified as a risk factor for ALS. METHODS: We examined levels of TDP-43 reporter activity, transcript and protein. Quantification was done using cell lines, induced pluripotent stem cells (iPSCs) and mouse brain. The target samples were treated with AHR agonists, including 6-Formylindolo[3,2-b]carbazole (FICZ, a potential endogenous ligand, 2,3,7,8-tetrachlorodibenzo(p)dioxin, and benzo(a)pyrene, an abundant carcinogen in cigarette smoke). The action of the agonists was inhibited by concomitant addition of AHR antagonists or by AHR-specific shRNA. RESULTS: We now report that AHR agonists induce up to a 3-fold increase in TDP-43 protein in human neuronal cell lines (BE-M17 cells), motor neuron differentiated iPSCs, and in murine brain. Chronic treatment with AHR agonists elicits over 2-fold accumulation of soluble and insoluble TDP-43, primarily because of reduced TDP-43 catabolism. AHR antagonists or AHR knockdown inhibits agonist-induced increases in TDP-43 protein and TARDBP transcription demonstrating that the ligands act through the AHR. CONCLUSIONS: These results provide the first evidence that environmental AHR ligands increase TDP-43, which is the principle pathological protein associated with ALS. These results suggest novel molecular mechanisms through which a variety of prevalent environmental factors might directly contribute to ALS. The widespread distribution of dioxins, PCBs and PAHs is considered to be a risk factor for cancer and autoimmune diseases, but could also be a significant public health concern for ALS.

Recruitment of breast cancer survivors and their caregivers: implications for dyad research and practice.

Breast cancer survivors' informal caregivers experience adverse health outcomes and could benefit from interventions. Studies of caregivers' participation in research, to date, have assumed heterosexuality. The aim of this study is to identify factors associated with caregiver participation among survivors with diversity in sexual orientation. We recruited breast cancer survivors into a telephone survey and asked them to invite a caregiver. Logistic regression identified factors associated with caregivers' participation. Among 297 survivors, 12 (4 %) had no caregivers, 82 (28 %) refused to provide caregiver information, 203 (68 %) provided caregiver contact, and 167 (56 %) had caregivers participate. Caregiver participation was more likely among sexual minority than heterosexual survivors (aOR: 1.89; 95 % CI: 1.08, 3.32), dyads with higher cohesion, and among caregivers who were partners. Caregiver participation was less likely among survivors with lower education and higher comorbidity. Findings provide insight into recruitment of diverse dyads into cancer survivorship research that will ultimately inform intervention design.

Fear of cancer recurrence in survivor and caregiver dyads: differences by sexual orientation and how dyad members influence each other.

PURPOSE: The purpose of this study was to identify explanatory factors of fear of recurrence (FOR) in breast cancer survivors of different sexual orientations and their caregivers and to assess the directionality in the survivor and caregiver dyads' FOR. METHODS: We recruited survivors of non-metastatic breast cancer of different sexual orientations and invited their caregivers into this study. Using a telephone survey, we collected data from 167 survivor and caregiver dyads. Using simultaneous equation models and a stepwise selection process, we identified the significant determinants of survivors' and caregivers' FOR and determined the directionality of survivors' and caregivers' FOR. Weighting the model by the inverse propensity score ensured that differences by sexual orientation in age and proportion of life in the caregiver-survivor relationship were accounted for. RESULTS: Caregivers' FOR predicted survivors' FOR, and sexual orientation had a significant effect on survivors' FOR, in that sexual minority women reported less FOR than heterosexual women. Other determinants of survivors' FOR included their medical characteristics, coresidence with caregivers, and caregivers' social support and use of counseling. Caregivers' FOR was related to their social support and survivors' medical characteristics. CONCLUSIONS: This study suggests a need for caregiver interventions. Because survivors' FOR is affected by caregivers' FOR, caregiver interventions will likely benefit survivors' FOR. IMPLICATIONS FOR CANCER SURVIVORS: Both sexual minority and heterosexual breast cancer survivors' FOR are affected by their caregivers' FOR, which suggests that the caregivers of breast cancer survivors are central for the survivors' well-being and shall therefore be integrated into the care process.

Prevention of Postoperative Venous Thromboembolism in Thoracic Surgical Patients: Implementation and Evaluation of a Caprini Risk Assessment Protocol.

BACKGROUND: Venous thromboembolism (VTE) can be a devastating postoperative complication, with about one-third of VTEs occurring post-discharge. We previously retrospectively evaluated the Caprini VTE risk assessment model (RAM) in postoperative lung and esophageal cancer patients, demonstrating that "high risk" patients were more likely to have a postoperative VTE. In this study, we sought to implement the RAM protocol in thoracic surgical patients to evaluate adherence, safety, and VTE outcomes. STUDY DESIGN: This prospective cohort study at a large safety net hospital included all surgically treated patients within the thoracic surgery division beginning in July 2014. Per RAM protocol, patients with high risk scores were prescribed a total of 30 days of postoperative daily enoxaparin prophylaxis, and moderate risk patients received a total of 10 postoperative days. Adherence and outcome audits were conducted. RESULTS: A total of 126 patients were included for analysis. Provider adherence to RAM score calculation was 99.2% (125 of 126), with appropriate post-discharge prophylaxis prescribed in 96.0% of cases. Twenty-four patients scored high risk (19.2%), 60 were moderate risk (48.0%), and 41 scored low risk (32.8%). Patient adherence to post-discharge enoxaparin prophylaxis was 97.2%. The overall VTE rate was 2.3%, with no post-discharge VTEs or adverse bleeding events. CONCLUSIONS: Implementation of a VTE risk assessment protocol with extended course prophylaxis in high risk patients is safe and feasible for providers and thoracic surgical patients at a large safety net institution with a diverse patient population. Follow-up studies are needed to assess efficacy of the RAM in this surgical population.

Evaluation of the Caprini Model for Venothromboembolism in Esophagectomy Patients.

BACKGROUND: Patients undergoing esophagectomy for cancer are in the highest-risk group for venous thromboembolism, with a 7.3% incidence reported by the National Surgical Quality Improvement Program. Venothromboembolism (VTE) doubles esophagectomy mortality. The Caprini risk assessment model (RAM) is a method to stratify postoperative thromboembolism risk for consideration of prolonged preventive anticoagulation in higher-risk patients. Our aim was to examine the potential use of this model for reducing the VTE incidence in esophagectomy patients. METHODS: The records of patients who underwent an esophagectomy by the thoracic surgery service at our institution between June 2005 and June 2013 were reviewed. The inclusion criteria were a diagnosis of esophageal cancer treated with esophagectomy (any approach) and with available 60-day postoperative follow-up. Exclusion criteria were the presence of an inferior vena cava filter or chronic anticoagulation therapy. The Caprini risk score and the number of VTE events were recorded retrospectively for each patient. RESULTS: Seventy patients satisfied eligibility criteria. The VTE incidence was 14.3%. Patients with esophageal thromboembolism had a higher Caprini score distribution than patients without thromboembolism (p < 0.001). Adjusted logistic regression analysis demonstrated increased odds of VTE with increasing score (p < 0.05), with good discrimination. CONCLUSIONS: In this first report examining the Caprini model categories in an esophagectomy population, the VTE incidence in true high-risk patients was high. From this retrospective calculation of risk and events, patients in the highest-risk Caprini group may benefit from an enhanced course of postoperative anticoagulation.