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.

Putting the Heme Back in Heme-Onc: an Evaluation of the Redesigned Hematology Track within the Dana Farber/Mass General Brigham Hematology-Oncology Fellowship.

In 2019, the Dana Farber/Mass General Brigham Hematology-Oncology Fellowship redesigned the 6-month Hematology training track/curriculum required for all fellows seeking to double board in hematology and oncology. Responding to both national and local trends suggesting a future shortage of hematologists, the goal of the redesign was to create a new curriculum that would increase fellow interest in hematology, improve fellows' clinical knowledge of hematology, and serve as an example to other Hematology-Oncology programs across the country. The revised track has now been in place for four years, and, in this paper, the authors present the fellow experience with the first four years of the redesigned curriculum. Based on the number of fellows who chose to complete the new curriculum, as well as the fellow evaluations and performance on the Hematology In-Training Exam, the authors conclude that the new curriculum has successfully increased both fellow interest in and knowledge of hematology.

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.

Resident-Reported Impact of a Novel Oncology Curriculum for Internal Medicine Residents.

The Accreditation Council of Graduate Medical Education mandates that all internal medicine residents gain exposure to internal medicine subspecialties including hematology and oncology. While many residents meet this criterion through inpatient oncology rotations, the current structure of many inpatient oncology rotations leaves little opportunity for formal education. We therefore designed a novel oncology curriculum consisting of one-page oncology teaching sheets to increase the number, breadth, and quality of formal teaching sessions on our resident inpatient oncology services. In order to evaluate the curriculum, we conducted pre- and post-intervention surveys of residents. From these surveys, we found that 72.2% of residents used the teaching sheets on their inpatient oncology rotation and that the teaching sheets led to an increase in the number of formal oncology teaching sessions (mean 3.4 ± 2.1 post-implementation vs 2.6 ± 2.0 pre-implementation, p = 0.008), the breadth of oncology topics taught (% reporting ≥ 5 topics; 26.1% vs 16.3%, p = 0.035), the proportion of residents reporting improvement in overall oncology knowledge (80.2% vs 62.4%, p = 0.012), and the proportion of residents reporting improvement in their ability to care for patients (70.8% vs 48.9%, p = 0.013). These results demonstrate that formal oncology teaching can be improved on inpatient oncology rotations through a simple and easily replicable oncology curriculum.

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.

Dana-Farber Cancer Institute/Mass General Brigham Fellowship Response to the COVID-19 Pandemic.

The coronavirus disease (COVID)-19 pandemic has affected graduate medical education training programs, including hematology-oncology fellowship programs, both across the United States and abroad. Within the Dana-Farber Cancer Institute/Mass General Brigham hematology-oncology fellowship program, fellowship leadership had to quickly reorganize the program's clinical, educational, and research structure to minimize the risk of COVID-19 spread to our patients and staff, allow fellows to assist in the care of patients with COVID-19, maintain formal didactics despite physical distancing, and ensure the mental and physical well-being of fellows. Following the first wave of patients with COVID-19, we anonymously surveyed the Dana-Farber Cancer Institute/Mass General Brigham first-year fellows to explore their perceptions regarding what the program did well and what could have been improved in the COVID-19 response. In this article, we present the feedback from our fellows and the lessons we learned as a program from this feedback. To our knowledge, this represents the first effort in the hematology-oncology literature to directly assess a hematology-oncology program's overall response to COVID-19 through direct feedback from fellows.

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.

Targeting the mTOR pathway in idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic illness of systemic inflammation and organ dysfunction, with unknown etiology. Although therapies targeting IL-6 have been proven effective, a subset of patients with iMCD are resistant to this approach. In this issue of the JCI, Fajgenbaum et al. performed an in-depth analysis of serum inflammatory markers in three iMCD patients refractory to IL-6 blockade, and identified activation of the mTOR pathway associated with symptom flares. Treatment with sirolimus, an mTOR inhibitor, induced remission in all three patients. This study models a precision medicine approach to discovering therapies for rare diseases.

Sleep disturbance and neurocognitive outcomes in older patients with breast cancer: Interaction with genotype.

BACKGROUND: Sleep disturbance and genetic profile are risks for cognitive decline in noncancer populations, yet their role in cancer-related cognitive problems remains understudied. This study examined whether sleep disturbance was associated with worse neurocognitive outcomes in breast cancer survivors and whether sleep effects on cognition varied by genotype. METHODS: Newly diagnosed female patients (n = 319) who were 60 years old or older and had stage 0 to III breast cancer were recruited from August 2010 to December 2015. Assessments were performed before systemic therapy and 12 and 24 months later. Neuropsychological testing measured attention, processing speed, executive function, learning, and memory; self-perceived cognitive functioning was also assessed. Sleep disturbance was defined by self-report of routine poor or restless sleep. Genotyping included APOE, BDNF, and COMT polymorphisms. Random effects fluctuation models tested associations of between-person and within-person differences in sleep, genotype, and sleep-genotype interactions and cognition and controlled for age, reading level, race, site, and treatment. RESULTS: One-third of the patients reported sleep disturbances at each time point. There was a sleep-APOE ε4 interaction (P = .001) in which patients with the APOE ε4 allele and sleep disturbances had significantly lower learning and memory scores than those who were APOE ε4-negative and without sleep disturbances. There was also a sleep disturbance-COMT genotype interaction (P = .02) in which COMT Val carriers with sleep disturbances had lower perceived cognition than noncarriers. CONCLUSIONS: Sleep disturbance was common and was associated with worse cognitive performance in older breast cancer survivors, especially those with a genetic risk for cognitive decline. Survivorship care should include sleep assessments and interventions to address sleep problems.

Reduced-Intensity Conditioning Regimens, Prior Chronic Lymphocytic Leukemia, and Graft-Versus-Host Disease Are Associated with Higher Rates of Skin Cancer after Allogeneic Hematopoietic Stem Cell Transplantation.

To assess incidence and risk factors for skin cancer associated with allogeneic hematopoietic stem cell transplantation, we evaluated 1,974 adult allogeneic hematopoietic stem cell transplantation patients from Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute who received transplants between January 1995 and July 2013 for hematologic malignancy and survived at least 100 days. Median age was 51.1 years, and median follow-up time was 3 years. Overall, 119 patients had 221 skin cancers. The incidences of squamous cell carcinomas (incidence rate ratio = 9.8; 95% confidence interval = 7.7-12.3), basal cell carcinomas (incidence rate ratio = 2.5; 95% confidence interval = 1.9-3.2), and melanoma (standardized incidence ratio = 3.3; 95% confidence interval = 1.7-5.9) were elevated in our cohort. In multivariable models, risk factors for squamous cell carcinomas were increased age (P < 0.0001), chronic lymphocytic leukemia (P = 0.02), and chronic graft-versus-host disease (P = 0.0002). Risk factors for basal cell carcinomas were chronic lymphocytic leukemia (P = 0.003), reduced-intensity conditioning (P = 0.02), acute graft-versus-host disease (P = 0.03), and chronic graft-versus-host disease (P = 0.003). To our knowledge, previously unreported risk factors in this contemporary cohort include prior CLL for squamous cell carcinoma and basal cell carcinoma and reduced-intensity conditioning for basal cell carcinoma. This study also supports chronic graft-versus-host disease as a risk factor for nonmelanoma skin cancer, particularly squamous cell carcinoma.

Local radiation and phototherapy are the most cost-effective treatments for stage IA mycosis fungoides: A comparative decision analysis model in the United States.

BACKGROUND: Treatments for early-stage mycosis fungoides (MF) include topical steroids, topical nitrogen mustard, topical bexarotene, narrowband ultraviolet B (NBUVB), psoralen plus ultraviolet A (PUVA), and local radiation. The relative cost-effectiveness of each treatment given the differences in treatment failure, disease progression, and therapy escalation is not established. OBJECTIVE: To compare the cost-effectiveness (CE) of treatment options for stage IA MF. METHODS: A state-transition model was constructed with health states of stage IA to stage IV disease, no MF, and death. Treatment-specific remission and relapse rates were obtained from the literature. Lifetime costs were calculated by accounting for medications, office visits, laboratory monitoring, related procedures, work absences, and travel. RESULTS: The order of CE of the study treatments was determined to be as follows: local radiation, $225,399 for 15.40 life-years (LYs); NBUVB, $344,728 for 15.17 LYs; PUVA, $371,741 for 15.07 LYs; topical corticosteroids, $469,354 for 14.65 LYs; topical nitrogen mustard, $951,662 for 14.29 LYs; and topical bexarotene, 11,892,496 for 13.55 LYs. Sensitivity analyses confirmed the CE rankings. LIMITATIONS: We assumed a constant probability of response, relapse rates, and 3-month treatment intervals. CONCLUSIONS: Local radiation is the most cost-effective treatment for limited local disease, whereas phototherapy (NBUVB or PUVA) is cost-effective for generalized disease. Our findings can serve to inform future studies and recommendations regarding selection of therapy for stage IA MF.

Cancer-Related Cognitive Outcomes Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study.

PURPOSE: To determine treatment and aging-related effects on longitudinal cognitive function in older breast cancer survivors. METHODS: Newly diagnosed nonmetastatic breast cancer survivors (n = 344) and matched controls without cancer (n = 347) 60 years of age and older without dementia or neurologic disease were recruited between August 2010 and December 2015. Data collection occurred during presystemic treatment/control enrollment and at 12 and 24 months through biospecimens; surveys; self-reported Functional Assessment of Cancer Therapy-Cognitive Function; and neuropsychological tests that measured attention, processing speed, and executive function (APE) and learning and memory (LM). Linear mixed-effects models tested two-way interactions of treatment group (control, chemotherapy with or without hormonal therapy, and hormonal therapy) and time and explored three-way interactions of ApoE (ε4+ v not) by group by time; covariates included baseline age, frailty, race, and cognitive reserve. RESULTS: Survivors and controls were 60 to 98 years of age, were well educated, and had similar baseline cognitive scores. Treatment was related to longitudinal cognition scores, with survivors who received chemotherapy having increasingly worse APE scores ( P = .05) and those initiating hormonal therapy having lower LM scores at 12 months ( P = .03) than other groups. These group-by-time differences varied by ApoE genotype, where only ε4+ survivors receiving hormone therapy had short-term decreases in adjusted LM scores (three-way interaction P = .03). For APE, the three-way interaction was not significant ( P = .14), but scores were significantly lower for ε4+ survivors exposed to chemotherapy (-0.40; 95% CI, -0.79 to -0.01) at 24 months than ε4+ controls (0.01; 95% CI, 0.16 to 0.18; P < .05). Increasing age was associated with lower baseline scores on all cognitive measures ( P < .001); frailty was associated with baseline APE and self-reported decline ( P < .001). CONCLUSION: Breast cancer systemic treatment and aging-related phenotypes and genotypes are associated with longitudinal decreases in cognitive function scores in older survivors. These data could inform treatment decision making and survivorship care planning.

Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3.

Gastrointestinal dysfunction in cystic fibrosis (CF) is a prominent source of pain among patients with CF. Linaclotide, a guanylate cyclase C (GCC) receptor agonist, is a US Food and Drug Administration-approved drug prescribed for chronic constipation but has not been widely used in CF, as the cystic fibrosis transmembrane conductance regulator (CFTR) is the main mechanism of action. However, anecdotal clinical evidence suggests that linaclotide may be effective for treating some gastrointestinal symptoms in CF. The goal of this study was to determine the effectiveness and mechanism of linaclotide in treating CF gastrointestinal disorders using CF mouse models. Intestinal transit, chloride secretion, and intestinal lumen fluidity were assessed in wild-type and CF mouse models in response to linaclotide. CFTR and sodium/hydrogen exchanger 3 (NHE3) response to linaclotide was also evaluated. Linaclotide treatment improved intestinal transit in mice carrying either F508del or null Cftr mutations but did not induce detectable Cl- secretion. Linaclotide increased fluid retention and fluidity of CF intestinal contents, suggesting inhibition of fluid absorption. Targeted inhibition of sodium absorption by the NHE3 inhibitor tenapanor produced improvements in gastrointestinal transit similar to those produced by linaclotide treatment, suggesting that inhibition of fluid absorption by linaclotide contributes to improved gastrointestinal transit in CF. Our results demonstrate that linaclotide improves gastrointestinal transit in CF mouse models by increasing luminal fluidity through inhibiting NHE3-mediated sodium absorption. Further studies are necessary to assess whether linaclotide could improve CF intestinal pathologies in patients. GCC signaling and NHE3 inhibition may be therapeutic targets for CF intestinal manifestations. NEW & NOTEWORTHY Linaclotide's primary mechanism of action in alleviating chronic constipation is through cystic fibrosis transmembrane conductance regulator (CFTR), negating its use in patients with cystic fibrosis (CF). For the first time, our findings suggest that in the absence of CFTR, linaclotide can improve fluidity of the intestinal lumen through the inhibition of sodium/hydrogen exchanger 3. These findings suggest that linaclotide could improve CF intestinal pathologies in patients.

Higher exosomal tau, amyloid-beta 42 and IL-10 are associated with mild TBIs and chronic symptoms in military personnel.

OBJECTIVE: Identify biomarkers in peripheral blood that relate to chronic post-concussive and behavioural symptoms following traumatic brain injuries (TBIs) to ultimately improve clinical management. RESEARCH DESIGN: We compared military personnel with mild TBIs (mTBIs) (n = 42) to those without TBIs (n = 22) in concentrations of tau, amyloid-beta (Aß42) and cytokines (tumour necrosis factor alpha (TNFα, interleukin (IL)-6 and -10) in neuronal-derived exosomes from the peripheral blood. We utilized nanosight technology coupled with ultra-sensitivity immunoassay methods. We also examined the impact of post-concussive and behavioural symptoms including depression and post-traumatic stress disorder (PTSD) on these neuronal-derived markers. RESULTS: We report that concentrations of exosomal tau (F1, 62 = 10.50), Aß42 (F1, 61 = 5.32) and IL-10 (F1, 59 = 4.32) were elevated in the mTBI group compared to the controls. Within the mTBI group, regression models show that post-concussive symptoms were most related to exosomal tau elevations, whereas exosomal IL-10 levels were related to PTSD symptoms. CONCLUSIONS: These findings suggest that chronic post-concussive symptoms following an mTBI relate to altered exosomal activity, and that greater tau pathology may underlie chronic post-concussive symptoms that develop following mTBIs. It also suggests that central inflammatory activity contributes to PTSD symptoms following an mTBI, providing necessary insights into the role of inflammation in chronic PTSD symptoms.

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.

The fasciacytes: A new cell devoted to fascial gliding regulation.

Hyaluronan occurs between deep fascia and muscle, facilitating gliding between these two structures, and also within the loose connective tissue of the fascia, guaranteeing the smooth sliding of adjacent fibrous fascial layers. It also promotes the functions of the deep fascia. In this study a new class of cells in fasciae is identified, which we have termed fasciacytes, devoted to producing the hyaluronan-rich extracellular matrix. Synthesis of the hyaluronan-rich matrix by these new cells was demonstrated by Alcian Blue staining, anti-HABP (hyaluronic acid binding protein) immunohistochemistry, and transmission electron microscopy. Expression of HAS2 (hyaluronan synthase 2) mRNA by these cells was detected and quantified using real time RT-PCR. This new cell type has some features similar to fibroblasts: they are positive for the fibroblast marker vimentin and negative for CD68, a marker for the monocyte-macrophage lineage. However, they have morphological features distinct from classical fibroblasts and they express the marker for chondroid metaplasia, S-100A4. The authors suggest that these cells represent a new cell type devoted to the production of hyaluronan. Since hyaluronan is essential for fascial gliding, regulation of these cells could affect the functions of fasciae so they could be implicated in myofascial pain. Clin. Anat. 31:667-676, 2018. © 2018 Wiley Periodicals, Inc.

The Impact of Using Different Reference Populations on Measurement of Breast Cancer-Related Cognitive Impairment Rates.

OBJECTIVE: To evaluate how use of different reference populations affects estimates of breast cancer-related cognitive impairment rates. METHODS: Patients aged ≥60 years with stage 0-3 breast cancer (n = 371) and matched non-cancer controls (n = 370) completed 13 neuropsychological tests prior to systemic therapy or at enrollment (controls). The tests captured three domains: attention, processing speed and executive function; learning and memory; and visual-spatial function. Domain-specific impairment was defined as having one test score 2 SD below or two or more test scores 1.5 SD below the reference population means. Different reference populations were used to define impairment: published normative data, study-specific controls, age and education-stratified controls, and age and education-adjusted controls. The associations between the resultant impairment rates and breast cancer (vs. control) were evaluated using chi-square tests and logistic regression models. Cohen's kappa coefficients were used to evaluate agreement of impairment rates between study-specific control performance and the other reference population groups. RESULTS: The patients and controls were aged 68.0 (SD 6.0) and 67.9 (SD 7.0) years, respectively. The association of breast cancer-control status with impairment did not differ based on reference group. Cognitive impairment based on published normative data yielded less agreement on impairment rates (κ = 0.22-0.89) than study-specific age and education-stratified control performance (κ = 0.62-1.00). CONCLUSION: The choice of reference populations did not affect conclusions about the association of cognition with breast cancer. However, while study-specific reference populations provided greater internal consistency in defining cognitive impairment, benchmarking against published normative data will enhance the ability to compare results across studies.

Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer's Disease.

Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer's disease (AD) biomarkers in the blood of AD mouse models and AD patients. The aim of this study was to examine whether a pramlintide challenge combined with a phosphatidylcholine (PC) profile diagnoses of AD and mild cognitive impairment (MCI) better than PC alone. Non-diabetic subjects with cognitive status were administered a single subcutaneous injection of 60 mcg of pramlintide under fasting condition. A total of 71 PCs, amyloid-ß peptide (Aß), and total tau (t-tau) in plasma at different time points were measured and treated as individual variables. A single injection of pramlintide altered the levels of 7 PCs in the blood, while a pramlintide injection plus food modulated the levels of 10 PCs in the blood (p < 0.05). The levels of 2 PCs in MCI and 12 PCs in AD in the pramlintide challenge were significantly lower than the ones in controls. We found that while some PCs were associated with only Aß levels, other PCs were associated with both Aß and t-tau levels. A receiver operating characteristic analysis of the PCs was combined with the Aß and t-tau data to produce an area under the curve predictive value of 0.9799 between MCI subjects and controls, 0.9794 between AD subjects and controls, and 0.9490 between AD and MCI subjects. A combination of AD biomarkers and a group of PCs post a pramlintide challenge may provide a valuable diagnostic and prognostic test for AD and MCI.

Risk of serious infections, cutaneous bacterial infections, and granulomatous infections in patients with psoriasis treated with anti-tumor necrosis factor agents versus classic therapies: Prospective meta-analysis of Psonet registries.

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy in psoriasis has been associated with an increased risk of serious infections compared with nonbiologic systemic therapies. OBJECTIVE: We sought to quantify the risk of: (1) serious infections (leading to hospitalization, sequelae, or death); and (2) "any infection," bacterial cutaneous infections, and granulomatous infections among patients receiving anti-TNF therapy compared with nonbiologics (acitretin, methotrexate, cyclosporine). METHODS: We used prospective meta-analysis to combine data from the Psocare registry (Italy), Biobadaderm registry (Spain), and Clalit Health Services database (Israel), including 17,739 patients and 23,357.5 person-years of follow-up. RESULTS: For serious infections, age, gender, and Charlson morbidity index adjusted hazard ratio of exposure to anti-TNFs compared with nonbiologics was 0.98 (95% confidence interval 0.80-1.19), for bacterial cutaneous infections it was 1.00 (95% confidence interval 0.62-1.61), and for granulomatous infections it was 1.23 (95% confidence interval 0.82-1.84). Using methotrexate as comparator and comparing first year of exposure with later exposure did not modify the results. For any infectious episode, risks and relative risks were heterogeneous among registries, probably because of different definitions of outcome. LIMITATIONS: There was lack of power to describe risk of single drugs. CONCLUSION: In current clinical practice, treatment with anti-TNF drugs was not associated with a higher risk of serious infections than treatment with nonbiologic systemic therapy.

Long-term trajectories of self-reported cognitive function in a cohort of older survivors of breast cancer: CALGB 369901 (Alliance).

BACKGROUND: The number of survivors of breast cancer aged ≥65 years ("older") is growing, but to the authors' knowledge, little is known regarding the cognitive outcomes of these individuals. METHODS: A cohort of cognitively intact older survivors with nonmetastatic, invasive breast cancer was recruited from 78 sites from 2004 through 2011; approximately 83.7% of the survivors (1280 survivors) completed baseline assessments. Follow-up data were collected at 6 months and annually for up to 7 years (median, 4.1 years). Cognitive function was self-reported using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30); scores ranged from 0 to 100, with a higher score indicating better function. Group-based trajectory modeling determined trajectories; women were assigned to a trajectory group based on the highest predicted probability of membership. Multinomial logistic regression evaluated the association between receipt of chemotherapy (with or without hormonal treatment) and trajectory group. RESULTS: Survivors were aged 65 to 91 years; approximately 41% received chemotherapy. There were 3 cognitive trajectories: "maintained high" (42.3% of survivors); "phase shift" (50.1% of survivors), with scores slightly below but parallel to maintained high; and "accelerated decline" (7.6% of survivors), with the lowest baseline scores and greatest decline (from 71.7 [standard deviation, 19.8] to 58.3 [standard deviation, 21.9]). The adjusted odds of being in the accelerated decline group (vs the maintained high group) were 2.1 times higher (95% confidence interval, 1.3-3.5) for survivors who received chemotherapy (with or without hormonal therapy) versus those treated with hormonal therapy alone. Greater comorbidity and frailty also were found to be associated with accelerated decline. CONCLUSIONS: Trajectory group analysis demonstrated that the majority of older survivors maintained good long-term self-reported cognitive function, and that only a small subset who were exposed to chemotherapy manifested accelerated cognitive decline. Future research is needed to determine factors that place some older survivors at risk of experiencing cognitive decline. Cancer 2016;122:3555-3563. © 2016 American Cancer Society.