Search

Primary progressive aphasia is a neurodegenerative disease that selectively impairs language without equivalent impairment of speech, memory or comportment. In 118 consecutive autopsies on patients with primary progressive aphasia, primary diagnosis was Alzheimer’s disease neuropathological changes (ADNC) in 42%, corticobasal degeneration or progressive supranuclear palsy neuropathology in 24%, Pick’s disease neuropathology in 10%, transactive response DNA binding proteinopathy type A [TDP(A)] in 10%, TDP(C) in 11% and infrequent entities in 3%. Survival was longest in TDP(C) (13.2 ± 2.6 years) and shortest in TDP(A) (7.1 ± 2.4 years). A subset of 68 right-handed participants entered longitudinal investigations. They were classified as logopenic, agrammatic/non-fluent or semantic by quantitative algorithms. Each variant had a preferred but not invariant neuropathological correlate. Seventy-seven per cent of logopenics had ADNC, 56% of agrammatics had corticobasal degeneration/progressive supranuclear palsy or Pick’s disease and 89% of semantics had TDP(C). Word comprehension impairments had strong predictive power for determining underlying neuropathology positively for TDP(C) and negatively for ADNC. Cortical atrophy was smallest in corticobasal degeneration/progressive supranuclear palsy and largest in TDP(A). Atrophy encompassed posterior frontal but not temporoparietal cortex in corticobasal degeneration/progressive supranuclear palsy, anterior temporal but not frontoparietal cortex in TDP(C), temporofrontal but not parietal cortex in Pick’s disease and all three lobes with ADNC or TDP(A). There were individual deviations from these group patterns, accounting for less frequent clinicopathologic associations. The one common denominator was progressive asymmetric atrophy overwhelmingly favouring the left hemisphere language network. Comparisons of ADNC in typical amnestic versus atypical aphasic dementia and of TDP in type A versus type C revealed fundamental biological and clinical differences, suggesting that members of each pair may constitute distinct clinicopathologic entities despite identical downstream proteinopathies. Individual TDP(C) participants with unilateral left temporal atrophy displayed word comprehension impairments without additional object recognition deficits, helping to dissociate semantic primary progressive aphasia from semantic dementia. When common and uncommon associations were considered in the set of 68 participants, one neuropathology was found to cause multiple clinical subtypes, and one subtype of primary progressive aphasia to be caused by multiple neuropathologies, but with different probabilities. Occasionally, expected clinical manifestations of atrophy sites were absent, probably reflecting individual peculiarities of language organization. The hemispheric asymmetry of neurodegeneration and resultant language impairment in primary progressive aphasia reflect complex interactions among the cellular affinities of the degenerative disease, the constitutive biology of language cortex, familial or developmental vulnerabilities of this network and potential idiosyncrasies of functional anatomy in the affected individual.

Objective: Telehealth is used in various healthcare settings with patient satisfaction and reduced patient cost. [1, 2] However, fertility care is a uniquely personal journey and patient attitudes towards telehealth are relatively unknown. We evaluated attitudes of fertility patients across the United States towards telehealth using a validated telehealth satisfaction and usefulness questionnaire. Materials and Methods: We conducted a cross-sectional survey study. An anonymous, web-based survey was distributed to national infertility groups between Feb-April 2021.The survey gathered demographic information and included the Telehealth Usability Questionnaire (TUQ), which assesses aspects of telehealth usability with a 7-point Likert scale (strongly disagree to strongly agree). We solicited general comments regarding telehealth for fertility care. The primary outcome was overall satisfaction using telehealth. We computed descriptive statistics to compare satisfied vs unsatisfied participants. Results: 104 respondents initiated and 74 completed the survey. Participants represented 24 different states and all regions of the United States. Most respondents were white (81.1%) with a median age of 35 years old. Most participants (80%) were satisfied using telehealth. Given low frequency of patient dissatisfaction, we were unable to perform statistical tests to compare demographic differences between satisfied and unsatisfied participants. Most (86.5%) respondents would use telehealth again. When given an option, 63.5% prefer in person for new patient visits. For follow up visits, 47.3% prefer telehealth and 27% had no preference. Only 25.7% preferred a follow up visit in person. Conclusions: Telehealth can improve access to care with high rates of patient satisfaction. Most fertility patients still prefer new visits be conducted in person. Impact Statement: Our findings suggest fertility clinics should continue to offer telehealth visits even after the end of the COVID-19 pandemic. References: 1. Alex Zhu, D., et al., TELEHEALTH FOR MALE-INFERTILITY IS FEASIBLE AND SAVES PATIENTS’ TIME AND MONEY. ASRM 2020 2. Tenforde, A.S., et al., Outpatient Physical, Occupational, and Speech Therapy Synchronous Telemedicine: A Survey Study of Patient Satisfaction with Virtual Visits During the COVID-19 Pandemic. Am J Phys Med Rehabil, 2020.

Purpose:Myelofibrosis is characterized by bone marrow fibrosis, atypical megakaryocytes, splenomegaly, constitutional symptoms, thrombotic and hemorrhagic complications, and a risk of evolution to acute leukemia. The JAK kinase inhibitor ruxolitinib provides therapeutic benefit, but the effects are limited. The purpose of this study was to determine whether targeting AURKA, which has been shown to increase maturation of atypical megakaryocytes, has potential benefit for patients with myelofibrosis.Patients and Methods:Twenty-four patients with myelofibrosis were enrolled in a phase I study at three centers. The objective of the study was to evaluate the safety and preliminary efficacy of alisertib. Correlative studies involved assessment of the effect of alisertib on the megakaryocyte lineage, allele burden, and fibrosis.Results:In addition to being well tolerated, alisertib reduced splenomegaly and symptom burden in 29% and 32% of patients, respectively, despite not consistently reducing the degree of inflammatory cytokines. Moreover, alisertib normalized megakaryocytes and reduced fibrosis in 5 of 7 patients for whom sequential marrows were available. Alisertib also decreased the mutant allele burden in a subset of patients.Conclusions:Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis. In this study, alisertib provided clinical benefit and exhibited the expected on-target effect on the megakaryocyte lineage, resulting in normalization of these cells and reduced fibrosis in the majority of patients for which sequential marrows were available. Thus, AURKA inhibition should be further developed as a therapeutic option in myelofibrosis.See related commentary by Piszczatowski and Steidl, p. 4868

Figure S1: Alisertib treatment did not result in a consistent cytokine response. Figure S2: Alisertib did not have a consistent effect on TGF-b levels. Figure S3: Alisertib induced GATA1 expression in the SET2 megakaryocytic cell line. Figure S4: AURKA inhibition induces megakaryocytic gene expression. Figure S5: Alisertib increases GATA1 expression in the bone marrow of patients on therapy. Table S1: Correlation of Genotype and prior JAK inhibitor therapy with response and adverse events Table S2: Summary of Treatment Related Adverse Events Table S3: Association between GATA1 staining, degree of fibrosis and clinical response

Survival is dismal for bevacizumab refractory high-grade glioma patients. We prospectively investigated the efficacy of re-irradiation, bevacizumab, and temozolomide in bevacizumab-naive and bevacizumab-exposed recurrent high-grade glioma, without volume limitations, in a single arm trial. Recurrent high-grade glioma patients were stratified based on WHO grade (4 vs. grade 3 lymphopenia and 2 with > grade 3 thrombocytopenia. No radiographic or clinical radiation necrosis occurred. Re-irradiation with bevacizumab and temozolomide is a safe and feasible salvage treatment for patients with large volume bevacizumab-refractory high-grade glioma. Patients further from their initial radiotherapy may derive greater benefit with this regimen.

Objectives Previous reports established the feasibility of a telehealth model for delivering speech–language therapy via Internet videoconferencing, which connects individuals with primary progressive aphasia (PPA) to an expert speech and language pathologist for treatment. This study reports feasibility of the same telehealth intervention in a larger set of progressive aphasia participants and explores factors potentially influencing functional intervention outcomes. Methods Participants with PPA or progressive aphasia in the context of a neurodegenerative dementia syndrome and their communication partners were enrolled into an 8-session intervention, with 3 evaluations (baseline, 2 months, and 6 months postenrollment). Half of the participants were randomized into a “check-in” group and received 3-monthly half-hour sessions postintervention. Mixed linear models with post hoc testing and percent change in area under the curve were used to examine communication confidence over time, as well as the influence of check-in sessions and the role of communication partner engagement on communication confidence. Results Communication confidence improved at the 2-month evaluation and showed no significant decline at the 6-month evaluation. Item-level analysis revealed gains in communication confidence across multiple communication contexts. Gains and maintenance of communication confidence were only present for the engaged communication partner group and were not bolstered by randomization to the check-in group. Discussion Internet-based, person-centered interventions demonstrate promise as a model for delivering speech–language therapy to individuals living with PPA. Maintenance is possible for at least 6 months postenrollment and is better for those with engaged communication partners, which supports the use of dyadic interventions.

Objective To study the reprometabolic syndrome in normal-weight, eumenorrheic women by infusing a combination of insulin and lipid. Women with obesity have been shown to have reduced gonadotropins and impaired luteinizing hormone (LH) and follicle-stimulating hormone (FSH) response to gonadotropin-releasing hormone (GnRH). Design Randomized crossover. Setting Academic medical center. Participant(s) Fifteen women, median age 32 (interquartile ranged [IQR] 26, 36) years and body mass index 21.9 (IQR 20.2, 22.9) kg/m2 were recruited. Intervention(s) Early follicular phase, 6-hour infusions of insulin (20–40 mU/m2 per minute) and lipid (Intralipid)—insulin/lipid infusion; or saline infusion (controls). The first 4 hours of each study assessed endogenous gonadotropins; at 4 hours, GnRH (75 ng/kg) bolus was administered and sampling continued until 6 hours. Main Outcome Measure(s) Linear mixed model analysis was used to determine differences between insulin/lipid and saline influence on endogenous LH pulse amplitude (primary outcome), mean FSH, and area under the curve (AUC) response to GnRH (secondary outcomes). Result(s) Twelve women completed both intended studies and an additional 3 women completed only 1 of the 2 studies. LH pulse amplitude, mean FSH, and both AUC responses to GnRH were reduced by insulin/lipid, mean FSH and AUC for LH were at or near statistical significance. LH response to GnRH was significantly reduced when 1 participant with very high LH and antimullerian hormone levels was excluded. Conclusion(s) Acute infusion of insulin/lipid to eumenorrheic, normal-weight women recapitulated the reprometabolic syndrome of obesity. These findings imply that specific circulating factors in obese women contribute to their subfertility and thus may be amenable to discovery and treatment. Clinical Trial Registration Number NCT02653092.

Financial conflicts of interest (COIs) represent a common and complex issue in hematology and oncology. However, little is known about the timing of when COIs begin to develop during a career trajectory. We evaluated self-reported COIs for junior faculty members at top cancer centers to determine how these financial relationships correlated with measures of academic career productivity.We analyzed data from 230 assistant professors at 10 academic cancer centers. Financial COIs were identified from the CMS Open Payments (Sunshine Act dollars) database. Self-reported COIs were obtained from American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) disclosures, and from disclosures in recent publications. Number of publications and h-index (defined as the largest number of publications [h] such that h publications each have at least h citations) were used as measures of academic productivity. Scatter plots and Spearman correlation coefficients were used to assess the relationship between COIs or Sunshine Act dollars with number of publications and h-index. Linear regression modeling was used to analyze the relationships between COIs or Sunshine Act dollars with number of publications and h-index, adjusting for years of experience since completing fellowship (YSF).A total of 46% of junior faculty had at least 1 COI. Number of COIs reported to ASCO/ASH was positively correlated with total Sunshine Act dollars (Spearman correlation, 0.53;Financial COIs increased with number of YSF. Measures of academic productivity were positively correlated with COIs (ASCO/ASH) and Sunshine Act dollars. These data suggest that the cultivation of industry relationships is associated with the early academic productivity of junior faculty.

IntroductionStudies using lipid infusions to raise fatty acid levels require heparin to release lipoprotein lipase (LPL), thus calling into question the appropriate control infusion for this type of study: saline alone or saline plus heparin. We aimed to evaluate whether the addition of heparin alone, in doses needed to release LPL, would alter circulating free fatty acids (FFAs) and/or affect gonadotropins.Materials and MethodsThis was a secondary analysis using combined data from eumenorrheic normal-weight women subjected to “control” conditions in 1 of 2 separate studies. In 1 study, participants received saline alone (group 1) as a control, and in the other study participants received saline alone and/or saline plus heparin (groups 2-3) as a control. Both studies performed early follicular phase, frequent blood sampling. FSH and LH were compared across groups and in conditions with and without heparin. Linear mixed models were used to analyze the data.ResultsLH did not differ across any of the 3 groups. Estimated means (SE) for FSH differed between groups but this difference was marginal (P = .05) after adjusting for anti-Mullerian hormone and unrelated to heparin infusion (group 1: 4.47 IU/L [SE 1.19], group 2: 8.01 IU/L [SE 1.14], group 3: 7.94 IU/L [SE 1.13]).ConclusionsHeparin does not exert major effects on gonadotropins when infused in quantities sufficient to release LPL. However, because it can release other vascular membrane-bound proteins, heparin should be considered part of the control infusions in lipid infusion studies where increased FFA levels are the goal.

Survival is dismal for bevacizumab refractory high-grade glioma patients. We prospectively investigated the efficacy of re-irradiation, bevacizumab, and temozolomide in bevacizumab-naïve and bevacizumab-exposed recurrent high-grade glioma, without volume limitations, in a single arm trial.Recurrent high-grade glioma patients were stratified based on WHO grade (4 vs.4) and prior exposure to bevacizumab (yes vs. no). Eligible patients received radiation using a simultaneous integrated boost technique (55 Gy to enhancing disease, 45 Gy to non-enhancing disease in 25 fractions) with bevacizumab 10 mg/kg every 2 weeks IV and temozolomide 75 mg/mFifty-four patients were enrolled. The majority (n = 36, 67%) were bevacizumab pre-exposed GBM. Median OS for all patients was 8.5 months and 7.9 months for the bevacizumab pre-exposed GBM group. Patients ≥ 36 months from initial radiation had a median OS of 13.3 months compared to 7.5 months for those irradiated36 months earlier (p0.01). FACT-Br and FACT-Fatigue scores initially declined during radiation but returned to pretreatment baseline. Treatment was well tolerated with 5 patients experiencinggrade 3 lymphopenia and 2 withgrade 3 thrombocytopenia. No radiographic or clinical radiation necrosis occurred.Re-irradiation with bevacizumab and temozolomide is a safe and feasible salvage treatment for patients with large volume bevacizumab-refractory high-grade glioma. Patients further from their initial radiotherapy may derive greater benefit with this regimen.

Background Pancreatic ductal adenocarcinoma (PDAC) remains resistant to chemotherapy and immunotherapy individually because of its desmoplastic stroma and immunosuppressive tumor microenvironment. Synergizing cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) immune checkpoint blockade with chemotherapy could overcome these barriers. Here we present results of a phase Ib trial combining ipilimumab and gemcitabine in advanced PDAC. Materials and Methods This was a single-institution study with a 3 + 3 dose-escalation design. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included determining the toxicity profile, objective response rate (ORR), median progression-free survival (PFS), and overall survival (OS). Results Twenty-one patients were enrolled, 13 during dose escalation and 8 at the MTD. The median age was 66 years, 62% were female, 95% had stage IV disease, and 67% had received at least one prior line of therapy. The primary objective to establish the MTD was achieved at doses of ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m2. The most common grade 3 or 4 adverse events were anemia (48%), leukopenia (48%), and neutropenia (43%). The ORR was 14% (3/21), and seven patients had stable disease. Median response duration for the three responders was 11 months, with one response duration of 19.8 months. Median PFS was 2.78 months (95% confidence interval [CI], 1.61–4.83 months), and median OS was 6.90 months (95% CI, 2.63–9.57 months). Conclusion Gemcitabine and ipilimumab is a safe and tolerable regimen for PDAC with a similar response rate to gemcitabine alone. As in other immunotherapy trials, responses were relatively durable in this study. Implications for Practice Gemcitabine and ipilimumab is a safe and feasible regimen for treating advanced pancreatic cancer. Although one patient in this study had a relatively durable response of nearly 20 months, adding ipilimumab to gemcitabine does not appear to be more effective than gemcitabine alone in advanced pancreatic cancer.

Purpose: Myelofibrosis is characterized by bone marrow fibrosis, atypical megakaryocytes, splenomegaly, constitutional symptoms, thrombotic and hemorrhagic complications, and a risk of evolution to acute leukemia. The JAK kinase inhibitor ruxolitinib provides therapeutic benefit, but the effects are limited. The purpose of this study was to determine whether targeting AURKA, which has been shown to increase maturation of atypical megakaryocytes, has potential benefit for patients with myelofibrosis. Patients and Methods: Twenty-four patients with myelofibrosis were enrolled in a phase I study at three centers. The objective of the study was to evaluate the safety and preliminary efficacy of alisertib. Correlative studies involved assessment of the effect of alisertib on the megakaryocyte lineage, allele burden, and fibrosis. Results: In addition to being well tolerated, alisertib reduced splenomegaly and symptom burden in 29% and 32% of patients, respectively, despite not consistently reducing the degree of inflammatory cytokines. Moreover, alisertib normalized megakaryocytes and reduced fibrosis in 5 of 7 patients for whom sequential marrows were available. Alisertib also decreased the mutant allele burden in a subset of patients. Conclusions: Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis. In this study, alisertib provided clinical benefit and exhibited the expected on-target effect on the megakaryocyte lineage, resulting in normalization of these cells and reduced fibrosis in the majority of patients for which sequential marrows were available. Thus, AURKA inhibition should be further developed as a therapeutic option in myelofibrosis. See related commentary by Piszczatowski and Steidl, p. 4868

Diffuse large B-cell lymphoma (DLBCL) transformed from follicular lymphoma (FL) (tDLBCL) has been traditionally associated with an aggressive course, but more recent studies have shown longer survivals. The clinical significance of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) is less clear. We compared outcomes of tDLBCL, cDLBCL/FL, and

PURPOSE Although alterations of concentrations in circulating steroids have been linked to single nucleotide polymorphisms (SNPs) of steroidogenic enzymes, we hypothesized that SNPs of such enzymes located within the breast affect local steroid concentrations more than products of such SNPs absorbed from the circulation. METHODS Steroids (estradiol, estrone, testosterone, androstenedione, DHEA, DHEA sulfate, progesterone) in nipple aspirate fluid (NAF) were purified by HPLC and they along with serum steroids were quantified by immunoassays. Polymorphisms of the transporter SLCO2B1 and enzymes HSD3B1, CYP19A1, HSD17B12, AKR1C3, CYP1B1, and SRD5A1 were measured in white blood cell DNA. RESULTS Steroid concentrations in NAF of subjects with homozygous minor genotypes differed from those with heterozygotes, i.e., SLCO2B1 (rs2851069) decreased DHEAS (p = 0.04), HSD17B12 (rs11555762) increased estradiol (p

Human immunodeficiency virus (HIV) vaccines have not been successful in clinical trials. Dimeric IgA (dIgA) in the form of secretory IgA is the most abundant antibody class in mucosal tissues, making dIgA a prime candidate for potential HIV vaccines. We coupled Positron Emission Tomography (PET) imaging and fluorescent microscopy of 64Cu-labeled, photoactivatable-GFP HIV (PA-GFP-BaL) and fluorescently labeled dIgA to determine how dIgA antibodies influence virus interaction with mucosal barriers and viral penetration in colorectal tissue. Our results show that HIV virions rapidly disseminate throughout the colon two hours after exposure. The presence of dIgA resulted in an increase in virions and penetration depth in the transverse colon. Moreover, virions were found in the mesenteric lymph nodes two hours after viral exposure, and the presence of dIgA led to an increase in virions in mesenteric lymph nodes. Taken together, these technologies enable in vivo and in situ visualization of antibody-virus interactions and detailed investigations of early events in HIV infection., Author summary Vaccines provide protection in humans by eliciting the production of antibodies when exposed to a specific pathogen. Currently, an effective human immunodeficiency virus (HIV) vaccine does not exist. Since the beginning of the HIV epidemic, approximately 38 million people have died, creating the need to develop an HIV vaccine. The most common antibody in the organs that are exposed to HIV is dimeric IgA (dIgA). Here, we used multiple imaging techniques to determine how HIV travels throughout the colon once introduced into the body and how dIgA influences HIV movement in the rectum. We found that dIgA increased the amount of HIV found in the colon, the distance it travelled, and the depth into tissues that HIV penetrated. dIgA also increased the amount of HIV in the mesenteric lymph nodes two hours after viral exposure. Our study shows these imaging technologies can be used to examine interactions between viruses and antibodies in early HIV infection in the natural context of the anatomy and physiology of the rhesus macaque model.

Understanding the earliest events of HIV sexual transmission is critical to develop and optimize HIV prevention strategies. To gain insights into the earliest steps of HIV rectal transmission, including cellular targets, rhesus macaques were intra-rectally challenged with a single-round SIV-based dual reporter that expresses luciferase and iRFP670 upon productive transduction. The vector was pseudotyped with the HIV-1 envelope JRFL. Regions of tissue containing foci of luminescent, transduced cells were identified macroscopically using an in vivo imaging system, and individual transduced cells expressing fluorescent protein were identified and phenotyped microscopically. This system revealed that anal and rectal tissues are both susceptible to transduction 48 hours after the rectal challenge. Detailed phenotypic analysis revealed that on average, 62% of transduced cells are CCR6+ T cells—the vast majority of which express RORγT, a Th17 lineage-specific transcription factor. The second most common target cells were immature dendritic cells at 20%. These two cell types were transduced at the rates that are four to five times higher than their relative abundances indicate. Our work demonstrates that Th17 T and immature dendritic cells are preferential initial targets of HIV/SIV rectal transmission.IMPORTANCEMen and women who participate in unprotected receptive anal intercourse are at high risk for acquiring HIV. While in vitro data have developed a framework for understanding HIV cell tropism, the initial target cells in the rectal mucosa have not been identified. In this study, we identify these early host cells by using an innovative rhesus macaque rectal challenge model and methodology, which we previously developed. Thus, by shedding light on these early HIV/SIV transmission events, this study provides a specific cellular target for future prevention strategies.

Context Obesity, is a state of chronic inflammation, characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism. We have defined the accompanying decreased Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), ovarian steroids and reduced pituitary response to Gonadotropin-releasing Hormone (GnRH) as Reprometabolic syndrome, a phenotype that can be induced in healthy normal weight women (NWW) by acute infusion of free fatty acids and insulin. Objective To identify potential mediators of insulin and lipid-related reproductive endocrine dysfunction. Design, setting, participants Secondary analysis of crossover study of eumenorrheic reproductive aged women of normal Body Mass Index (BMI) (2) at an academic medical center. Intervention Participants underwent 6-hour infusions of either saline/heparin or insulin plus fatty acids (Intralipid plus heparin), in the early follicular phase of sequential menstrual cycles, in random order. Euglycemia was maintained by glucose infusion. Frequent blood samples were obtained. Main outcome measures Pooled serum from each woman was analyzed for cytokines, interleukins, chemokines, adipokines, Fibroblast Growth Factor-21 (FGF-21) and markers of endoplasmic reticulum (ER) stress (CHOP and GRP78). Wilcoxon signed-rank tests were used to compare results across experimental conditions. Results Except for Macrophage Inflammatory Protein-1β (MIP-1β), no significant differences were observed in serum levels of any of the inflammatory signaling or ER stress markers tested. Conclusion Acute infusion of lipid and insulin, to mimic the metabolic syndrome of obesity, was not associated with an increase in inflammatory markers. These results imply that the endocrine disruption and adverse reproductive outcomes of obesity are not a consequence of the ambient inflammatory environment but may be mediated by direct lipotoxic effects on the hypothalamic-pituitary-ovarian (HPO) axis.

The neurofibrillary tangles (NFT) and amyloid‐ß plaques (AP) that comprise Alzheimer’s disease (AD) neuropathology are associated with neurodegeneration and microglial activation. Activated microglia exist on a dynamic spectrum of morphologic subtypes that include resting, surveillant microglia capable of converting to activated, hypertrophic microglia closely linked to neuroinflammatory processes and AD neuropathology in amnestic AD. However, quantitative analyses of microglial subtypes and neurons are lacking in non‐amnestic clinical AD variants, including primary progressive aphasia (PPA‐AD). PPA‐AD is a language disorder characterized by cortical atrophy and NFT densities concentrated to the language‐dominant hemisphere. Here, a stereologic investigation of five PPA‐AD participants determined the densities and distributions of neurons and microglial subtypes to examine how cellular changes relate to AD neuropathology and may contribute to cortical atrophy. Adjacent series of sections were immunostained for neurons (NeuN) and microglia (HLA‐DR) from bilateral language and non‐language regions where in vivo cortical atrophy and Thioflavin‐S‐positive APs and NFTs were previously quantified. NeuN‐positive neurons and morphologic subtypes of HLA‐DR‐positive microglia (i.e., resting [ramified] microglia and activated [hypertrophic] microglia) were quantified using unbiased stereology. Relationships between neurons, microglia, AD neuropathology, and cortical atrophy were determined using linear mixed models. NFT densities were positively associated with hypertrophic microglia densities (P, Quantitative analyses of microglial subtypes and neurons are lacking in non‐amnestic clinical Alzheimer's disease (AD) variants, including primary progressive aphasia (PPA‐AD). Our findings provide converging evidence of divergent roles for microglial subtypes in patterns of neurodegeneration, which includes hypertrophic microglia likely driving a neuroinflammatory response more sensitive to neurofibrillary tangles than amyloid‐beta plaques in PPA‐AD. Moreover, the accumulation of both neurofibrillary tangles and activated hypertrophic microglia in association with low neuron densities suggest they may collectively contribute to focal neurodegeneration characteristic of PPA‐AD.

Study ObjectivesSlow wave and spindle coupling supports memory consolidation, and loss of coupling is linked with cognitive decline and neurodegeneration. Coupling is proposed to be a possible biomarker of neurological disease, yet little is known about the different subtypes of coupling that normally occur throughout human development and aging. Here we identify distinct subtypes of spindles within slow wave upstates and describe their relationships with sleep stage across the human lifespan.MethodsCoupling within a cross-sectional cohort of 582 subjects was quantified from stages N2 and N3 sleep across ages 6-88 years old. Results were analyzed across the study population via mixed model regression. Within a subset of subjects, we further utilized coupling to identify discrete subtypes of slow waves by their coupled spindles.ResultsTwo different subtypes of spindles were identified during the upstates of (distinct) slow waves: an “early-fast” spindle, more common in stage N2 sleep, and a “late-fast” spindle, more common in stage N3. We further found stages N2 and N3 sleep are composed of two discrete subtypes of slow waves, each identified by their unique coupled-spindle timing and frequency. The relative contribution of coupling subtypes shifts across the human lifespan, and a deeper sleep phenotype prevails during old age.ConclusionsDistinct subtypes of slow waves and coupled spindles form the composite of slow wave sleep. Our findings support a model of sleep-dependent synaptic regulation via discrete slow wave/spindle coupling subtypes and advance a conceptual framework for the development of coupling-based biomarkers in age-associated neurological disease.Statement of SignificanceSlow waves of nonrapid eye movement sleep couple with sleep spindles in a process hypothesized to support memory functions. This coupling has recently gained interest as a possible biomarker of cognitive aging and onset of Alzheimer’s disease. Most studies have been limited by an assumption that all slow waves (and coupled spindles) are fundamentally the same physiological events. Here we demonstrate that distinct subtypes of slow waves and their coupled spindles can be identified in human sleep. A mixture of different slow wave and spindle subtypes shifts in composition during lighter versus deeper sleep, and aging favors the deep sleep subtypes. These data should inform any future attempts to use slow wave sleep as a biomarker or clinical interventional target.

Background The lifetime risk of breast and ovarian cancer is significantly higher among women with genetic susceptibility or a strong family history. However, current risk assessment tools and clinical practices may identify only 10% of asymptomatic carriers of susceptibility genes. Bright Pink developed the Assess Your Risk (AYR) tool to estimate breast and ovarian cancer risk through a user-friendly, informative web-based quiz for risk assessment at the population level. Objective This study aims to present the AYR tool, describe AYR users, and present evidence that AYR works as expected by comparing classification using the AYR tool with gold standard genetic testing guidelines. Methods The AYR is a recently developed population-level risk assessment tool that includes 26 questions based on the National Comprehensive Cancer Network (NCCN) guidelines and factors from other commonly used risk assessment tools. We included all women who completed the AYR between November 2018 and January 2019, with the exception of self-reported cancer or no knowledge of family history. We compared AYR classifications with those that were independently created using NCCN criteria using measures of validity and the McNemar test. Results There were 143,657 AYR completions, and most participants were either at increased or average risk for breast cancer or ovarian cancer (137,315/143,657, 95.59%). Using our estimates of increased and average risk as the gold standard, based on the NCCN guidelines, we estimated the sensitivity and specificity for the AYR algorithm–generated risk categories as 100% and 89.9%, respectively (P Conclusions These results demonstrate that Bright Pink’s AYR is an accurate tool for use by the general population to identify women at increased risk of breast and ovarian cancer. We plan to validate the tool longitudinally in future studies, including the impact of race, ethnicity, and age on breast and ovarian cancer risk assessment.

Background: Subfertility in obese women is associated with chronic pituitary suppression, reduced sensitivity to GnRH and decreased sex steroid production. We have found evidence for a combined effect of hyperinsulinemia and high circulating fatty acids to acutely (4h infusion) suppress pituitary gonadotropin secretion and are currently investigating the effects of one-month exposure to a eucaloric high-fat diet (HFD) on gonadotropin levels in lean women. The aim of this study is to examine the effect of the one-month HFD on physical activity and body composition. Methods: 12 normal weight (BMI < 25 kg/m2), normally cycling female participants of reproductive age were given a one-month eucaloric HFD, from the onset of menses in one cycle through the next, with 48% calories from fat. A Fitbit was provided to monitor changes in daily activity and sleep throughout the study. Measurement of gonadotropin pulsatility and reproductive hormones were done using frequent blood sampling and daily urine excretion, respectively. These measurements were obtained for a total of 4 menstrual cycles: 1 pre-diet cycle, the HFD cycle, and 2 post-diet cycles. DEXA body composition was measured at baseline and at the end of the 2nd post diet cycle. Pre and post diet comparisons were done using linear mixed model testing and reported as estimated means ± standard error. Results: Mean number of daily steps were (9,226 ± 1,140) pre diet, (9,132 ± 1,140) during the diet and (7,533 ± 1,140) post diet. Daily active calories were (1,982 ± 99) pre diet, (1,975 ± 99) during the diet and (1,856 ± 99) post diet. Means in the HFD cycle did not differ from the pre-diet cycle. Daily sleeping minutes pre diet were (443 ± 19), (451 ± 20) during the diet and (412 ± 19) post diet, with no statistical difference between the 3 time points. BMI did not differ between pre-diet (21.84 ± 0.52) and post-diet (21.77 ± 0.52). DEXA body composition measurements indicated a statistically significant decrease in total fat percentage, (32.26 ± 1.53) pre diet and (31.31 ± 1.53) post diet, which does not appear clinically significant as the difference of less than 1% falls within the anticipated measurement error of the method. Visceral fat volume (cm3) did not differ between pre diet (299.51 ± 27.76) and post diet (295.53 ± 27.76). Conclusions: The complete cohort has not yet been fully recruited and analyzed. These preliminary findings indicate that women consuming a one-month, HFD maintain their usual level of physical activity and sleep patterns, and do not appear to sustain change in visceral fat. Further accrual of participants should clarify the small decrease in total body fat observed without a change in BMI. Supported by HD087314 ROI to NS UL1TR002535 to the Colorado Clinical and Translational Sciences Institute.

Guidelines recommend that all pregnant women should be offered prenatal genetic counseling, which includes discussions of aneuploidy and carrier screening. Previous studies have demonstrated racial and ethnic disparities in the completion of prenatal genetic testing, but few studies have evaluated for disparities in the offering of these tests. Prenatal genetic screening is a covered provision of Colorado Medicaid. We hypothesized that in the absence of a financial barrier, disparities in prenatal genetic counseling would be eliminated.To evaluate disparities in prenatal genetic counseling by directly assessing if patients received counseling at the time of their first prenatal visit.This retrospective cross-sectional study included patients presenting for their first prenatal visit at20 weeks' gestation. Patients who completed prenatal genetic testing were classified as counseled, and the remaining patients' medical records were reviewed. Moreover, patients were divided into 2 groups based on their counseling status (yes or no), separately for aneuploidy and carrier screening.Of 1103 patients who met the inclusion criteria, 97.2% were counseled for aneuploidy screening, whereas 73.3% were counseled on carrier screening. For aneuploidy, younger age, Black race, a relationship status of single, and presentation at a later gestational age were associated with lack of aneuploidy counseling on univariate analysis. After multivariable analysis, only maternal age (odds ratio, 1.09; 95% confidence interval, 1.01-1.19) and gestational age (odds ratio, 0.84; 95% confidence interval, 0.76-0.93) were statistically significantly associated with aneuploidy counseling. Treatment by a physician care team, having a comorbidity score of ≥1, and presenting at a later gestational age were associated with not receiving carrier screening counseling (univariate analysis). Multivariable analysis indicated significant associations with gestational age (odds ratio, 0.90; 95% confidence interval, 0.86-0.94) and having a comorbidity (odds ratio, 0.72; 95% confidence interval, 0.55-0.94).Prenatal genetic counseling was less likely to be provided to women who present for prenatal care at a later gestational age. This finding was of concern because women who are less privileged were more likely to present to prenatal care at a later gestational age. Providing access to early prenatal care and developing specialized care pathways for women entering prenatal care in the second trimester of pregnancy could address disparities in prenatal genetic counseling.

Background Metastatic prostate cancer is incurable, but systemic therapies can improve quality of life and prolong survival. Accurate perceptions of treatment risks and benefits are vital as patients with metastatic disease make treatment decisions. We assessed treatment‐related expectations for benefit among patients with metastatic prostate cancer and explored associated sociodemographic characteristics. Methods Men with metastatic prostate cancer (N = 100) completed surveys assessing their treatment‐related expectations for cancer cure, symptom relief, and prolonged life expectancy. Frequencies were used to describe the proportions of reported expectations. Fisher's exact tests were used to assess the associations of sociodemographic characteristics with treatment expectations. Results One third (33%) of participants believed treatment was at least a little likely to cure their metastatic cancer. Most participants believed treatment could provide symptom relief (76%) and extend life expectancy (95%). Among participants reporting that cancer cure was at least a little likely vs not at all, more men identified as non‐white (24% vs 5%; P = .01), self‐reported good health (90% vs 58%; P, Despite having incurable disease, approximately one‐third of men with metastatic prostate cancer hold the inaccurate belief that systemic treatment is at least a little likely to cure their cancer. Being of non‐white race, better self‐perceived health, and greater optimism were associated with this inaccurate belief.

Heterozygous loss-of-function mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A). PGRN is a highly conserved, secreted glycoprotein and functions in the central nervous system as a key modulator of microglial function. Hence, altered microglial function caused by PGRN deficiency may be tied to the pathogenesis of FTLD-TDP. Our previous studies showed that haploinsufficiency of GRN mutations extends to microglial PGRN expression in the hippocampal CA1 region. In this study, we found that the CA1 sector was associated with less neuronal loss and more frequent TDP-43 inclusions in FTLD-TDP type A cases with GRN mutations than in sporadic cases. In addition, the CA1 region in GRN mutation cases contained more rod-like microglia, which also had reduced PGRN expression. These findings suggest that the profile of TDP-43 inclusions, neuronal number, and microgliosis in the CA1 sector of FTLD-TDP type A cases may be influenced by GRN gene expression status.

The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language-based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid-s plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA-AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA-AD participants with in vivo magnetic resonance imaging scans 7-30 months before death and acquired stereologic estimates of NFTs and dense-core APs visualized with the Thioflavin-S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non-language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non-language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA-AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.

Introduction Primary progressive aphasia (PPA) displays variable progression trajectories that require further elucidation. Methods Longitudinal quantitation of atrophy and language over 12 months was completed for PPA patients with and without positive amyloid PET (PPA Aβ+ and PPA Aβ− ), an imaging biomarker of underlying Alzheimer's disease. Results Over 12 months, both PPA groups showed significantly greater cortical atrophy rates in the left versus right hemisphere, with a more widespread pattern in PPA Aβ+ . The PPA Aβ+ group also showed greater decline in performance on most language tasks. There was no obligatory relationship between the logopenic PPA variant and amyloid status. Effect sizes from quantitative MRI data were more robust than neuropsychological metrics. Discussion Preferential language network neurodegeneration is present in PPA irrespective of amyloid status. Clinical and anatomical progression appears to differ for PPA due to Alzheimer's disease versus non–Alzheimer's disease neuropathology, a distinction that may help to inform prognosis and the design of intervention trials.

Background Cancer five-year survival rates have improved to 85% for pediatric, adolescent and young adults, creating opportunities to optimize long-term health and quality of life (QoL) in survivorship1. Infertility and adverse reproductive health outcomes significantly alter QoL and affect 12-88% of at-risk survivors2-6. National guidelines recommend fertility preservation (FP) counseling prior to cancer therapies in reproductive age survivors. However, implementation of guidelines remains a challenge and reproductive late effects (LE) beyond infertility remain under addressed. To bridge this gap, we describe the early stages of development of a national database designed to create a framework for data sharing to facilitate research and improve fertility and reproductive health outcomes. Methods A multidisciplinary team of FP experts, biostatisticians, and informaticists examined three existing databases to define a standard set of variables to incorporate into a pilot database. The pilot sites include Children's Hospital Colorado and University of Colorado Hospital and will expand to additional sites within the Oncofertility Consortium. The population includes males and females ages 1 month to 39 years with medical conditions and/or treatments associated with fertility impairment. In addition, we assessed a subset of variables (age, diagnosis and attempted FP) to determine feasibility. Results We created a well-defined data dictionary after evaluating existing and potential new variables. We included common variables such as cancer treatments and fertility assessments and expanded to include reproductive LE. The latter includes radiation-induced uterine/vaginal injury, genital graft-versus-host disease, hypogonadism, and sexual dysfunction. To illustrate feasibility, we identified 126 patients at the pilot sites from January 2020 to September 2020. Of those, 48% were females ages 6-38 (median 21) and 52% were males ages 1-39 (median 19) years. Leukemia (18%), sarcoma (14%), lymphoma (11%), and breast (11%) were the most common diagnoses. Fourteen patients received gonadotoxic therapies for non-malignant conditions. FP was pursued in 32% of females and 84% of males. Results for reproductive LE variables are being quantified. Conclusions A standardized clinical outcomes database that is utilized by a growing network of FP and reproductive health programs will help strengthen research through data sharing and expedite implementation of clinical guidelines. Future steps are to (1) scale to additional sites, (2) refine and prioritize variables to reflect practices across centers, (3) automate data import, and (4) refine the process of initiating hypothesis-driven research across centers.

HIV prevention method preferences were evaluated among 512 U.S. men who have sex with men (MSM; median age: 22 years). Approximately 90 % consistently preferred one option across pairwise comparisons of condoms, daily oral pre-exposure prophylaxis (PrEP), and long-acting PrEP delivered via either an injectable or one of two types of PrEP implants differing in visibility. Condoms were most frequently preferred (33.8 %), followed by non-visible implants (21.5 %), and oral PrEP (17.0 %); HIV risk was reported by more choosing implants. In a follow-up question comparing the four PrEP options only, daily oral pills and non-visible implants were most frequently preferred (35.5 and 34.3 %, respectively), followed by injections (25.2 %) and visible implants (4.3 %). An inductive, open-coding approach determined that convenience, duration of protection, and privacy were the most commonly cited reasons for a PrEP method choice, and associated with self-report of HIV risk. Tailoring PrEP product development to privacy and other concerns important to those at highest HIV risk may improve HIV prevention.

The difficulty in detecting rare infected cells immediately after mucosal HIV transmission has hindered our understanding of the initial cells targeted by the virus. Working with the macaque-simian immunodeficiency virus (SIV) vaginal challenge model, we developed methodology to identify discrete foci of SIV (mac239) infection 48 hours after vaginal inoculation. We find infectious foci throughout the reproductive tract, from labia to ovary. Phenotyping infected cells reveals that SIV has a significant bias for infection of CCR6+ CD4+ T cells. SIV infected cells expressed the transcriptional regulator RORγt confirming that the initial target cells are specifically of the Th17 lineage. Furthermore, we detect host responses to infection, as evidenced by apoptosis, cell lysis, and phagocytosis of infected cells. Thus, our analysis identifies Th17 lineage CCR6+ CD4+ T cells as primary targets of SIV during vaginal transmission. This opens new opportunities for interventions to protect these cells and prevent HIV transmission.

2080 Background: Financial conflict of interest (COI) represents a complex issue in hematology and oncology. Little is known about when COIs develop during a career and if these correlate with early career success. We evaluated self-reported COIs for junior faculty members at 10 academic cancer centers and examined if these financial relationships with industry correlated with measures of academic career success. Methods: The study evaluated 229 assistant professors from the top 10 cancer centers based on the 2018 US News Cancer rankings. Faculty characteristics were determined from hospital websites including the number of years since completing fellowship. Data regarding National Institute of Health (NIH) funding were obtained. Industry funds (Sunshine Act funds; SAF) were identified from the Centers for Medicare & Medicaid Services (CMS) Open Payments database from 2013-2017. Self-reported COIs were obtained from the American Society of Clinical Oncology (ASCO) or American Society of Hematology (ASH) disclosures databases, and through review of disclosures from recent publications. Measures of academic success included h-index and number of publications. We assessed the influence of number of COIs and SAF received on measures of academic success. Results: Of the 229 included faculty, 45% were female, 39% graduated fellowship in 2015 or later, 35% were double-boarded, 40% had dual degrees and 15% received NIH funding. Approximately 46% of faculty had at least 1 COI. COIs (ASCO/ASH) were positively correlated with COIs self-reported in publications and total SAF (Spearman correlations 0.57 and 0.54, both P < 0.01). The development of COIs and the number of SAF increased with years in practice (Spearman correlations 0.37 and 0.28, both P < 0.01). COIs and SAF correlated with h-index (Spearman correlation 0.40 and 0.41, both P < 0.01). After adjusting for years since fellowship, linear regression demonstrated that log-transformed h-index and number of publications were associated with SAF (P < 0.01) and COIs (ASCO/ASH) (P = 0.01). Conclusions: Financial COIs were present in nearly half of the faculty and increased with more time since completing fellowship. Measures of academic success were positively correlated with COIs (ASCO/ASH) and SAF. These data suggest that cultivating industry relationships may aid faculty in establishing early academic success.

e17552 Background: Multiple treatments with similar efficacy exist for mPC, leaving patients (pts) with complicated treatment choices. Shared decision-making (SDM) can facilitate treatment decisions. The extent to which SDM is used in mPC is unknown. We assessed mPC pt, caregiver, and physician perceptions of decision locus of control (DLOC) (SDM vs. physician- or pt-directed decisions), and the degree of agreement between groups. Methods: Pt/caregiver/physician triads completed surveys of decision-making practices between 12/2016 and 11/2017 after a clinic visit in which a decision occurred. Pts were included only if they had a caregiver present. To evaluate the degree of agreement between pt, caregiver, and physician perceptions of DLOC, we used the quadratic-weighted kappa coefficient (κ). Agreement was evaluated on an overall basis and by pt age group (5-year increments). Results: 50 pt/caregiver/physician triads participated, with median pt age of 72 yo. Most pts were white (96%) and married (90%). A majority of pts, caregivers, and physicians reported SDM (66%, 56%, and 52%, respectively). No group reported completely pt-directed decisions. Pts and physicians demonstrated agreement about DLOC for most encounters (weighted κ = 0.35; P = 0.01). Overall, pts and physicians agreed on the DLOC in 44% of cases, and SDM was the most common agreed-upon DLOC (36%). Relative to physicians, 34% of pts reported more pt influence on DLOC, and 22% of pts reported less pt influence on DLOC. In contrast, caregiver reports of DLOC were independent of physician reports (weighted κ = 0.23; P = 0.55). Overall, caregivers and physicians agreed on DLOC in 38% of cases, and SDM was the most common agreed-upon DLOC (32%). Relative to physicians, 46% of caregivers reported more pt influence on DLOC and 16% of caregivers reported less pt influence on DLOC. There was a statistically significant difference in the degree of agreement by pt age group between pts and physicians (P = 0.045) and caregivers and physicians (P = 0.002), although no specific pattern according to pt age was noted. Conclusions: A majority of pts, caregivers, and physicians reported SDM occurring in routine clinical visits for mPC. Pts reported a higher degree of agreement with their physicians in DLOC than caregivers. Both pts and caregivers perceived greater pt influence on treatment choice than physicians. Efforts to explore the association between SDM, pt satisfaction, and quality of life are ongoing.

Technology-enhanced antenatal diet and lifestyle intervention could prevent excess gestational weight gain and benefit mother and child.A randomized clinical trial.Overweight and obese ethnically diverse pregnant women in Chicago, Illinois, were enrolled between October 2012 and December 2015, with antenatal data collection completed by July 2016. Analysis was completed June 2017.Participants were randomized when their fetus was gestational age 16 weeks to dietitian-led Dietary Approaches to Stop Hypertension diet and physical activity coaching that was received as three individual and six group counseling sessions by phone and webinar. A commercially available smartphone application was used for self-monitoring diet and physical activity. Telephone, text message prompts, and e-mail reminders encouraged adherence and website viewing. Usual-care, "web-watcher" participants were e-mailed biweekly newsletters and publicly available maternity website links.The primary outcome was gestational weight gain measured at baseline, 24 weeks, and 35.0-36.6 weeks. Secondary outcomes included weekly rate of gestational weight gain, newborn anthropometrics, maternal diet quality, physical activity, and blood pressure.Among 281 participants randomized (n=140 in intervention, n=141 in usual care, BMI 25 to40, and age range 18-40 years), 37% were non-white and 274 completed antenatal data collection (n=139 in the intervention group and n=135 in the usual-care group). Gestational weight gain differed significantly by intervention group (difference, 1.7kg, p=0.01) and rate of weight gain was 0.4 (SD=0.2) vs 0.5 (SD=0.2) kg/week. No significant differences were noted in birth weight, percentage body fat, or adverse pregnancy outcomes, but more cesarean sections (55 [40%] vs 37 [27%]) occurred among the intervention group.Technology-enhanced Dietary Approaches to Stop Hypertension diet and lifestyle intervention resulted in significantly less total gestational weight gain over 35 weeks with no adverse infant outcomes. Nutrient quality improved without an adverse impact on rate of prematurity. Increased cesarean delivery requires further exploration. The National Academy of Medicine goals were not achieved by the majority of participants. Obesity prevention preconception is needed.This study is registered at www.clinicaltrials.gov NCT01631747.

Low-Vt ventilation lowers mortality in patients with acute respiratory distress syndrome (ARDS) but is underused. Little is known about clinician attitudes toward and perceived barriers to low-Vt ventilation use and their association with actual low-Vt ventilation use.The objectives of this study were to assess clinicians' attitudes toward and perceived barriers to low-Vt ventilation (Vt6.5 ml/kg predicted body weight) in patients with ARDS, to identify differences in attitudes and perceived barriers among clinician types, and to compare attitudes toward and perceived barriers to actual low-Vt ventilation use in patients with ARDS.We conducted a survey of critical care physicians, nurses, and respiratory therapists at four non-ARDS Network hospitals in the Chicago region. We compared survey responses with performance in a cohort of 362 patients with ARDS.Survey responses included clinician attitudes toward and perceived barriers to low-Vt ventilation use. We also measured low-Vt ventilation initiation by these clinicians in 347 patients with ARDS initiated after ARDS onset as well as correlation with clinician attitudes and perceived barriers. Of 674 clinicians surveyed, 467 (69.3%) responded. Clinicians had positive attitudes toward and perceived few process barriers to ARDS diagnosis or initiation of low-Vt ventilation. Physicians had more positive attitudes and perceived fewer barriers than nurses or respiratory therapists. However, use of low-Vt ventilation by all three clinician groups was low. For example, whereas physicians believed that 92.5% of their patients with ARDS warranted treatment with low-Vt ventilation, they initiated low-Vt ventilation for a median (interquartile range) of 7.4% (0 to 14.3%) of their eligible patients with ARDS. Clinician attitudes and perceived barriers were not correlated with low-Vt ventilation initiation.Clinicians had positive attitudes toward low-Vt ventilation and perceived few barriers to using it, but attitudes and perceived process barriers were not correlated with actual low-Vt ventilation use, which was low. Implementation strategies should be focused on examining other issues, such as ARDS recognition and process solutions, to improve low-Vt ventilation use.

Background: Suicidality has rarely been studied in HIV-infected patients in sub-Saharan Africa. This study explored suicidal behavior in a clinic sample of people living with HIV, in Nigeria. Methods: Consecutive patients were interviewed using the Composite International Diagnostic Interview (CIDI-10.0) and the World Health Organization Quality of Life (WHO-QOL-HIV-BREF). Associations of suicidal behavior were explored using logistic regression models. Results: In this sample of 828 patients (71% female, mean age 41.3 ± 10 years), prevalence of suicidal behaviors were 15.1%, 5.8%, and 3.9% for suicidal ideation, plans, and attempts, respectively. Women were more likely than men to report suicidal ideation (odds ratio 1.7; 95% confidence interval 1.05-2.64). Depression and/or anxiety disorder was associated with increased odds of all suicidal behaviors. Suicidal behavior was associated with significantly lower overall and domain scores on the WHO-QOL. Conclusion: Suicidal behaviors were common and significantly associated with the presence of mental disorders and lower quality of life.

Background: Immune checkpoint blockade is emerging as an important immunotherapeutic strategy in esophageal cancer, yet response rates remain low. IDO1 is a rate-limiting immunosuppressive enzyme that may contribute to resistance to immune checkpoint blockade in human cancer, and may be an important immunotherapeutic target. The expression pattern of IDO1 across esophageal cancer histologies remains poorly understood. Here, we utilize immunohistochemistry to characterize the expression pattern and relevance of IDO1 in esophageal cancer. Methods: Tumor microarray containing samples of surgically resected esophageal carcinoma and normal esophageal tissue were stained for IDO1 and CD3ϵ (marker of T-cell infiltration). Demographic and staging data were collected. Light microscopic immunoscoring analysis was performed. Correlations were analyzed using Fisher’s exact test. Results: 192 samples were assessed (180 esophageal carcinoma, 12 normal esophageal tissue.) Median age was 60 years (range 34-78). 69.3% of patients were male. Of the 180 esophageal carcinoma samples, 150 (83.3%) squamous cell carcinoma, 16 (8.9%) adenocarcinoma, 13 (7.2%) small cell carcinoma, 7 (3.9%) undifferentiated carcinoma, 2 (1.1%) carcinoid, 2 (1.1%) adenosquamous carcinoma, and 2 (1.1%) adenoid cystic carcinoma. IDO1 was positive in 81 samples (45.0%) overall with 52.0% in squamous cell carcinoma and 46.7% in adenocarcinoma. Positive IDO1 was associated with higher stage and nodal positivity (P=0.04). T-cell infiltration in esophageal carcinoma specimens was present in 133 samples (73.9%). IDO1 positivity correlated with increased T-cell infiltration (P Conclusions: Here our study suggests that expression of IDO1 is positive in almost half of esophageal tumors, and is associated with T-cell infiltration. Additionally, positive IDO1 was associated with higher likelihood of nodal involvement and more advanced stage. These data suggest that IDO1 may play a role in adaptive immune resistance in T-cell inflamed tumors, and that incorporating IDO1 inhibition into an immunotherapeutic strategy in esophageal cancer may enhance T-cell mediated anti-tumor effect. Citation Format: Ari J. Rosenberg, Derek A. Wainwright, Angela J. Fought, Lijie Zhai, Kristen Lauing, Victoria M. Villaflor. Indoleamine 2,3 dioxegenase 1 (IDO1) and T-cell infiltration in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2341.

Background: Nipple aspiration fluid (NAF) use as a biosample is limited by the variable yield across studies. We investigated the endocrine determinants of yield in an ongoing breast cancer case–control study. Methods: One-hundred and eighteen women yielding ≥2 μL NAF and 120 non-yielders were included; serum hormones were measured; differences in median hormones were assessed using the Wilcoxon rank-sum test. ORs and 95% confidence intervals (95% CI) for yielder status relative to hormone levels were estimated using logistic regression, adjusting for parity and lactation, and, in premenopausal women, menstrual cycle phase (MCP). Results: Prolactin concentrations were higher in yielders than non-yielders (premenopausal: 7.6 and 2.5 ng/mL, P < 0.01; postmenopausal 5.3 and 2.2 ng/mL; P < 0.01). Among premenopausal-yielders, estradiol was lower (64.3 vs. 90.5 pg/mL, MCP-adjusted P = 0.02). In separate menopausal status and parity-adjusted models, significant case–control differences persisted in prolactin: case OR 1.93 (95% CI, 1.35–2.77), control OR 1.64 (95% CI, 1.17–2.29). Premenopausal control yielders had higher progesterone (OR, 1.70; 95% CI, 1.18–2.46) and sex-hormone binding-globulin (OR, 2.09; 95% CI, 1.08–4.05) than non-yielders. Among parous women, further adjustment for lactation suggested a stronger positive association of serum prolactin with yield in cases than controls. Conclusion: NAF-yielders show higher prolactin than non-yielders, regardless of menopause and parity; implications of this and other endocrine differences on NAF biomarkers of breast cancer risk deserve further study. Impact: NAF yield is associated with a distinct endocrine environment that must be considered in studies of NAF-based breast cancer risk markers. Cancer Epidemiol Biomarkers Prev; 22(12); 2277–84. ©2013 AACR.

Post-discharge morbidity and mortality for acute heart failure (AHF) patients remains high. Although the adverse effects of neurohormonal activation are well known in chronic HF, the prognostic significance of serum aldosterone in patients hospitalized for AHF has not been well studied.A secondary analysis was carried out of the placebo arm (n = 1850) from the EVEREST trial which had aldosterone measured at baseline. All patients were hospitalized for worsening HF and had an LVEF40%. The median follow-up was 9.9 months. The association between serum aldosterone levels at baseline and the independently adjudicated outcomes [all-cause mortality (ACM) and the combined outcome of cardiovascular mortality (CVM) and HF re-hospitalization] were explored with multivariable Cox models. Median aldosterone levels increased during the hospital stay from 11 ng/dL at baseline to 15 ng/dL at discharge (P0.001) and remained increased after discharge (16 ng/dL at 24 weeks, P0.001). After adjusting for potential confounders, higher baseline aldosterone levels were associated with an increased risk for ACM and CVM or HF re-hospitalization [hazard ratio (HR) 1.49, 95% confidence intrerval (CI) 1.11-1.99; and HR 1.40, 95% CI 1.11-1.78, respectively, in the highest quartile when compared with the lowest].In patients with LVEF40% hospitalized for AHF and receiving standard therapy, serum aldosterone levels correlated with worse post-discharge outcomes. Aldosterone levels increase during AHF hospitalization and remain increased long after discharge. These results suggest that further modulation of the renin-angiotensin-aldosterone system in patients admitted with worsening HF might favourably improve post-discharge outcomes.

Aims We evaluated the impact of diabetes mellitus (DM) and diabetic therapy on outcomes in patients with reduced ejection fraction (EF) after hospitalization for heart failure (HF). DM is prevalent in patients hospitalized with HF, yet inconclusive data exist on the post-discharge outcomes of this patient population. Methods and results Post-hoc analysis was performed on the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) study, a randomized trial of patients hospitalized with HF (n = 4133) with median follow-up of 9.9 months. DM status was determined from intake questionnaires and cross-verified by medication history. Univariate relationships were examined using χ[2] test, t-test, and Wilcoxon tests. The two primary outcomes of (i) all-cause mortality (ACM) and (ii) cardiovascular mortality or HF hospitalization (CVM + HFH) were assessed for those with and without DM and by diabetic treatment strategy using log rank tests and multivariable Cox regression models. DM was present in 40% of participants. Patients with DM were more likely to have hypertension, coronary artery disease, and chronic kidney disease. Diabetes was associated with ACM and CVM + HFH (both P < 0.001). Following multivariate risk adjustment, DM was associated with ACM, but this estimate was imprecise [hazard ratio (HR) 1.16; 95% confidence interval (CI) 1.00–1.34] and remained associated with CVM or HFH (HR 1.17; 95% CI 1.04–1.31). Diabetic control strategy did not independently affect outcomes. Conclusion Diabetes is common in patients hospitalized for heart failure with a reduced EF. These patients have a higher post-discharge CVM and higher HF hospitalizations compared with patients with no diabetes. Different diabetic treatment regimens did not appear to influence post-discharge outcomes.