Specific Phobia, Fear, and the Autism Spectrum in Children and Adolescents: Adapting OST for ASD.

Fears and phobias are a common mental health concern for youth, and particularly for autistic youth. The following review briefly summarizes the extant literature on specific phobias and specific phobias in autistic youth. The evidence base is briefly highlighted pointing to the strong base behind behavioral and cognitive-behavioral treatments and techniques. A broad discussion of key evidence-based treatment findings is presented, leading up to the impactful work of Thomas H. Ollendick in researching Öst's One-Session Treatment (OST) with children and adolescents. OST for child specific phobias is discussed, and particular emphasis is given to this treatment's ongoing adaptation for use with youth on the autism spectrum.

Methodological examination of the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Score.

The objective of this study was to examine the impact of methodological changes to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Score on associations with risk for all-cause mortality, cancer mortality, and cancer risk jointly among older adults in the NIH-AARP Diet and Health Study. Weights were incorporated for each Score component; a continuous point scale was developed in place of the Score's fully discrete cut-points; and cut-point values were changed for physical activity and red meat based on evidence-based recommendations. Exploratory aims also examined the impact of separating components with more than one sub-component and whether all components were necessary to retain within this population utilizing a penalized scoring approach. Findings suggested weighting the original 2018 WCRF/AICR Score improved the score's predictive performance in association with all-cause mortality and provided more precise estimates in relation to cancer risk and mortality outcomes. The importance of healthy weight, physically activity, and plant-based foods in relation to cancer and overall mortality risk were highlighted in this population of older adults. Further studies are needed to better understand the consistency and generalizability of these findings across other populations.

Measuring Paranoid Beliefs in Adolescents: A Comparison of the Revised-Green et al.'s Paranoid Thoughts Scale (R-GPTS) and the Bird Checklist of Adolescent Paranoia (B-CAP).

Research on paranoid beliefs in adolescents is in its infancy. Valid and reliable assessments are essential to advancing the field, yet there is no current consensus as to which are optimal to use in this population. This study compared the psychometric properties of two measures of paranoia in a general population adolescent sample. A cross-sectional study with quota sampling (gender and age) recruited adolescents (14-17 years) from the UK (n = 262) and USA (n = 200), who completed the Revised Green et al. Paranoid Thoughts Scale (R-GPTS) and the Bird Checklist for Adolescent Paranoia (B-CAP). We assessed factor structures, intercorrelations, overlap of participants identified as at-risk for paranoid thoughts via both scales, convergent validity (scales with one another) and discriminant validity (distress, wellbeing, bullying and discrimination). Both scales performed equally well in terms of factorial validity. Intercorrelations between the subscales and with general distress were high for both measures. However, a substantial percentage of participants were identified as having paranoid beliefs according to the R-GPTS but not the B-CAP. Furthermore, the B-CAP showed a very high correlations (0.69 ≤ r ≤ 0.79) with self-reported bullying experiences, which bordered on multicollinearity. Findings highlight the possibility that B-CAP may risk confounding paranoid beliefs with exposure to bullying more so than R-GPTS, and that B-CAP may miss instances of elevated paranoia that are captured by the R-GPTS. Future research needs to further explore this by validating both scales with an external (e.g., interview-based) criterion for paranoia.

Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy.

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of protein phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor-suppressive resistance. Significance: A therapy consisting of deliberate hyperactivation of oncogenic signaling combined with perturbation of the stress responses that result from this is very effective in animal models of colon cancer. Resistance to this therapy is associated with loss of oncogenic signaling and reduced oncogenic capacity, indicative of tumor-suppressive drug resistance.

Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria.

Cerebral malaria is the deadliest complication that can arise from Plasmodium infection. CD8 T-cell engagement of brain vasculature is a putative mechanism of neuropathology in cerebral malaria. To define contributions of brain endothelial cell major histocompatibility complex (MHC) class I antigen-presentation to CD8 T cells in establishing cerebral malaria pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules, specifically from brain endothelium. This strategy allowed us to avoid off-target effects on iron homeostasis and class I-like molecules, which are known to perturb Plasmodium infection. This is the first endothelial-specific ablation of individual class-I molecules enabling us to interrogate these molecular interactions. In these studies, we interrogated human and mouse transcriptomics data to compare antigen presentation capacity during cerebral malaria. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we observed that H-2Kb and H-2Db class I molecules regulate distinct patterns of disease onset, CD8 T-cell infiltration, targeted cell death and regional blood-brain barrier disruption. Strikingly, ablation of either molecule from brain endothelial cells resulted in reduced CD8 T-cell activation, attenuated T-cell interaction with brain vasculature, lessened targeted cell death, preserved blood-brain barrier integrity and prevention of ECM and the death of the animal. We were able to show that these events were brain-specific through the use of parabiosis and created the novel technique of dual small animal MRI to simultaneously scan conjoined parabionts during infection. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium differentially regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria.

Senescent and disease-associated microglia are modifiable features of aged brain white matter.

Brain white matter tracts undergo structural and functional changes linked to late-life cognitive decline, but the cellular and molecular contributions to their selective vulnerability are not well defined. In naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampus-adjacent white matter. Through gold-standard gene expression and immunolabeling combined with high-dimensional spatial mapping, we identified microglial cell fates in aged white matter characterized by aberrant morphology, microenvironment reorganization, and expression of senescence and DAM markers, including galectin 3 (GAL3/Lgals3), B-cell lymphoma 2 (Bcl2), and cyclin dependent kinase inhibitors, including Cdkn2a/p16ink4a. Pharmacogenetic or pharmacological targeting of p16ink4a or BCL2 reduced white matter GAL3+ DAM abundance and rejuvenated microglial fimbria organization. Our results demonstrate dynamic changes in microglial identity in aged white matter that can be reverted by senotherapeutic intervention to promote homeostatic maintenance in the aged brain.

An effective live-attenuated Zika vaccine candidate with a modified 5' untranslated region.

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that has caused devastating congenital Zika syndrome (CZS), including microcephaly, congenital malformation, and fetal demise in human newborns in recent epidemics. ZIKV infection can also cause Guillain-Barré syndrome (GBS) and meningoencephalitis in adults. Despite intensive research in recent years, there are no approved vaccines or antiviral therapeutics against CZS and adult Zika diseases. In this report, we developed a novel live-attenuated ZIKV strain (named Z7) by inserting 50 RNA nucleotides (nt) into the 5' untranslated region (UTR) of a pre-epidemic ZIKV Cambodian strain, FSS13025. We used this particular ZIKV strain as it is attenuated in neurovirulence, immune antagonism, and mosquito infectivity compared with the American epidemic isolates. Our data demonstrate that Z7 replicates efficiently and produces high titers without causing apparent cytopathic effects (CPE) in Vero cells or losing the insert sequence, even after ten passages. Significantly, Z7 induces robust humoral and cellular immune responses that completely prevent viremia after a challenge with a high dose of an American epidemic ZIKV strain PRVABC59 infection in type I interferon (IFN) receptor A deficient (Ifnar1-/-) mice. Moreover, adoptive transfer of plasma collected from Z7 immunized mice protects Ifnar1-/- mice from ZIKV (strain PRVABC59) infection. These results suggest that modifying the ZIKV 5' UTR is a novel strategy to develop live-attenuated vaccine candidates for ZIKV and potentially for other flaviviruses.

Distinct spatial immune microlandscapes are independently associated with outcomes in triple-negative breast cancer.

The utility of spatial immunobiomarker quantitation in prognostication and therapeutic prediction is actively being investigated in triple-negative breast cancer (TNBC). Here, with high-plex quantitative digital spatial profiling, we map and quantitate intraepithelial and adjacent stromal tumor immune protein microenvironments in systemic treatment-naïve (female only) TNBC to assess the spatial context in immunobiomarker-based prediction of outcome. Immune protein profiles of CD45-rich and CD68-rich stromal microenvironments differ significantly. While they typically mirror adjacent, intraepithelial microenvironments, this is not uniformly true. In two TNBC cohorts, intraepithelial CD40 or HLA-DR enrichment associates with better outcomes, independently of stromal immune protein profiles or stromal TILs and other established prognostic variables. In contrast, intraepithelial or stromal microenvironment enrichment with IDO1 associates with improved survival irrespective of its spatial location. Antigen-presenting and T-cell activation states are inferred from eigenprotein scores. Such scores within the intraepithelial compartment interact with PD-L1 and IDO1 in ways that suggest prognostic and/or therapeutic potential. This characterization of the intrinsic spatial immunobiology of treatment-naïve TNBC highlights the importance of spatial microenvironments for biomarker quantitation to resolve intrinsic prognostic and predictive immune features and ultimately inform therapeutic strategies for clinically actionable immune biomarkers.

Capturing nystagmus in the emergency room: posterior circulation stroke versus acute vestibular neuritis.

OBJECTIVES: To compare acute nystagmus characteristics of posterior circulation stroke (PCS) and acute vestibular neuritis (AVN) in the emergency room (ER) within 24 h of presentation. METHODS: ER-based video-nystagmography (VNG) was conducted, recording ictal nystagmus in 101 patients with PCS (on imaging) and 104 patients with AVN, diagnosed on accepted clinical and vestibular test criteria. RESULTS: Patients with stroke in the brainstem (38/101, affecting midbrain (n = 7), pons (n = 19), and medulla (n = 12)), cerebellum (31/101), both (15/101) or other locations (17/101) were recruited. Common PCS territories included posterior-inferior-cerebellar-artery (41/101), pontine perforators (18/101), multiple-territories (17/101) and anterior-inferior-cerebellar-artery (7/101). In PCS, 44/101 patients had no spontaneous nystagmus. Remaining PCS patients had primary position horizontal (44/101), vertical (8/101) and torsional (5/101) nystagmus. Horizontal nystagmus was 50% ipsiversive and 50% contraversive in lateralised PCS. Most PCS patients with horizontal nystagmus (28/44) had unidirectional "peripheral-appearing" nystagmus. 32/101 of PCS patients had gaze-evoked nystagmus. AVN affected the superior, inferior or both divisions of the vestibular nerve in 55/104, 4/104 and 45/104. Most (102/104) had primary position horizontal nystagmus; none had gaze-evoked nystagmus. Two inferior VN patients had contraversive torsional-downbeat nystagmus. Horizontal nystagmus with SPV ≥ 5.8 °/s separated AVN from PCS with sensitivity and specificity of 91.2% and 83.0%. Absent nystagmus, gaze-evoked nystagmus, and vertical-torsional nystagmus were highly specific for PCS (100%, 100% and 98.1%). CONCLUSION: Nystagmus is often absent in PCS and always present in AVN. Unidirectional 'peripheral-appearing' horizontal nystagmus can be seen in PCS. ER-based VNG nystagmus assessment could provide useful diagnostic information when separating PCS from AVN.

Cancer and Vascular Comorbidity Effects on Dementia Risk and Neuropathology in the Oldest-Old.

BACKGROUND: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. OBJECTIVE: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. METHODS: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. RESULTS: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95-106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19-0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39-163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17-0.78]; p < 0.01) and lower Braak stage (p = 0.01). CONCLUSION: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-ß plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

APOBEC Mutational Signatures in Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancers Are Associated With Poor Outcomes on CDK4/6 Inhibitors and Endocrine Therapy.

PURPOSE: APOBEC mutagenesis underlies somatic evolution and accounts for tumor heterogeneity in several cancers, including breast cancer (BC). In this study, we evaluated the characteristics of a real-world cohort for time-to-treatment discontinuation (TTD) and overall survival on CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) and immune checkpoint inhibitors. METHODS: Comprehensive genomic profiling results from 29,833 BC samples were analyzed for tumor mutational burden and APOBEC signatures. For clinical outcomes, a deidentified nationwide (United States-based) BC Clinico-Genomic Database (CGDB) was evaluated with log-rank and Cox models. Patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) BC who received first-line ET and CDK4/6i were included. Eligible patients from Mayo Clinic and Duke University were HR+ HER2- BC with sequencing data between September 2013 and July 2020. RESULTS: Of 29,833 samples sequenced, 7.9% were APOBEC+ with a high rate in invasive lobular carcinoma (16.7%) and in metastatic tumors (9.7%) relative to locally biopsied BC (4.3%; P < .001). In CGDB, 857 patients with HR+ HER2- BC received ET plus CDK4/6i in the first line. APOBEC+ patients had significantly shorter TTD on ET plus CDK4/6i than APOBEC- patients, 7.8 (95% CI, 4.3 to 14.6) versus 12.4 months (95% CI, 11.2 to 14.1; hazard ratio, 1.6; 95% CI, 1.03 to 2.39; P = .0036). Clinical benefit to immune checkpoint inhibitors was observed in HR+ HER2-, APOBEC+, tumor mutational burden-high patients, with four of nine CGDB patients (TTD 0.3-11.3 months) and four of six patients in Duke/Mayo cohorts (TTD 0.9-40.5 months) with a TTD of ≥ 3 months. CONCLUSION: APOBEC+ HR+ HER2- patients had shorter TTD on first-line ET plus CDK4/6i relative to APOBEC- patients. Further research is needed to optimize the treatment of APOBEC+ HR+ HER2- BC and to investigate the efficacy of immunotherapeutic strategies in this population.

Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance.

Cellular senescence is a plausible mediator of inflammation-related tissue dysfunction. In the aged brain, senescent cell identities and the mechanisms by which they exert adverse influence are unclear. Here we used high-dimensional molecular profiling, coupled with mechanistic experiments, to study the properties of senescent cells in the aged mouse brain. We show that senescence and inflammatory expression profiles increase with age and are brain region- and sex-specific. p16-positive myeloid cells exhibiting senescent and disease-associated activation signatures, including upregulation of chemoattractant factors, accumulate in the aged mouse brain. Senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro. Activated resident and infiltrating immune cells increase in the aged brain and are partially restored to youthful levels through p16-positive senescent cell clearance in female p16-InkAttac mice, which is associated with preservation of cognitive function. Our study reveals dynamic remodeling of the brain immune cell landscape in aging and suggests senescent cell targeting as a strategy to counter inflammatory changes and cognitive decline.

Evidence of cerebellar TDP-43 loss of function in FTLD-TDP.

Frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) is a neurodegenerative disease primarily affecting the frontal and/or temporal cortices. However, a growing body of evidence suggests that the cerebellum contributes to biochemical, cognitive, and behavioral changes in FTLD-TDP. To evaluate cerebellar TDP-43 expression and function in FTLD-TDP, we analyzed TDP-43 protein levels and the splicing of a TDP-43 target, STMN2, in the cerebellum of 95 FTLD-TDP cases and 25 non-neurological disease controls. Soluble TDP-43 was decreased in the cerebellum of FTLD-TDP cases but a concomitant increase in insoluble TDP-43 was not seen. Truncated STMN2 transcripts, an indicator of TDP-43 dysfunction, were elevated in the cerebellum of FTLD-TDP cases and inversely associated with TDP-43 levels. Additionally, lower cerebellar TDP-43 associated with a younger age at disease onset. We provide evidence of TDP-43 loss of function in the cerebellum in FTLD-TDP, supporting further investigation into this understudied brain region.

Towards defining morphologic parameters of normal parous and nulliparous breast tissues by artificial intelligence.

BACKGROUND: Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described. METHODS: Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors ≤ 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean "capillary" area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fisher's exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: ≤ 5 years versus remote birth: > 5 years]) using multivariable regression models. RESULTS: Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p < 0.001). Differences in TDLU counts and average acini size persisted for > 5 years postpartum, whereas increases in immune cells were most marked ≤ 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. CONCLUSIONS: Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.

Adaptive immune signature in HER2-positive breast cancer in NCCTG (Alliance) N9831 and NeoALTTO trials.

Trastuzumab acts in part through the adaptive immune system. Previous studies showed that enrichment of immune-related gene expression was associated with improved outcomes in HER2-positive (HER2+) breast cancer. However, the role of the immune system in response to lapatinib is not fully understood. Gene expression analysis was performed in 1,268 samples from the North Central Cancer Treatment Group (NCCTG) N9831 and 244 samples from the NeoALTTO trial. In N9831, enrichment of CD45 and immune-subset signatures were significantly associated with improved outcomes. We identified a novel 17-gene adaptive immune signature (AIS), which was found to be significantly associated with improved RFS among patients who received adjuvant trastuzumab (HR 0.66, 95% CI 0.49-0.90, Cox regression model p = 0.01) but not in patients who received chemotherapy alone (HR 0.96, 95% CI 0.67-1.40, Cox regression model p = 0.97). This result was validated in NeoALTTO. Overall, AIS-low patients had a significantly lower pathologic complete response (pCR) rate compared with AIS-high patients (χ2 p < 0.0001). Among patients who received trastuzumab alone, pCR was observed in 41.7% of AIS-high patients compared with 9.8% in AIS-low patients (OR of 6.61, 95% CI 2.09-25.59, logistic regression model p = 0.003). More importantly, AIS-low patients had a higher pCR rate with an addition of lapatinib (51.1% vs. 9.8%, OR 9.65, 95% CI 3.24-36.09, logistic regression model p < 0.001). AIS-low patients had poor outcomes, despite receiving adjuvant trastuzumab. However, these patients appear to benefit from an addition of lapatinib. Further studies are needed to validate the significance of this signature to identify patients who are more likely to benefit from dual anti-HER2 therapy. ClinicalTrials.gov Identifiers: NCT00005970 (NCCTG N9831) and NCT00553358 (NeoALTTO).

Beta-2 Adrenergic Receptor Gene Expression in HER2-Positive Early-Stage Breast Cancer Patients: A Post-hoc Analysis of the NCCTG-N9831 (Alliance) Trial.

BACKGROUND: Beta-2 adrenergic receptor (ß2AR) modulates immune activation and may enhance trastuzumab activity. We assessed the impact of ß2AR gene (ADRB2) expression on the outcomes of patients with HER2-positive early-stage breast cancer enrolled on the NCCTG-N9831 trial. PATIENTS AND METHODS: This is a post-hoc analysis of the NCCTG-N9831 trial, which compared chemotherapy (arm A) versus chemotherapy plus trastuzumab (arms B&C) as adjuvant treatment of patients with HER2-positive early-stage breast cancer, with disease-free survival (DFS) as primary endpoint. Gene expression levels retrieved by DASL assay were used to classify patients as ADRB2-high or ADRB2-low. Hazard ratios (HRs) were calculated by a Cox proportional model adjusted for prognostic variables and ADRB2 expression. Correlations between ADRB2 expression and stromal tumor-infiltrating lymphocyte (TIL) levels were assessed with Pearson coefficient. A multivariable Cox regression model with interaction term was performed to assess the interaction between ADRB2 expression and treatment arm; and ADRB2 expression and a 8-gene signature previously shown to predict trastuzumab benefit. RESULTS: Overall, 1,282 patients were included (ADRB2-high [N = 944] / ADRB2-low [N = 338]). A high expression of ADRB2 was associated with a longer DFS (P = .01) in the overall population. The addition of trastuzumab to chemotherapy improved DFS only in patients with ADRB2-high tumors (P < .01). ADRB2 expression was correlated with TIL levels (r = 0.24, P < .001). No association between ADRB2 expression and the 8-gene trastuzumab benefit signature was observed (P = .32). CONCLUSION: Our findings suggest that a high ADRB2 expression is a favorable prognostic factor and may identify patients with HER2-positive early-stage breast cancer who benefit from adjuvant trastuzumab. TRIAL REGISTRATION: clinicaltrials.gov NCT00005970.

Prevalence and temporal trends of anemia in patients with heart failure.

BACKGROUND: Anemia is an important comorbidity in heart failure (HF), and it is associated with increased adverse disease experience and mortality. Previous reports have focused mainly on HF presenting in healthcare settings. We, therefore, set out to establish the nationwide prevalence and temporal trends of anemia in community-based patients with HF in the US. AIM: To establish the nationwide prevalence and temporal trends of anemia in community-based patients with HF in the US. DESIGN: The NHANES dataset, conducted by the CDC National Center for Health Statistics was used to collect nationally representative data on the health and nutritional status of the non-institutionalized US population. METHODS: We utilized the National Health and Nutrition Examination data collected over five survey cycles (2007-16). Included were participants aged 20-80 years with self-reported diagnosis of HF. Anemia was defined using 2 sex specific cut offs of 13 and 12 g/dl (cutoff 1), and 12 and 11 g/dl (cutoff 2), for men and women, respectively. The Chi square test was used to compare prevalence across different categories and survey cycles. Data analysis was done using STATA 16 with P-values < 0.05 considered statistically significant. RESULTS: The median hemoglobin in all HF patients was 13.5 g/dl (IQR 12.4-14.5). The prevalence of anemia among community-based patients with HF in the US was 21.34% (cutoff 1) and 9.03% (cutoff 2) and has been stable from 2007 to 2016. The burden of anemia was disproportionately higher in NH Blacks (34.48%, 95% CI 27.12-42.67) and those with BMI < 25 Kg/m2 (17.4%, 95% CI 10.9-26.64). CONCLUSION: The prevalence of anemia in patients with HF in the US is at least 9% and has remained stable over the past decade. This high persistent burden with limited proven interventions should spur further efforts aimed at identifying impactful ways of addressing anemia in patients with HF.

A semiparametric risk score for physical activity.

We develop a generalized partially additive model to build a single semiparametric risk scoring system for physical activity across multiple populations. A score comprised of distinct and objective physical activity measures is a new concept that offers challenges due to the nonlinear relationship between physical behaviors and various health outcomes. We overcome these challenges by modeling each score component as a smooth term, an extension of generalized partially linear single-index models. We use penalized splines and propose two inferential methods, one using profile likelihood and a nonparametric bootstrap, the other using a full Bayesian model, to solve additional computational problems. Both methods exhibit similar and accurate performance in simulations. These models are applied to the National Health and Nutrition Examination Survey and quantify nonlinear and interpretable shapes of score components for all-cause mortality.

Best Practices for Spatial Profiling for Breast Cancer Research with the GeoMx® Digital Spatial Profiler.

Breast cancer is a heterogenous disease with variability in tumor cells and in the surrounding tumor microenvironment (TME). Understanding the molecular diversity in breast cancer is critical for improving prediction of therapeutic response and prognostication. High-plex spatial profiling of tumors enables characterization of heterogeneity in the breast TME, which can holistically illuminate the biology of tumor growth, dissemination and, ultimately, response to therapy. The GeoMx Digital Spatial Profiler (DSP) enables researchers to spatially resolve and quantify proteins and RNA transcripts from tissue sections. The platform is compatible with both formalin-fixed paraffin-embedded and frozen tissues. RNA profiling was developed at the whole transcriptome level for human and mouse samples and protein profiling of 100-plex for human samples. Tissue can be optically segmented for analysis of regions of interest or cell populations to study biology-directed tissue characterization. The GeoMx Breast Cancer Consortium (GBCC) is composed of breast cancer researchers who are developing innovative approaches for spatial profiling to accelerate biomarker discovery. Here, the GBCC presents best practices for GeoMx profiling to promote the collection of high-quality data, optimization of data analysis and integration of datasets to advance collaboration and meta-analyses. Although the capabilities of the platform are presented in the context of breast cancer research, they can be generalized to a variety of other tumor types that are characterized by high heterogeneity.

Factors associated with reported likelihood to get vaccinated for COVID-19 in a nationally representative US survey.

OBJECTIVES: Although general principles related to vaccination hesitancy have been well researched, reports on reluctance to be vaccinated for coronavirus disease 2019 (COVID-19) in the United States are somewhat surprising, given the disease's substantive disruption of everyday life. However, the landscape in which people are making COVID-19 vaccination decisions has recently evolved with releases of encouraging vaccine-related data and changes to official messaging about the virus. Therefore, this study sought to identify factors associated with reported likelihood to get vaccinated for COVID-19 among US adults in late January 2021. STUDY DESIGN: We used the Prolific online research panel to survey a nationally representative sample of 1017 US adults. METHODS: Respondents were asked about their behavioral intentions toward COVID-19 vaccination, trust in science, perceptions related to COVID-19, and selected sociodemographic factors. We computed associations between those 11 independent variables and likelihood to get vaccinated for COVID-19 using multiple linear regression. RESULTS: Around 73.9% of respondents indicated at least some likelihood to get vaccinated for COVID-19. Trust in science and perceived seriousness of COVID-19 were positively associated with intention to get vaccinated, and identifying as Black or African American was negatively associated with intention to get vaccinated. Other factors were moderately, weakly, or not at all associated with intention. CONCLUSIONS: Building trust in science and truthfully emphasizing the seriousness of catching COVID-19 should be further researched for their potential to support campaigns to encourage COVID-19 vaccination. Data continue to suggest the importance of dialogue with Black communities about COVID-19 vaccination.