Adjustment For Multiple Comparisons Research Articles

Utility of CT texture analysis to differentiate olfactory neuroblastoma from sinonasal squamous cell carcinoma

The purpose of this study was to examine differences in texture features between olfactory neuroblastoma (ONB) and sinonasal squamous cell carcinoma (SCC) on contrast-enhanced CT (CECT) images, and to evaluate the predictive accuracy of texture analysis compared to radiologists’ interpretations. Forty-three patients with pathologically-diagnosed primary nasal and paranasal tumor (17 ONB and 26 SCC) were included. We extracted 42 texture features from tumor regions on CECT images obtained before treatment. In univariate analysis, each texture features were compared, with adjustment for multiple comparisons. In multivariate analysis, the elastic net was used to select useful texture features and to construct a texture-based prediction model with leave-one-out cross-validation. The prediction accuracy was compared with two radiologists’ visual interpretations. In univariate analysis, significant differences were observed for 28 of 42 texture features between ONB and SCC, with areas under the receiver operating characteristic curve between 0.68 and 0.91 (median: 0.80). In multivariate analysis, the elastic net model selected 18 texture features that contributed to differentiation. It tended to show slightly higher predictive accuracy than radiologists’ interpretations (86% and 74%, respectively; P = 0.096). In conclusion, several texture features contributed to differentiation of ONB from SCC, and the texture-based prediction model was considered useful.

White Matter Connectivity in Incident Mild Cognitive Impairment: A Diffusion Spectrum Imaging Study of World Trade Center Responders at Midlife.

Background:Individuals who participated in response efforts at the World Trade Center (WTC) following 9/11/2001 are experiencing elevated incidence of mild cognitive impairment (MCI) at midlife.Objective:We hypothesized that white matter connectivity measured using diffusion spectrum imaging (DSI) would be restructured in WTC responders with MCI versus cognitively unimpaired responders.Methods:Twenty responders (mean age 56; 10 MCI/10 unimpaired) recruited from an epidemiological study were characterized using NIA-AA criteria alongside controls matched on demographics (age/sex/occupation/race/education). Axial DSI was acquired on a 3T Siemen’s Biograph mMR scanner (12-channel head coil) using a multi-band diffusion sequence. Connectometry examined whole-brain tract-level differences in white matter integrity. Fractional anisotropy (FA), mean diffusivity (MD), and quantified anisotropy were extracted for region of interest (ROI) analyses using the Desikan-Killiany atlas.Results:Connectometry identified both increased and decreased connectivity within regions of the brains of responders with MCI identified in the corticothalamic pathway and cortico-striatal pathway that survived adjustment for multiple comparisons. MCI was also associated with higher FA values in five ROIs including in the rostral anterior cingulate; lower MD values in four ROIs including the left rostral anterior cingulate; and higher MD values in the right inferior circular insula. Analyses by cognitive domain revealed nominal associations in domains of response speed, verbal learning, verbal retention, and visuospatial learning.Conclusions:WTC responders with MCI at midlife showed early signs of neurodegeneration characterized by both increased and decreased white matter diffusivity in regions commonly affected by early-onset Alzheimer’s disease.

Prevalence and cardiometabolic correlates of ketohexokinase gene variants among UK Biobank participants.

Essential fructosuria (EF) is a benign, asymptomatic, autosomal recessive condition caused by loss-of-function variants in the ketohexokinase gene and characterized by intermittent appearance of fructose in the urine. Despite a basic understanding of the genetic and molecular basis of EF, relatively little is known about the long-term clinical consequences of ketohexokinase gene variants. We examined the frequency of ketohexokinase variants in the UK Biobank sample and compared the cardiometabolic profiles of groups of individuals with and without these variants alone or in combination. Study cohorts consisted of groups of participants defined based on the presence of one or more of the five ketohexokinase gene variants tested for in the Affymetrix assays used by the UK Biobank. The rs2304681:G>A (p.Val49Ile) variant was present on more than one-third (36.8%) of chromosomes; other variant alleles were rare (<1%). No participants with the compound heterozygous genotype present in subjects exhibiting the EF phenotype in the literature (Gly40Arg/Ala43Thr) were identified. The rs2304681:G>A (p.Val49Ile), rs41288797 (p.Val188Met), and rs114353144 (p.Val264Ile) variants were more common in white versus non-white participants. Otherwise, few statistically or clinically significant differences were observed after adjustment for multiple comparisons. These findings reinforce the current understanding of EF as a rare, benign, autosomal recessive condition.

Genomic Characterization of de novo Metastatic Breast Cancer

In contrast to recurrence after initial diagnosis of stage I-III breast cancer [recurrent metastatic breast cancer (rMBC)], de novo metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS). Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC. When comparing primary tumors by subtype, MYB amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, P = 0.0005, q = 0.111). Mutations in KMTD2, SETD2, and PIK3CA were more prevalent, and TP53 and BRCA1 less prevalent, in primary HR+/HER2- tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; P = 0.008, q = 0.107), MYC (79.7 vs. 23.3 months; P = 0.0003, q = 0.011), and cell-cycle (122.7 vs. 54.9 months; P = 0.034, q = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC (P = 0.041). Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments.

Serum antioxidant vitamin concentrations and oxidative stress markers associated with symptoms and severity of premenstrual syndrome: a prospective cohort study

BackgroundIt has been suggested that premenstrual syndrome (PMS) may derive from either elevated oxidative stress or reduced antioxidant vitamin levels in the body; however, these relationships have been minimally studied in a large cohort of healthy women. Our objective was to estimate the association between serum concentrations of antioxidant vitamins (A, C, and E) and markers of oxidative stress (F2-isoprostane) with symptoms and severity of PMS.MethodsThe BioCycle study was a prospective cohort study following 259 healthy premenopausal women aged 18–44 years for up to 2 menstrual cycles. Frequency/severity of 20 PMS symptoms were assessed via questionnaires 4 times/cycle, and antioxidant vitamins and oxidative stress biomarkers were measured up to 8 times/cycle to correspond with specific cycle phases. Generalized linear models were used to estimate associations between mean antioxidant concentrations and oxidative stress biomarkers with PMS symptoms and severity; linear mixed models were used to evaluate associations with symptom severity scores within groups (e.g. depression, cravings, pain).ResultsHigher concentrations of serum antioxidant vitamins were largely not associated with prevalence or severity of PMS symptoms. Though a few associations were observed, only associations between mean γ-tocopherol and decreased odds of swelling of the hands/feet survived adjustment for multiple comparisons (OR 0.33, 95% CI 0.16, 0.65, per ug/dL). However, F2-isoprostanes were associated with prevalence and severity of several symptoms specifically related to depression and cravings (depression score β = 0.07, 95% CI 0.02, 0.12, per 10 ug/dL; cravings score β = 0.16, 95% CI 0.10, 0.22, per 10 ug/dL), as well as with classification of PMS severity (OR 1.07, 95% CI 1.01, 1.14, per 10 pg/dL), with these associations surviving adjustment for false discovery rate.ConclusionsF2-isoprostanes, but not antioxidant vitamins, were associated with select PMS symptoms, as well as symptom and severity categories. Specific symptom relationships merit further research.

Abstract PO063: Transcriptomic analysis identifies changes in gene expression in Actinic Keratoses after treatment with imiquimod and differential gene expression

Abstract Background: The presence of actinic keratoses (AKs) increases a patient’s risk of developing squamous cell carcinoma (SCC) by greater than six-fold. It is difficult to predict which AKs will progress to become SCC, and topical treatments such as imiquimod are used to treat the entire affected field indiscriminately, effectively eliminating AKs in 50% of patients but sometimes resulting in severe inflammation and pain. Defining biomarkers to predict response to treatment would be helpful to guide therapy. Objectives: To evaluate the effect of imiquimod on the tumor microenvironment by measuring transcriptomic differences in AKs before and after treatment in patients treated with imiquimod. Methods: Biopsies were collected prospectively from 21 patients with presumptive AK and examined histologically. All patients were treated with imiquimod 3.75% on a short cyclical treatment regimen. 19 patients had available pre-treatment AK biopsies and 14 patients had paired pre- and post-treatment biopsies. RNA was extracted and transcriptomic analyses of 788 genes were performed using the nanoString assay. Results: Imiquimod significantly decreased total number of AKs by study endpoint at week 14 (p&amp;lt;0.0001). Post-imiquimod therapy, levels of CDK1, CXCL13, IL1B, GADPH, TTK, ILF3, EWSR1, BIRC5, PLAUR, ISG20, and C1QBP were significantly lower (p&amp;lt;0.05 after adjustment for multiple comparisons), with CXCL13 and IL1B showing a greater than 2-log2 fold decrease in expression post-treatment. Complete responders (CR) exhibited a distinct pattern of inflammatory gene expression pre-treatment relative to incomplete responders (IR), with significant alterations in 15 inflammatory pathways (p&amp;lt;0.05) reflecting differential expression of 103 genes, of which 95 were upregulated in CR (p&amp;lt;0.05). Presence of adverse effects was found to be related to an improved treatment response. Conclusions: NanoString analysis of AKs pre- and post-treatment with imiquimod shows downregulation of genes implicated in oncogenesis and immune suppression. Differences in gene expression were found between pre-treatment samples in CR versus IR, suggesting that higher levels of inflammation pre-treatment may play a part in regression of AKs. Further, presence of adverse effects in response to therapy was associated with an improved response to imiquimod. These findings show that the pre-treatment immune micro-environment impacts responsiveness of AKs to imiquimod and that clinical inflammation during treatment is associated with AK resolution. Further characterization of the immune micro-environment in AKs may help develop biomarkers predictive of response to topical immune modulators and may guide therapy in patients with high numbers of AKs at risk for SCC. Citation Format: Megan H. Trager, Emanuelle Rizk, Sharon Rose, Branden Lau, Ben Fullerton, Kuixi Zhu, Jaya Pradhan, Michael Moore, Ayush Chandra, Margaret Bogardus, Giselle Singer, Robyn Gartrell-Corrado, Rui Chang, Larisa Geskin, Yvonne Saenger, Gary Goldenbery. Transcriptomic analysis identifies changes in gene expression in Actinic Keratoses after treatment with imiquimod and differential gene expression [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO063.

283 The surprising impact of maternal weight on the success of external cephalic version

Maternal obesity is considered an impediment for a successful external cephalic version (ECV). We aimed to evaluate the impact of maternal pre-pregnancy body mass index (BMI) and weight gain during pregnancy (WG) on the success rate of ECV. Retrospective analysis of the United States (US) Natality Live Birth database from the Centers for Disease Control and Prevention (2016-2018). The data were analyzed for singleton term births following an ECV attempt with a birth weight between 2500 and 5000 grams. Women were divided into several groups based on their BMI and WG. The success rates of ECV were compared among the different BMI and WG categories using the Pearson chi-square test with the Bonferroni adjustment for multiple comparisons. A logistic regression was used to calculate the independent contribution of maternal BMI and WG to the success of ECV, after controlling for maternal race/ethnicity, parity and neonatal birth weight. Results were displayed as odds ratios with 95% confidence intervals, and statistical significance was determined as a p-value below 0.05. Of the 11,150,527 live births in 2016 to 2018, 26,255 women who underwent an ECV attempt met the inclusion criteria. The overall ECV success rate was 52.75% (13,850 women). The success rates of ECV for the different BMI and WG categories ranged from 47.43% to 55.18% (Table 1). Although the overall differences in the success rates were small, a logistic regression model demonstrates that the odds for a successful ECV consistently decline with increasing BMI and with increasing WG (Table 2). We document a significant association between increases in both maternal BMI and WG and lower success rates of ECV. Nevertheless, given the small magnitude of these differences, with the exception of Extreme Obesity, these statistically significant differences are not clinically significant. Clinicians should therefore not rely heavily on maternal weight when considering an ECV attempt.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Association Between the ACA Medicaid Expansions and Changes in Cardiovascular Risk Factors Among Low-Income Individuals.

Evidence is limited as to whether the introduction of the Affordable Care Act (ACA)'s Medicaid expansions was associated with improvements in cardiovascular risk factors at the population level. To examine the association between the ACA Medicaid expansions and changes in cardiovascular risk factors among low-income individuals during the first 3years of the implementation of the ACA Medicaid expansions at the national level. A quasi-experimental difference-in-differences (DID) analysis to compare outcomes before (2005-2012) and after (2015-2016) the implementation of the ACA Medicaid expansions between individuals in states that expanded Medicaid and individuals in non-expansion states. A nationally representative sample of individuals aged 19-64years with family incomes below 138% of the federal poverty level from the 2005-2016 National Health and Nutrition Examination Survey (NHANES). ACA Medicaid expansions. Cardiovascular risk factors included (1) systolic and diastolic blood pressure, (2) hemoglobin A1c (HbA1c) level, and (3) cholesterol levels (low-density lipoproteincholesterol, triglyceride, and high-density lipoprotein cholesterol). A total of 9177 low-income individuals were included in our analysis. We found that the ACA Medicaid expansions were associated with a lower systolic blood pressure (DID estimate, - 3.03mmHg; 95% CI, - 5.33mmHg to - 0.73mmHg; P = 0.01; P = 0.03 after adjustment for multiple comparisons) and lower HbA1c level (DID estimate, - 0.14 percentage points [pp]; 95% CI, - 0.24pp to - 0.03pp; P = 0.01; P = 0.03 after adjustment for multiple comparisons). We found no evidence that diastolic blood pressure and cholesterol levels changed following the ACA Medicaid expansions. Using the nationally representative data of individuals who were affected by the ACA, we found that the ACA Medicaid expansions were associated with a modest improvement in cardiovascular risk factors related to hypertension and diabetes during the first 3years of implementation.

Prenatal Exposure to General Anesthesia and Childhood Behavioral Deficit.

Exposure to surgery and anesthesia in early childhood has been found to be associated with an increased risk of behavioral deficits. While the US Food and Drug Administration (FDA) has warned against prenatal exposure to anesthetic drugs, little clinical evidence exists to support this recommendation. This study evaluates the association between prenatal exposure to general anesthesia due to maternal procedures during pregnancy and neuropsychological and behavioral outcome scores at age 10. This is an observational cohort study of children born in Perth, Western Australia, with 2 generations of participants contributing data to the Raine Study. In the Raine Study, the first generation (Gen1) are mothers enrolled during pregnancy, and the second generation (Gen2) are the children born to these mothers from 1989 to 1992 with neuropsychological and behavioral tests at age 10 (n=2024). In the primary analysis, 6 neuropsychological and behavioral tests were evaluated at age 10: Raven's Colored Progressive Matrices (CPM), McCarron Assessment of Neuromuscular Development (MAND), Peabody Picture Vocabulary Test (PPVT), Symbol Digit Modality Test (SDMT) with written and oral scores, Clinical Evaluation of Language Fundamentals (CELF) with Expressive, Receptive, and Total language scores, and Child Behavior Checklist (CBCL) with Internalizing, Externalizing, and Total behavior scores. Outcome scores of children prenatally exposed to general anesthesia were compared to children without prenatal exposure using multivariable linear regression models adjusting for demographic and clinical covariates (sex, race, income, and maternal education, alcohol or tobacco use, and clinical diagnoses: diabetes, epilepsy, hypertension, psychiatric disorders, or thyroid dysfunction). Bonferroni adjustment was used for the 6 independent tests in the primary analysis, so a corrected P value <.0083 (P = .05 divided by 6 tests, or a 99.17% confidence interval [CI]) was required for statistical significance. Among 2024 children with available outcome scores, 22 (1.1%) were prenatally exposed to general anesthesia. Prenatally exposed children had higher CBCL Externalizing behavioral scores (score difference of 6.1 [99.17% CI, 0.2-12.0]; P = .006) than unexposed children. Of 6 tests including 11 scores and subscores, only CBCL Externalizing behavioral scores remained significant after multiple comparisons adjustment with no significant differences found in any other score. Prenatal exposure to general anesthetics is associated with increased externalizing behavioral problems in childhood. However, given the limitations of this study and that avoiding necessary surgery during pregnancy can have significant detrimental effects on the mother and the child, further studies are needed before changes to clinical practice are made.

Peripheral microangiopathy\xa0in precapillary pulmonary hypertension: a nailfold video capillaroscopy prospective study

BackgroundAlthough pulmonary vascular bed has been the main subject of research for many years in pulmonary hypertension (PH), interest has recently started to divert towards the possibility of a co-existing peripheral microangiopathy. The aim of the current study was to investigate the presence of nailfold video-capillaroscopic (NVC) structural changes in patients with precapillary PH and to identify possible associations of NVC measurements with markers of disease severity.MethodsΑ prospective case–control study was performed in 28 consecutive patients with precapillary PH [14 with idiopathic pulmonary arterial hypertension (IPAH) and 14 with chronic thromboembolic pulmonary hypertension (CTEPH)] and 30 healthy controls. NVC quantitative and qualitative parameters were evaluated using Optilia Digital Capillaroscope. To ensure inter-observer repeatability capillaroscopic images were reviewed by two independent investigators. For multiple comparisons among continuous variables, one-way ANOVA or the Kruskal–Wallis test were used. Differences between the groups were tested with post-hoc analysis with adjustment for multiple comparisons (Bonferroni test).ResultsBoth IPAH (71.4% were women, mean age 53.1 ± 13.4 years) and CTEPH (64.3% women, mean age 60.9 ± 14.4 years) groups presented reduced capillary density compared to healthy controls (8.4 ± 1.2 loops/mm and 8.0 ± 1.2 loops/mm vs. 9.7 ± 0.81 loops/mm, p < 0.001) and increased loop width (15.7 ± 3.9 μm and 15.8 ± 1.9 μm vs. 11.5 ± 2.3 μm, p < 0.001). More than half of patients with IPAH presented microhaemorrhages on capillary nailfold, while increased shape abnormalities in capillary morphology and more capillary thrombi per linear mm were detected in patients with CTEPH compared to patients with IPAH and healthy controls. All PH patients presented a non-specific NVC pattern compared to controls (p < 0.001).ConclusionThe findings of the study reveal a degree of significant peripheral microvascular alterations in patients with IPAH and CTEPH, suggesting a generalized impairment of peripheral microvasculature in pulmonary vascular disease.

Specific Dimensions of Depression Have Different Associations With Cognitive Decline in Older Adults With Type 2 Diabetes.

Depression is highly frequent in older adults with type 2 diabetes and is associated with cognitive impairment, yet little is known about how various depression dimensions differentially affect cognition. We investigated longitudinal associations of specific depression dimensions with cognitive decline. Participants (N = 1,002) were from the Israel Diabetes and Cognitive Decline study, were ≥65 years of age, had type 2 diabetes, and were not experiencing dementia at baseline. Participants underwent a comprehensive neuropsychological battery at baseline and every 18 months thereafter, including domains of episodic memory, attention/working memory, semantic categorization/language, and executive function, and Z-scores of each domain were averaged and further normalized to calculate global cognition. Depression items from the 15-item Geriatric Depression Scale were measured at each visit and subcategorized into five dimensions: dysphoric mood, withdrawal-apathy-vigor (entitled apathy), anxiety, hopelessness, and memory complaint. Random coefficients models examined the association of depression dimensions with baseline and longitudinal cognitive functioning, adjusting for sociodemographics and baseline characteristics, including cardiovascular risk factors, physical activity, and use of diabetes medications. In the fully adjusted model at baseline, all dimensions of depression, except for anxiety, were associated with some aspect of cognition (P values from 0.01 to <0.001). Longitudinally, greater apathy scores were associated with faster decline in executive function (P = 0.004), a result that withstood adjustment for multiple comparisons. Associations of other depression dimensions with cognitive decline were not significant (P > 0.01). Apathy was associated with a faster cognitive decline in executive function. These findings highlight the heterogeneity of depression as a clinical construct rather than as a single entity and point to apathy as a specific risk factor for cognitive decline among older adults with type 2 diabetes.

Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects

Mounting evidence shows that physical exercise modulates systemic inflammation. However, its effect on cerebrospinal fluid (CSF) immune-marker profiles in man are largely unknown. We here report a study on healthy subjects (n = 27, males = 12, mean age 28.7, range 22–52) allocated to either an acute exercise setting over four consecutive days, or a training intervention over 4 weeks. Paired plasma and CSF samples collected at baseline, after 7 days of exercise abstention, and the day after completion of the exercise interventions, were analyzed for protein inflammation markers using a multiplex proximity extension assay and neurotransmitters and kynurenine pathway (KP) metabolites using liquid chromatography, respectively. Routine cell counts, and albumin, immunoglobulin G and neurofilament light chain concentrations in CSF remained unchanged in both paradigms, while several inflammatory proteins became upregulated after acute exercise. However, only changes in three CSF (vascular endothelial growth factor-A, interleukin-7 and matrix metalloproteinase-10) and 12 plasma proteins reached significance levels after adjustment for multiple comparisons and exclusion of less stable proteins. Similarly, KP metabolites only changed among participants after acute exercise, while neurotransmitter levels, except for increased CSF serine, remained stable. Both in plasma and CSF changes in KP metabolites and inflammatory proteins correlated, suggesting that these processes are functionally linked. These findings suggest that acute aerobic physical exercise affects immune markers and KP metabolites systemically and in the CSF.

In Search for the Meaning of Illness: Content of Narrative Discourse Is Related to Cognitive Deficits in Stroke Patients.

Stroke survivors undergo a thorough cognitive diagnosis that often involves administration of multiple standardized tests. However, patient’s narrative discourse can provide clinicians with additional knowledge on patient’s subjective experience of illness, attitude toward current situation, and motivation for treatment. We evaluated the methods of analyzing thematic content and story types in relationship to cognitive impairment in stroke survivors with no aphasia (including 9 left hemisphere damage – LHD patients, and 16 right hemisphere damage – RHD patients). Cognitive impairment was evaluated in comparison to a group of 25 patients with orthopaedic injury not involving the brain. Our findings primarily show that higher elaboration on own cognitive problems, physical ailments or coping strategies in LHD patients and cognitive problems, emotional issues and circumstances of illness onset in RHD patients is related to deficits in executive functions and retrieval of information from memory. Furthermore, RHD patients who use more chaos story type show lower executive functioning. However, these results did not survive the significance threshold of p < 0.05 after Bonferroni adjustment for multiple comparisons. In conclusion, this study provides preliminary evidence that stroke survivor’s narrative can constitute an additional source of clinically-relevant information regarding patient’s experience of illness and attitude toward recovery. This knowledge can aid clinicians and nurses in everyday interactions with the patients and support individualized strategy to treatment. Still, the current results need be confirmed with future studies in a larger cohort of stroke patients.

Differences in the Selection of Health State Utility Values by Sponsorship in Published Cost-Effectiveness Analyses.

Health state utility values (HSUVs) are among the most influential attributes of cost-effectiveness analyses (CEAs). Our objective was to evaluate whether industry-funded studies select systematically different HSUVs as compared with studies without industry funding. Among 10 diseases with high disease burden in the United States, we further identified 31 progressive health states. We then searched the Tufts Medical Center's CEA Registry to identify studies that included HSUVs and were submitted to the registry between 2002 and 2019. Two reviewers mapped the free-text descriptions of health states onto the 31 predefined health states. We analyzed the effect of industry funding on the point estimates of these HSUVs with a beta regression. We also analyzed the difference between related health states within studies by funding source with a linear regression. After identifying 26,222 HSUVs from 4198 CEAs, we matched 2573 HSUVs to the 31 predefined health states. We observed large variations within each health state: 12 of 31 health states included a range of HSUVs greater than 0.5. The point estimate model showed 1 statistically significant difference of 31 comparisons between studies with any industry funding and those without. The utility difference model found 3 significant differences out of 39 comparisons between CEAs with any industry funding and those without. Inclusion of unpublished CEAs may have affected our conclusions about the effect of industry funding on selection of HSUVs. We also relied on free-text descriptions of health states available in the CEA Registry and did not include adjustment for multiple comparisons. Limited evidence exists that industry-funded studies select different HSUVs compared to non-industry-funded studies for the health states we considered.

Plasma angiopoietin-2 is associated with age-related deficits in cognitive sub-scales in Ugandan children following severe malaria

BackgroundElevated angiopoietin-2 (Angpt-2) concentrations are associated with worse overall neurocognitive function in severe malaria survivors, but the specific domains affected have not been elucidated.MethodsUgandan children with severe malaria underwent neurocognitive evaluation a week after hospital discharge and at 6, 12 and 24 months follow-up. The relationship between Angpt-2 concentrations and age-adjusted, cognitive sub-scale z-scores over time were evaluated using linear mixed effects models, adjusting for disease severity (coma, acute kidney injury, number of seizures in hospital) and sociodemographic factors (age, gender, height-for-age z-score, socio-economic status, enrichment in the home environment, parental education, and any preschool education of the child). The Mullen Scales of Early Learning was used in children < 5 years and the Kaufman Assessment Battery for Children 2nd edition was used in children ≥ 5 years of age. Angpt-2 levels were measured on admission plasma samples by enzyme-linked immunosorbent assay. Adjustment for multiple comparisons was conducted using the Benjamini–Hochberg Procedure of False Discovery Rate.ResultsIncreased admission Angpt-2 concentration was associated with worse outcomes in all domains (fine and gross motor, visual reception, receptive and expressive language) in children < 5 years of age at the time of severe malaria episode, and worse simultaneous processing and learning in children < 5 years of age at the time of severe malaria who were tested when ≥ 5 years of age. No association was seen between Angpt-2 levels and cognitive outcomes in children ≥ 5 years at the time of severe malaria episode, but numbers of children and testing time points were lower for children ≥ 5 years at the time of severe malaria episode.ConclusionElevated Angpt-2 concentration in children with severe malaria is associated with worse outcomes in multiple neurocognitive domains. The relationship between Angpt-2 and worse cognition is evident in children < 5 years of age at the time of severe malaria presentation and in selected domains in older years.

Longitudinal Trajectories in Cortical Thickness and Volume Atrophy: Superior Cognitive Performance Does Not Protect Against Brain Atrophy in Older Adults.

Background:Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable.Objective:Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years.Methods:Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70 + at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30–44 years old, and in the unimpaired range for all other cognitive domains over the course of the study.Results:In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-β negative individuals in the analyses, again there were no significant differences between SCPs and TOAs.Conclusion:The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age.

Tongue microbiome in children with autism spectrum disorder

ABSTRACT Background: A few recent studies have characterized the salivary microbiome in association with Autism Spectrum Disorder (ASD). Here, we sought to assess if there is an association between the tongue microbiome and ASD. Methods: Tongue scrapping samples were obtained from 25 children with ASD and 38 neurotypical controls. The samples were sequenced for the 16S rRNA gene (V1-V3) and the resultant high-quality reads were assigned to the species-level using our previously described BLASTn-based algorithm. Downstream analyses of microbial profiles were conducted using QIIME, LEfSe, and R. Results: Independent of grouping, Prevotella, Streptococcus, Leptotrichia, Veillonella, Haemophilus and Rothia accounted for > 60% of the average microbiome. Haemophilus parainfluenzae, Rothia mucilaginosa, Prevotella melaninogenica and Neisseria flavescens/subflava were the most abundant species. Species richness and diversity did not significantly differ between the study groups. Thirteen species and three genera were differentially abundant between the two groups, e.g. enrichment of Actinomyces odontolyticus and Actinomyces lingnae and depletion of Campylobacter concisus and Streptococcus vestibularis in the ASD group. However, none of them withstood adjustment for multiple comparisons. Conclusion: The tongue microbiome of children with ASD was not significantly different from that of healthy control children, which is largely consistent with results from the literature.

Polymorphisms in oxidative stress, metabolic detoxification, and immune function genes, maternal exposure to ambient air pollution, and risk of preterm birth in Taiyuan, China

Exposure to air pollutants may be associated with preterm birth (PB) through oxidative stress, metabolic detoxification, and immune system processes. However, no study has investigated the interactive effects of maternal air pollution and genetic polymorphisms in these pathways on risk of PB. The study included 126 PB and 310 term births. A total of 177 single nucleotide polymorphisms (SNPs) in oxidative stress, immune function, and metabolic detoxification-related genes were examined and analyzed. The China air quality index (AQI) was used as an overall estimation of ambient air pollutants. Among 177 SNPs, four SNPs (GPX4-rs376102, GLRX-rs889224, VEGFA-rs3025039, and IL1A-rs3783550) were found to have significant interactions with AQI on the risk of PB (Pinteraction were 0.001, 0.003, 0.03, and 0.04, respectively). After being stratified by the maternal genotypes in these four SNPs, 1.38 to 1.76 times of the risk of PB were observed as per interquartile range increase in maternal AQI among women who carried the GPX4-rs376102 AC/CC genotypes, the GLRX-rs889224 TT genotype, the VEGFA-rs3025039 CC genotype, or the IL1A-rs3783550 GT/TT genotypes. After adjustment for multiple comparisons, only GPX4-rs376102 and AQI interaction remained statistically significant (false discovery rate (FDR)=0.17). After additional stratification by preeclampsia (PE) status, a strongest association was observed in women who carried the GPX4-rs376102 AC/CC genotypes (OR, 2.26; 95% CI, 1.41–3.65, Pinteraction=0.0002, FDR=0.035) in the PE group. Our study provided the first evidence that association between maternal air pollution and PB risk may be modified by the genetic polymorphisms in oxidative stress and immune function genes. Future large studies are necessary to replicate and confirm the observed associations.

MYC DNA Methylation in Prostate Tumor Tissue Is Associated with Gleason Score.

Increasing evidence suggests a role of epigenetic mechanisms at chromosome 8q24, an important cancer genetic susceptibility region, in prostate cancer. We investigated whether MYC DNA methylation at 8q24 (six CpG sites from exon 3 to the 3′ UTR) in prostate tumor was associated with tumor aggressiveness (based on Gleason score, GS), and we incorporated RNA expression data to investigate the function. We accessed radical prostatectomy tissue for 50 Caucasian and 50 African American prostate cancer patients at the University of Maryland Medical Center, selecting an equal number of GS 6 and GS 7 cases per group. MYC DNA methylation was lower in tumor than paired normal prostate tissue for all six CpG sites (median difference: −14.74 to −0.20 percentage points), and we observed similar results for two nearby sites in The Cancer Genome Atlas (p < 0.0001). We observed significantly lower methylation for more aggressive (GS 7) than less aggressive (GS 6) tumors for three exon 3 sites (for CpG 212 (chr8:128753145), GS 6 median = 89.7%; GS 7 median = 85.8%; p-value = 9.4 × 10−4). MYC DNA methylation was not associated with MYC expression, but was inversely associated with PRNCR1 expression after multiple comparison adjustment (q-value = 0.04). Findings suggest that prostate tumor MYC exon 3 hypomethylation is associated with increased aggressiveness.

Genetic associations with a fever after measles-containing vaccines

ABSTRACT Children have elevated fever risk 1 to 2 weeks after the first dose of a measles-containing vaccine (MCV), which is likely affected by genetic, immunologic, and clinical factors. Fever after MCV is associated with febrile seizures, though may also be associated with higher measles antibody titers. This exploratory study investigated genetic and immunologic associations with a fever after MCV. Concurrent with a randomized Phase 3 clinical trial of 12–15-month-olds who received their first measles-mumps-rubella (MMR) vaccine in which parents recorded post-vaccination temperatures daily, we consented a subset to collect additional blood and performed human leukocyte antigens (HLA) typing. Association between fever 5–12 days after MMR (“MMR-associated”) and HLA type was assessed using logistic regression. We compared 42-day post-vaccination geometric mean titers (GMT) to measles between children who did and did not have fever using a t-test. We enrolled 86 children and performed HLA typing on 82; 13 (15.1%) had MMR-associated fever. Logistic regressions identified associations between MMR-associated fever and HLA Class I loci A-29:02 (P = .036), B-57:01 (P = .018), C-06:02 (P = .006), C-14:02 (P = .022), and Class II loci DRB1-15 (P = .045). However, Bonferroni's adjustment for multiple comparisons suggests that these associations could have been due to chance. Ninety-eight percent of children had protective antibody titers to measles; however, GMT was higher among those with fever compared with children without fever (P = .006). Fever after the measles vaccine correlated with genetic factors and higher immune response. This study suggests a possible genetic susceptibility to MMR-associated fever.