Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk.

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10-8); rs79942605 (OR = 2.17, P = 2.81×10-8) and rs208908 (OR = 0.70, P = 4.54×10-8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Identification of genetically predicted DNA methylation markers associated with non-small cell lung cancer risk among 34,964 cases and 448,579 controls.

BACKGROUND: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated. METHODS: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways. RESULTS: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10-6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10-3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified. CONCLUSIONS: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby. PLAIN LANGUAGE SUMMARY: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer.

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1ß pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization.

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10-4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR = .011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR = .036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.

Markers of Quality Care for Newly Diagnosed People With Epilepsy on Medicaid.

BACKGROUND: For newly diagnosed people with epilepsy (PWE), proper treatment is important to improve outcomes, yet limited data exist on markers of quality care. OBJECTIVE: Examine markers of quality care for newly diagnosed PWE. METHODS: Using Medicaid claims data (2010-2014) for 15 states we identified adults 18-64 years of age diagnosed with incident epilepsy in 2012 or 2013. We built 5 sequential logistic regression models to evaluate: (1) seeing a neurologist; (2) diagnostic evaluation; (3) antiepileptic medication adherence; (4) serum drug levels checked; and (5) being in the top quartile of number of negative health events (NHEs). We adjusted for demographics, comorbidities, county-level factors, and the outcomes from all prior models. RESULTS: Of 25,663 PWE, 37.3% saw a neurologist, with decreased odds for those of older age, those residing in counties with low-density of neurologists, and certain race/ethnicities; about 57% of PWE received at least 1 diagnostic test; and nearly 62% of PWE were adherent to their medication. The most common comorbidities were hypertension (37.1%) and psychoses (26.9%). PWE with comorbidities had higher odds of seeing a neurologist and to have NHEs. Substance use disorders were negatively associated with medication adherence and positively associated with high NHEs. CONCLUSIONS: There are notable differences in demographics among people with incident epilepsy who do or do not see a neurologist. Differences in NHEs persist, even after controlling for neurologist care and diagnostic evaluation. Continued attention to these disparities and comorbidities is needed in the evaluation of newly diagnosed PWE.

The Incidence of Amyotrophic Lateral Sclerosis in Ohio 2016-2018: The Ohio Population-Based ALS Registry.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal, neuromuscular disease with no cure. ALS incidence rates have not been assessed specifically in Ohio, yet the state contains both metropolitan and rural areas with a variety of environmental factors that could contribute to disease etiology. We report the incidence of ALS in Ohio residents diagnosed from October 2016 through September 2018. METHODS: We engaged practitioners from 9 Ohio sites to identify newly diagnosed ALS patients and to complete case report forms with demographic and clinical information. ALS was diagnosed according to the Awaji criteria and classified as either definite, probable, or possible. We developed a method to estimate missing cases using a Poisson regression model to impute cases in counties with evidence of undercounting. RESULTS: We identified 333 newly diagnosed ALS patients residing in Ohio during the 2-year index period and found incidence rates varied in the 88 state counties. After incorporating the estimated 27% of missing cases, the corrected crude annual incidence was 1.96/100,000 person-years, and the age- and gender-standardized incidence was 1.71/100,000 person-years (standardized to the 2010 US census). DISCUSSION/CONCLUSION: The estimated Ohio incidence of ALS is overall similar to that reported in other states in the USA. This study reveals a geospatial variation in incidence within the state, and areas with higher rates warrant future investigation.

Features of intracranial interictal epileptiform discharges associated with memory encoding.

OBJECTIVE: Interictal epileptiform discharges (IEDs) were shown to be associated with cognitive impairment in persons with epilepsy. Previous studies indicated that IED rate, location, timing, and spatial relation to the seizure onset zone could predict an IED's impact on memory encoding and retrieval if they occurred in lateral temporal, mesial temporal, or parietal regions. In this study, we explore the influence that other IED properties (e.g., amplitude, duration, white matter classification) have on memory performance. We were specifically interested in investigating the influence that lateral temporal IEDs have on memory encoding. METHODS: Two hundred sixty-one subjects with medication-refractory epilepsy undergoing intracranial electroencephalographic monitoring performed multiple sessions of a delayed free-recall task (n = 671). Generalized linear mixed models were utilized to examine the relationship between IED properties and memory performance. RESULTS: We found that increased IED rate, IEDs propagating in white matter, and IEDs localized to the left middle temporal region were associated with poorer memory performance. For lateral temporal IEDs, we observed a significant interaction between IED white matter categorization and amplitude, where IEDs with an increased amplitude and white matter propagation were associated with reduced memory performance. Additionally, changes in alpha power after an IED showed a significant positive correlation with memory performance. SIGNIFICANCE: Our results suggest that IED properties may be useful for predicting the impact an IED has on memory encoding. We provide an essential step toward understanding pathological versus potentially beneficial interictal epileptiform activity.

Risk factors for amyotrophic lateral sclerosis: A regional United States case-control study.

Most amyotrophic lateral sclerosis (ALS) cases are considered sporadic, without a known genetic basis, and environmental exposures are thought to play a causal role. To learn more about sporadic ALS etiology, we recruited n = 188 ALS patients from northern New England and Ohio and matched controls 2:1 from the general population of the same regions. Questionnaires evaluated the association between a variety of lifestyle, behavioral (ie, hobbies and activities), and occupational factors and the risk of ALS, including the duration of time between exposure and ALS onset, and exposure frequency. Head trauma was associated with increased ALS risk (adjusted odds ratio [OR] 1.60 95% confidence interval [CI] 1.04-2.45), with significantly greater effects for injuries occurring 10 or more years prior to symptom onset (P = .037). ALS risk was increased for those reporting severe electrical burns (adjusted OR 2.86, 95% CI 1.37-6.03), with odds ratios highest for burns after age 30 (OR 3.14), and for burns 10 or more years prior to symptom onset (OR 3.09). Hobbies involving lead were the most strongly associated with ALS risk (adjusted OR 2.92, 95% CI 1.45-5.91). Exposures to lead 20 or more years prior to diagnosis had larger effect sizes compared to those occurring more recently. Holding a job in mechanics, painting, or construction was associated with ALS. The identification of these specific environmental factors associated with ALS highlight the need for future prospective and laboratory studies to assess causality, biological mechanisms, and find prevention or treatment opportunities.

Factors associated with suicidal ideation in an epilepsy center in Northern New England.

Suicidal ideation (SI), defined as thoughts and feelings of ending one's life, is a known risk factor for completed suicide. Although studies show that rates of SI are elevated in persons with epilepsy (PWE) compared to the general population, it is presently unclear how disease, social, and psychological factors contribute to its frequency and severity. With an overarching goal to develop a screening tool for suicide prevention, the objective of this study was to understand the rate, severity, and factors associated with SI in a large cohort of PWE. A generalized linear mixed model was used to test the relationship between changes in SI and disease, social, and psychological variables in 2450 PWE over a period of four years. The prevalence of SI was 23.6%. Associated disease factors included increased seizure frequency, severity, and recency. SI was impacted by employment status, but not by driving. Depression scores and aggression were highly associated with frequency and severity of SI. These findings highlight that disease, social, and psychological factors impact levels of SI in PWE and that screening for suicide prevention in PWE should include measures of such factors.

Genome-wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk.

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 × 10-8 ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 × 10-7 ; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83 × 10-7 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 × 10-8 ). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.

Transcriptome-wide association study reveals candidate causal genes for lung cancer.

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.

Molecular genetic profiling reveals novel association between FLT3 mutation and survival in glioma.

INTRODUCTION: Recent molecular characterization of gliomas has uncovered somatic gene variation and DNA methylation changes that are associated with etiology, prognosis, and therapeutic response. Here we describe genomic profiling of gliomas assessed for associations between genetic mutations and patient outcomes, including overall survival (OS) and recurrence-free survival (RFS). METHODS: Mutations in a 50-gene cancer panel, 1p19q co-deletion, and MGMT promoter methylation (MGMT methylation) status were obtained from tumor tissue of 293 glioma patients. Multivariable regression models for overall survival (OS) and recurrence-free survival (RFS) were constructed for MGMT methylation, 1p19q co-deletion, and gene mutations controlling for age, treatment status, and WHO grade. RESULTS: Mutational profiles of gliomas significantly differed based on WHO Grade, such as high prevalence of BRAF V600E, IDH1, and PTEN mutations in WHO Grade I, II/III, and IV tumors, respectively. In multivariate regression analysis, MGMT methylation and IDH1 mutations were significantly associated with improved OS (HR = 0.44, p = 0.0004 and HR = 0.21, p = 0.007, respectively), while FLT3 and TP53 mutations were significantly associated with poorer OS (HR = 19.46, p < 0.0001 and HR = 1.67, p = 0.014, respectively). MGMT methylation and IDH1 mutations were the only significant alterations associated with improved RFS in the model (HR = 0.42, p < 0.0001 and HR = 0.37, p = 0.002, respectively). These factors were then included in a combined model, which significantly exceeded the predictive value of the base model alone (age, surgery, radiation, chemo, grade) (likelihood ratio test OS p = 1.64 × 10-8 and RFS p = 3.80 × 10-7). CONCLUSIONS: This study highlights the genomic landscape of gliomas in a single-institution cohort and identifies a novel association between FLT3 mutation and OS in gliomas.

Antiepileptic drug effects on subjective and objective cognition.

RATIONALE: Cognitive impairment is one of the most common complaints for persons with epilepsy (PWE). These impairments are not only associated with seizures, but are also regularly reported as adverse effects of antiepileptic drugs (AEDs). Previous studies have examined cognitive effects of both AED monotherapy and polytherapy, yet there is limited research on these differences with respect to both subjective and objective cognition. The current study uses data from previous research conducted by the Centers for Disease Control and Prevention (CDC)-sponsored Managing Epilepsy Well (MEW) Network collaborative. We used three distinct archival datasets from the following: (1) the HOBSCOTCH efficacy trial at Dartmouth-Hitchcock Medical Center (HOB-1), (2) the multisite replication trial (HOB-2), and (3) epilepsy self-management research conducted at the NYU School of Medicine. METHODS: This retrospective analysis combined baseline data from three datasets to determine how the number of AEDs and the type of AEDs were associated with subjective (patient-reported) and objective (examiner-assessed) cognition. Subjective cognition was captured using the cognitive subscale of the Quality of Life in Epilepsy Inventory (QOLIE-31) in all three datasets (n = 224), while objective cognition was measured using the Repeated Battery for the Assessment of Neuropsychological Status (RBANS) in the HOB-1 dataset (n = 65) and the Brief Test of Adult Cognition by Telephone (BTACT) in the HOB-2 dataset (n = 91). Multivariable linear regression was utilized for our initial assessments, followed by propensity score matching to provide stronger control of covariates. Matching was based on significantly different covariates, such as education, depression, and history of prior epilepsy surgery. Nonparametric statistical tests were utilized to compare these matched subjects. RESULTS: Subjective cognitive impairment was significantly worse among individuals on polytherapy (2 + AEDs) compared with those on monotherapy (1 AED) (adjusted p  =  0.041). These findings were consistent with our propensity score matched comparison of monotherapy and polytherapy, which indicated that polytherapy was associated with worse overall subjective cognition (adjusted p = 0.01), in addition to impairments on the RBANS (Total score p = 0.05) and specific subdomains of the BTACT (Episodic Verbal Memory p < 0.01, Working Memory p < 0.01, Processing Speed p < 0.01). Interestingly, older generation AEDs were associated with better language performance than newer generation and combined generation AED therapy (RBANS Language p = 0.03). These language-specific findings remained significant after controlling for the effects of topiramate and zonisamide (p = 0.04). CONCLUSIONS: A greater number of AEDs is significantly and negatively associated with subjective and objective cognition in PWE, and is in line with previous research. Antiepileptic drug type did not, in itself, appear to be associated with subjective cognition. Our findings suggest that ineffective AEDs should be replaced, rather than introducing additional AEDs to a treatment regimen. Further, while subjective and objective cognition assessments were both sensitive at detecting differences based on AED status, the neuropsychological objective subdomains offer additional and specific insights into how cognition is impaired with AEDs.

Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci.

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

Balance and reaction time do not rapidly improve off antiseizure drugs.

OBJECTIVE: People with epilepsy (PWE) exercise less than the general population and describe a lower level of fitness. Exercise improves comorbidities associated with epilepsy and may help seizure control. We aimed to record balance and reaction time in patients undergoing antiseizure drug (ASD) taper in the epilepsy monitoring unit (EMU) to determine if there is a reversible, dose-dependent effect of these medications. METHODS: We tested 21 patients and 21 controls using a Wii Balance Board (WBB) and online reaction time test. The patients were recruited during an EMU stay and were tested before and after medication taper. Drug levels were also checked. Sway from center of pressure (COP) and speed of sway were tested with eyes open on two legs, eyes closed on two legs, and eyes open on one leg. Reaction time was tested. RESULTS: Compared with controls, patients on ASDs had more sway from COP (with eyes open on two legs: p = 0.0022 in the anterior-posterior axis and p = 0.022 in the medial-lateral axis using linear regression) and worse reaction time (p < 0.001 using linear regression, adjusted for age and gender). There was no difference in reaction time or sway from COP between trials 1 and 2, before and after stopping ASDs (p = 0.2 using a paired t test for reaction time and p = 0.08 using a paired t test for speed of sway with eyes closed). There was no relationship between time since last seizure or duration of seizures and balance or reaction time. DISCUSSION: Balance and reaction time in patients on ASD is impaired compared with controls. There is no immediate improvement in these measures following ASD withdrawal. This difference may result from vestibular or cerebellar effects. More research is needed to determine the individual effects of particular medications on balance and reaction time.

Short-term survival after colorectal cancer in a screened versus unscreened population.

Aims: United States' (US) colorectal cancer (CRC) screening and treatment practices seek to reduce mortality. We examined the survival of US patients compared with patients in the virtually unscreened Norwegian population. Methods: We compared short-term survival after CRC between the US and Norway using relative survival (RS) and excess mortality (EMR) analyses. The CRC patients were aged 50 and older diagnosed in the US (Surveillance, Epidemiology and End Results registry, 2004, N=9511) and in Norway (Cancer Registry of Norway, 2003-2005, N=8256). Results: Death occurred within three years for 39% of the CRC patients. Stage distributions were more favorable for US patients. Stage-specific survival was similar for localized and regional cancers, but more favorable for US distant cancers. In multivariate models of patient, tumor and treatment characteristics, patients (especially below age 80) in the US experienced longer survival (EMR 0.9, CI 0.8-0.9). Stage-specific analyses showed, however, that survival for localized cancers was relatively shorter in the US than in Norway (EMR 1.4, CI 1.1-1.8), but longer for distant cancers (EMR 0.8, CI 0.7-0.8). Conclusions: The enhanced survival for US CRC patients likely reflects a screening-related earlier diagnostic stage distribution, as well as prioritized life extension for patients with metastatic cancers, reflecting vastly different health care systems in the two countries. CRC screening is currently under consideration in Norway. For survival outcomes, the current findings do not discourage such an implementation. Other screening-related aspects such as feasibility and cost-benefit are, however, also relevant and warrant further research within a socialized health system.

Changes in Primary Care Health Care Utilization after Inclusion of Epidemiologic Data in Lumbar Spine MR Imaging Reports for Uncomplicated Low Back Pain.

Purpose To determine whether inclusion of an epidemiologic statement in radiology reports of lumbar magnetic resonance (MR) imaging influences downstream health care utilization in the primary care population. Materials and Methods Beginning July 1, 2013, a validated epidemiologic statement regarding prevalence of common findings in asymptomatic patients was included in all lumbar MR imaging reports at a tertiary academic medical center. Data were collected from July 1, 2012, through June 30, 2014, and retrospective analysis was completed in September 2016. The electronic medical record was reviewed to capture health care utilization rates in patients for 1 year after index MR imaging. Of 4527 eligible adult patients with low back pain referred for lumbar spine MR imaging during the study period, 375 patients had their studies ordered by in-network primary care providers, did not have findings other than degenerative disease, and had at least one follow-up encounter within the system within 1 year of index MR imaging. In the before-and-after study design, a pre-statement-implementation cohort was compared with a post-statement-implementation cohort by using univariate and multivariate statistical models to evaluate treatment utilization rates in these groups. Results Patients in the statement group were 12% less likely to be referred to a spine specialist (137 of 187 [73%] vs 159 of 188 [85%]; P = .007) and were 7% less likely to undergo repeat imaging (seven of 187 [4%] vs 20 of 188 [11%]; P = .01) compared with patients in the nonstatement group. The intervention was not associated with any change in narcotic prescription (53 of 188 [28%] vs 54 of 187 [29%]; P = .88) or with the rate of low back surgery (24 of 188 [13%] vs 16 of 187 [9%]; P = .19). Conclusion In this study, inclusion of a simple epidemiologic statement in lumbar MR imaging reports was associated with decreased utilization in high-cost domains of low back pain management. © RSNA, 2018.

Risk Factors for Diagnosis of Colorectal Cancer at a Late Stage: a Population-Based Study.

BACKGROUND: Late-stage colorectal cancer (CRC) is associated with significantly less effective treatment and poorer survival than early-stage colorectal cancer. OBJECTIVE: Identify and assess patient characteristics, demographic factors, and lifestyle factors that are associated with late-stage colorectal cancer at diagnosis. APPROACH: We linked two longstanding statewide, population-based registry databases: the New Hampshire Colonoscopy Registry and the New Hampshire State Cancer Registry, to assess the associations between patient characteristics and late-stage CRC diagnoses. The State Cancer Registry provided information on cancer stage and the Colonoscopy Registry provided detailed information on patient characteristics and lifestyle factors, allowing these factors to be analyzed in relation to colorectal cancer stage. KEY RESULTS: The risk of late-stage CRC diagnosis was highest among those diagnosed at a young age (< 50 years old) (OR 1.81, 95% CI 1.27-2.58). Those with Medicaid were also at increased risk, particularly < 65 years of age (OR 2.32, 95% CI 1.05-5.26). A family or personal history of polyps and/or CRC was associated with early stage at diagnosis (p = 0.014). CONCLUSIONS: Public health outreach and screening efforts should focused on patients at risk of late-stage CRC to encourage earlier diagnosis and prevention. Underserved patients have a lower rate of CRC screening and an increased risk of late-stage CRC, emphasizing the critical need to reach these populations. Further investigation of susceptibility characteristics and the effectiveness of non-invasive early screening techniques is warranted to address the late-stage CRC diagnoses in young individuals.

Toenail mercury Levels are associated with amyotrophic lateral sclerosis risk.

INTRODUCTION: Mercury is a neurotoxic metal that is potentially a risk factor for amyotrophic lateral sclerosis (ALS). Consumption of methylmercury contaminated fish is the primary source of US population exposure to mercury. METHODS: We used inductively coupled plasma mass spectrometry to measure levels of mercury in toenail samples from patients with ALS (n = 46) and from controls (n = 66) as a biomarker of mercury exposure. RESULTS: Patients with ALS had higher toenail mercury levels (odds ratio 2.49, 95% confidence interval 1.18-5.80, P = 0.024) compared with controls, adjusted for age and sex. We also estimated the amount of mercury consumed from finfish and shellfish and found toenail mercury levels elevated overall among patients with ALS and controls in the top quartile for consumption (P = 0.018). DISCUSSION: Biomarker data show that ALS is associated with increased with mercury levels, which were related to estimated methylmercury intake via fish. Replication of these associations in additional populations is warranted. Muscle Nerve, 2018.