Ultrasound Probe Pose Classification for Task Recognition in Central Venous Catheterization.

Central Line Tutor is a system that facilitates real-time feedback during training for central venous catheterization. One limitation of Central Line Tutor is its reliance on expensive, cumbersome electromagnetic tracking to facilitate various training aids, including ultrasound task identification and segmentation of neck vasculature. The purpose of this study is to validate deep learning methods for vessel segmentation and ultrasound pose classification in order to mitigate the system's reliance on electromagnetic tracking. A large dataset of segmented and classified ultrasound images was generated from participant data captured using Central Line Tutor. A U-Net architecture was used to perform vessel segmentation, while a shallow Convolutional Neural Network (CNN) architecture was designed to classify the pose of the ultrasound probe. A second classifier architecture was also tested that used the U-Net output as the CNN input. The mean testing set Intersect over Union score for U-Net cross-validation was 0.746 ± 0.052. The mean test set classification accuracy for the CNN was 92.0% ± 3.0, while the U-Net + CNN achieved 92.7% ± 2.1%. This study highlights the potential for deep learning on ultrasound images to replace the current electromagnetic tracking-based methods for vessel segmentation and ultrasound pose classification, and represents an important step towards removing the electromagnetic tracker altogether. Removing the need for an external tracking system would significantly reduce the cost of Central Line Tutor and make it far more accessible to the medical trainees that would benefit from it most.

Management and cleanup of legacy radium-contaminated sites in the United States.

The hazards associated with radium-containing materials were largely unknown when they were first introduced into household and other products over a century ago. Radium was also originally thought to have beneficial health properties, leading to confusion amongst the public about the safety of radium in household products and food items. When the adverse health effects associated with radium were discovered and became well known, radium products became unpopular and were prohibited in some countries. In the United States, after the hazards associated with radium became known, radium was first regulated by individual states in the late 1920s and early 1930s. Later, the US Nuclear Regulatory Commission (NRC) was given a role in the regulation of discrete sources of radium with the passage of the Energy Policy Act of 2005. After passage of the Act, the NRC began to systematically identify sites around the country where radium was used and reached out to site owners to determine whether existing radium contamination could pose a risk to public health and safety and the environment. The NRC devised a graded approach in response to its new regulatory responsibilities to address potential public health and safety issues at legacy radium sites. By September 2019, the NRC had dispositioned all the sites that were identified as having potential contamination from historical radium within its regulatory purview in non-Agreement States. The staff worked with site owners and federal, state and local officials, as needed, to properly disposition the sites to ensure that each site either meets the applicable criteria for unrestricted use or has controls in place to limit access during remediation so that no site poses an unacceptable risk to public health and safety and the environment.

Impact of socio-economic deprivation on endometrial cancer survival in the North West of England: a prospective database analysis.

OBJECTIVE: To assess the impact of socio-economic deprivation on endometrial cancer survival. DESIGN: Single-centre prospective database study. SETTING: North West England. POPULATION: Women with endometrial cancer treated between 2010 and 2015. METHODS: Areal-level socio-economic status, using the English indices of multiple deprivation from residential postcodes, was analysed in relation to survival using Kaplan-Meier estimation and multivariable Cox regression. MAIN OUTCOME MEASURES: Overall survival, cancer-specific survival and patterns and rates of recurrence. RESULTS: A total of 539 women, with a median age of 66 years (interquartile range, IQR 56-73 years) and a body mass index (BMI) of 32 kg/m2 (IQR 26-39 kg/m2 ), were included in the analysis. Women in the most deprived social group were younger (median 64 years, IQR 55-72 years) and more obese (median 34 kg/m2 , IQR 28-42 kg/m2 ) than women in the least deprived group (median age 68 years, IQR 60-74 years; BMI 29 kg/m2 , IQR 25-36 kg/m2 ; P = 0.002 and <0.001, respectively). There were no differences in endometrial cancer type, stage or grade between social groups. There was no difference in recurrence rates, however, women in the middle and most deprived social groups were more likely to present with distant/metastatic recurrence (80.6 and 79.2%, respectively) than women in the least deprived group (43.5%, P < 0.001). Women in the middle and most deprived groups had a two-fold (adjusted hazard ratio, HR = 2.00, 95% CI 1.07-3.73, P = 0.030) and 53% (adjusted HR = 1.53, 95% CI 0.77-3.04, P = 0.221) increase in cancer-specific mortality compared with women in the least deprived group. There were no differences in overall survival. CONCLUSIONS: We found that socio-economically deprived women with endometrial cancer were more likely to develop fatal recurrence. Larger studies are needed to confirm these findings and to identify modifiable contributing factors. TWEETABLE ABSTRACT: Socio-economic deprivation is linked to an increased risk of death from endometrial cancer in the North West of England.

Examining the initial usability, acceptability and feasibility of a digital mental health intervention for college students in India.

Generalised anxiety disorder (GAD) is prevalent among college students in India; however, barriers like stigma, treatment accessibility and cost prevent engagement in treatment. Web- and mobile-based, or digital, mental health interventions have been proposed as a potential solution to increasing treatment access. With the ultimate goal of developing an engaging digital mental health intervention for university students in India, the current study sought to understand students' reactions to a culturally and digitally adapted evidence-based cognitive behavioural therapy (CBT) for GAD intervention. Specifically, through theatre testing and focus groups with a non-clinical sample of 15 college students in India, the present study examined initial usability, acceptability and feasibility of the "Mana Maali Digital Anxiety Program." Secondary objectives comprised identifying students' perceived barriers to using the program and eliciting recommendations. Results indicated high usability, with the average usability rating ranking in the top 10% of general usability scores. Participants offered actionable changes to improve usability and perceived acceptability among peers struggling with mental health issues. Findings highlight the benefits of offering digital resources that circumvent barriers associated with accessing traditional services. Results build on existing evidence that digital interventions can be a viable means of delivering mental healthcare to large, defined populations.

Electrostatic subframing and compressive-sensing video in transmission electron microscopy.

We present kilohertz-scale video capture rates in a transmission electron microscope, using a camera normally limited to hertz-scale acquisition. An electrostatic deflector rasters a discrete array of images over a large camera, decoupling the acquisition time per subframe from the camera readout time. Total-variation regularization allows features in overlapping subframes to be correctly placed in each frame. Moreover, the system can be operated in a compressive-sensing video mode, whereby the deflections are performed in a known pseudorandom sequence. Compressive sensing in effect performs data compression before the readout, such that the video resulting from the reconstruction can have substantially more total pixels than that were read from the camera. This allows, for example, 100 frames of video to be encoded and reconstructed using only 15 captured subframes in a single camera exposure. We demonstrate experimental tests including laser-driven melting/dewetting, sintering, and grain coarsening of nanostructured gold, with reconstructed video rates up to 10 kHz. The results exemplify the power of the technique by showing that it can be used to study the fundamentally different temporal behavior for the three different physical processes. Both sintering and coarsening exhibited self-limiting behavior, whereby the process essentially stopped even while the heating laser continued to strike the material. We attribute this to changes in laser absorption and to processes inherent to thin-film coarsening. In contrast, the dewetting proceeded at a relatively uniform rate after an initial incubation time consistent with the establishment of a steady-state temperature profile.

Holocene El Niño-Southern Oscillation variability reflected in subtropical Australian precipitation.

The La Niña and El Niño phases of the El Niño-Southern Oscillation (ENSO) have major impacts on regional rainfall patterns around the globe, with substantial environmental, societal and economic implications. Long-term perspectives on ENSO behaviour, under changing background conditions, are essential to anticipating how ENSO phases may respond under future climate scenarios. Here, we derive a 7700-year, quantitative precipitation record using carbon isotope ratios from a single species of leaf preserved in lake sediments from subtropical eastern Australia. We find a generally wet (more La Niña-like) mid-Holocene that shifted towards drier and more variable climates after 3200 cal. yr BP, primarily driven by increasing frequency and strength of the El Niño phase. Climate model simulations implicate a progressive orbitally-driven weakening of the Pacific Walker Circulation as contributing to this change. At centennial scales, high rainfall characterised the Little Ice Age (~1450-1850 CE) in subtropical eastern Australia, contrasting with oceanic proxies that suggest El Niño-like conditions prevail during this period. Our data provide a new western Pacific perspective on Holocene ENSO variability and highlight the need to address ENSO reconstruction with a geographically diverse network of sites to characterise how both ENSO, and its impacts, vary in a changing climate.

The contribution of alternative splicing to genetic risk for psychiatric disorders.

A genetic contribution to psychiatric disorders has clearly been established and genome-wide association studies now provide the location of risk genes and genetic variants associated with risk. However, the mechanism by which these genes and variants contribute to psychiatric disorders is mostly undetermined. This is in part because non-synonymous protein coding changes cannot explain the majority of variants associated with complex genetic traits. Based on this, it is predicted that these variants are causing gene expression changes, including changes to alternative splicing. Genetic changes influencing alternative splicing have been identified as risk factors in Mendelian disorders; however, currently there is a paucity of research on the role of alternative splicing in complex traits. This stems partly from the difficulty of predicting the role of genetic variation in splicing. Alterations to canonical splice site sequences, nucleotides adjacent to splice junctions, and exonic and intronic splicing regulatory sequences can influence splice site choice. Recent studies have identified global changes in alternatively spliced transcripts in brain tissues, some of which correlate with altered levels of splicing trans factors. Disease-associated variants have also been found to affect cis-acting splicing regulatory sequences and alter the ratio of alternatively spliced transcripts. These findings are reviewed here, as well as the current datasets and resources available to study alternative splicing in psychiatric disorders. Identifying and understanding risk variants that cause alternative splicing is critical to understanding the mechanisms of risk as well as to pave the way for new therapeutic options.

Intermittent Access to Ethanol Induces Escalated Alcohol Consumption in Primates.

BACKGROUND: Escalation of voluntary alcohol drinking is characteristic of alcohol addiction and can be induced in rodents using intermittent access to alcohol. This model has been used to evaluate candidate therapeutics, but key systems involved in the transition into alcohol addiction, such as CRF, differ in their organization between rodents and primates. We examined the ability of an intermittent access schedule to induce escalation of voluntary alcohol drinking in non-human primates and used this model to assess the role of corticotropin releasing hormone (CRF) signaling in this process. METHODS: Four young adult male rhesus macaques were given access to an 8.4% alcohol solution every other weekday (EOD; M, W, F), while four other young adult males were given the same solution every weekday (ED; M-F). Subjects were then administered a CRF1 antagonist, antalarmin. RESULTS: EOD increased alcohol intake by up to 50% over baseline, with a more pronounced increase immediately following reintroduction of alcohol. For the morning/daytime sessions, EOD subjects increased their consumption by 83% over baseline. Differences between ED and EOD schedules emerged quickly, and EOD-induced escalation resulted in pharmacologically active BAC's. EOD-induced alcohol consumption was insensitive to CRFR1 blockade by antalarmin, but subjects with high CSF levels of CRF were more responsive. CONCLUSIONS: Similar to what has been observed in rodents, intermittent access results in an escalation of voluntary alcohol drinking in non-human primates. In contrast to findings in rats, recruitment of the CRF system does not seem to be involved in the escalated alcohol drinking observed under these conditions, though individual differences in CRF system activity may play a role.

ECG predictors of T wave oversensing in subcutaneous implantable cardioverter defibrillators.

BACKGROUND: T wave oversensing (TWOS) is the commonest cause of inappropriate shocks in subcutaneous implantable cardioverter defibrillators (S-ICDs). We hypothesise that predictors of TWOS can be derived from surface ECG parameters. METHODS: In a cohort of SICD recipients in two UK centres, all patients who had TWOS (study group) were compared to all those who had not (control group). The pre-implant screen was scanned and the R wave, T wave amplitudes, QRS interval, time to peak T wave, QT interval and R:T ratio was measured using digital callipers. Logistic regression was performed to identify ECG predictors of TWOS. RESULTS: One hundred one patients were studied. Six (5.9%) had TWOS. The mean age of the population was 58.6±18years and the median follow-up was 19.5months. By univariate analysis, the predictors of TWOS are QRS duration (140.7±28.7 vs. 105.9±24.6, P=0.007), time to peak T wave (corrected for heart rate, pTc) (403.9±22.6 vs. 347.8±41.4, P=0.006), QTc interval (500.4±41.2 vs. 446.8±49.7, P=0.021), and R:T ratio (3.5±1.1 vs. 9.5±13.2, P=0.034). By multivariate analysis, time to pTc is the most predictive of TWOS. A time to pTc of 390ms cut-off point provided a sensitivity 38.5%, a specificity of 98.9%, a positive predictive value for TWOS of 83.3%, and a negative predictive value of 91.6% (AUC=0.687). CONCLUSION: In this study, time to pTc is the most powerful ECG predictor of TWOS.

Visual Field Dependence Is Associated with Reduced Postural Sway, Dizziness and Falls in Older People Attending a Falls Clinic.

Moving visual fields can have strong destabilising effects on balance, particularly when visually perceived motion does not correspond to postural movements. This study investigated relationships between visual field dependence (VFD), as assessed using the roll vection test, and reported dizziness, falls and sway under eyes open, eyes closed and optokinetic conditions. Ninety five falls clinic attendees undertook the roll vection test (i.e. attempted to align a rod to the vertical while exposed to a rotating visual field). Sway was assessed under different visual conditions by centre of pressure movement. Participants also completed questionnaires on space and motion discomfort, fear of falling, depression and anxiety. Thirty four (35.8%) participants exhibited VFD, i.e. had an error > 6.5º in the roll vection test. Compared to participants without VFD, participants with VFD demonstrated less movement of the centre of pressure across all visual conditions, were more likely to report space and motion discomfort and to have suffered more multiple falls in the past year. VFD was independent of fear of falling, anxiety and depression. VFD in a falls clinic population is associated with reduced sway possibly due to a stiffening strategy to maintain stance, dizziness symptoms and an increased risk of falls.

Decoding the non-coding genome: elucidating genetic risk outside the coding genome.

Current evidence emerging from genome-wide association studies indicates that the genetic underpinnings of complex traits are likely attributable to genetic variation that changes gene expression, rather than (or in combination with) variation that changes protein-coding sequences. This is particularly compelling with respect to psychiatric disorders, as genetic changes in regulatory regions may result in differential transcriptional responses to developmental cues and environmental/psychosocial stressors. Until recently, however, the link between transcriptional regulation and psychiatric genetic risk has been understudied. Multiple obstacles have contributed to the paucity of research in this area, including challenges in identifying the positions of remote (distal from the promoter) regulatory elements (e.g. enhancers) and their target genes and the underrepresentation of neural cell types and brain tissues in epigenome projects - the availability of high-quality brain tissues for epigenetic and transcriptome profiling, particularly for the adolescent and developing brain, has been limited. Further challenges have arisen in the prediction and testing of the functional impact of DNA variation with respect to multiple aspects of transcriptional control, including regulatory-element interaction (e.g. between enhancers and promoters), transcription factor binding and DNA methylation. Further, the brain has uncommon DNA-methylation marks with unique genomic distributions not found in other tissues - current evidence suggests the involvement of non-CG methylation and 5-hydroxymethylation in neurodevelopmental processes but much remains unknown. We review here knowledge gaps as well as both technological and resource obstacles that will need to be overcome in order to elucidate the involvement of brain-relevant gene-regulatory variants in genetic risk for psychiatric disorders.

Minimizing right ventricular pacing in pacemaker patients with intact and compromised atrioventricular conduction : Results from the EVITA Trial.

INTRODUCTION: Unnecessary ventricular pacing is associated with increased morbidity and mortality. Over the years different algorithms have been developed to reduce right ventricular pacing. OBJECTIVES: Goal of the present study was to test the efficacy of the ventricular intrinsic preference (VIP) algorithm in patients with atrioventricular intact (AVi) and atrioventricular compromised (AVc) AV-conduction. METHODS: Evaluation of VIP feature in pacemaker patients (EVITA) was a multicenter, prospective, randomized trial (Trials.gov Identifier: NCT00366158). In total, 389 patients were randomized to AVc group: n = 140/132 VIP OFF/VIP On, AVi group: n = 54/63 VIP OFF/VIP ON). One-month post-implantation AV conduction testing (AVc: PR/AR interval > 210 ms) was performed. Follow-up visits occurred 6 and 12 months after DDD-pacemaker implantation. RESULTS: In AVi and AVc-patients initiation of the VIP feature significantly reduced incidence of ventricular pacing (AVi: 53 ± 38 vs. 9 ± 21%, p = 0.0001; AVc: 79 ± 31 vs. 28 ± 35%, p = 0.0001). DDD-pacemaker implantation per se significantly reduced incidence of AF in VIP ON (AVi 27 vs. 0%, p < 0.0001; AVc 29 vs. 3%, p < 0.0001) and VIP OFF patients (AVi 43 vs. 4%, p < 0.0001; AVc 33 vs. 3, p < 0.0001), without significant differences between VIP ON and OFF groups (p > 0.05). In the AVc group activation of VIP significantly reduced incidence of adverse events (AE). All-cause mortality was not significantly different in VIP ON (n = 5) and VIP OFF (n = 4, p > 0.05) patients. CONCLUSION: AV search hysteresis (VIP) markedly reduces ventricular pacing both in patients with normal AV conduction and in patients with prolonged PR interval or intermittent AV block.

Six minutes of walking leads to reduced lower limb strength and increased postural sway in people with Multiple Sclerosis.

BACKGROUND: Fatigue, lower limb weakness and poor balance can significantly limit safe mobility in people with Multiple Sclerosis (MS). Further research is required to elucidate relationships among these factors. OBJECTIVE: To investigate the effect of walking-induced fatigue on lower limb strength and postural sway in people with moderately disabling MS. METHODS: Thirty-four people (26 female) with moderate MS (mean Expanded Disability Status Scale of 3.7 ± 0.7) underwent assessments of acute fatigue, postural sway and lower limb strength before and after six-minute conditions of seated rest and walking. A matched sample of 10 healthy controls also undertook identical assessments before and after a six-minute walk. RESULTS: Significant time by condition effects for all assessment measures indicated the six-minute walk induced fatigue with associated increases in postural sway and reductions in lower limb strength in people with MS. Increases in sway with eyes closed correlated with increases in acute fatigue and self-reported impact of fatigue on physical and psychological functioning. No changes were observed in healthy controls. CONCLUSION: People with MS show signs of fatigue after 6 minutes of walking, including strength and balance deficits. These findings have implications for both mobility and fall risk in this group.

Association of the KCNJ5 gene with Tourette Syndrome and Attention-Deficit/Hyperactivity Disorder.

Linkage and association of Tourette Syndrome (TS) and Attention-Deficit/Hyperactivity Disorder (ADHD) have previously been reported in the 11q24 chromosomal region. To identify the risk gene within the region we studied the potassium inwardly-rectifying channel J5 (KCNJ5) gene in a sample of 170 nuclear families with TS. We genotyped eight markers across the gene and observed biased transmission of haplotypes from parents to probands in this sample. We then tested these markers in an independent sample of 242 nuclear families with ADHD and found the same haplotype was significantly over transmitted to ADHD probands. Screening of the coding region of KCNJ5 in 48 probands with TS did not identify any variation that could explain the association of the haplotype. We also genotyped two microsatellite markers, one in the promoter and the other in the 3' region and found no evidence for association for either marker for TS, however, we found significant evidence for association with the 3' repeat and ADHD. A small gene (c11orf45) of unknown function lies within the first intron of KCNJ5 that is transcribed in the opposite orientation and this gene may regulate the expression of KCNJ5. We studied the correlation of the expression of KCNJ5 and the antisense transcript in brain tissues from control individuals and found that the antisense transcript and the short KCNJ5 isoform are co-expressed in three brain regions. The results of this study indicate that KCNJ5 is associated with TS and ADHD in our samples, however, the functional variant(s) remain to be identified.

Association of the ROBO1 gene with reading disabilities in a family-based analysis.

Linkage studies have identified a locus on chromosome 3 as reading disabilities (RD) and speech and sound disorder (SSD) susceptibility region, with both RD and SSD sharing similar phonological processing and phonological memory difficulties. One gene in this region, roundabout homolog 1 (ROBO1), has been indicated as a RD candidate and has shown significant association with measures of phonological memory in a population-based sample. In this study, we conducted a family-based association analysis using two independent samples collected in Toronto and Calgary, Canada. Using the two samples, we tested for association between ROBO1 single nucleotide polymorphisms (SNPs) and RD, along with quantitative measures for reading, spelling and phonological memory. One SNP, rs331142, which was selected based on its correlation with ROBO1 expression in brain tissue, was found to be significantly associated with RD in the Toronto sample with over transmission of the minor C allele (P = 0.001), correlated with low expression. This SNP is located ~200 bp from a putative enhancer and results for a marker within the enhancer, rs12495133, showed evidence for association with the same allele in both the Toronto and Calgary samples (P = 0.005 and P = 0.007). These results support previous associations between ROBO1 and RD, as well as correlation with low gene expression, suggesting a possible mechanism of risk conferred by this gene.

Long-term fracture rates seen with continued ibandronate treatment: pooled analysis of DIVA and MOBILE long-term extension studies.

UNLABELLED: Ibandronate reduces the risk of vertebral and non-vertebral fractures versus placebo in postmenopausal women with osteoporosis. This analysis, in which fractures were reported as safety events, showed that long-term use of ibandronate was associated with low fracture rates over 5 years of treatment. INTRODUCTION: A previous post-hoc meta-analysis of 2-3 year studies found that ibandronate regimens with annual cumulative exposure (ACE) of ≥10.8 mg reduced the risk of vertebral and nonvertebral fractures (NVFs) versus placebo in postmenopausal women. This post-hoc analysis used individual patient data from the 2-year monthly oral ibandronate in ladies (MOBILE) and dosing intravenous administration (DIVA) studies, including the 3-year long-term extensions (LTEs), to assess fracture risk in patients treated with ibandronate for 5 years. METHODS: Patients treated for 2 years in MOBILE with monthly oral ibandronate 150 mg (n = 176) and in DIVA with IV ibandronate every 2 months 2 mg (n = 253) or quarterly 3 mg (n = 263) who continued on the same regimens for 3 additional years in the LTEs were included. Three-year placebo data (n = 1,924) were obtained from the ibandronate osteoporosis vertebral fracture trial in North America and Europe (BONE) and IV Fracture Prevention trials. The primary endpoint was clinical fracture rate; clinical fracture data were collected as adverse events. Time to fracture was analyzed using Kaplan-Meier and statistical analysis was conducted using the log-rank test. All clinical fractures included all NVFs and symptomatic vertebral fractures. RESULTS: For ibandronate regimens with ACE ≥10.8 mg, time to fracture was significantly longer for all clinical fractures, NVFs, and clinical vertebral fractures versus placebo (P = 0.005). For all fracture types, the rate of fracture appeared stable during the 5-year treatment period. CONCLUSION: In women with postmenopausal osteoporosis, continuous treatment with ibandronate over 5 years results in low sustained clinical fracture rate.

A family-based association analysis and meta-analysis of the reading disabilities candidate gene DYX1C1.

Reading disabilities (RD) have a significant genetic basis and have shown linkage to multiple regions including chromosome 15q. Dyslexia susceptibility 1 candidate gene 1 (DYX1C1) on chromosome 15q21 was originally proposed as a candidate gene with two potentially functional polymorphisms at the -3G/A and 1249G/T positions showing association with RD. However, subsequent studies have yielded mixed results. We performed a literature review and meta-analysis of the -3G/A and 1249G/T polymorphisms, including new unpublished data from two family-based samples. Ten markers in DYX1C1 were genotyped in the two independently ascertained samples. Single marker and -3G/A:1249G/T haplotype analyses were performed for RD in both samples, and quantitative trait analyses using standardized reading-related measures was performed in one of the samples. For the meta-analysis, we used a random-effects model to summarize studies that tested for association between -3G/A or 1249G/T and RD. No significant association was found between the DYX1C1 SNPs and RD or any of the reading-related measures tested after correction for the number of tests performed. The previously reported risk haplotype (-3A:1249T) was not biased in transmission. A total of 9 and 10 study samples were included in the meta-analysis of the -3G/A and 1249G/T polymorphisms, respectively. Neither polymorphism reached statistical significance, but the heterogeneity for the 1249G/T polymorphism was high. The results of this study do not provide evidence for association between the putatively functional SNPs -3G/A and 1249G/T and RD.

Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.