bluuebunny/crossref_metadata_2025_split huggingface dataset:
Singapore Undiagnosed Disease Program: Genomic Analysis aids Diagnosis and Clinical Management
Authors: Bhatia Neha S , Lim Jiin Ying , Bonnard Carine , Kuan Jyn-Ling , Brett Maggie , Wei Heming , Cham Breana , Chin Huilin , Bosso-Lefevre Celia , Dharuman Perumal , Escande-Beillard Nathalie , Devasia Arun George , Goh Chew Yin Jasmine , Kam Sylvia , Liew Wendy Kein-Meng , Liew Woei Kang , Lin Grace , Jain Kanika , Ng Alvin Yu-Jin , Subramanian Deepa , Xie Min , Tan Yuen-Ming , Tawari Nilesh R , Tiang Zenia , Ting Teck Wah , Tohari Sumanty , Tong Cheuk Ka , Lezhava Alexander , Ng Sarah B , Law Hai Yang , Venkatesh Byrappa , Tomar Swati , Sethi Raman , Tan Grace , Shanmugasundaram Arthi , Goh Denise Li-Meng , Lai Poh San , Lai Angeline , Tan Ee Shien , Ng Ivy , Reversades Bruno , Tan Ene Choo , Foo Roger , Jamuar Saumya Shekhar 
Published: August 2020

ObjectiveUse next-generation sequencing (NGS) technology to improve our diagnostic yield in patients with suspected genetic disorders in the Asian setting.DesignA diagnostic study conducted between 2014 and 2019 (and ongoing) under the Singapore Undiagnosed Disease Program. Date of last analysis was 1 July 2019.SettingInpatient and outpatient genetics service at two large academic centres in Singapore.PatientsInclusion criteria: patients suspected of genetic disorders, based on abnormal antenatal ultrasound, multiple congenital anomalies and developmental delay. Exclusion criteria: patients with known genetic disorders, either after clinical assessment or investigations (such as karyotype or chromosomal microarray).InterventionsUse of NGS technology—whole exome sequencing (WES) or whole genome sequencing (WGS).Main outcome measures(1) Diagnostic yield by sequencing type, (2) diagnostic yield by phenotypical categories, (3) reduction in time to diagnosis and (4) change in clinical outcomes and management.ResultsWe demonstrate a 37.8% diagnostic yield for WES (n=172) and a 33.3% yield for WGS (n=24). The yield was higher when sequencing was conducted on trios (40.2%), as well as for certain phenotypes (neuromuscular, 54%, and skeletal dysplasia, 50%). In addition to aiding genetic counselling in 100% of the families, a positive result led to a change in treatment in 27% of patients.ConclusionGenomic sequencing is an effective method for diagnosing rare disease or previous ‘undiagnosed’ disease. The clinical utility of WES/WGS is seen in the shortened time to diagnosis and the discovery of novel variants. Additionally, reaching a diagnosis significantly impacts families and leads to alteration in management of these patients.
De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features
Authors: Malhotra Alka , Ziegler Alban , Shu Li , Perrier Renee , Amlie-Wolf Louise , Wohler Elizabeth , Lygia de Macena Sobreira Nara , Colin Estelle , Vanderver Adeline , Sherbini Omar , Stouffs Katrien , Scalais Emmanuel , Serretti Alessandro , Barth Magalie , Navet Benjamin , Rollier Paul , Xi Hui , Wang Hua , Zhang Hainan , Perry Denise L , Ferrarini Alessandra , Colombo Roberto , Pepler Alexander , Schneider Adele , Tomiwa Kiyotaka , Okamoto Nobuhiko , Matsumoto Naomichi , Miyake Noriko , Taft Ryan , Mao Xiao , Bonneau Dominique 
Published: August 2020

ObjectiveTo determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes.MethodsHere we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher.ResultsLMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms.ConclusionThese findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.
Advances in the management of diabetes: new devices for type 1 diabetes
Authors: Wunna Wunna , Tsoutsouki Jovanna , Chowdhury Aisha , Chowdhury Tahseen Ahmad 
Published: August 2020

ABSTRACTType 1 diabetes (T1D) is an autoimmune condition that affects a significant number of people worldwide, with higher prevalence in white European populations. The condition is responsible for a high burden of microvascular complications, especially when poorly controlled. The condition is also burdensome on the patient and has major psychosocial and occupational impacts. It requires lifelong frequent blood glucose monitoring and regular insulin injections. Important technological advances in the management of T1D have occurred in recent years. These include the advent of new glucose testing devices using interstitial glucose, and new insulin delivery devices. These technologies may improve quality of life, and glucose management in this condition. This review aims to outline the current advances in the management of T1D for the general physician, with a particular focus on new technologies.
Watching the watchmen: an evaluation of educational supervision in a busy district general hospital
Authors: Heining Christopher James , Wheeler Marie , Fletcher Peter 
Published: August 2020

AbstractIntroductionEducational supervisors (ESs) play a critical role in the training of Foundation doctors. Many hospital trusts do not currently offer formal mechanisms to ensure the quality of supervision is at a high standard. Our Trust wanted to empower trainees to offer objective feedback on the quality of the supervisors.MethodsWe introduced a feedback form sent to all Foundation doctors at our Trust. The questionnaire was designed to identify whether ESs were meeting their responsibilities as defined by the Health Education England South West’s Severn Deanery. We collected data throughout the academic year 2017–2018 (Year 1) as a pilot, before rolling out the definitive questionnaire with minor modifications from 2018 to 2019 (Year 2).ResultsAll respondents met with their supervisor within the first month of the placement and 90.7% of the trainees found it easy to meet with their supervisor. The Trust received generally very good feedback for all of its supervisors. Low numbers (4/120 trainees) reported supervisors not engaging with the exception reporting process.ConclusionOur Trust provides ESs of a high standard. The authors believe collecting feedback for ESs will achieve three things: 1) Drive up standards through increasing accountability of ESs receiving objective feedback. This will be of critical importance in the context of the severe acute respiratory syndrome coronavirus 2 pandemic and the changes to our work it has necessitated. 2) Empower trainees to make informed decisions about where they wish to train and under which supervisors. 3) Facilitate revalidation and appraisal for supervisors by collecting data from trainees on the quality of their supervision.
Comparison of five major airflow limitation criteria to identify high-risk individuals with COPD: a contemporary population-based cohort
Authors: Çolak Yunus , Nordestgaard Børge G , Vestbo Jørgen , Lange Peter , Afzal Shoaib 
Published: August 2020

BackgroundDifferent airflow limitation criteria are often used to diagnose COPD. We investigated head-to-head whether Global Initiative for Chronic Obstructive Lung Disease (GOLD) (FEV1/FVC <0.70) and four lower limit of normal (LLN) (FEV1/FVC <LLN) criteria to diagnose airflow limitation differ in identifying individuals at risk of COPD exacerbations and mortality.Methods108 246 individuals aged 20–100 years randomly selected from the general population were followed from 2003 through 2018 to determine risk of COPD exacerbations, respiratory mortality and all-cause mortality. LLN criteria used equations from Global Lung Initiative (GLI), National Health and Nutrition Examination Survey (NHANES), European Community for Steel and Coal (ECSC) and Copenhagen City Heart Study (CCHS)/Copenhagen General Population Study (CGPS).ResultsPrevalence of airflow limitation was 17% for GOLD, 8.6% for GLI, 10% for NHANES, 8.2% for ECSC and 14% for CCHS/CGPS. During 14.4 years follow-up, we observed 2745 COPD exacerbations, 762 respiratory deaths and 10 338 all-cause deaths. Comparing individuals with versus without airflow limitation, HRs for COPD exacerbations were 17 (95% CI 14 to 20) for GOLD, 21 (18 to 24) for GLI, 20 (17 to 23) for NHANES, 21 (18 to 24) for ECSC and 18 (16 to 21) for CCHS/CGPS. Corresponding HRs for respiratory mortality were 3.7 (3.1 to 4.3), 6.4 (5.6 to 7.5), 5.7 (4.9 to 6.6), 6.2 (5.3 to 7.2) and 4.5 (3.9 to 5.2), and for all-cause mortality 1.5 (1.4 to 1.5), 1.9 (1.8 to 2.0), 1.8 (1.7 to 1.9), 1.9 (1.8 to 2.0) and 1.7 (1.6 to 1.7), respectively. Differences in Harrell’s C were minute for these outcomes; nonetheless, Harrell’s C was slightly higher for LLN criteria compared with GOLD for mortality outcomes.ConclusionsThe prevalence of airflow limitation ranged from 8% to 17% using GOLD and four different LLN criteria; however, identified individuals with the five different criteria had similar risk of COPD exacerbations and mortality.
Potential-field modelling of the prospective Chibougamau area (northeastern Abitibi subprovince, Quebec, Canada) using geological, geophysical, and petrophysical constraints
Authors: Maleki Amir , Smith Richard , Eshaghi Esmaeil , Mathieu Lucie , Snyder David , Naghizadeh Mostafa 
Published: August 2020

This paper focusses on obtaining a better understanding of the subsurface geology of the Chibougamau area, in the northeast of the Abitibi greenstone belt (Superior craton), using geophysical data collected along a 128 km long traverse with a rough southwest–northeast orientation. We have constructed two-dimensional (2D) models of the study area that are consistent with newly collected gravity data and high-resolution magnetic data sets. The initial models were constrained at depth by an interpretation of a new seismic section and at surface by the bedrock geology and known geometry of lithological units. The attributes of the model were constrained using petrophysical measurements so that the final model is compatible with all available geological and geophysical data. The potential-field data modelling resolved the geometry of plutons and magnetic bodies that are transparent on seismic sections. The new model is consistent with the known structural geology, such as open folding, and provides an improvement in estimating the size, shape, and depth of the Barlow and Chibougamau plutons. The Chibougamau pluton is known to be associated with Cu–Au magmatic-hydrothermal mineralisation and, as the volume and geometry of intrusive bodies is paramount to the exploration of such mineralisation, the modelling presented here provides a scientific foundation to exploration models focused on such mineralisation.
Using Latent Class Modeling to Jointly Characterize Economic Stress and Multipollutant Exposure
Authors: Larsen Alexandra , Kolpacoff Viktoria , McCormack Kara , Seewaldt Victoria , Hyslop Terry 
Published: August 2020

Abstract

Background:
Work is needed to better understand how joint exposure to environmental and economic factors influence cancer. We hypothesize that environmental exposures vary with socioeconomic status (SES) and urban/rural locations, and areas with minority populations coincide with high economic disadvantage and pollution.

Methods:
To model joint exposure to pollution and SES, we develop a latent class mixture model (LCMM) with three latent variables (SES Advantage, SES Disadvantage, and Air Pollution) and compare the LCMM fit with K-means clustering. We ran an ANOVA to test for high exposure levels in non-Hispanic black populations. The analysis is at the census tract level for the state of North Carolina.

Results:
The LCMM was a better and more nuanced fit to the data than K-means clustering. Our LCMM had two sublevels (low, high) within each latent class. The worst levels of exposure (high SES disadvantage, low SES advantage, high pollution) are found in 22% of census tracts, while the best levels (low SES disadvantage, high SES advantage, low pollution) are found in 5.7%. Overall, 34.1% of the census tracts exhibit high disadvantage, 66.3% have low advantage, and 59.2% have high mixtures of toxic pollutants. Areas with higher SES disadvantage had significantly higher non-Hispanic black population density (NHBPD; P &lt; 0.001), and NHBPD was higher in areas with higher pollution (P &lt; 0.001).

Conclusions:
Joint exposure to air toxins and SES varies with rural/urban location and coincides with minority populations.

Impact:
Our model can be extended to provide a holistic modeling framework for estimating disparities in cancer survival.
See all articles in this CEBP Focus section, “Environmental Carcinogenesis: Pathways to Prevention.”
Risks of Second Primary Gynecologic Cancers following Ovarian Cancer Treatment in Asian Ethnic Subgroups in the United States, 2000–2016
Authors: Mukand Nita H. , Zolekar Ashwini , Ko Naomi Y. , Calip Gregory S. 
Published: August 2020

Abstract

Background:
The differential occurrence of second primary cancers by race following ovarian cancer is poorly understood. Our objective was to determine the incidence of second primary gynecologic cancers (SPGC) following definitive therapy for ovarian cancer. Specifically, we aimed to determine differences in SPGC incidence by Asian ethnic subgroups.

Methods:
We identified 27,602 women ages 20 years and older and diagnosed with first primary epithelial ovarian cancer between 2000 and 2016 who received surgery and chemotherapy in 18 population-based Surveillance, Epidemiology and End Results Program registries. We compared the incidence of SPGC with expected incidence rates in the general population of women using estimated standardized incidence ratios (SIR) and 95% confidence intervals (CI).

Results:
The incidence of SPGC was lower among White women (SIR = 0.73; 95% CI, 0.59–0.89), and higher among Black (SIR = 1.80; 95% CI, 0.96–3.08) and Asian/Pacific Islander (API) women (SIR = 1.83; 95% CI, 1.07–2.93). Increased risk of vaginal cancers was observed among all women, although risk estimates were highest among API women (SIR = 26.76; 95% CI, 5.52–78.2) and were also significant for risk of uterine cancers (SIR = 2.53; 95% CI, 1.35–4.33). Among API women, only Filipinas had significantly increased incidence of SPGC overall including both uterine and vaginal cancers.

Conclusions:
Risk of SPGC following treatment of ovarian cancer differs by race and ethnicity, with Filipina women having the highest rates of second gynecologic cancers among Asian women.

Impact:
Ensuring access and adherence to surveillance may mitigate ethnic differences in the early detection and incidence of second gynecologic cancers.
Disparities in the Occurrence of Late Effects following Treatment among Adolescent and Young Adult Melanoma Survivors
Authors: Gingrich Alicia A. , Sauder Candice A.M. , Goldfarb Melanie , Li Qian , Wun Ted , Keegan Theresa H.M. 
Published: August 2020

Abstract

Background:
Melanoma is the third most common cancer in the adolescent and young adult (AYA) population; however, no studies have addressed the occurrence of adverse health conditions following melanoma treatment in these survivors.

Methods:
Data for patients ages 15 to 39 years diagnosed with cutaneous melanoma from 1996 to 2012 and surviving ≥2 years were obtained from the California Cancer Registry and linked to statewide hospitalization data. The influence of age at diagnosis, sex, race/ethnicity, neighborhood socioeconomic status (SES), health insurance, and surgery on the development of adverse health conditions was evaluated using Cox proportional hazards regression models.

Results:
Of 8,259 patients, 35.3% were male, 83.3% were non-Hispanic White, 82.4% had private health insurance, and 60.5% were considered high SES. In Cox regression models, males had an increased risk of developing adverse health conditions across all systems, including cardiac [HR, 1.73, 95% confidence interval (CI), 1.47–2.03], lymphedema (HR, 1.56; 95% CI, 1.37–1.77), hematologic disorders (HR, 1.17; 95% CI, 1.03–1.33), major infection/sepsis (HR, 1.59; 95% CI, 1.39–1.82), and second cancers (HR, 1.51; 95% CI, 1.31–1.74). Patients with public/no insurance (vs. private) had a greater risk of developing all studied adverse health conditions, including subsequent cancers (HR, 2.34; 95% CI, 1.94–2.82). AYA patients residing in low SES neighborhoods had similar increased risk of developing adverse health conditions.

Conclusions:
Of AYA melanoma survivors, males, those with public/no health insurance, and those living in low SES neighborhoods had a greater likelihood of developing adverse health conditions.

Impact:
Strategies to improve surveillance and secondary prevention of these adverse health conditions are needed among AYA melanoma survivors, specifically for the at-risk populations identified.
Long-term Outcomes for Extraskeletal Myxoid Chondrosarcoma: A SEER Database Analysis
Authors: Wagner Michael J. , Chau Bonny , Loggers Elizabeth T. , Pollack Seth M. , Kim Teresa S. , Kim Edward Y. , Thompson Matthew J. , Harwood Jared L. , Cranmer Lee D. 
Published: August 2020

Abstract

Background:
Extraskeletal myxoid chondrosarcoma (EMCS) is a rare tumor that typically has an indolent course but high rate of recurrence. We queried the Surveillance, Epidemiology, and End Results (SEER) database to assess factors associated with metastasis, treatment, and survival.

Methods:
We queried the SEER 1973–2016 database for patients with myxoid chondrosarcoma (ICD-O-3: 9231/3). Kaplan–Meier analyses and Cox proportional hazard models assessed effects on overall survival (OS) of demographics and clinical characteristics. Logistic regression assessed associations between tumor location and distant disease. Primary analysis was a complete case analysis; multiple imputation (MI) was used in a sensitivity analysis.

Results:
Locoregional disease (LRD) was found in 373 (85%) of patients. In univariate analysis with LRD, surgery correlated with superior OS [HR = 0.27; 95% confidence interval (CI), 0.16–0.47]; chemotherapy and radiotherapy associated with inferior OS (HR = 1.90; 95% CI, 1.11–3.27 and HR = 1.45; 95% CI, 1.03–2.06, respectively). No treatment modality associated with OS in the adjusted, complete case model. In the adjusted sensitivity analysis, surgery associated with superior outcomes (HR = 0.36; 95% CI, 0.19–0.69). There was no OS difference by primary tumor site. 10-year OS with distant disease was 10% (95% CI, 2%–25%).

Conclusions:
Surgery in LRD associated with improved OS in univariate analysis and adjusted models correcting for missing data. There was no OS benefit with chemotherapy or radiotherapy.

Impact:
This represents the largest report of EMCS with long-term follow-up. Despite the reputedly indolent nature of EMCS, outcomes with metastatic disease are poor. We provide OS benchmarks and guidance for stratification in future prospective trials.
Early-Life Cardiorespiratory Fitness and Long-term Risk of Prostate Cancer
Authors: Crump Casey , Stattin Pär , Brooks James D. , Stocks Tanja , Sundquist Jan , Sieh Weiva , Sundquist Kristina 
Published: August 2020

AbstractBackground:Adolescence is a period of rapid prostatic growth, yet is understudied for susceptibility for future risk of prostate cancer. We examined cardiorespiratory fitness (CRF) in late adolescence in relation to long-term prostate cancer risk.Methods:A population-based cohort study was conducted of all 699,125 Swedish military conscripts during 1972–1985 (97%–98% of 18-year-old men) in relation to risk of prostate cancer overall, aggressive prostate cancer, and prostate cancer mortality during 1998–2017 (ages 50–65 years). CRF was measured by maximal aerobic workload, and prostate cancer was ascertained using the National Prostate Cancer Register. Muscle strength was examined as a secondary predictor.Results:In 38.8 million person-years of follow-up, 10,782 (1.5%) men were diagnosed with prostate cancer. Adjusting for sociodemographic factors, height, weight, and family history of prostate cancer, high CRF was associated with a slightly increased risk of any prostate cancer [highest vs. lowest quintile: incidence rate ratio (IRR), 1.10; 95% CI, 1.03–1.19; P = 0.008], but was neither significantly associated with aggressive prostate cancer (1.01; 0.85–1.21; P = 0.90) nor prostate cancer mortality (1.24; 0.73–2.13; P = 0.42). High muscle strength also was associated with a modestly increased risk of any prostate cancer (highest vs. lowest quintile: IRR, 1.14; 95% CI, 1.07–1.23; P &lt; 0.001), but neither with aggressive prostate cancer (0.88; 0.74–1.04; P = 0.14) nor prostate cancer mortality (0.81; 0.48–1.37; P = 0.43).Conclusions:High CRF or muscle strength in late adolescence was associated with slightly increased future risk of prostate cancer, possibly related to increased screening, but neither with risk of aggressive prostate cancer nor prostate cancer mortality.Impact:These findings illustrate the importance of distinguishing aggressive from indolent prostate cancer and assessing for potential detection bias.
Associations of Novel Dietary and Lifestyle Inflammation Scores with Incident, Sporadic Colorectal Adenoma
Authors: Byrd Doratha A. , Judd Suzanne , Flanders W. Dana , Hartman Terryl J. , Fedirko Veronika , Bostick Roberd M. 
Published: August 2020

Abstract

Background:
Colorectal carcinogenesis is mechanistically linked to inflammation and is highly associated with diet and lifestyle factors that may affect chronic inflammation. We previously developed dietary (DIS) and lifestyle (LIS) inflammation scores, comprising inflammation biomarker–weighted components, to characterize the collective contributions of 19 food groups and four lifestyle exposures to systemic inflammation. Both scores were more strongly directly associated with circulating inflammation biomarkers in three validation populations, including a subset of the study population described below, than were the previously reported dietary inflammatory index and empirical dietary inflammatory pattern.

Methods:
We calculated the DIS and LIS in three pooled case–control studies of incident, sporadic colorectal adenoma (N = 765 cases and 1,986 controls) with extensive dietary and lifestyle data, and investigated their associations with adenoma using multivariable unconditional logistic regression.

Results:
For those in the highest (more proinflammatory) relative to the lowest (more anti-inflammatory) quintiles of the DIS and LIS, the multivariable-adjusted ORs were 1.31 [95% confidence interval (CI), 0.98–1.75; Ptrend = 0.09] and 1.98 (95% CI, 1.48–2.66; Ptrend &lt; 0.001), respectively. These associations were strongest for adenomas with high-risk characteristics and among men. Those in the highest relative to the lowest joint DIS/LIS quintile had a 2.65-fold higher odds (95% CI, 1.77–3.95) of colorectal adenoma.

Conclusions:
These results support that diets and lifestyles with higher balances of pro- to anti-inflammatory exposures may be associated with higher risk for incident, sporadic colorectal adenoma.

Impact:
Our findings support further investigation of the DIS and LIS in relation to colorectal neoplasms.