Citations

AbstractIntroductionMAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD).MethodsUsing Alzheimer's Disease Genetics Consortium (ADGC) genome‐wide association study (GWAS) data (n = 18,841), we conducted a MAPT H1/H2 haplotype–stratified association to discover MAPT haplotype–specific AD risk loci.ResultsWe identified 11 loci—5 in H2‐non‐carriers and 6 in H2‐carriers—although none of the MAPT haplotype–specific associations achieved genome‐wide significance. The most significant H2 non‐carrier–specific association was with a NECTIN2 intronic (P = 1.33E‐07) variant, and that for H2 carriers was near NKX6‐1 (P = 1.99E‐06). The GABRG2 locus had the strongest epistasis with MAPT H1/H2 variant rs8070723 (P = 3.91E‐06). Eight of the 12 genes at these loci had transcriptome‐wide significant differential expression in AD versus control temporal cortex (q < 0.05). Six genes were members of the brain transcriptional co‐expression network implicated in “synaptic transmission” (P = 9.85E‐59), which is also enriched for neuronal genes (P = 1.0E‐164), including MAPT.DiscussionThis stratified GWAS identified loci that may confer AD risk in a MAPT haplotype–specific manner. This approach may preferentially enrich for neuronal genes implicated in synaptic transmission.

Abstract We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, &lt;1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was &lt;1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.

Rationale, aims, and objectives: Post-hospitalization follow-up within 30 days following discharge has been shown to positively impact time to readmission, healthcare costs, and patient self-reported adherence and satisfaction. We aimed to improve resident satisfaction with the process of establishing post-hospitalization, primary care provider (PCP) follow-up. Methods: In this quality improvement study we surveyed all internal medicine residents at our institution regarding their satisfaction with the process of establishing PCP follow-up at the time of hospital discharge. A streamlined process was developed and two subsequent interventions were enacted; a dedicated teaching session and distribution of pocket cards outlining the process. Residents were then surveyed following each intervention to assess for impact on overall satisfaction and burden of work. Results: Initially, 77.3% of residents were not satisfied with the process of establishing post-hospitalization PCP follow-up. Following the first intervention there was a trend towards increasing satisfaction rates by 16.7% (p= 0.20), and after the second intervention there was a statistically significant increase in satisfaction rates from baseline by 44% (p= 0.007). There was also a reduction in the feeling of workload burden associated with establishing PCP follow-up from 32% to 25%, and over 67% of participants either agreed or strongly agreed that the workload was not too burdensome. Conclusion: This quality improvement initiative established that resident physicians at our institution previously found the process of establishing PCP follow-up at the time of patient discharge both confusing and burdensome. Through the implementation of our interventions we were able to achieve our aims of improving resident satisfaction.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Abstract Background The objectives of this study were to characterize (1) epidemiology of brain metastases at the time of primary cancer diagnosis, (2) incidence and trends of synchronous brain metastases from 2010 to 2015, and (3) overall survival (OS) of patients with synchronous brain metastases. Methods A total of 42 047 patients with synchronous brain metastases from 2010 to 2015 were identified from the Surveillance, Epidemiology, and End Results database. Descriptive analysis was utilized to analyze demographics and incidence. The Kaplan–Meier method and a Cox proportional hazards model were utilized to evaluate potential prognostic factors for OS. Results The majority of patients were diagnosed from age older than 50 (91.9%). Common primary sites included lung (80%), melanoma (3.8%), breast (3.7%), and kidney/renal pelvis (3.0%). Among pediatric patients, common primaries included kidney/renal pelvis and melanomas. The incidence was roughly 7.3 persons/100 000. Synchronous brain metastases were associated with significantly poorer OS compared to extracranial metastases alone (hazard ratio [HR] =1.56; 95% CI: 1.54–1.58; P &lt; .001). Among patients with brain metastases, male gender (HR = 1.60 vs 1.52), age older than 65 years (HR = 1.60 vs 1.46), synchronous liver, bone, or lung metastases (HR = 1.61 vs 1.49), and earlier year of diagnosis (HR = 0.98 for each year following 2010) were associated with significantly poorer OS. Conclusions The vast majority of brain metastases are from lung primaries. Synchronous brain metastases are associated with poorer OS compared to extracranial metastases alone.

Cold‐water swimming is a recreational activity that may become a future Winter Olympic event. However, unintentional cold‐water exposure can lead to hypothermia or death. Changes in body temperature are known to diminish swimming performance in persons experiencing hypothermia, although thermal changes during recreational exposure are not well characterized. This study examined skin temperature responses to a one‐kilometer swim in normal and cold‐water. Competitive swimmers (2 male and 2 female; age 44±17 years; BMI 24±2) completed a one‐kilometer swim (22 laps × 75 foot lengths) under free‐living indoor (25.5°C water and 25.0°C air) and cold outdoor (10.9°C water and 6.5°C) conditions. Skin temperature was determined with a digital infrared camera on the center of right palm, cubital fossa of arm, lateral aspect of pectoral muscle, cheek, and average of the four locations at 8.7±1.7 minutes before the swim (pre), then 0.6±0.2 and 6.4±2.1 minutes after the swim. Data (mean±SD) was analyzed with repeated measures ANOVA with significance if P<0.05. Swimmers completed the indoor and outdoor swim events in 20.7±1.7 and 21.8±1.1 minutes respectively. Average indoor skin temperature at −8.7, +0.6 and +6.4 minutes was 94.0±1.7, 85.3±1.9, and 88.1±2.2°C. Average outdoor skin temperature at −8.7, +0.6 and +6.4 minutes was 83.0±3.6, 53.5±2.3, and 67.7±2.0°C. At all times average outdoor skin temperature was lower than indoor, with the lowest temperature 0.6 minutes post‐swim. Palm indoor temperature at −8.7, +0.6 and +6.4 minutes was 91.6±3.9, 83.1±0.5, and 87.3±5.0°C. Palm outdoor temperature at −8.7, +0.6 and +6.4 minutes was 75.1±7.9, 47.4±2.7, and 58.1±2.7°C. At all times outdoor palm temperature was lower than indoor, with the lowest temperature 0.6 minutes post‐swim. Similar thermal responses were observed in the cheek, cubital fossa and pectoral locations. While time to complete the indoor and outdoor one km swims were similar, swimming in cold water was associated with delayed rewarming in the palm and cheek relative to cubital fossa and pectoral muscle.

Cold‐water swimming is a recreational activity that may become a future Winter Olympic event. However, unintentional cold‐water exposure can lead to arrhythmias, changes in electrocardiogram (ECG) appearance, and death. This study sought to characterize cardiac responses to recreational one‐kilometer swims performed in normal and cold‐water. Competitive swimmers (2 male 2 female; age 44±17 years; BMI 24±2) completed a one‐kilometer swim (22 laps × 75‐foot lengths) under free‐living indoor (25.5°C water and 25.0°C air) and cold outdoor (10.9°C water and 6.5°C) conditions. Continuous ECGs were obtained with a waterproof recording system (Actiwave, CamNtech Inc., Boerne, TX). ECG PR‐, QT‐, and RR‐intervals (sec), ventricular diastole (sec), and heart rate (beats/minute) were measured 8.7±1.7 minutes before the swim, then 0.6±0.2, 3.0±0.0 and 6.4±2.1 minutes after the swim. Data (mean±SD) was analyzed with repeated measures ANOVA with significance if P<0.05. Swimmers completed the indoor and outdoor swim events in 20.7±1.7 and 21.8±1.1 minutes, respectively. For the indoor swim, PR‐interval (sec) at −8.7, +0.6, +3, and +6.4 minutes was 0.12±0.01, 0.12±0.01, 0.11±0.01, and 0.12±0.01, and PR‐interval for the outdoor swim at −8.7, +0.6, +3.0 and +6.4 minutes was 0.13±0.01, 0.13±0.01, 0.13±0.01, and 0.14±0.01 (sec). PR‐interval was significantly longer at +6.4 minutes post cold‐water swim. For the indoor swim, ventricular diastole (sec) at −8.7, +0.6, +3, and +6.4 minutes was 0.37±0.06, 0.22±0.04, 0.30±0.01, and 0.32±0.05 (sec), and for the outdoor swim at −8.7, +0.6, +3.0 and +6.4 minutes ventricular diastole was 0.35±0.08, 0.19±0.02, 0.30±0.04, and 0.24±0.06 (sec). Ventricular diastole was significantly shorter at +6.4 minutes post cold‐water swim. No significant changes were observed for QT‐interval, RR‐interval, and heart rate between swim conditions. These parameters were also assessed for the ECG recordings collected during the 20.7±1.7‐minute normal and 21.8±1.1‐minute cold‐water swims to characterize the physiological response during swim exercise. This study of normal and cold‐water one‐kilometer recreational swimmers determined that a waterproof ECG could generate a continuous record of changes in cardiac function. During cold‐water swim recovery (+6.4 minutes) PR interval was lengthened and ventricular diastole was shortened suggesting an influence of temperature on cardiac function.

Background The objectives of this study were to characterize the risk of death (1) from the primary cancer vs competing cause of death; and (2) from various causes of death vs the general poplation. The relative risk of death after a pediatric cancer diagnosis versus the general population and the risk of death from a primary cancer diagnosis versus competing causes of death. Methods This retrospective, population‐based study used the Surveillance, Epidemiology, and End Results database (1980‐2015) and included patients aged 0 to 19 years at the time of diagnosis. Observed deaths were calculated; the risk of death versus the general population was assessed with standardized mortality ratios (SMRs). Competing risk models for the cause of death were performed. Results There were 58,356 patients who were diagnosed, and the mortality rate was 22.8%. To assess causes of death, 6996 patients who died during the study period were included (45,580 total person‐years at risk): 5128 (73%) died of their primary cancer, and 1868 (27%) died of a competing cause. Among all patients, the rate of death from the index cancer was higher than the rate of death from another cause within the first 5 years after diagnosis. The risk of death from a nonprimary cancer began to supersede the rate of death from the primary cancer 10 years after diagnosis for patients with germ cell tumors, lymphomas, and sarcomas. SMRs for the primary cancer were highest within the first 5 years after diagnosis for all cancers (SMRs, 100‐50,000; P < .0001). The risk of death from competing causes (heart disease, suicide, and sepsis) was elevated (SMR, >100; P < .001). The risk of dying of heart disease was high, especially for patients with astrocytomas (SMR, 47.84; 95% confidence interval [CI], 27.87‐76.59) and neuroblastomas (SMR, 98.59; 95% CI, 47.28‐181.32). The risk of dying of suicide was high in most patients, particularly for those with osteosarcomas (SMR, 111.40; 95% CI, 2.82‐620.69), Hodgkin lymphomas (SMR, 62.35; 95% CI, 34.89‐102.83), and gonadal germ cell tumors (SMR, 28.97; 95% CI, 12.51‐57.09). Conclusions The cause of death for patients with gonadal germ cell tumors, lymphomas, and sarcomas is more commonly a secondary cancer or noncancerous cause than the primary disease; their risk of death from competing causes (heart disease, suicide, and sepsis) rises throughout life.

Abstract Direct detection methods for Treponema pallidum include dark-field microscopy (DFM), direct fluorescence antibody (DFA) testing, immunohistochemistry (IHC), and nucleic acid amplification tests (NAATs). Here, we reviewed the relevant syphilis diagnostic literature to address 2 main questions with respect to T. pallidum direct detection techniques: “What are the performance characteristics for each direct detection test for T. pallidum and what are the optimal specimen types for each test?” and “What options are available for T. pallidum molecular epidemiology?” To answer these questions, we searched 5 electronic databases (OVID Medline, OVID Embase, CINAHL, Cochrane Library, and Scopus) from 1964 to 2017 using relevant search terms and identified 1928 articles, of which 37 met our inclusion criteria. DFM and DFA sensitivities ranged from 73% to 100% in cases of primary syphilis; and while sensitivity using silver stain histopathology for T. pallidum was generally low (0%–41%), higher performance characteristics were observed for T. pallidum–specific IHC (49–92%). Different genes have been targeted by T. pallidum–specific NAATs, with the majority of studies indicating that sensitivity is primarily dependent on the type of collected biological sample, with highest sensitivity observed in primary lesion exudate (75–95%). Given the rising incidence of syphilis, the development of direct, Food and Drug Administration–cleared T. pallidum NAATs should be considered an immediate priority.

55 Background: To compare the predictive ability of health utility mapping algorithms derived using cross-sectional and longitudinal data specific to the Expanded Prostate Cancer Index Composite (EPIC). Methods: This mapping study utilized data from an international, multicenter, randomized controlled trial of patients with low-risk prostate cancer conducted by NRG Oncology (NCT00331773). Health-related quality-of-life (HRQoL) data were collected using EPIC, and health utilities were obtained using EuroQOL-5D (EQ5D) at baseline and 6, 12 and 24 months post-intervention. Data were split into an estimation sample (70%) and a validation sample (30%). Ordinary Least Squares (OLS) regression models were estimated using baseline cross-sectional data as well as pooled data from all assessment periods. Random effects (RE) specifications that explicitly model the longitudinal nature of the data were also estimated. Candidate models were selected based on root mean square error (RMSE). Results: A total of 196 (147) patients in the estimation sample had complete EQ5D and EPIC domain (subdomain) data at all time points. OLS models using combined data outperformed the counter-part RE models as well as OLS models using baseline data in the five-fold cross-validation. Addition of covariates to the models resulted in improved predictive ability. In the external validation, when only EPIC domain/ subdomain data are available, the OLS model using combined data predicted EQ5D utilities better than the counterpart RE model and OLS model using baseline data (RMSE=0.121108 & 0.111345). OLS model using baseline data outperformed other model types for algorithms with EPIC domains and demographics (RMSE=0.121757), while RE models outperformed the other two model types for algorithms with EPIC subdomains and demographic data, (0.112782) and for algorithms with EPIC domains/ subdomains, demographics, and clinical covariates (RMSE=0.123589 & 0.163093). Conclusions: While algorithms using pooled data outperformed other model types in internal validation, RE models showed better predictive ability in external validation for algorithms with covariates. Clinical trial information: NCT00331773.