Search

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) represents an important but limited treatment for patients with severe COVID-19. We assessed the effects of an educational intervention on a persons ECMO care preference and examined whether patients and providers had similar ECMO preferences. METHODS: In the Video+Survey group, patients watched an educational video about ECMOs purpose, benefits, and risks followed by an assessment of ECMO knowledge and care preferences in seven scenarios varying by hypothetical patient age, function, and comorbidities. Patients in the Survey Only group and providers didnt watch the video. Logistic regression was used to estimate the probability of agreement for each ECMO scenario between the two patient groups and then between all patients and providers. RESULTS: Video+Survey patients were more likely (64% vs. 17%; p = 0.02) to correctly answer all ECMO knowledge questions than Survey Only patients. Patients in both groups agreed that ECMO should be considered across all hypothetical scenarios, with predicted agreement above 65%. In adjusted analyses, patients and providers had similar predicted agreement for ECMO consideration across six of the seven scenarios, but patients showed greater preference (84% vs. 41%, p = 0.003) for the scenario of a functionally dependent 65-year-old with comorbidities than providers. DISCUSSION AND CONCLUSIONS: An educational video increased a persons ECMO knowledge but did not change their ECMO preferences. Clinicians were less likely than patients to recommend ECMO for older adults, so advanced care planning discussion between patients and providers about treatment options in critically ill patients with COVID-19 is critical.

BackgroundInformation about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes in the setting of Omicron variant transmission and COVID-19 vaccination is limited.ObjectiveTo measure the effectiveness of nirmatrelvir-ritonavir and molnupiravir for outpatient treatment of COVID-19.DesignThree retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir.SettingVeterans Health Administration (VHA).ParticipantsNonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022.InterventionNirmatrelvir-ritonavir or molnupiravir pharmacotherapy.MeasurementsIncidence of any hospitalization or all-cause mortality at 30 days and from 31 to 180 days.ResultsEighty-seven percent of participants were male; the median age was 66 years, and 18% were unvaccinated. Compared with matched untreated control participants, those treated with nirmatrelvir-ritonavir (n = 9607) had lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1000 participants; risk difference [RD], -8.25 [95% CI, -12.27 to -4.23] per 1000 participants) and death (1.25 vs. 5.47 per 1000 participants; RD, -4.22 [CI, -5.45 to -3.00] per 1000 participants). Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02]). Molnupiravir-treated participants (n = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1000 participants at 30 days; RD, -10.42 [CI, -13.49 to -7.35] per 1000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization. A difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants.LimitationThe date of COVID-19 symptom onset for most veterans was unknown.ConclusionNirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death. Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals.Primary funding sourceU.S. Department of Veterans Affairs.

SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of EIF2AK1 inhibitors to overcome transfusion dependency in patients with SF3B1-mutant MDS-RS with impaired red blood cell production.SignificanceMDS-RS are characterized by significant anemia. Patients with MDS-RS die from a shortage of red blood cells and the side effects of iron overload due to their constant need for transfusions. Our study has implications for the development of therapies to achieve long-lasting hematologic responses. This article is highlighted in the In This Issue feature, p. 476.

OBJECTIVE: In a large multisite cohort of Veterans who underwent Roux-en-Y gastric bypass (RYGB) or laparoscopic sleeve gastrectomy (LSG), initiation of (ie, incident) and persistence of (ie, continuation of preoperative) depression treatment are compared with matched nonsurgical controls. BACKGROUND: Bariatric surgery has been associated with short-term improvements in depression but less is known about longer term outcomes. METHODS: In a retrospective cohort study, we matched 1713 Veterans with depression treatment who underwent bariatric surgery in Veterans Administration bariatric centers from fiscal year 2001 to 2016 to 15,056 nonsurgical controls using sequential stratification and examined the persistence of depression treatment via generalized estimating equations. Incidence of depression treatment was compared using Cox regression models between 2227 surgical patients and 20,939 matched nonsurgical controls without depression treatment at baseline. RESULTS: In surgical patients with depression treatment at baseline, the use of postsurgical depression treatment declined over time for both surgical procedures, but postsurgical patients had greater use of depression treatment at 5 years [RYGB: odds ratio=1.24, 95% confidence interval (CI): 1.04-1.49; LSG: odds ratio=1.27, 95% CI: 1.04-1.56] compared with controls. Among those without depression treatment at baseline, bariatric surgery was associated with a higher incidence of depression treatment compared with matched controls (RYGB: hazard ratio=1.34, 95% CI: 1.17-1.53; LSG: hazard ratio at 1-5 years=1.27, 95% CI: 1.10-1.47). CONCLUSIONS: Bariatric surgery was associated with a greater risk of postoperative incident depression treatment and greater persistence of postoperative depression treatment. Depression may worsen for some patients after bariatric surgery, so clinicians should carefully monitor their patients for depression postoperatively.

OBJECTIVE: To examine outpatient care fragmentation and its association with future hospitalization among patients at high risk for hospitalization. DATA SOURCES: Veterans Affairs (VA) and Medicare data. STUDY DESIGN: We conducted a longitudinal study, using logistic regression to examine how outpatient care fragmentation in FY14 (as measured by number of unique providers, Breslaus Usual Provider of Care (UPC), Bice-Boxermans Continuity of Care Index (COCI), and Modified Modified Continuity Index (MMCI)) was associated with all-cause hospitalizations and hospitalizations related to ambulatory care sensitive conditions (ACSC) in FY15. We also examined how fragmentation varied by patients age, gender, race, ethnicity, marital status, rural status, history of homelessness, number of chronic conditions, Medicare utilization, and mental health care utilization. DATA EXTRACTION METHODS: We extracted data for 130,704 VA patients ≥65 years old with a hospitalization risk ≥90th percentile and ≥ four outpatient visits in the baseline year. PRINCIPAL FINDINGS: The mean (SD) of FY14 outpatient visits was 13.2 (8.6). Fragmented care (more providers, less care with a usual provider, more dispersed care based on COCI) was more common among patients with more chronic conditions and those receiving mental health care. In adjusted models, most fragmentation measures were not associated with all-cause hospitalization, and patients with low levels of fragmentation (more concentrated care based on UPC, COCI, and MMCI) had a higher likelihood of an ACSC-related hospitalization (AOR, 95% CI = 1.21 (1.09-1.35), 1.27 (1.14-1.42), and 1.28 (1.18-1.40), respectively). CONCLUSIONS: Contrary to expectations, outpatient care fragmentation was not associated with elevated all-cause hospitalization rates among VA patients in the top 10th percentile for risk of admission; in fact, fragmented care was linked to lower rates of hospitalization for ACSCs. In integrated settings such as the VA, multiple providers, and dispersed care might offer access to timely or specialized care that offsets risks of fragmentation, particularly for conditions that are sensitive to ambulatory care.

The cross-sectiondesign of cos (θ) superconducting magnets is historically developed in a two-step process: initially, the coil geometry is defined on the basis of magnetic optimizations; then, the structure is designed around the coil. The first step searches for the best coil cross-section maximizing the magnetic field, margin, field quality and conductor efficiency. The latter step aims at limiting the coil stresses and deformations. However, the coil design, defined with the initial magnetic optimization, can influence the mechanical behaviour of the magnet, altering, for example, the peak stress during operation. As the critical current is a function of the applied strain, the mechanical implications of the coil cross-section design can limit the achievable performance. In this paper we propose an integrated optimization process that targets the peak stress on the conductor in addition to the magnetic objectives. The results are presented for a sample high-field Nb3 Sn dipole: a 4-layer design aiming at ultimate conductor performance.

Infinium methylation arrays are not available for the vast majority of non-human mammals. Moreover, even if species-specific arrays were available, probe differences between them would confound cross-species comparisons. To address these challenges, we developed the mammalian methylation array, a single custom array that measures up to 36k CpGs per species that are well conserved across many mammalian species. We designed a set of probes that can tolerate specific cross-species mutations. We annotate the array in over 200 species and report CpG island status and chromatin states in select species. Calibration experiments demonstrate the high fidelity in humans, rats, and mice. The mammalian methylation array has several strengths: it applies to all mammalian species even those that have not yet been sequenced, it provides deep coverage of conserved cytosines facilitating the development of epigenetic biomarkers, and it increases the probability that biological insights gained in one species will translate to others.

BackgroundOpioid analgesics are often prescribed to manage pain after bariatric surgery, which may develop into chronic prescription opioid use (CPOU) in opioid-naïve patients. Bariatric surgery may affect opioid use in those with or without presurgical CPOU.ObjectiveTo compare CPOU persistence and incidence in a large multisite cohort of veterans undergoing bariatric surgery (open Roux-en-Y gastric bypass, laparoscopic RYGB, or laparoscopic sleeve gastrectomy) and matched nonsurgical controls.SettingVeterans Administration hospitals.MethodsIn a retrospective cohort study, we matched 1117 surgical patients with baseline CPOU to 9531 nonsurgical controls, and 2822 surgical patients without CPOU at baseline to 26,392 nonsurgical controls using sequential stratification. CPOU persistence in veterans with baseline CPOU was estimated using generalized estimating equations by procedure type. CPOU incidence in veterans without baseline CPOU was estimated in Cox regression models by procedure type because postoperative pain, complications, and absorption may differ by procedure.ResultsIn veterans with baseline CPOU, postsurgical CPOU declined over time for each surgical procedure; these trends did not differ between surgical patients and nonsurgical controls. In veterans without baseline CPOU, compared with nonsurgical controls, bariatric patients had higher CPOU incidence within 5 years after open Roux-en-Y gastric bypass (hazard ratio = 1.19; 95% confidence interval: 1.06-1.34) or laparoscopic open Roux-en-Y gastric bypass (hazard ratio = 1.22, 95% confidence interval: 1.06-1.41). Veterans undergoing laparoscopic sleeve gastrectomy had higher CPOU incidence 1 to 5 years after surgery (hazard ratio = 1.28; 95% confidence interval: 1.05-1.56) than nonsurgical controls.ConclusionsBariatric surgery was associated with greater risk of CPOU incidence in patients without baseline CPOU but was not associated with greater CPOU persistence.

Diagnostic and molecular genetic testing are key in advancing the treatment of acute myeloid leukemia (AML), yet little is known about testing patterns outside of clinical trials, especially in older patients. We analyzed diagnostic and molecular testing patterns over time in 565 patients aged ≥ 55 years with newly diagnosed AML enrolled in the Connect® MDS/AML Disease Registry (NCT01688011) in the United States. Diagnostic data were recorded at enrolment and compared with published guidelines. The percentage of bone marrow blasts was reported for 82.1% of patients, and cellularity was the most commonly reported bone marrow morphological feature. Flow cytometry, karyotyping, molecular testing, and fluorescence in situ hybridization were performed in 98.8%, 95.4%, 75.9%, and 75.7% of patients, respectively. Molecular testing was done more frequently at academic than community/government sites (84.3% vs 70.2%; P

This work describes an approach for the interactive visual analysis of large-scale simulations, where numerous superlevel set components and their evolution are of primary interest. The approach first derives, at simulation runtime, a specialized Cinema database that consists of images of component groups, and topological abstractions. This database is processed by a novel graph operation-based nested tracking graph algorithm (GO-NTG) that dynamically computes NTGs for component groups based on size, overlap, persistence, and level thresholds. The resulting NTGs are in turn used in a feature-centered visual analytics framework to query specific database elements and update feature parameters, facilitating flexible post hoc analysis.

This work describes an approach for the interactive visual analysis of large-scale simulations, where numerous superlevel set components and their evolution are of primary interest. The approach first derives, at simulation runtime, a specialized Cinema database that consists of images of component groups, and topological abstractions. This database is processed by a novel graph operation-based nested tracking graph algorithm (GO-NTG) that dynamically computes NTGs for component groups based on size, overlap, persistence, and level thresholds. The resulting NTGs are in turn used in a feature-centered visual analytics framework to query specific database elements and update feature parameters, facilitating flexible post hoc analysis.

Background: Care teams are increasingly expected to attend to the needs of patient's personal caregivers (e.g., family members). Improving communication among oncologists, patients with advanced cancer, and their personal caregivers might enhance caregivers' experiences of end-of-life (EoL) cancer care and bereavement outcomes. Objective: To explore the effects of the Values and Options in Cancer Care intervention on caregivers' experiences of EoL care and bereavement outcomes. Design: We developed a brief behavioral intervention to improve communication among oncologists, patients with advanced cancer, and their personal caregivers. The intervention was designed to help patients/caregivers ask questions, express concerns, and help oncologists respond effectively. We randomly assigned oncologists (and their patients/caregivers) to the intervention or usual care. Setting/Subjects: Medical oncologists in NY and CA; patients/personal caregivers with advanced cancer. Measurements: Two months after the patient's death, caregivers completed three instruments assessing their experiences of EoL care. Seven months after the patient's death, caregivers completed the Prolonged Grief Disorder-13 (PG-13; primary prespecified outcome), the Purpose-in-Life scale, and scales assessing mental health function, depression, and anxiety. Results: The intervention did not significantly improve caregivers' scores on the PG-13 (p = 0.21), mental health function, depression, or anxiety, but it did improve purpose-in-life scores (p = 0.018). Cohen's d (95% confidence interval) for all three experiences of EoL care outcomes were promising, ranging from 0.22 (-0.19 to 0.63) to 0.39 (-0.07 to 0.86) although none was statistically significant. Conclusion: Preliminary findings show promise that scalable interventions in cancer care settings may improve caregiver experiences with cancer care and some bereavement outcomes.

Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of TP53 mutations, identified in 55% of patients. TP53 mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality (p 10%), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse TP53 mutations and can be refined by considering clinical and karyotype features.

Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of TP53 mutations, identified in 55% of patients. TP53 mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality (p 10%), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse TP53 mutations and can be refined by considering clinical and karyotype features.

Smallholder production is a significant contributor to rural livelihoods and rural economies in much of the developing world. Yet, there is evidence of increasing disengagement in some regions, including southern Africa. However, there has been little consideration of the rates and the livelihood, ecological and policy implications of such. In this paper we examine previous studies on rates of deactivation of crop fields by smallholders in the communal areas of South Africa, supported by repeat photo images and case study material. Together these various methods show that it is a widespread phenomenon occurring at variable rates. Over short periods deactivation of crop fields can be balanced through some reactivation or intensification of homegardens. But over longer periods there is a net decline in the area of fields cultivated in many areas, with corresponding increases in the area of fallow land which, through time, may undergo changes towards more natural vegetation. We review the drivers of this deactivation of field cropping, and then contemplate the possible socio-economic and ecological implications at local and national scales. We show that there are numerous and profound implications that require greater understanding and policy responses.

Smallholder production is a significant contributor to rural livelihoods and rural economies in much of the developing world. Yet, there is evidence of increasing disengagement in some regions, including southern Africa. However, there has been little consideration of the rates and the livelihood, ecological and policy implications of such. In this paper we examine previous studies on rates of deactivation of crop fields by smallholders in the communal areas of South Africa, supported by repeat photo images and case study material. Together these various methods show that it is a widespread phenomenon occurring at variable rates. Over short periods deactivation of crop fields can be balanced through some reactivation or intensification of homegardens. But over longer periods there is a net decline in the area of fields cultivated in many areas, with corresponding increases in the area of fallow land which, through time, may undergo changes towards more natural vegetation. We review the drivers of this deactivation of field cropping, and then contemplate the possible socio-economic and ecological implications at local and national scales. We show that there are numerous and profound implications that require greater understanding and policy responses.

Background and aimsCannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants.MethodsA twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals.ResultsThe twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P  0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant.ConclusionAge at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

IntroductionOnline Diabetes Prevention Programs (DPPs) can be scaled up and delivered broadly. However, little is known about real-world effectiveness and how outcomes compare with in-person DPP. This study examined online DPP weight loss and participation outcomes and secondarily compared outcomes among participating individuals with parallel in-person interventions.Study designA large non-randomized trial supplemented by a comparative analysis of participating individuals from a concurrent trial of two parallel in-person programs: in-person DPP and the Veterans Administration's standard of care weight loss program (MOVE!).Setting/participantsObese/overweight Veterans with prediabetes enrolled in online DPP (n = 268) between 2013 and 2014. Similar eligibility criteria were used to enroll in-person participants between 2012 and 2014 (n = 273 in-person DPP, n = 114 MOVE!) within a separate trial.InterventionOnline DPP included a virtual group format, live e-coach, weekly modules delivered asynchronously, and wireless home scales. In-person programs included eight to 22 group-based, face-to-face sessions.Main outcomes measuresWeight change at 6 and 12 months using wirelessly uploaded home scale data or electronic medical record weights from clinical in-person visits. Outcomes were analyzed between 2015 and 2017.ResultsFrom 1,182 invitations, 268 (23%) participants enrolled in online DPP. Among these, 158 (56%) completed eight or more modules; mean weight change was -4.7kg at 6 months and -4.0kg at 12 months. In a supplemental analysis of participants completing one or more sessions/modules, online DPP participants were most likely to complete eight or more sessions/modules (87% online DPP vs 59% in-person DPP vs 55% MOVE!, p

Cardioviruses cause diseases in many animals including, in rare cases, humans. Although they share common features with all picornaviruses, cardioviruses have unique properties that distinguish them from other family members, including enteroviruses. One feature shared by all picornaviruses is the covalent attachment of VPg to the 5' end of genomic RNA via a phosphotyrosyl linkage. For enteroviruses, this linkage is cleaved by a host cell protein, TDP2. Since TDP2 is divergently required during enterovirus infections, we determined if TDP2 is necessary during infection by the prototype cardiovirus, EMCV. We found that EMCV yields are reduced in the absence of TDP2. We observed a decrease in viral protein accumulation and viral RNA replication in the absence of TDP2. In contrast to enterovirus infections, we found that TDP2 is modified at peak times of EMCV infection. This finding suggests a unique mechanism for cardioviruses to regulate TDP2 activity during infection.

Cardioviruses cause diseases in many animals including, in rare cases, humans. Although they share common features with all picornaviruses, cardioviruses have unique properties that distinguish them from other family members, including enteroviruses. One feature shared by all picornaviruses is the covalent attachment of VPg to the 5' end of genomic RNA via a phosphotyrosyl linkage. For enteroviruses, this linkage is cleaved by a host cell protein, TDP2. Since TDP2 is divergently required during enterovirus infections, we determined if TDP2 is necessary during infection by the prototype cardiovirus, EMCV. We found that EMCV yields are reduced in the absence of TDP2. We observed a decrease in viral protein accumulation and viral RNA replication in the absence of TDP2. In contrast to enterovirus infections, we found that TDP2 is modified at peak times of EMCV infection. This finding suggests a unique mechanism for cardioviruses to regulate TDP2 activity during infection.

Cardioviruses cause diseases in many animals including, in rare cases, humans. Although they share common features with all picornaviruses, cardioviruses have unique properties that distinguish them from other family members, including enteroviruses. One feature shared by all picornaviruses is the covalent attachment of VPg to the 5' end of genomic RNA via a phosphotyrosyl linkage. For enteroviruses, this linkage is cleaved by a host cell protein, TDP2. Since TDP2 is divergently required during enterovirus infections, we determined if TDP2 is necessary during infection by the prototype cardiovirus, EMCV. We found that EMCV yields are reduced in the absence of TDP2. We observed a decrease in viral protein accumulation and viral RNA replication in the absence of TDP2. In contrast to enterovirus infections, we found that TDP2 is modified at peak times of EMCV infection. This finding suggests a unique mechanism for cardioviruses to regulate TDP2 activity during infection.

BackgroundThe Diabetes Prevention Program (DPP) is an effective lifestyle intervention to reduce incidence of type 2 diabetes. However, there are gaps in knowledge about how to implement DPP. The aim of this study was to evaluate implementation of DPP via assessment of a clinical demonstration in the Veterans Health Administration (VHA).MethodsA 12-month pragmatic clinical trial compared weight outcomes between the Veterans Affairs Diabetes Prevention Program (VA-DPP) and the usual care MOVE!® weight management program (MOVE!). Eligible participants had a body mass index (BMI) ≥30 kg/m2 (or BMI ≥ 25 kg/m2 with one obesity-related condition), prediabetes (glycosylated hemoglobin (HbA1c) 5.7-6.5% or fasting plasma glucose (FPG) 100-125 mg/dL), lived within 60 min of their VA site, and had not participated in a weight management program within the last year. Established evaluation and implementation frameworks were used to guide the implementation evaluation. Implementation barriers and facilitators, delivery fidelity, participant satisfaction, and implementation costs were assessed. Using micro-costing methods, costs for assessment of eligibility and scheduling and maintaining adherence per participant, as well as cost of delivery per session, were also assessed.ResultsSeveral barriers and facilitators to Reach, Adoption, Implementation, Effectiveness and Maintenance were identified; barriers related to Reach were the largest challenge encountered by site teams. Fidelity was higher for VA-DPP delivery compared to MOVE! for five of seven domains assessed. Participant satisfaction was high in both programs, but higher in VA-DPP for most items. Based on micro-costing methods, cost of assessment for eligibility was $68/individual assessed, cost of scheduling and maintaining adherence was $328/participant, and cost of delivery was $101/session.ConclusionsMulti-faceted strategies are needed to reach targeted participants and successfully implement DPP. Costs for assessing patients for eligibility need to be carefully considered while still maximizing reach to the targeted population.

BackgroundThe Diabetes Prevention Program (DPP) is an effective lifestyle intervention to reduce incidence of type 2 diabetes. However, there are gaps in knowledge about how to implement DPP. The aim of this study was to evaluate implementation of DPP via assessment of a clinical demonstration in the Veterans Health Administration (VHA).MethodsA 12-month pragmatic clinical trial compared weight outcomes between the Veterans Affairs Diabetes Prevention Program (VA-DPP) and the usual care MOVE!® weight management program (MOVE!). Eligible participants had a body mass index (BMI) ≥30 kg/m2 (or BMI ≥ 25 kg/m2 with one obesity-related condition), prediabetes (glycosylated hemoglobin (HbA1c) 5.7-6.5% or fasting plasma glucose (FPG) 100-125 mg/dL), lived within 60 min of their VA site, and had not participated in a weight management program within the last year. Established evaluation and implementation frameworks were used to guide the implementation evaluation. Implementation barriers and facilitators, delivery fidelity, participant satisfaction, and implementation costs were assessed. Using micro-costing methods, costs for assessment of eligibility and scheduling and maintaining adherence per participant, as well as cost of delivery per session, were also assessed.ResultsSeveral barriers and facilitators to Reach, Adoption, Implementation, Effectiveness and Maintenance were identified; barriers related to Reach were the largest challenge encountered by site teams. Fidelity was higher for VA-DPP delivery compared to MOVE! for five of seven domains assessed. Participant satisfaction was high in both programs, but higher in VA-DPP for most items. Based on micro-costing methods, cost of assessment for eligibility was $68/individual assessed, cost of scheduling and maintaining adherence was $328/participant, and cost of delivery was $101/session.ConclusionsMulti-faceted strategies are needed to reach targeted participants and successfully implement DPP. Costs for assessing patients for eligibility need to be carefully considered while still maximizing reach to the targeted population.

IntroductionThis clinical demonstration trial compared the effectiveness of the Veterans Affairs Diabetes Prevention Program (VA-DPP) with an evidence-based usual care weight management program (MOVE!®) in the Veterans Health Administration health system.DesignProspective, pragmatic, non-randomized comparative effectiveness study of two behavioral weight management interventions.Setting/participantsObese/overweight Veterans with prediabetes were recruited from three geographically diverse VA sites between 2012 and 2014.InterventionVA-DPP included 22 group-based intensive lifestyle change sessions.Main outcome measuresWeight change at 6 and 12 months, hemoglobin A1c (HbA1c) at 12 months, and VA health expenditure changes at 15 months were assessed using VA electronic health record and claims data. Between- and within-group comparisons for weight and HbA1c were done using linear mixed-effects models controlling for age, gender, race/ethnicity, baseline outcome values, and site. Analyses were conducted in 2015-2016.ResultsA total of 387 participants enrolled (273 VA-DPP, 114 MOVE!). More VA-DPP participants completed at least one (73.3% VA-DPP vs 57.5% MOVE! p=0.002); four (57.5% VA-DPP vs 42.5% MOVE!, p=0.007); and eight or more sessions (42.5% VA-DPP vs 31% MOVE!, p=0.035). Weight loss from baseline was significant at both 6 (p

Tracking graphs are a well established tool in topological analysis to visualize the evolution of components and their properties over time, i.e., when components appear, disappear, merge, and split. However, tracking graphs are limited to a single level threshold and the graphs may vary substantially even under small changes to the threshold. To examine the evolution of features for varying levels, users have to compare multiple tracking graphs without a direct visual link between them. We propose a novel, interactive, nested graph visualization based on the fact that the tracked superlevel set components for different levels are related to each other through their nesting hierarchy. This approach allows us to set multiple tracking graphs in context to each other and enables users to effectively follow the evolution of components for different levels simultaneously. We demonstrate the effectiveness of our approach on datasets from finite pointset methods, computational fluid dynamics, and cosmology simulations.

Variations in the transport current of a superconducting magnet cause several types of transitory losses. Due to its relatively short time constant, usually of the order of a few tens of milliseconds, interfilament coupling loss can have a significant effect on the coil protection against overheating after a quench. This loss is deposited in the strands and can facilitate a more homogeneous transition to the normal state of the coil turns. Furthermore, the presence of local interfilament coupling currents reduces the magnet's differential inductance, which in turn provokes a faster discharge of the transport current. The lumped-element dynamic electrothermal model of a superconducting magnet has been developed to reproduce these effects. Simulations are compared to experimental electrical transients and found in good agreement. After its validation, the model can be used for predicting the performance of quench protection systems based on energy extraction, quench heaters, the newly developed coupling-loss-induced quench protection system, or combinations of those. The impact of interfilament coupling loss on each protection system is discussed.

Tracking graphs are a well established tool in topological analysis to visualize the evolution of components and their properties over time, i.e., when components appear, disappear, merge, and split. However, tracking graphs are limited to a single level threshold and the graphs may vary substantially even under small changes to the threshold. To examine the evolution of features for varying levels, users have to compare multiple tracking graphs without a direct visual link between them. We propose a novel, interactive, nested graph visualization based on the fact that the tracked superlevel set components for different levels are related to each other through their nesting hierarchy. This approach allows us to set multiple tracking graphs in context to each other and enables users to effectively follow the evolution of components for different levels simultaneously. We demonstrate the effectiveness of our approach on datasets from finite pointset methods, computational fluid dynamics, and cosmology simulations.

In 2016, the Veterans Health Administration (VHA) held a Weight Management State of the Art conference to identify evidence gaps and develop a research agenda for population-based weight management for veterans. Included were behavioral, pharmacologic, and bariatric surgery workgroups. This article summarizes the bariatric surgery workgroup (BSWG) findings and recommendations for future research. The BSWG agreed that there is evidence from randomized trials and large observational studies suggesting that bariatric surgery is superior to medical therapy for short- and intermediate-term remission of type 2 diabetes, long-term weight loss, and long-term survival. Priority evidence gaps include long-term comorbidity remission, mental health, substance abuse, and health care costs. Evidence of the role of endoscopic weight loss options is also lacking. The BSWG also noted the limited evidence regarding optimal timing for bariatric surgery referral, barriers to bariatric surgery itself, and management of high-risk bariatric surgery patients. Clinical trials of pre- and post-surgery interventions may help to optimize patient outcomes. A registry of overweight and obese veterans and a workforce assessment to determine the VHA's capacity to increase bariatric surgery access were recommended. These will help inform policy modifications and focus the research agenda to improve the ability of the VHA to deliver population-based weight management.

Variations in the transport current of a superconducting magnet cause several types of transitory losses. Due to its relatively short time constant, usually of the order of a few tens of milliseconds, interfilament coupling loss can have a significant effect on the coil protection against overheating after a quench. This loss is deposited in the strands and can facilitate a more homogeneous transition to the normal state of the coil turns. Furthermore, the presence of local interfilament coupling currents reduces the magnet's differential inductance, which in turn provokes a faster discharge of the transport current. The lumped-element dynamic electrothermal model of a superconducting magnet has been developed to reproduce these effects. Simulations are compared to experimental electrical transients and found in good agreement. After its validation, the model can be used for predicting the performance of quench protection systems based on energy extraction, quench heaters, the newly developed coupling-loss-induced quench protection system, or combinations of those. The impact of interfilament coupling loss on each protection system is discussed.

The Food and Drug Administration Adverse Event Reporting System (FAERS) remains the primary source for post-marketing pharmacovigilance. The system is largely un-curated, unstandardized, and lacks a method for linking drugs to the chemical structures of their active ingredients, increasing noise and artefactual trends. To address these problems, we mapped drugs to their ingredients and used natural language processing to classify and correlate drug events. Our analysis exposed key idiosyncrasies in FAERS, for example reports of thalidomide causing a deadly ADR when used against myeloma, a likely result of the disease itself; multiplications of the same report, unjustifiably increasing its importance; correlation of reported ADRs with public events, regulatory announcements, and with publications. Comparing the pharmacological, pharmacokinetic, and clinical ADR profiles of methylphenidate, aripiprazole, and risperidone, and of kinase drugs targeting the VEGF receptor, demonstrates how underlying molecular mechanisms can emerge from ADR co-analysis. The precautions and methods we describe may enable investigators to avoid confounding chemistry-based associations and reporting biases in FAERS, and illustrate how comparative analysis of ADRs can reveal underlying mechanisms.

Modeling accurately electro-thermal transients occurring in a superconducting magnet is challenging. The behavior of the magnet is the result of complex phenomena occurring in distinct physical domains (electrical, magnetic and thermal) at very different spatial and time scales. Combined multi-domain effects significantly affect the dynamic behavior of the system and are to be taken into account in a coherent and consistent model. A new methodology for developing a Lumped-Element Dynamic Electro-Thermal (LEDET) model of a superconducting magnet is presented. This model includes non-linear dynamic effects such as the dependence of the magnet's differential self-inductance on the presence of inter-filament and inter-strand coupling currents in the conductor. These effects are usually not taken into account because superconducting magnets are primarily operated in stationary conditions. However, they often have significant impact on magnet performance, particularly when the magnet is subject to high ramp rates. Following the LEDET method, the complex interdependence between the electro-magnetic and thermal domains can be modeled with three sub-networks of lumped-elements, reproducing the electrical transient in the main magnet circuit, the thermal transient in the coil cross-section, and the electro-magnetic transient of the inter-filament and inter-strand coupling currents in the superconductor. The same simulation environment can simultaneously model macroscopic electrical transients and phenomena at the level of superconducting strands. The model developed is a very useful tool for reproducing and predicting the performance of conventional quench protection systems based on energy extraction and quench heaters, and of the innovative CLIQ protection system as well.

© 2016 Modeling accurately electro-thermal transients occurring in a superconducting magnet is challenging. The behavior of the magnet is the result of complex phenomena occurring in distinct physical domains (electrical, magnetic and thermal) at very different spatial and time scales. Combined multi-domain effects significantly affect the dynamic behavior of the system and are to be taken into account in a coherent and consistent model. A new methodology for developing a Lumped-Element Dynamic Electro-Thermal (LEDET) model of a superconducting magnet is presented. This model includes non-linear dynamic effects such as the dependence of the magnet's differential self-inductance on the presence of inter-filament and inter-strand coupling currents in the conductor. These effects are usually not taken into account because superconducting magnets are primarily operated in stationary conditions. However, they often have significant impact on magnet performance, particularly when the magnet is subject to high ramp rates. Following the LEDET method, the complex interdependence between the electro-magnetic and thermal domains can be modeled with three sub-networks of lumped-elements, reproducing the electrical transient in the main magnet circuit, the thermal transient in the coil cross-section, and the electro-magnetic transient of the inter-filament and inter-strand coupling currents in the superconductor. The same simulation environment can simultaneously model macroscopic electrical transients and phenomena at the level of superconducting strands. The model developed is a very useful tool for reproducing and predicting the performance of conventional quench protection systems based on energy extraction and quench heaters, and of the innovative CLIQ protection system as well.

Protection against the effects of a quench is a crucial challenge for 16-T-class superconducting dipole magnets for a future 100-TeV Hadron collider. To avoid damage due to overheating of the coil's hot spot, heat generated during the quench has to be homogeneously distributed in the winding pack by quickly and uniformly transferring to the normal-state voluminous coil sections. Conventional protection systems rely on quench heaters placed on the outer surfaces of the coils. However, this technique has to confront significant challenges in order to achieve the fast transitions required by high magnetic field magnets. The recently developed coupling-loss-induced quench (CLIQ) utilizes interfilament coupling loss as an effective intrawire heat deposition mechanism, which, in principle, is faster than thermal diffusion. Furthermore, the CLIQ technology is based on simple and robust electrical components in contact with the coil only in a limited number of easily accessible and well-insulated points. Hence, expected occurrence of failure and electrical breakdown is significantly reduced. As a case study, the design of a CLIQ-based protection system for a 14-m-long 16-T Nb 3Sn block-coil dipole magnet is demonstrated here. Various magnet design features can be adjusted to improve CLIQ performance and optimize its integration in the magnet system. CLIQ provides future magnet designers with a solution for a very effective, yet electrically robust, quench protection system, resulting in better magnet performance and lower cost than would be possible with a traditional approach to magnet protection.

Conventional quench protection systems for high-magnetic-field superconducting magnets are based on external heaters composed of resistive strips in close contact with the coil and rely on thermal diffusion across insulation layers on the order of tens of micrometers. The large contact areas between the coil and the heater strips, and the thin insulation between them required for an effective protection constitute a significant risk of electrical breakdown and one of the most common causes of magnet damage. Coupling-loss-induced quench (CLIQ) technology offers a valid option for a time-and cost-effective repair of magnets with failing heater-based protection systems. In fact, its effective heating mechanism utilizing coupling loss, its robust electrical design, and its fast implementation, as compared to alternative repair options, constitute definite advantages over the conventional technology. In the past years, CLIQ was successfully implemented on various coils in a single-magnet configuration. Now the design of a CLIQ-based protection system integrated in a chain of series-connected magnets is presented. The protection of a chain of superconducting magnets usually is considerably more challenging than the protection of stand-alone magnets due to the increased energy stored in the circuit and the presence of transitory effects. The effectiveness of this new method is demonstrated by means of electrothermal simulations modeling the transition to the normal state and the temperature evolution in one quenched magnet, and the electrodynamics of the entire magnet chain.

The coupling-loss-induced quench (CLIQ) is an innovative system for the protection of superconducting magnets. Its energy-deposition mechanism, based on coupling loss generated directly in the superconductor, is fundamentally faster than heat diffusion, upon which traditional quench-heater-based systems rely. CLIQ electrical design relies on simple and robust components, i.e., easy to install and be replaced in case of damage. After being successfully tested on model magnets of different geometries and types of superconductor, CLIQ is now applied for the first time for the protection of a full-scale dipole magnet. For this purpose, a 14-m-long LHC twin-aperture dipole magnet is equipped with CLIQ terminals and two 80-mF 500-V CLIQ units are connected to its windings. Experimental results obtained under various operating conditions convincingly show that a CLIQ-based quench protection system can effectively protect large-scale magnets by quickly and homogeneously transferring to the normal-state voluminous regions of the winding packs. A developed dedicated simulation code correctly reproduces the complex electrothermal transient occurring during a CLIQ discharge. The successful test completes the development program of CLIQ quench protection systems, which has convincingly demonstrated the maturity and readiness of the system for application in large-scale magnet systems.

Protection against the effects of a quench is a crucial challenge for 16-T-class superconducting dipole magnets for a future 100-TeV Hadron collider. To avoid damage due to overheating of the coil's hot spot, heat generated during the quench has to be homogeneously distributed in the winding pack by quickly and uniformly transferring to the normal-state voluminous coil sections. Conventional protection systems rely on quench heaters placed on the outer surfaces of the coils. However, this technique has to confront significant challenges in order to achieve the fast transitions required by high magnetic field magnets. The recently developed coupling-loss-induced quench (CLIQ) utilizes interfilament coupling loss as an effective intrawire heat deposition mechanism, which, in principle, is faster than thermal diffusion. Furthermore, the CLIQ technology is based on simple and robust electrical components in contact with the coil only in a limited number of easily accessible and well-insulated points. Hence, expected occurrence of failure and electrical breakdown is significantly reduced. As a case study, the design of a CLIQ-based protection system for a 14-m-long 16-T Nb 3Sn block-coil dipole magnet is demonstrated here. Various magnet design features can be adjusted to improve CLIQ performance and optimize its integration in the magnet system. CLIQ provides future magnet designers with a solution for a very effective, yet electrically robust, quench protection system, resulting in better magnet performance and lower cost than would be possible with a traditional approach to magnet protection.

Conventional quench protection systems for high-magnetic-field superconducting magnets are based on external heaters composed of resistive strips in close contact with the coil and rely on thermal diffusion across insulation layers on the order of tens of micrometers. The large contact areas between the coil and the heater strips, and the thin insulation between them required for an effective protection constitute a significant risk of electrical breakdown and one of the most common causes of magnet damage. Coupling-loss-induced quench (CLIQ) technology offers a valid option for a time-and cost-effective repair of magnets with failing heater-based protection systems. In fact, its effective heating mechanism utilizing coupling loss, its robust electrical design, and its fast implementation, as compared to alternative repair options, constitute definite advantages over the conventional technology. In the past years, CLIQ was successfully implemented on various coils in a single-magnet configuration. Now the design of a CLIQ-based protection system integrated in a chain of series-connected magnets is presented. The protection of a chain of superconducting magnets usually is considerably more challenging than the protection of stand-alone magnets due to the increased energy stored in the circuit and the presence of transitory effects. The effectiveness of this new method is demonstrated by means of electrothermal simulations modeling the transition to the normal state and the temperature evolution in one quenched magnet, and the electrodynamics of the entire magnet chain.

The coupling-loss-induced quench (CLIQ) is an innovative system for the protection of superconducting magnets. Its energy-deposition mechanism, based on coupling loss generated directly in the superconductor, is fundamentally faster than heat diffusion, upon which traditional quench-heater-based systems rely. CLIQ electrical design relies on simple and robust components, i.e., easy to install and be replaced in case of damage. After being successfully tested on model magnets of different geometries and types of superconductor, CLIQ is now applied for the first time for the protection of a full-scale dipole magnet. For this purpose, a 14-m-long LHC twin-aperture dipole magnet is equipped with CLIQ terminals and two 80-mF 500-V CLIQ units are connected to its windings. Experimental results obtained under various operating conditions convincingly show that a CLIQ-based quench protection system can effectively protect large-scale magnets by quickly and homogeneously transferring to the normal-state voluminous regions of the winding packs. A developed dedicated simulation code correctly reproduces the complex electrothermal transient occurring during a CLIQ discharge. The successful test completes the development program of CLIQ quench protection systems, which has convincingly demonstrated the maturity and readiness of the system for application in large-scale magnet systems.

The coupling-loss induced quench system (CLIQ) is an innovative method for the protection of high-field superconducting magnets. With respect to the conventional method based on quench heaters, it offers significant advantages in terms of electrical robustness and energy-deposition velocity. Its effective intrawire heating mechanism targets a fast and homogeneous transition to the normal state of the winding pack, hence assuring a quick magnet discharge and avoiding overheating of the coil's hot spot. Furthermore, it is possible to implement CLIQ as a time- and cost-effective repair solution for the protection of existing magnets with broken quench heaters. After being successfully tested on model magnets of different geometries and made of different types of superconductor, CLIQ is now applied for the first time for the protection of a full-scale quadrupole magnet at the CERN magnet test facility. One aperture of a 3.4-m-long LHC matching quadrupole magnet is equipped with dedicated terminals to allow the connection of a CLIQ system. Experimental results convincingly show that CLIQ can protect this coil over the entire range of operating conditions. The complex electrothermal transients during a CLIQ discharge are successfully reproduced by means of a 2-D model. The test is part of the RD program of CLIQ quench protection systems, which has convincingly demonstrated the maturity of this technology and its effectiveness also for large-scale magnet systems. The proposed CLIQ-based solution for the quench protection of the LHC matching quadrupole magnet is now ready to be implemented in the LHC machine if needed.

The goal of the High Luminosity LHC project is upgrading the LHC in order to increase its luminosity by a factor of five. To achieve this, 24 150-mm-aperture 12-T Nb 3Sn quadrupole magnets are to be installed close to the two interaction regions at ATLAS and CMS. This new generation of high-field magnets poses a significant challenge concerning the protection of the coils in the case of a quench. The very high stored energy per unit volume requires a fast and effective quench heating system in order to limit the hot-spot temperature and hence avoid damage due to overheating. Conventional protection systems based on quench heaters have a limited response time due to the thermal insulation between the heater and the coil. An advanced solution for the protection of high-field magnets is the coupling-loss induced quench (CLIQ) system, recently developed at CERN. Due to its fast intrawire energy-deposition mechanism, CLIQ is a very effective, yet electrically robust, quench protection system. Various protection scenarios, including quench heaters, CLIQ, or combinations of the two methods, are analyzed and discussed, with the aim of minimizing the coil's hot-spot temperature and thermal gradients during the discharge. The proposed design assures a fully redundant system.

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P

UnlabelledViruses of the Enterovirus genus of picornaviruses, including poliovirus, coxsackievirus B3 (CVB3), and human rhinovirus, commandeer the functions of host cell proteins to aid in the replication of their small viral genomic RNAs during infection. One of these host proteins is a cellular DNA repair enzyme known as 5' tyrosyl-DNA phosphodiesterase 2 (TDP2). TDP2 was previously demonstrated to mediate the cleavage of a unique covalent linkage between a viral protein (VPg) and the 5' end of picornavirus RNAs. Although VPg is absent from actively translating poliovirus mRNAs, the removal of VPg is not required for the in vitro translation and replication of the RNA. However, TDP2 appears to be excluded from replication and encapsidation sites during peak times of poliovirus infection of HeLa cells, suggesting a role for TDP2 during the viral replication cycle. Using a mouse embryonic fibroblast cell line lacking TDP2, we found that TDP2 is differentially required among enteroviruses. Our single-cycle viral growth analysis shows that CVB3 replication has a greater dependency on TDP2 than does poliovirus or human rhinovirus replication. During infection, CVB3 protein accumulation is undetectable (by Western blot analysis) in the absence of TDP2, whereas poliovirus protein accumulation is reduced but still detectable. Using an infectious CVB3 RNA with a reporter, CVB3 RNA could still be replicated in the absence of TDP2 following transfection, albeit at reduced levels. Overall, these results indicate that TDP2 potentiates viral replication during enterovirus infections of cultured cells, making TDP2 a potential target for antiviral development for picornavirus infections.ImportancePicornaviruses are one of the most prevalent groups of viruses that infect humans and livestock worldwide. These viruses include the human pathogens belonging to the Enterovirus genus, such as poliovirus, coxsackievirus B3 (CVB3), and human rhinovirus. Diseases caused by enteroviruses pose a major problem for public health and have significant economic impact. Poliovirus can cause paralytic poliomyelitis. CVB3 can cause hand, foot, and mouth disease and myocarditis. Human rhinovirus is the causative agent of the common cold, which has a severe economic impact due to lost productivity and severe health consequences in individuals with respiratory dysfunction, such as asthma. By gaining a better understanding of the enterovirus replication cycle, antiviral drugs against enteroviruses may be developed. Here, we report that the absence of the cellular enzyme TDP2 can significantly decrease viral yields of poliovirus, CVB3, and human rhinovirus, making TDP2 a potential target for an antiviral against enterovirus infections.

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P

The coupling-loss induced quench system (CLIQ) is an innovative method for the protection of high-field superconducting magnets. With respect to the conventional method based on quench heaters, it offers significant advantages in terms of electrical robustness and energy-deposition velocity. Its effective intrawire heating mechanism targets a fast and homogeneous transition to the normal state of the winding pack, hence assuring a quick magnet discharge and avoiding overheating of the coil's hot spot. Furthermore, it is possible to implement CLIQ as a time- and cost-effective repair solution for the protection of existing magnets with broken quench heaters. After being successfully tested on model magnets of different geometries and made of different types of superconductor, CLIQ is now applied for the first time for the protection of a full-scale quadrupole magnet at the CERN magnet test facility. One aperture of a 3.4-m-long LHC matching quadrupole magnet is equipped with dedicated terminals to allow the connection of a CLIQ system. Experimental results convincingly show that CLIQ can protect this coil over the entire range of operating conditions. The complex electrothermal transients during a CLIQ discharge are successfully reproduced by means of a 2-D model. The test is part of the RD program of CLIQ quench protection systems, which has convincingly demonstrated the maturity of this technology and its effectiveness also for large-scale magnet systems. The proposed CLIQ-based solution for the quench protection of the LHC matching quadrupole magnet is now ready to be implemented in the LHC machine if needed.

The goal of the High Luminosity LHC project is upgrading the LHC in order to increase its luminosity by a factor of five. To achieve this, 24 150-mm-aperture 12-T Nb 3Sn quadrupole magnets are to be installed close to the two interaction regions at ATLAS and CMS. This new generation of high-field magnets poses a significant challenge concerning the protection of the coils in the case of a quench. The very high stored energy per unit volume requires a fast and effective quench heating system in order to limit the hot-spot temperature and hence avoid damage due to overheating. Conventional protection systems based on quench heaters have a limited response time due to the thermal insulation between the heater and the coil. An advanced solution for the protection of high-field magnets is the coupling-loss induced quench (CLIQ) system, recently developed at CERN. Due to its fast intrawire energy-deposition mechanism, CLIQ is a very effective, yet electrically robust, quench protection system. Various protection scenarios, including quench heaters, CLIQ, or combinations of the two methods, are analyzed and discussed, with the aim of minimizing the coil's hot-spot temperature and thermal gradients during the discharge. The proposed design assures a fully redundant system.

UnlabelledViruses of the Enterovirus genus of picornaviruses, including poliovirus, coxsackievirus B3 (CVB3), and human rhinovirus, commandeer the functions of host cell proteins to aid in the replication of their small viral genomic RNAs during infection. One of these host proteins is a cellular DNA repair enzyme known as 5' tyrosyl-DNA phosphodiesterase 2 (TDP2). TDP2 was previously demonstrated to mediate the cleavage of a unique covalent linkage between a viral protein (VPg) and the 5' end of picornavirus RNAs. Although VPg is absent from actively translating poliovirus mRNAs, the removal of VPg is not required for the in vitro translation and replication of the RNA. However, TDP2 appears to be excluded from replication and encapsidation sites during peak times of poliovirus infection of HeLa cells, suggesting a role for TDP2 during the viral replication cycle. Using a mouse embryonic fibroblast cell line lacking TDP2, we found that TDP2 is differentially required among enteroviruses. Our single-cycle viral growth analysis shows that CVB3 replication has a greater dependency on TDP2 than does poliovirus or human rhinovirus replication. During infection, CVB3 protein accumulation is undetectable (by Western blot analysis) in the absence of TDP2, whereas poliovirus protein accumulation is reduced but still detectable. Using an infectious CVB3 RNA with a reporter, CVB3 RNA could still be replicated in the absence of TDP2 following transfection, albeit at reduced levels. Overall, these results indicate that TDP2 potentiates viral replication during enterovirus infections of cultured cells, making TDP2 a potential target for antiviral development for picornavirus infections.ImportancePicornaviruses are one of the most prevalent groups of viruses that infect humans and livestock worldwide. These viruses include the human pathogens belonging to the Enterovirus genus, such as poliovirus, coxsackievirus B3 (CVB3), and human rhinovirus. Diseases caused by enteroviruses pose a major problem for public health and have significant economic impact. Poliovirus can cause paralytic poliomyelitis. CVB3 can cause hand, foot, and mouth disease and myocarditis. Human rhinovirus is the causative agent of the common cold, which has a severe economic impact due to lost productivity and severe health consequences in individuals with respiratory dysfunction, such as asthma. By gaining a better understanding of the enterovirus replication cycle, antiviral drugs against enteroviruses may be developed. Here, we report that the absence of the cellular enzyme TDP2 can significantly decrease viral yields of poliovirus, CVB3, and human rhinovirus, making TDP2 a potential target for an antiviral against enterovirus infections.

BackgroundThe Diabetes Prevention Program (DPP) study showed that lifestyle intervention resulted in a 58% reduction in incidence of type 2 diabetes among individuals with prediabetes. Additional large randomized controlled trials have confirmed these results, and long-term follow-up has shown sustained benefit 10-20 years after the interventions ended. Diabetes is a common and costly disease, especially among Veterans, and despite strong evidence supporting the feasibility of type 2 diabetes prevention, the DPP has not been widely implemented. The first aim of this study will evaluate implementation of the Veterans Affairs (VA) DPP in three VA medical centers. The second aim will assess weight and hemoglobin A1c (A1c) outcomes, and the third aim will determine the cost-effectiveness and budget impact of implementation of the VA DPP from a health system perspective.Methods/designThis partnered multi-site non-randomized systematic assignment study will use a highly pragmatic hybrid effectiveness-implementation type III mixed methods study design. The implementation and administration of the VA DPP will be funded by clinical operations while the evaluation of the VA DPP will be funded by research grants. Seven hundred twenty eligible Veterans will be systematically assigned to the VA DPP clinical demonstration or the usual care VA MOVE!® weight management program. A multi-phase formative evaluation of the VA DPP implementation will be conducted. A theoretical program change model will be used to guide the implementation process and assess applicability and feasibility of the DPP for VA. The Consolidated Framework for Implementation Research (CFIR) will be used to guide qualitative data collection, analysis, and interpretation of barriers and facilitators to implementation. The RE-AIM framework will be used to assess Reach, Effectiveness, Adoption, Implementation, and Maintenance of the VA DPP. Twelve-month weight and A1c change will be evaluated for the VA DPP compared to the VA MOVE!ProgramMediation analyses will be conducted to identify whether program design differences impact outcomes.DiscussionFindings from this pragmatic evaluation will be highly applicable to practitioners who are tasked with implementing the DPP in clinical settings. In addition, findings will determine the effectiveness and cost-effectiveness of the VA DPP in the Veteran population.

ObjectiveDespite the potentially life-saving effects of stem cell transplant (SCT), many transplant patients experience traumatic stress reactions due to mortality threat, interpersonal isolation, financial and occupational loss, and invasive medical procedures. Emerging evidence suggests that trauma-related stress symptoms (TSS) predict significant health complications following SCT. The aim of the current prospective study was to examine TSS in the acute aftermath of SCT as a predictor of neutrophil recovery following SCT, a crucial component of immune defense against infection.MethodsFifty-one autologous SCT recipients were assessed for TSS 7 days after SCT. Patients' absolute neutrophil counts were collected from medical charts for the first 30 days following SCT. Hierarchical linear growth modeling was used to test the hypothesis that TSS at day 7 would be associated with delayed recovery of neutrophil counts from days 9 to 30 post SCT, that is, when neutrophil counts began to recover.ResultsAs hypothesized, TSS measured 7 days after SCT was significantly associated with slower neutrophil recovery even after pre-existing TSS, depression, distress related to physical symptoms, and potential medical confounds were statistically controlled. Exploratory analyses showed that of the TSS symptom clusters, re-experiencing symptoms and hyperarousal symptoms predicted neutrophil recovery, whereas avoidance symptoms did not.ConclusionThough traumatic stress symptoms may be a normative response to SCT, our findings suggest that TSS following SCT may interfere with neutrophil recovery and overall health. These results provide further insight as to potential mechanisms by which traumatic stress translates to poor medical outcomes for SCT patients.

ObjectiveDespite the potentially life-saving effects of stem cell transplant (SCT), many transplant patients experience traumatic stress reactions due to mortality threat, interpersonal isolation, financial and occupational loss, and invasive medical procedures. Emerging evidence suggests that trauma-related stress symptoms (TSS) predict significant health complications following SCT. The aim of the current prospective study was to examine TSS in the acute aftermath of SCT as a predictor of neutrophil recovery following SCT, a crucial component of immune defense against infection.MethodsFifty-one autologous SCT recipients were assessed for TSS 7 days after SCT. Patients' absolute neutrophil counts were collected from medical charts for the first 30 days following SCT. Hierarchical linear growth modeling was used to test the hypothesis that TSS at day 7 would be associated with delayed recovery of neutrophil counts from days 9 to 30 post SCT, that is, when neutrophil counts began to recover.ResultsAs hypothesized, TSS measured 7 days after SCT was significantly associated with slower neutrophil recovery even after pre-existing TSS, depression, distress related to physical symptoms, and potential medical confounds were statistically controlled. Exploratory analyses showed that of the TSS symptom clusters, re-experiencing symptoms and hyperarousal symptoms predicted neutrophil recovery, whereas avoidance symptoms did not.ConclusionThough traumatic stress symptoms may be a normative response to SCT, our findings suggest that TSS following SCT may interfere with neutrophil recovery and overall health. These results provide further insight as to potential mechanisms by which traumatic stress translates to poor medical outcomes for SCT patients.

BackgroundThe Diabetes Prevention Program (DPP) study showed that lifestyle intervention resulted in a 58% reduction in incidence of type 2 diabetes among individuals with prediabetes. Additional large randomized controlled trials have confirmed these results, and long-term follow-up has shown sustained benefit 10-20 years after the interventions ended. Diabetes is a common and costly disease, especially among Veterans, and despite strong evidence supporting the feasibility of type 2 diabetes prevention, the DPP has not been widely implemented. The first aim of this study will evaluate implementation of the Veterans Affairs (VA) DPP in three VA medical centers. The second aim will assess weight and hemoglobin A1c (A1c) outcomes, and the third aim will determine the cost-effectiveness and budget impact of implementation of the VA DPP from a health system perspective.Methods/designThis partnered multi-site non-randomized systematic assignment study will use a highly pragmatic hybrid effectiveness-implementation type III mixed methods study design. The implementation and administration of the VA DPP will be funded by clinical operations while the evaluation of the VA DPP will be funded by research grants. Seven hundred twenty eligible Veterans will be systematically assigned to the VA DPP clinical demonstration or the usual care VA MOVE!® weight management program. A multi-phase formative evaluation of the VA DPP implementation will be conducted. A theoretical program change model will be used to guide the implementation process and assess applicability and feasibility of the DPP for VA. The Consolidated Framework for Implementation Research (CFIR) will be used to guide qualitative data collection, analysis, and interpretation of barriers and facilitators to implementation. The RE-AIM framework will be used to assess Reach, Effectiveness, Adoption, Implementation, and Maintenance of the VA DPP. Twelve-month weight and A1c change will be evaluated for the VA DPP compared to the VA MOVE!ProgramMediation analyses will be conducted to identify whether program design differences impact outcomes.DiscussionFindings from this pragmatic evaluation will be highly applicable to practitioners who are tasked with implementing the DPP in clinical settings. In addition, findings will determine the effectiveness and cost-effectiveness of the VA DPP in the Veteran population.