A structural variation reference for medical and population genetics.

Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

Advancing One human-animal-environment Health for global health security: what does the evidence say?

In this Series paper, we review the contributions of One Health approaches (ie, at the human-animal-environment interface) to improve global health security across a range of health hazards and we summarise contemporary evidence of incremental benefits of a One Health approach. We assessed how One Health approaches were reported to the Food and Agricultural Organization of the UN, the World Organisation for Animal Health (WOAH, formerly OIE), and WHO, within the monitoring and assessment frameworks, including WHO International Health Regulations (2005) and WOAH Performance of Veterinary Services. We reviewed One Health theoretical foundations, methods, and case studies. Examples from joint health services and infrastructure, surveillance-response systems, surveillance of antimicrobial resistance, food safety and security, environmental hazards, water and sanitation, and zoonoses control clearly show incremental benefits of One Health approaches. One Health approaches appear to be most effective and sustainable in the prevention, preparedness, and early detection and investigation of evolving risks and hazards; the evidence base for their application is strongest in the control of endemic and neglected tropical diseases. For benefits to be maximised and extended, improved One Health operationalisation is needed by strengthening multisectoral coordination mechanisms at national, regional, and global levels.

Cigarette smoking decline among US young adults from 2000 to 2019, in relation to state-level cigarette price and tobacco control expenditure.

OBJECTIVE: To investigate the association of state-level cigarette price and tobacco control expenditure with the large 2000-2019 decline in cigarette smoking among US 18-24 year-olds. METHODS: Smoking behaviour was assessed in the 24 most populous US states using the 1992-2019 Tobacco Use Supplements to the Current Population Survey; association with price and expenditure was tested using adjusted logistic regression. States were ranked by inflation-adjusted average price and tobacco control expenditure and grouped into tertiles. State-specific time trends were estimated, with slope changes in 2001/2002 and 2010/2011. RESULTS: Between 2000 and 2010, the odds of smoking among US young adults decreased by a third (adjusted OR, AOR 0.68, 95% CI 0.56 to 0.84). By 2019, these odds were one-quarter of their 2000 level (AOR 0.24, 95% CI 0.19 to 0.31). Among states in the lowest tertile of price/expenditure tobacco control activity, initially higher young adult smoking decreased by 13 percentage points from 2010 to 2018-2019, to a prevalence of 5.6% (95% CI 4.5% to 6.8%), equal to that in the highest tobacco-control tertile of states (6.5%, 95% CI 5.2% to 7.8%). Neither state tobacco control spending (AOR 1.0, 95% CI 0.999 to 1.002) nor cigarette price (AOR 0.96, 95% CI: 0.92 to 1.01) were associated with young adult smoking in statistical models. In 2019, seven states had prevalence over 3 SDs higher than the 24-state mean. CONCLUSION: National programmes may have filled a gap in state-level interventions, helping drive down the social acceptability of cigarette smoking among young adults across all states. Additional interventions are needed to assist high-prevalence states to further reduce smoking.

Inclusive ABO-Incompatible Listing for Pediatric Heart Transplantation Results in Comparable Post-Transplant Rejection-Free Survival in a Single-Center Series.

ABO-incompatible (ABOi) heart transplantation (HT) has increased organ availability for infants with end-stage heart failure. Despite increasing adoption of ABOi listing for HT, data remain limited regarding pre- and post-HT immunologic profiles to guide listing practices and post-HT follow-up. Thus, the purpose of this study was to evaluate post-HT outcomes at a single center employing inclusive ABOi listing irrespective of pre-HT isohemagglutinin titers. All HT recipients listed at less than 24 months of age at our institution from 2010-2020 were included. Pre- and post-operative variables were compared for ABOi and ABO-compatible (ABOc) recipients. Separate iso-IgG and iso-IgM titers were monitored pre- and post-HT. Primary outcomes were compared between ABOi versus ABOc groups at mid-term follow-up. 51 HTs were performed on 50 patients from 2010-2020 (ABOi, N = 13; ABOc, N = 38). Six ABOi recipients received intra-operative plasma exchange for elevated titers (greater than 1:8 for IgG or IgM or reverse type greater than 2 +). Treated rejection, DSA, CAV, primary graft failure, need for re-HT, and survival were comparable between ABOi and ABOc groups at mid-term follow-up. An inclusive approach to ABOi HT listing for infants less than 24 months of age results in comparable post-transplant rejection-free survival, CAV, and prevalence of DSA at mid-term follow-up. These data define a potential role for specific IgM and IgG testing to promote understanding of risk stratification in pediatric ABOi listing, and support an inclusive strategy irrespective of high pre-HT titers to expand the number of available donor hearts for infants and older children awaiting HT.

Importance of Various E-Cigarette Device and E-Liquid Characteristics by Smoking Status among Young Adults Who Vape.

BACKGROUND: E-cigarette product characteristics are known to influence appeal among young adults. Understanding which characteristics appeal to individuals with (vs. without) a history of combusted tobacco use is essential for developing effective tobacco control policies. METHODS: Anonymous, self-report data were collected from young adults (18-30 years) who had used e-cigarettes in the past 30 days (n = 295) online via Prolific from September-October 2019. Using a visual analogue scale (range: 0-100), participants rated the importance of ten e-cigarette device and nine e-liquid characteristics. Adjusted linear regression models were used to evaluate the association of combusted tobacco use status (never, former, current) with mean rating scores for each of the nineteen characteristics. RESULTS: The most important e-cigarette device characteristics were price (Mean = 81.1; [SD = 17.9]), size (Mean = 75.5 [SD = 20.9]), and hit strength (Mean = 73.8 [SD = 20.4]) while the most important e-liquid characteristics were flavor (M = 85.1 [SD = 16.3]), price (M = 80.9 [SD = 18.4]), and nicotine level (M = 77.8 [18.9]). Differences by combusted tobacco use status were observed for device brand, temperature/voltage, customizability, color, and popularity, with the highest ratings generally observed among those concurrently using combustible tobacco products. For e-liquids, differences by use status were observed for flavor, price, and bottle type. Notably, those concurrently using combusted products rated flavor as less important than those with no history of combustible tobacco use (B=-5.01[95%CI=-9.97, -0.05]). CONCLUSIONS: The self-rated importance of e-cigarette device and e-liquid attributes varies by combustible tobacco use status among young adults which may be used to inform regulatory decisions regarding e-cigarette product characteristics.

Complement Cross Talks With H-K-ATPase to Upregulate Runx2 in Human Aortic Valve Interstitial Cells.

INTRODUCTION: Calcific aortic valve disease (CAVD) is a slowly progressive fibro-calcific valve leaflet disorder. The underlying pathophysiology is complex and not yet well understood. Complement is known to play a role in the pathogenesis of CAVD by upregulating Runx2 to induce profibrogenic change in human aortic valve interstitial cells (AVICs). Furthermore, H-K-ATPase has independently been shown to induce tissue calcification. Therefore, we hypothesized that complement cross talks with H-K-ATPase to upregulate Runx2 in human AVICs. MATERIALS AND METHODS: Human AVICs were isolated from normal and calcified aortic valves. Cells were treated with a variation of complement, H-K-ATPase, or ERK1/2 inhibitors. H-K-ATPase and its association with complement in AVICs were investigated by reverse transcriptase-polymerase chain reaction, immunofluorescence, and Western blot. RESULTS: Calcified human AVICs expressed significantly higher H-K-ATPase level than normal human AVICs. Presence of complement C3 with H-K-ATPase is found in AVICs after complement treatment. Complement induced both H-K-ATPase and Runx2 expression in AVICs, which was associated with increased phosphorylation of ERK1/2 and its downstream molecule p-70 S6. Pharmacological inhibition of either H-K-ATPase or Erk1/2 abolished complement-induced Runx2 expression. CONCLUSIONS: These findings indicate that complement cross talks with H-K-ATPase to upregulate Runx2 in human AVICs by activation of ERK1/2 signaling pathways. The study revealed the potential role of H-K-ATPase in the pathogenesis of CAVD and therapeutically targeting either complement system or H-K-ATPase may limit the development of CAVD.

Differentiating Reasons for Young Adult E-cigarette Use Using Maximum Difference Choice Models.

INTRODUCTION: Understanding the reasons young adults use e-cigarettes (ie, vape)-and whether these motivations vary across groups-is essential for informing tobacco regulatory efforts. AIMS AND METHODS: An online panel of young adults who vape (n = 230; age = 18-30 years) completed a maximum difference discrete choice task for 15 reasons for vaping. Over 9 choice sets, participants were presented a subset of 5 reasons and selected the most and least important. Hierarchical bayesian analysis estimated the relative importance of each reason. Latent class analysis (LCA) identified groups with similarly ranked reasons for use. Multinomial regression evaluated the association between sample characteristics and class membership. RESULTS: Overall, relaxation had the highest probability of being the most important reason for use (14.8%), followed by harm reduction (13.2%), and flavors (10.3%). LCA identified five distinct classes, based on top reasons for use: 1. cessation (cigarette cessation [20.2%]; n = 80); 2. dependence (relaxation [20.5%] and unable to quit [19.2%]; n = 21); 3. relaxation (relaxation [20.6%]; n = 66); 4. socializing (socializing [22.2%]; n = 27); and 5. variable (boredom [10.5%] and acceptability [10.2%]; n = 36). Participants who were older, smoked cigarettes, or vaped more frequently were more likely to belong to the cessation class while those who were younger or more e-cigarette dependent were more likely to belong to the dependence class. CONCLUSIONS: Perceived reasons why young adults vape are highly heterogeneous and dependent on the type of user. Tobacco regulatory efforts targeting distinct types of vapers are needed to minimize the adverse public health impact of vaping without compromising appeal for smoking cessation. IMPLICATIONS: E-cigarette use remains high among young adults, with flavors, cost, and harm reduction (vs. combustible cigarettes) among the mostly commonly reported reasons for use. Yet, little is known about how relatively important these reasons are to the individual. Leveraging a maximum difference task, young adults' reasons for use were evaluated on a common interval scale and groups sharing similar reasons identified. Smoking cessation, dependence, relaxation, socialization, and boredom were respectively the most important reasons for use among five classes of vapers. E-cigarette regulatory policies should consider the distinct reasons for use as to not compromise their appeal for smoking cessation.

RETRACTED: Changes in Tobacco Dependence and Association With Onset and Progression of Use by Product Type From Wave 1 to Wave 3 of the Population Assessment of Tobacco and Health (PATH) Study.

INTRODUCTION: This study examined trajectories of tobacco dependence (TD) in relation to changes in tobacco product use and explored the effects of product-specific adding, switching, or discontinued use on dependence over time. AIMS AND METHODS: Data were analyzed from the first three waves of the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative, longitudinal study of adults and youth in the United States. Data included 9556 Wave 1 (2013/2014) adult current established tobacco users who completed all three interviews and had established use at ≥2 assessments. Groups included cigarettes-only users, e-cigarettes-only users, cigars-only users, hookah-only users, any smokeless-only users, cigarette + e-cigarette dual users, and multiple product users. A validated 16-item scale assessed TD across product users. RESULTS: Wave 1 e-cigarette-only users' who maintained exclusive e-cigarette use increased levels of TD through Wave 3 as did those who added or switched to another product. Wave 1 multiple product users' TD decreased across waves. TD for all other Wave 1 user groups remained about the same. For Wave 1 cigarette-only smokers, switching to another product or moving to a pattern of no established use was associated with lower levels of TD than smokers whose use stayed the same. Movement to no established use of any tobacco product was consistently associated with lower TD for all other product users. CONCLUSIONS: Except for Wave 1 e-cigarette-only users, TD among US tobacco product users was stable over time, with daily users less likely to vary from baseline. IMPLICATIONS: The level of TD among most US tobacco users was stable over the first three waves of the PATH Study and trends in levels of TD were predominantly unrelated to changes in patterns of continued product use. Stable levels of TD suggest a population at persistent risk of health impacts from tobacco. Wave 1 e-cigarette users, including those maintaining exclusive e-cigarette use, experienced increasing levels of TD over time, perhaps because of increases in quantity or frequency of their e-cigarette product use or increasing efficiency of nicotine delivery over time.

Changes in Tobacco Dependence and Association With Onset and Progression of Use by Product Type From Waves 1 to 3 of the Population Assessment of Tobacco and Health (PATH) Study.

INTRODUCTION: This study examined trajectories of tobacco dependence (TD) in relationship to changes in tobacco product use, and explored the effects of product-specific adding, switching, or discontinued use on dependence over time. AIMS AND METHODS: Data were analyzed from the first three waves from the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative, longitudinal study of adults and youth in the United States. Data included 9556 wave 1 (2013-2014) adult current established tobacco users aged 18 or older who completed all three interviews and had established use at ≥2 assessments. Mutually exclusive groups included: users of cigarettes only, e-cigarettes only, cigars only, hookah only, any smokeless only, cigarette + e-cigarette dual users, and other multiple product users. A validated 16-item scale assessed TD across product users. RESULTS: People who used e-cigarettes exclusively at wave 1 had small increases in TD through wave 3. Wave 1 multiple product users' TD decreased across waves. TD for all other wave 1 user groups remained about the same. For wave 1 cigarette only smokers, switching to another product was associated with lower levels of TD than smokers whose use stayed the same. Movement to no established use of any tobacco product was consistently associated with lower TD for all product users. CONCLUSIONS: Except for wave 1 e-cigarette only users (who experienced small increases in TD), TD among U.S. tobacco product users was stable over time, with daily users less likely to vary from baseline. IMPLICATIONS: The level of TD among most U.S. tobacco users was stable over the first three waves of the PATH Study and trends in levels of TD were predominantly unrelated to changes in patterns of continued product use. Stable levels of TD suggest a population at persistent risk of health impacts from tobacco. Wave 1 e-cigarette users experienced small increases in levels of TD over time, perhaps due to increases in quantity or frequency of their e-cigarette use or increasing efficiency of nicotine delivery over time.

Evaluating US smokers' willingness to pay for different cigarette packaging designs before and after real-world exposure in a randomised trial.

INTRODUCTION: Removal of tobacco industry branding from cigarette packs may reduce their appeal. Adding graphic warning labels (GWLs) should enhance this effect. We investigate whether willingness to pay for various packaging designs changes after 3 months' use of: (1) US branded packs without GWLs (US), (2) non-branded packs without GWLs (Blank), and (3) rotating non-branded packs with GWLs (gangrene; throat cancer; neonatal baby) covering >75% of pack (GWL). METHODS: Californian adult daily smokers not planning to quit (n=287; 56% female; mean age=39.6) completed a discrete choice purchase task before and after 3 months' experience using one of three packaging options. Conjoint analysis and pre-post modelling evaluated the change in importance of pack attributes and willingness to pay for US, Blank or GWL (blindness; teeth; gangrene) pack designs. RESULTS: Price determined ~70% of purchase choices, while pack design determined ~22%. Irrespective of intervention arm, US packaging generated appeal valuations compared with Blank packaging, while GWLs consistently provoked strong aversive valuations at baseline and follow-up. Compared with the US pack arm, using GWL packs for 3 months decreased willingness to pay for US packaging (ß=-$0.38, 95% CI -0.76 to 0.00). Wear-out effects were detected in the discount needed to willingly purchase the gangrene-GWL pack (ß=$0.49, 95% CI 0.16 to 0.82) and Blank pack (ß=$0.42, 95% CI 0.09 to 0.74) but not for GWLs (blindness, teeth) not used in trial. CONCLUSION: Compared with US branded packs, the negative valuation of non-branded GWL packs attenuates with even 3 months' use but does not generalise to non-used GWLs. This suggests that GWLs should be regularly refreshed. The appeal valuation of industry imagery suggests that the US plan to retain such imagery on packs may ameliorate the effect of GWLs.

Effect of sweet flavouring on the rewarding and reinforcing value of cigarillo use among young adults.

INTRODUCTION: Cigarillos dominate the US cigar market, and young adults largely drive use. While young adults prefer flavoured to non-flavoured cigarillos, especially those flavoured to taste like fruit or other sweets, the factors that underlie this preference have received little attention. We sought to determine if key indicators of abuse liability, the rewarding and reinforcing effects, are greater for sweet versus non-flavoured cigarillos. METHODS: Young adults (18-24 years old) completed three laboratory visits assessing the subjective rewarding value (exposure paradigm), relative reinforcing value (computerised choice task) and absolute reinforcing value (ad libitum cigarillo smoking session) of sweet-flavoured versus non-flavoured cigarillos. General linear regression models were fit with the appropriate family link for each outcome measure. RESULTS: Young adults rated sweet-flavoured cigarillos as more rewarding (estimated marginal mean (EMM) =4.52, 95% CI 4.00 to 5.03) than the non-flavoured cigarillo (EMM=3.31, 95% CI 2.80 to 3.83; B=1.20, 95% CI 0.80 to 1.60, p<0.001). The reinforcing value of sweet-flavoured cigarillos, measured by break point, was higher relative to non-flavoured cigarillos (6.34 out of 10), especially among young adults with a preference for flavoured cigarillos (B=1.94, 95% CI 0.71 to 3.18, p=0.003). Young adults took 1.9 times the number of puffs (35.75 vs 19.95) from sweet-flavoured cigarillos compared with non-flavoured cigarillos (Rate Ratio =1.94, 95% CI 1.30 to 2.90, p<0.001). CONCLUSIONS: Sweet flavouring increases the abuse liability of cigarillos among young adults as reflected in greater liking, motivation to use and actual use. Banning sweet flavouring in cigarillos may diminish their use in young adults.Trial registration number CT.gov (NCT05092919).

Declines in cigarette smoking among US adolescents and young adults: indications of independence from e-cigarette vaping surge.

OBJECTIVE: To compare trends in cigarette smoking and nicotine vaping among US population aged 17-18 years and 18-24 years. METHODS: Regression analyses identified trends in ever and current use of cigarettes and e-cigarettes, using three US representative surveys from 1992 to 2022. RESULTS: From 1997 to 2020, cigarette smoking prevalence among those aged 18-24 years decreased from 29.1% (95% CI 27.4% to 30.7%) to 5.4% (95% CI 3.9% to 6.9%). The decline was highly correlated with a decline in past 30-day smoking among those aged 17-18 years (1997: 36.8% (95% CI 35.6% to 37.9%; 2022: 3.0% (95% CI 1.8% to 4.1%). From 2017 to 2019, both ever-vaping and past 30-day nicotine vaping (11.0% to 25.5%) surged among those 17-18 years, however there was no increase among those aged 18-24 years. Regression models demonstrated that the surge in vaping was independent of the decline in cigarette smoking. In the 24 most populous US states, exclusive vaping did increase among those aged 18-24 years, from 1.7% to 4.0% to equivalent to 40% of the decline in cigarette smoking between 2014-15 and 2018-19. Across these US states, the correlation between the changes in vaping and smoking prevalence was low (r=0.11). In the two US states with >US$1/fluid mL tax on e-cigarettes in 2017, cigarette smoking declined faster than the US average. CONCLUSIONS: Since 1997, a large decline in cigarette smoking occurred in the US population under age 24 years, that was independent of the 2017-19 adolescent surge in past 30-day e-cigarette vaping. Further research is needed to assess whether the 2014-15 to 2018-19 increase in exclusive vaping in those aged 18-24 years is a cohort effect from earlier dependence on e-cigarette vaping as adolescents.

Role of affective reactivity induced by cigarette packaging including graphic warning labels: the CASA Study.

OBJECTIVE: To identify whether three types of cigarette pack designs, including three versions of graphic warning label (GWL) plain packs, one GWL absent and branding absent pack (blank) and the smoker's own GWL absent and branding present pack (US), elicit different valence, type and levels of affect. DESIGN: US daily smokers (n=324) were asked to handle each of the five pack types and 'think aloud' their reactions. To avoid a muted familiarity response, exposure to their own US pack followed exposure to at least one GWL plain pack. Reactions were scored on a reactivity scale (-3 to +3) and the text was coded for speech polarity (-1 to +1) and emotive word frequency. RESULTS: Reactivity scores had excellent inter-rater reliability (agreement ≥86%; intraclass correlation coefficient ≥0.89) and were correlated with speech polarity (r=0.21-0.37, p<0.001). When considering their US pack, approximately two-thirds of smokers had a low (31.5%) to medium (34.6%) positive response (reactivity=1.29; polarity=0.14) with expressed feelings of joy and trust. Blank packaging prompted a largely (65.4%) neutral response (reactivity=0.03; polarity=0.00). The gangrenous foot GWL provoked mostly medium (46.9%) to high (48.1%) negative responses (reactivity=-2.44; polarity=-0.20), followed by neonatal baby (reactivity=-1.85; polarity=-0.10) and throat cancer (reactivity=-1.76; polarity=-0.08) warnings. GWLs varied in their elicitation of disgust, anger, fear and sadness. CONCLUSION: Initial reactions to GWL packs, a blank pack, and smokers' current US pack reflected negative, neutral, and positive affect, respectively. Different versions of the GWL pack elicited different levels and types of immediate negative affect.

Effectiveness of e-cigarettes as aids for smoking cessation: evidence from the PATH Study cohort, 2017-2019.

OBJECTIVE: To assess the effectiveness of e-cigarettes in smoking cessation in the USA from 2017 to 2019, given the 2017 increase in high nicotine e-cigarette sales. METHODS: In 2017, the PATH Cohort Study included data on 3578 previous year smokers with a recent quit attempt and 1323 recent former smokers. Respondents reported e-cigarettes or other products used to quit cigarettes and many covariates associated with e-cigarette use. Study outcomes were 12+ months of cigarette abstinence and tobacco abstinence in 2019. We report weighted unadjusted estimates and use propensity score matched analyses with 1500 bootstrap samples to estimate adjusted risk differences (aRD). RESULTS: In 2017, 12.6% (95% CI 11.3% to 13.9%) of recent quit attempters used e-cigarettes to help with their quit attempt, a decline from previous years. Cigarette abstinence for e-cigarette users (9.9%, 95% CI 6.6% to 13.2%) was lower than for no product use (18.6%, 95% CI 16.0% to 21.2%), and the aRD for e-cigarettes versus pharmaceutical aids was -7.3% (95% CI -14.4 to -0.4) and for e-cigarettes versus any other method was -7.7% (95% CI -12.2 to -3.2). Only 2.2% (95% CI 0.0% to 4.4%) of recent former smokers switched to a high nicotine e-cigarette. Subjects who switched to e-cigarettes appeared to have a higher relapse rate than those who did not switch to e-cigarettes or other tobacco, although the difference was not statistically significant. CONCLUSIONS: Sales increases in high nicotine e-cigarettes in 2017 did not translate to more smokers using these e-cigarettes to quit smoking. On average, using e-cigarettes for cessation in 2017 did not improve successful quitting or prevent relapse.

Effects of cigarette package colors and warning labels on marlboro smokers' risk beliefs, product appraisals, and smoking behavior: a randomized trial.

OBJECTIVE: Plain packaging and graphic warning labels are two regulatory strategies that may impact cigarette risk beliefs and reduce consumption, but data are needed to better understand how smokers respond to such regulations. METHODS: Adult, daily, Marlboro non-menthol smokers (Red [n = 141] or Gold [n = 43]) completed a mixed factorial randomized trial. Participants smoked their usual cigarettes during baseline (5-days) and were randomized to receive cigarette packs with a warning label manipulation (graphic vs. text-only). Within each warning label condition, participants completed three within-subjects pack color manipulations (red, gold, plain), each lasting 15 days. Participants were blinded to the fact that all packs contained their usual cigarettes. Mixed-effects models examined between- and within-subject differences on risk beliefs, product perceptions, and smoking behavior. RESULTS: Warning type and package color did not impact cigarette consumption or subjective ratings. However, use increased in all conditions (2.59-3.59 cigarettes per day) relative to baseline. While smokers largely held correct risk beliefs at baseline (Mean = 6.02, SE = 0.17, Range:0-8), the cumulative number of incorrect or uncertain cigarette risk beliefs increased from baseline in all pack color manipulations in the text (IRR range = 1.70-2.16) and graphic (IRR range = 1.31-1.70) warning conditions. Across all pack color periods, those in the graphic (vs. text) warning condition had reduced odds of reporting their study cigarettes as 'safer' than regular cigarettes (OR range = 0.22-0.32). CONCLUSIONS: Pack color modification may increase uncertainty about several key cigarette risk beliefs, though graphic warnings may attenuate these effects. Regulatory agencies could consider supporting policy changes with information campaigns to maximize public knowledge. TRIAL REGISTRATION: November 25, 2014; Registration number: NCT02301351.

Left Ventricular Dysfunction Following the Ross-Konno Reconstruction is Independent of the Operation.

The Ross-Konno (RK) operation is a well-established surgical treatment for combined left ventricular outflow tract obstruction and aortic valve pathology in children. Prior study has demonstrated that mechanical and electrical dyssynchrony exist post-RK compared to normal controls. The purpose of this study was to evaluate myocardial function pre- and post-RK as defined by echocardiography. Patients undergoing the RK operation (n = 13; median age: 1.3 years; range: 0.5-13.3 years) were evaluated by echocardiography at defined timepoints: pre-RK, post-RK, 1-year post-RK, and 2 years post-RK. Defined parameters of left ventricular performance were analyzed: systolic mechanical dyssynchrony (M-Dys), global left ventricular circumferential strain (GCS), and diastolic relaxation fraction (DRF). Patients with post-operative atrioventricular block (n = 6) were analyzed separately. No pre- versus post-RK differences existed in M-Dys, GCS, or DRF in patients both with and without post-RK atrioventricular block. Further, 1- and 2-year follow-up post-RK demonstrated significant heterogeneity in evaluated parameters of function with no pre- and post-RK differences in M-Dys, GCS, or DRF. Mechanical dyssynchrony exists post-RK reconstruction in both short- and long-term follow-up yet these echocardiographic parameters of ventricular performance are independent of the RK operation. Further study is, therefore, warranted to define causal relationships for observed short- and long-term ventricular dysfunction post-RK as the findings of the present study suggest a deleterious mechanism apart from the technical RK reconstruction.

Magnetic Interactions of the Centrosymmetric Skyrmion Material Gd_{2}PdSi_{3}.

The experimental realization of magnetic skyrmion crystals in centrosymmetric materials has been driven by theoretical understanding of how a delicate balance of anisotropy and frustration can stabilize topological spin structures in applied magnetic fields. Recently, the centrosymmetric material Gd_{2}PdSi_{3} was shown to host a field-induced skyrmion crystal, but the skyrmion stabilization mechanism remains unclear. Here, we employ neutron-scattering measurements on an isotopically enriched polycrystalline Gd_{2}PdSi_{3} sample to quantify the interactions that drive skyrmion formation. Our analysis reveals spatially extended interactions in triangular planes, and large ferromagnetic interplanar magnetic interactions that are modulated by the Pd/Si superstructure. The skyrmion crystal emerges from a zero-field helical magnetic order with magnetic moments perpendicular to the magnetic propagation vector, indicating that the magnetic dipolar interaction plays a significant role. Our experimental results establish an interaction space that can promote skyrmion formation, facilitating identification and design of centrosymmetric skyrmion materials.

Spiral Spin Liquid on a Honeycomb Lattice.

Spiral spin liquids are correlated paramagnetic states with degenerate propagation vectors forming a continuous ring or surface in reciprocal space. On the honeycomb lattice, spiral spin liquids present a novel route to realize emergent fracton excitations, quantum spin liquids, and topological spin textures, yet experimental realizations remain elusive. Here, using neutron scattering, we show that a spiral spin liquid is realized in the van der Waals honeycomb magnet FeCl_{3}. A continuous ring of scattering is directly observed, which indicates the emergence of an approximate U(1) symmetry in momentum space. Our work demonstrates that spiral spin liquids can be achieved in two-dimensional systems and provides a promising platform to study the fracton physics in spiral spin liquids.

Line-Graph Approach to Spiral Spin Liquids.

Competition among exchange interactions is able to induce novel spin correlations on a bipartite lattice without geometrical frustration. A prototype example is the spiral spin liquid, which is a correlated paramagnetic state characterized by subdimensional degenerate propagation vectors. Here, using spectral graph theory, we show that spiral spin liquids on a bipartite lattice can be approximated by a further-neighbor model on the corresponding line-graph lattice that is nonbipartite, thus broadening the space of candidate materials that may support the spiral spin liquid phases. As illustrations, we examine neutron scattering experiments performed on two spinel compounds, ZnCr_{2}Se_{4} and CuInCr_{4}Se_{8}, to demonstrate the feasibility of this new approach and expose its possible limitations in experimental realizations.