tbuckley/cabot-search huggingface dataset:
Impact of introducing a minimum alcohol tax share in retail prices on alcohol-attributable mortality in the WHO European Region: A modelling study
Authors: Maria Neufeld, Pol Rovira, Carina Ferreira-Borges, Carolin Kilian, Franco Sassi, Aurelijus Veryga, Jürgen Rehm
Journal: The Lancet Regional Health - Europe (2022)

Alcohol use and its burden constitute one of the largest public health challenges in the WHO European Region. Raising alcohol taxes is a cost-effective "best buy" measure to reduce alcohol consumption, but its implementation remains uneven. This paper provides an overview of existing tax structures in 50 countries and subregions of the Region, estimates their proportions of tax on retail prices of beer, wine, and spirits, and quantifies the number of deaths that could be averted annually if these tax shares were raised to a minimum level.Review of databases and statistical reports on taxes and mean retail prices of alcohol beverages in the Region. Affordability was calculated based on alcohol prices, adjusted for differences in purchasing power. Consumption changes and averted mortality were modelled assuming two scenarios. In Scenario 1, a minimum excise tax share level of 25% of the beverage-specific retail price was assumed for all countries. In Scenario 2, in addition to a minimum excise tax share level of 15% it was assumed that per unit of ethanol minimal retail prices were the same irrespective of alcoholic beverages (equalisation). Sensitivity analyses were conducted for different price elasticities.Alcohol is very affordable in the Region and alcohol taxes have clearly been under-utilized as a public health measure, constituting on average only 5·7%, 14·0% and 31·3% of the retail prices of wine, beer, and spirits, respectively. Tax shares were higher in the eastern part of the Region compared to the EU, where various countries did not have excise taxes on wine. Annually, the introduction of a minimum tax share of 25% (Scenario 1) could avert 40,033 (95% CI: 38,054-46,097) deaths in the WHO European Region (with 753,454,300 inhabitants older than 15 years of age). If a 15% tax share with equalisation were implemented (Scenario 2), 132,906 (95% CI: (124,691-151,674) deaths could be averted. All sensitivity analyses with different elasticities yielded outcomes close to those of the main analyses.Similar to tobacco taxes, increasing alcohol taxes should be considered to be a health-based measure aimed at saving lives. Many countries have hesitated to apply higher taxes to alcohol, but the present results show a clear health benefit as a result of implementing a minimum tax share.This work was supported by the National Institute on Alcohol Abuse and Alcoholism (1R01AA028224) and the Canadian Institutes of Health Research, Institute of Neurosciences, and Mental Health and Addiction (SMN-13950).
Adjustable intragastric balloon for treatment of obesity: a multicentre, open-label, randomised clinical trial
Authors: Barham K Abu Dayyeh, Daniel B Maselli, Babusai Rapaka, Thomas Lavin, Mark Noar, Hisham Hussan, Christopher G Chapman, Violeta Popov, Pichamol Jirapinyo, Andres Acosta, Eric J Vargas, Andrew C Storm, Fateh Bazerbachi, Marvin Ryou, Matthew French, Sabrena Noria, Daniel Molina, Christopher C Thompson
Journal: The Lancet (2021)
Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer
Authors: Amy C. Mandigo, Ayesha A. Shafi, Jennifer J. McCann, Wei Yuan, Talya S. Laufer, Denisa Bogdan, Lewis Gallagher, Emanuela Dylgjeri, Galina Semenova, Irina A. Vasilevskaya, Matthew J. Schiewer, Chris M. McNair, Johann S. de Bono, Karen E. Knudsen
Journal: Cancer Research (2021)

Abstract The retinoblastoma tumor suppressor (RB) is a critical regulator of E2F-dependent transcription, controlling a multitude of protumorigenic networks including but not limited to cell-cycle control. Here, genome-wide assessment of E2F1 function after RB loss in isogenic models of prostate cancer revealed unexpected repositioning and cooperation with oncogenic transcription factors, including the major driver of disease progression, the androgen receptor (AR). Further investigation revealed that observed AR/E2F1 cooperation elicited novel transcriptional networks that promote cancer phenotypes, especially as related to evasion of cell death. These observations were reflected in assessment of human disease, indicating the clinical relevance of the AR/E2F1 cooperome in prostate cancer. Together, these studies reveal new mechanisms by which RB loss induces cancer progression and highlight the importance of understanding the targets of E2F1 function. Significance: This study identifies that RB loss in prostate cancer drives cooperation between AR and E2F1 as coregulators of transcription, which is linked to the progression of advanced disease.
Secondary Cytoreductive Surgery in Platinum-Sensitive Recurrent Ovarian Cancer: A Meta-Analysis
Authors: Min-Hyun Baek, Eun Young Park, Hyeong In Ha, Sang-Yoon Park, Myong Cheol Lim, Christina Fotopoulou, Robert E. Bristow
Journal: Journal of Clinical Oncology (2022)

PURPOSE The survival impact of secondary cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer was studied. METHODS We identified published studies from 1983 to 2021 following our inclusion criteria from MEDLINE, EMBASE, and Cochrane library. To integrate the effect size of single-arm studies, meta-analysis was performed using death rate as a primary outcome. The effect of complete cytoreduction and optimal cytoreduction on survival was evaluated using meta-regression. The pooled death rate was presented with a 95% CI. The publication bias was evaluated with the funnel plot and Egger's test, and sensitivity analysis was performed. To overcome missing death rates, the linear regression model was performed on log-transformed median overall survival (OS) time using study size as a weight. RESULTS Thirty-six studies with 2,805 patients reporting death rates were used for this meta-analysis of the 80 eligible studies. There was strong heterogeneity, with the P value of the Cochrane Q test of &lt; 0.0001 and Higgins's I 2 statistics of 86%; thus, we considered a random effect model. The pooled death rate was 44.2% (95% CI, 39.0 to 49.5), and both the complete and optimal cytoreductions were associated with better survival outcomes as significant moderators in the meta-regression model ( P &lt; .001 and P = .005, respectively). Although 14 studies were located outside the funnel plot, Egger's test indicated no publication bias ( P = .327). A sensitivity analysis excluding 14 studies showed similar results. In the linear regression model on the basis of 57 studies, the median OS time increased by 8.97% and 7.04% when the complete and optimal cytoreduction proportion increased by 10%, respectively, after adjusting other variables. CONCLUSION Secondary cytoreductive surgery, resulting in maximal tumor resection, significantly prolongs OS in platinum-sensitive recurrent ovarian cancer.
99mTc-TRODAT-1 SPECT Revealed That Striatal Dopamine Transport Availability Significantly Decreases in Late Mid-Aged Healthy Taiwanese and Then Remains Stable
Authors: Skye Hsin-Hsien Yeh, Chi-Jung Tsai, Tsung-Hsun Yu, Yung-Hsiao Chiang, Shinn-Zong Lin, Nan-Jing Peng, Wen-Sheng Huang
Journal: Clinical Nuclear Medicine (2022)

Objectives Neuroimaging studies in the past 20 years have documented an age-related decline in striatal dopamine transporters (DATs), which is a marker of dopaminergic neurodegeneration; however, concerns about ethnic variations in the decline in DAT with age have not been addressed. The purpose of this study was to assess the rate of striatal DAT loss in healthy Taiwanese adults using kit-based 99m Tc-TRODAT-1, a radioligand for DAT SPECT. Patients and Methods Fifty healthy subjects (mean age ± SD, 63 ± 12 years; range, 30–80 years) were studied. 99m Tc-TRODAT-1 was prepared from a lyophilized kit. Brain DAT SPECT imaging was acquired between 165 and 195 minutes postinjection (~740 MBq or 20 mCi) using a dual-head camera equipped with fan-beam collimators (Helix SPX; GE). Specific uptake in the striatum (ST), caudate nucleus (CA), and putamen (PU) were calculated from reconstructed transaxial slices at the level of maximal striatal activity. Occipital cortices were used as reference areas. Data were presented as specific binding ratios. Results Age had a significant moderate to large negative effect on striatal DAT, which declined by −25.7% ± 6.10% between the ages of 30 and 80 years, equivalent to 6.4% loss per decade. The rates of decline in the CA and PU were 6.9% and 7.3% per decade, respectively. Conclusions This study suggests ethnic variations may not significantly affect the age-related decline in DAT. The data generated in this study could also be used as a reference to estimate DAT loss/occupancy in patients with DAT-related diseases.
PCSK9 Activity Is Potentiated Through HDL Binding
Authors: Sean A. Burnap, Katherine Sattler, Raimund Pechlaner, Elisa Duregotti, Ruifang Lu, Konstantinos Theofilatos, Kaloyan Takov, Gerd Heusch, Sotirios Tsimikas, Carlos Fernández-Hernando, Sarah E. Berry, Wendy L. Hall, Marlene Notdurfter, Gregorio Rungger, Bernhard Paulweber, Johann Willeit, Stefan Kiechl, Bodo Levkau, Manuel Mayr
Journal: Circulation Research (2021)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and high-density lipoprotein (HDL) remains unexplored.This study sought to interrogate the novel relationship between PCSK9 and HDL in humans.Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck (n=656) study revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein-C3, an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 times points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apolipoprotein-C3 from HDL and lower levels of small HDL as measured by nuclear magnetic resonance. Crosslinking mass spectrometry (XLMS) upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin and apolipoprotein-E within the HDL proteome, that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalisation and multimerisation.This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipaemia as a driver of PCSK9 and apolipoprotein-C3 release from HDL.
Shorter serial intervals in SARS-CoV-2 cases with Omicron BA.1 variant compared with Delta variant, the Netherlands, 13 to 26 December 2021
Authors: Jantien A Backer, Dirk Eggink, Stijn P Andeweg, Irene K Veldhuijzen, Noortje van Maarseveen, Klaas Vermaas, Boris Vlaemynck, Raf Schepers, Susan van den Hof, Chantal BEM Reusken, Jacco Wallinga
Journal: Eurosurveillance (2022)

The SARS-CoV-2 Omicron variant has a growth advantage over the Delta variant because of higher transmissibility, immune evasion or shorter serial interval. Using S gene target failure (SGTF) as indication for Omicron BA.1, we identified 908 SGTF and 1,621 non-SGTF serial intervals in the same period. Within households, the mean serial interval for SGTF cases was 0.2-0.6 days shorter than for non-SGTF cases. This suggests that the growth advantage of Omicron is partly due to a shorter serial interval.
Molluscum Contagiosum
Authors: Rebecca F Silverman, Roman Shinder
Journal: New England Journal of Medicine (2022)

A 60-year-old man with HIV infection presented with a 4-month history of lesions on his eyelids and face. Intracytoplasmic eosinophilic inclusion bodies were observed in a biopsy specimen, confirming a diagnosis of molluscum contagiosum.
Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial
Authors: Javed Butler, Gerasimos Filippatos, Tariq Jamal Siddiqi, Martina Brueckmann, Michael Böhm, Vijay K. Chopra, João Pedro Ferreira, James L. Januzzi, Sanjay Kaul, Ileana L. Piña, Piotr Ponikowski, Sanjiv J. Shah, Michele Senni, Ola Vedin, Subodh Verma, Barbara Peil, Stuart J. Pocock, Faiez Zannad, Milton Packer, Stefan D. Anker
Journal: Circulation (2021)

Patients with heart failure with preserved ejection fraction have significant impairment in health-related quality of life. In the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), we evaluated the efficacy of empagliflozin on health-related quality of life in patients with heart failure with preserved ejection fraction and whether the clinical benefit observed with empagliflozin varies according to baseline health status. Health-related quality of life was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12, 32, and 52 weeks. Patients were divided by baseline KCCQ Clinical Summary Score (CSS) tertiles, and the effect of empagliflozin on outcomes was examined. The effect of empagliflozin on KCCQ-CSS, Total Symptom Score, and Overall Summary Score was evaluated. Responder analyses were performed to compare the odds of improvement and deterioration in KCCQ related to treatment with empagliflozin. The effect of empagliflozin on reducing the risk of time to cardiovascular death or heart failure hospitalization was consistent across baseline KCCQ-CSS tertiles (hazard ratio, 0.83 [95% CI, 0.69-1.00], 0.70 [95% CI, 0.55-0.88], and 0.82 [95% CI, 0.62-1.08] for scores <62.5, 62.5-83.3, and ≥83.3, respectively; P trend=0.77). Similar results were seen for total heart failure hospitalizations. Patients treated with empagliflozin had significant improvement in KCCQ-CSS versus placebo (+1.03, +1.24, and +1.50 at 12, 32, and 52 weeks, respectively; P<0.01); similar results were seen for Total Symptom Score and Overall Summary Score. At 12 weeks, patients on empagliflozin had higher odds of improvement ≥5 points (odds ratio, 1.23 [95% CI, 1.10-1.37]), ≥10 points (odds ratio, 1.15 [95% CI, 1.03-1.27]), and ≥15 points (odds ratio, 1.13 [95% CI, 1.02-1.26]) and lower odds of deterioration ≥5 points in KCCQ-CSS (odds ratio, 0.85 [95% CI, 0.75-0.97]). A similar pattern was seen at 32 and 52 weeks, and results were consistent for Total Symptom Score and Overall Summary Score. In patients with heart failure with preserved ejection fraction, empagliflozin reduced the risk for major heart failure outcomes across the range of baseline KCCQ scores. Empagliflozin improved health-related quality of life, an effect that appeared early and was sustained for at least 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057951.
Interpreting success or failure of peanut oral immunotherapy
Authors: Shijie Cao, Cathryn R. Nagler
Journal: Journal of Clinical Investigation (2022)

Peanut oral immunotherapy (OIT) was recently approved by the US FDA. However, not all patients respond to OIT, and there is a high likelihood of regaining sensitization to peanuts after cessation of treatment. It is important, therefore, to identify biomarkers that impact and predict OIT outcomes. In this issue of the JCI, Monian, Tu, and colleagues describe distinct subsets of peanut-reactive CD4+ Th cell phenotypes and gene signatures with relevance to OIT outcomes using single-cell RNA-Seq and paired T cell receptor (TCR) α/β sequencing. The insights obtained will inform the development of therapeutics that target these Th cell phenotypes or deplete peanut-specific Th2 cells to achieve sustained nonresponsiveness in food allergy.
EBV Infection in Epithelial Malignancies Induces Resistance to Antitumor Natural Killer Cells via F3-Mediated Platelet Aggregation
Authors: Xiaobing Duan, Haiwen Chen, Xiang Zhou, Pingjuan Liu, Xiao Zhang, Qian Zhu, Ling Zhong, Wanlin Zhang, Shanshan Zhang, Xinyu Zhang, Yanhong Chen, Yan Zhou, Chaopin Yang, Qisheng Feng, Yi-Xin Zeng, Miao Xu, Tong Xiang
Journal: Cancer Research (2022)

Nasopharyngeal carcinoma (NPC) and Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) are two major EBV-associated epithelial malignancies, both of which are characterized by the infiltration of a large number of lymphocytes, including natural killer (NK) cells. Although NK cells can prevent the development of EBV-associated epithelial malignancies, EBV-infected tumor cells often develop resistance to surveillance by NK cells. Elucidating the interactions between NK cells and EBV-infected tumor cells will facilitate the development of more effective NK-mediated therapies for treating EBV-associated malignancies. Here we investigated the cytotoxic function of NK cells in EBV-associated epithelial malignancies and discovered that EBV infection-induced upregulation of F3 expression correlates with NK-cell dysfunction in NPC and EBVaGC. The subsequent inhibitory effect of F3-mediated platelet aggregation on NK-cell function was verified in vitro and in vivo. Mechanistically, EBV latent membrane protein 2A (LMP2A) mediated upregulation of F3 through the PI3K/AKT signaling pathway. In an NPC xenograft mouse model, inhibition of F3 restored the antitumor function of NK cells and showed therapeutic efficacy when administered with NK-cell transfer. On the basis of these findings, EBV infection induces F3-mediated platelet aggregation that inhibits the antitumor function of NK cells, providing a rationale for developing and combining NK-cell-based therapies with F3 inhibitors to treat EBV-associated epithelial malignancies.This study reveals a mechanism by which EBV-associated epithelial malignancies escape NK-cell-mediated immune surveillance, providing a new target for improving NK-cell immunotherapy.
Randomized Phase III Study of Gefitinib Versus Cisplatin Plus Vinorelbine for Patients With Resected Stage II-IIIA Non–Small-Cell Lung Cancer With <i>EGFR</i> Mutation (IMPACT)
Authors: Hirohito Tada, Tetsuya Mitsudomi, Toshihiro Misumi, Kenji Sugio, Masahiro Tsuboi, Isamu Okamoto, Yasuo Iwamoto, Noriaki Sakakura, Shunichi Sugawara, Shinji Atagi, Toshiaki Takahashi, Hidetoshi Hayashi, Morihito Okada, Hidetoshi Inokawa, Hiroshige Yoshioka, Kazuhisa Takahashi, Masahiko Higashiyama, Ichiro Yoshino, Kazuhiko Nakagawa
Journal: Journal of Clinical Oncology (2021)

To investigate the efficacy of gefitinib as an adjuvant therapy for non-small-cell lung cancer patients with EGFR mutation.IMPACT (WJOG6410L; University Hospital Medical Information Network Clinical Trials Registry: UMIN000006252), a randomized, open-label, phase III study, included patients with completely resected pathologic stage II-III non-small-cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R) during September 2011 to December 2015. Patients were randomly assigned to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles. The primary end point was disease-free survival (DFS).Overall, 234 patients were randomly assigned. Among 232 eligible patients (116 each; excluding two who withdrew consent), the median DFS was 35.9 and 25.1 months in the gefitinib and cis/vin groups, respectively. However, Kaplan-Meier curves crossed around 4 years after surgery with no statistically significant difference (stratified log-rank P = .63; hazard ratio by stratified Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival (OS) was also not different (stratified log-rank P = .89; hazard ratio = 1.03; 95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in 0 and three patients in the gefitinib and cis/vin groups, respectively.Although adjuvant gefitinib appeared to prevent early relapse, it did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant gefitinib in the selected patient subsets, especially those deemed ineligible for platinum-doublet adjuvant therapy; however, this was not a noninferiority trial.
Abstract MP28: Associations Of Adverse Childhood Family Environment With Adult Sedentary Behavior And Physical Activity: The Coronary Artery Risk Development In Young Adults (CARDIA) Study
Authors: Melissa A Jones, Nathaniel D Jenkins, Kelley P Gabriel, Catarina I Kiefe, David R Jacobs, Kiarri N Kershaw, Kara M Whitaker
Journal: Circulation (2022)

Introduction: Adverse family environment (AFE) in childhood may have deleterious health effects; however, whether these exposures relate to health promoting behaviors in adulthood is unknown. We hypothesize that AFE in childhood will be associated with higher sedentary behavior (SED), and lower light- (LPA) and moderate-to-vigorous (MVPA) physical activity in adulthood and that associations will be moderated by social network size or social support. Methods: This was an analysis of 2,127 CARDIA study participants. AFE in childhood was self-reported in year 15 (2000-2001) and categorized as low, moderate, or high adversity using a 7-item questionnaire. Average SED, LPA, and MVPA (min/day) were measured using year 20 (2005-2006) accelerometry data and exercise units/day of MVPA was self-reported. Linear regression models examined associations of AFE in childhood with accelerometer measured SED, LPA, MVPA and self-reported MVPA in adulthood. We further tested for interactions between AFE and adult social network size or social support with each activity outcome and stratified analyses if interactions were p&lt;0.10. Results: Participants were 57% female and 45.3 ± 3.5 years of age. High AFE (versus low) was only associated with lower SED (ß: -10.72 min/day, p=0.039). Interaction analyses identified a significant social network x AFE interaction with SED and social support x AFE interaction with self-reported MVPA. In stratified analyses, those with small social network and high AFE had lower SED (ß: -17.99 min/day, p=0.015) compared small social network and low AFE. Those with high social support and high AFE had significantly lower self-reported MVPA (ß: -44.74 exercise units/day, p=0.026) compared to high social support and low AFE (Table). Conclusions: In conclusion, high AFE, among those with a small social network, was related to lower SED and among those with high social support, lower self-reported MVPA. These data are hypothesis generating as associations were in unexpected directions.