bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of e-cigarette warning letters issued by the Food and Drug Administration in 2020 and 2021
Authors: Schillo Barbara A , Bertrand Adrian , Briggs Jodie , Kierstead Elexis C , Silver Nathan A , Yoon Stephanie N , Diaz Megan C 
Published: October 2022

PurposeThis study analyses the Food and Drug Administration (FDA) warning letters sent to e-cigarette companies from 1 January 2020 to 9 September 2021. Study results can inform regulation of e-cigarettes.MethodologyWarning letters retrieved from FDA’s website were coded for company type (retailer, manufacturer or distributor), location (domestic or international), infractions listed (PMTA (premarket tobacco product application), selling to minors, advertising to youth or packaging violation/mislabelling), product type (e-liquid, device or both), flavour (fruit, candy, tobacco, menthol/mint, concept flavour) and consequence (civil money penalties, product seizure and injunction, product detention and refusal of entry to the USA, no-tobacco-sales order, criminal prosecution).ResultsOf 303 coded letters (126 from 2020 and 177 from 2021), 97.4% were sent to small online retailers. Overall, 94.1% of the companies cited were located within the USA, 75.2% of the infractions were identified by reviewing a company’s website and 70.5% were PMTA violations. In 2020, 55.6% of infractions were PMTA violations; in 2021, nearly all infractions were PMTA violations. The letters cited 880 products; 92.2% of which were e-liquid products, with 32.4% fruit and 31.1% concept flavours.DiscussionWarning letters targeted small online retailers rather than large e-cigarette brands or products most used by youth: pod mods and disposables. The focus of these enforcement actions comprises a small share of the market and the impact on use was likely minimal. With PMTA decisions pending for the largest brands of e-cigarettes, the FDA should use its enforcement powers to target manufacturers, distributors and sellers of the tobacco products that have the greatest impact on youth and products that provide no public health benefit.
Fish length back-calculation from scales: advancing methodology and correction of bias
Authors: Bailey Colin J. , Wilson Kyle L. , More O’Ferrall Mikayla , Moore Jonathan W. 
Published: October 2022

Fish length back-calculation from hard structures (e.g., scales, otoliths, spines, etc.) is a commonly used method to reconstruct individual growth rates and sizes at age/stage in the absence of an intensive sampling–resampling timeseries. However, reliable estimates via these methods require the empirical validation of multiple assumptions about the growth of these hard structures. Here, we focus on reducing bias in scale-based back-calculations and validating proposed improvements using archived scales from a wild population of anadromous steelhead trout ( Oncorhynchus mykiss). We first describe a series of back-calculation problems and propose solutions that can be integrated into common back-calculation methods. We then compare back-calculation accuracy, precision, and bias between proposed solutions and traditional forms of two back-calculation methods: Fraser–Lee and Body-Proportional. We discovered that the assumption that rapid growth begins immediately after juvenile steelhead pass downstream of the fish fence (300 m upstream of the ocean) was invalid and required a correction factor to prevent overestimating fish length by an average of 14%. The proposed modified methods we described performed better than traditional back-calculation methods. Overall, these findings can improve estimates of fish length from scale-based back-calculations and illustrate the importance of validating key assumptions.
Reflections of geodiversity–culture relationships within the concept of abiotic ecosystem services
Authors: Kubalíková Lucie , Coratza Paola 
Published: October 2022

Abstract
Relationships between geodiversity and culture are very close and frequent, and they are reflected in numerous and different areas, situations or levels. The purpose of this chapter is not to give an exhaustive overview of how geodiversity influences culture and vice versa (as this topic has already been thoroughly explored in numerous works), but it aims to analyse the relationship geodiversity–culture within the concept of abiotic ecosystem services (or geosystem services). This relationship is best visible and recognizable within the cultural and, eventually, knowledge services; however, other types of services (provisioning, supporting) are relevant too. Moreover, the relationship geodiversity–culture is reflected in everyday life, for example, in language; thus, a quick insight into these topics is also presented. Anchoring the geodiversity–culture relationships within the concept of abiotic ecosystem services may provide a framework for future interdisciplinary studies and may contribute to the better understanding of protection, conservation and sustainable use not only of geoheritage but of geodiversity as a whole.
Vaccination with Designed Neopeptides Induces Intratumoral, Cross-reactive CD4+ T-cell Responses in Glioblastoma
Authors: Wang Jian , Weiss Tobias , Neidert Marian C. , Toussaint Nora C. , Naghavian Reza , Sellés Moreno Carla , Foege Magdalena , Tomas Ojer Paula , Medici Gioele , Jelcic Ivan , Schulz Daniel , Rushing Elisabeth , Dettwiler Susanne , Schrörs Barbara , Shin Joo Heon , McKay Ron , Wu Catherine J. , Lutterotti Andreas , Sospedra Mireia , Moch Holger , Greiner Erich F. , Bodenmiller Bernd , Regli Luca , Weller Michael , Roth Patrick , Martin Roland 
Published: October 2022

Abstract

Purpose:
The low mutational load of some cancers is considered one reason for the difficulty to develop effective tumor vaccines. To overcome this problem, we developed a strategy to design neopeptides through single amino acid mutations to enhance their immunogenicity.

Experimental Design:
Exome and RNA sequencing as well as in silico HLA-binding predictions to autologous HLA molecules were used to identify candidate neopeptides. Subsequently, in silico HLA-anchor placements were used to deduce putative T-cell receptor (TCR) contacts of peptides. Single amino acids of TCR contacting residues were then mutated by amino acid replacements. Overall, 175 peptides were synthesized and sets of 25 each containing both peptides designed to bind to HLA class I and II molecules applied in the vaccination. Upon development of a tumor recurrence, the tumor-infiltrating lymphocytes (TIL) were characterized in detail both at the bulk and clonal level.

Results:
The immune response of peripheral blood T cells to vaccine peptides, including natural peptides and designed neopeptides, gradually increased with repetitive vaccination, but remained low. In contrast, at the time of tumor recurrence, CD8+ TILs and CD4+ TILs responded to 45% and 100%, respectively, of the vaccine peptides. Furthermore, TIL-derived CD4+ T-cell clones showed strong responses and tumor cell lysis not only against the designed neopeptide but also against the unmutated natural peptides of the tumor.

Conclusions:
Turning tumor self-peptides into foreign antigens by introduction of designed mutations is a promising strategy to induce strong intratumoral CD4+ T-cell responses in a cold tumor like glioblastoma.
Comprehensive Molecular Characterization of Gallbladder Carcinoma and Potential Targets for Intervention
Authors: Giraldo Nicolas A. , Drill Esther , Satravada Baby A. , Dika Imane El , Brannon A. Rose , Dermawan Josephine , Mohanty Abhinita , Ozcan Kerem , Chakravarty Debyani , Benayed Ryma , Vakiani Efsevia , Abou-Alfa Ghassan K. , Kundra Ritika , Schultz Nikolaus , Li Bob T. , Berger Michael F. , Harding James J. , Ladanyi Marc , O'Reilly Eileen M. , Jarnagin William , Vanderbilt Chad , Basturk Olca , Arcila Maria E. 
Published: October 2022

AbstractPurpose:Gallbladder carcinoma (GBC) is an uncommon and aggressive disease, which remains poorly defined at a molecular level. Here, we aimed to characterize the molecular landscape of GBC and identify markers with potential prognostic and therapeutic implications.Experimental Design:GBC samples were analyzed using the MSK-IMPACT (Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets) platform (targeted NGS assay that analyzes 505 cancer-associated genes). Variants with therapeutic implications were identified using OncoKB database. The associations between recurrent genetic alterations and clinicopathologic characteristics (Fisher exact tests) or overall survival (univariate Cox regression) were evaluated. P values were adjusted for multiple testing.Results:Overall, 244 samples (57% primary tumors and 43% metastases) from 233 patients were studied (85% adenocarcinomas, 10% carcinomas with squamous differentiation, and 5% neuroendocrine carcinomas). The most common oncogenic molecular alterations appeared in the cell cycle (TP53 63% and CDKN2A 21%) and RTK_RAS pathways (ERBB2 15% and KRAS 11%). No recurrent structural variants were identified. There were no differences in the molecular landscape of primary and metastasis samples. Variants in SMAD4 and STK11 independently associated with reduced survival in patients with metastatic disease. Alterations considered clinically actionable in GBC or other solid tumor types (e.g., NTRK1 fusions or oncogenic variants in ERBB2, PIK3CA, or BRCA1/2) were identified in 35% of patients; 18% of patients with metastatic disease were treated off-label or enrolled in a clinical trial based on molecular findings.Conclusions:GBC is a genetically diverse malignancy. This large-scale genomic analysis revealed alterations with potential prognostic and therapeutic implications and provides guidance for the development of targeted therapies.
Ubiquitinated PCNA Drives USP1 Synthetic Lethality in Cancer
Authors: Simoneau Antoine , Engel Justin L. , Bandi Madhavi , Lazarides Katherine , Liu Shangtao , Meier Samuel R. , Choi Ashley H. , Zhang Hongxiang , Shen Binzhang , Martires Lauren , Gotur Deepali , Pham Truc V. , Li Fang , Gu Lina , Gong Shanzhong , Zhang Minjie , Wilker Erik , Pan Xuewen , Whittington Douglas A. , Throner Scott , Maxwell John P. , Chen Yingnan , Yu Yi , Huang Alan , Andersen Jannik N. , Feng Tianshu 
Published: October 2022

Abstract
CRISPR Cas9-based screening is a powerful approach for identifying and characterizing novel drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacologic inhibition of USP1 leads to decreased DNA synthesis concomitant with S-phase–specific DNA damage. Genome-wide CRISPR-Cas9 screens identify RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition is associated with reduced PCNA protein levels. Ectopic expression of WT or ubiquitin-dead K164R PCNA reverses USP1 inhibitor sensitivity. Our results show, for the first time, that USP1 dependency hinges on the aberrant processing of mono- and polyubiquitinated PCNA. Moreover, this mechanism of USP1 dependency extends beyond BRCA1/2 mutant tumors to selected BRCA1/2 WT cancer cell lines enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant tumors. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to posttranslational modifications of PCNA. Taken together, USP1 inhibition may represent a novel therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.
Validation of Polygenic Risk Scores for Coronary Heart Disease in a Middle Eastern Cohort Using Whole Genome Sequencing
Authors: Saad Mohamad , El-Menyar Ayman , Kunji Khalid , Ullah Ehsan , Al Suwaidi Jassim , Kullo Iftikhar J. 
Published: October 2022

Background:
Enthusiasm for using polygenic risk scores (PRSs) in clinical practice is tempered by concerns about their portability to diverse ancestry groups, thus motivating genome-wide association studies in non-European ancestry cohorts.

Methods:
We conducted a genome-wide association study for coronary heart disease in a Middle Eastern cohort using whole genome sequencing and assessed the performance of 6 PRSs developed with methods including LDpred (PGS000296), metaGRS (PGS000018), Pruning and Thresholding (PGS000337), and an EnsemblePRS we developed. Additionally, we evaluated the burden of rare variants in lipid genes in cases and controls. Whole genome sequencing at 30× coverage was performed in 1067 coronary heart disease cases (mean age=59 years; 70.3% males) and 6170 controls (mean age=40 years; 43.5% males).

Results:

The majority of PRSs performed well; odds ratio (OR) per 1 SD increase (OR
1sd
) was highest for PGS000337 (OR
1sd
=1.81, 95% CI [1.66–1.98],
P
=3.07×10
−41
). EnsemblePRS performed better than individual PRSs (OR
1sd
=1.8, 95% CI [1.66–1.96],
P
=5.89×10
−44
). The OR for the 10th decile versus the remaining deciles was >3.2 for PGS000337, PGS000296, PGS000018, and reached 4.58 for EnsemblePRS. Of 400 known genome-wide significant loci, 33 replicated at
P
<10
−4
. However, the 9p21 locus did not replicate. Six suggestive (
P
<10
−5
) new loci/genes with plausible biological function were identified (eg,
CORO7
,
RBM47
,
PDE4D
). The burden of rare functional variants in
LDLR
,
APOB
,
PCSK9
, and
ANGPTL4
was greater in cases than controls.

Conclusions:
Overall, we demonstrate that PRSs derived from European ancestry genome-wide association studies performed well in a Middle Eastern cohort, suggesting these could be used in the clinical setting while ancestry-specific PRSs are developed.
Cost-Effectiveness of Empagliflozin in Patients With Heart Failure and Preserved Ejection Fraction
Authors: Zhou Jennifer , Liew Danny , Kaye David M. , Zoungas Sophia , Stub Dion 
Published: October 2022

Background:
Empagliflozin is the first medication to demonstrate clinical benefit in patients with heart failure with preserved ejection fraction, but its cost-effectiveness is unknown. We aimed to evaluate the cost-effectiveness of adding empagliflozin to standard therapy in patients with heart failure with preserved ejection fraction.

Methods:
A Markov model from the perspective of the Australian health care system was constructed to compare empagliflozin plus standard care to standard care alone among a hypothetical cohort of patients with heart failure with preserved ejection fraction. Clinical probabilities were derived from The EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction). Costs and utilities were derived from published sources. The main outcome was the incremental cost-effectiveness ratio per quality-adjusted life-year gained. Deterministic and probabilistic sensitivity analyses were performed to assess model uncertainty. Costs and benefits were discounted at 5% annually.

Results:
Over a lifetime, the addition of empagliflozin to standard care prevented 167 heart failure hospitalizations and 155 heart failure-related urgent care visits for every 1000 patients treated and increased mean quality-adjusted survival by 0.16 quality adjusted life-years per patient. Mean lifetime costs in the empagliflozin and standard care groups were AUD$63 218 and AUD$58 478 per patient, respectively. This resulted in an incremental cost-effectiveness ratio of AUD$29 202 per quality adjusted life-year gained. In probabilistic sensitivity analyses, empagliflozin was cost-effective in 85% of 10 000 Monte Carlo simulations at a willingness-to-pay threshold of AUD$50 000 per quality adjusted life-year gained.

Conclusions:
In patients with heart failure with preserved ejection fraction, adding empagliflozin to standard care is likely to be cost-effective when compared with standard care alone in the Australian health care setting.
Inpatient Quality-of-Care Measures for Heart Failure: Treatment Gaps and Opportunities in the Contemporary Era
Authors: Warner Alberta L. , Lu Lingyun , Ghaznavi Zunera , Jackevicius Cynthia A. 
Published: October 2022

Background:
Quality of care measures are vital tools to assess processes of care within and between health care systems. The 2020 American College of Cardiology/AHA performance measures for heart failure provide a new set of such measures. We evaluated the achievement of these and other performance measures within the Veterans Affairs hospital system in a contemporary cohort of patients hospitalized for heart failure.

Methods:
Hospital discharges from January 2010 to February 2021 with a primary diagnosis of heart failure (n=289 810) were evaluated. Adherence to each measure was determined using the measure’s stated definition and by site.

Results:
Among patients with reduced ejection fraction (53.0%), beta blocker use was high (89.0%), ACE (angiotensin-converting enzyme) inhibitor, angiotensin receptor blocker, or angiotensin receptor-neprilysin inhibitor (ARNI) use decreased over time (75.3% in 2010, 55.8% in 2020), and hydralazine/nitrate use in eligible Black patients (19.3%) was low. While 68.1% were eligible for ARNI, only 6.0% received them, reaching 17.2% by 2020. Mineralocorticoid receptor antagonists were used in 49.3% of those eligible; laboratory testing 7 days after their initiation was 73.0%, detecting hyperkalemia in 2.2%, although it occurred in 13.7% by 90 days. Achievement of ≥50% target dose was low (beta blocker 45.9%, ACE inhibitor/angiotensin receptor blocker 31.6%, ARNI 19.0%) and for ACE inhibitor/angiotensin receptor blocker/ARNI, decreased over time. Discharge appointments were 56.2% at 7 days and 78.8% at 14 days. Cardiac rehabilitation referral was low (10.5%) but increased. There were significant site-level differences, particularly for hydralazine, ARNI, devices, and cardiac rehabilitation.

Conclusions:
Important inpatient quality of care measures can be readily measured across the Veterans Administration health care system from electronic health records. Treatment gaps and site-level differences persisted into the contemporary era and will likely be exacerbated as newer treatments are added to this complex baseline. These measures and methods also offer the opportunity to target global, local, and individual processes of care for innovative quality improvement initiatives.
Rare Variants in Genes Encoding Subunits of the Epithelial Na
+
Channel Are Associated With Blood Pressure and Kidney Function
Authors: Blobner Brandon M. , Kirabo Annet , Kashlan Ossama B. , Sheng Shaohu , Arnett Donna K. , Becker Lewis C. , Boerwinkle Eric , Carlson Jenna C. , Gao Yan , Gibbs Richard A. , He Jiang , Irvin Marguerite R. , Kardia Sharon L.R. , Kelly Tanika N. , Kooperberg Charles , McGarvey Stephen T. , Menon Vipin K. , Montasser May E. , Naseri Take , Redline Susan , Reiner Alexander P. , Reupena Muagututi‘a S. , Smith Jennifer A. , Sun Xiao , Vaidya Dhananjay , Viaud-Martinez Karine A. , Weeks Daniel E. , Yanek Lisa R. , Zhu Xiaofeng ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium*, Minster Ryan L. , Kleyman Thomas R. 
Published: October 2022

Background:

The epithelial Na
+
channel (ENaC) is intrinsically linked to fluid volume homeostasis and blood pressure. Specific rare mutations in
SCNN1A
,
SCNN1B
, and
SCNN1G
, genes encoding the α, β, and γ subunits of ENaC, respectively, are associated with extreme blood pressure phenotypes. No associations between blood pressure and
SCNN1D
, which encodes the δ subunit of ENaC, have been reported. A small number of sequence variants in ENaC subunits have been reported to affect functional transport in vitro or blood pressure. The effects of the vast majority of rare and low-frequency ENaC variants on blood pressure are not known.

Methods:
We explored the association of low frequency and rare variants in the genes encoding ENaC subunits, with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure. Using whole-genome sequencing data from 14 studies participating in the Trans-Omics in Precision Medicine Whole-Genome Sequencing Program, and sequence kernel association tests.

Results:

We found that variants in
SCNN1A
and
SCNN1B
were associated with diastolic blood pressure and mean arterial pressure (
P
<0.00625). Although
SCNN1D
is poorly expressed in human kidney tissue,
SCNN1D
variants were associated with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure (
P
<0.00625). ENaC variants in 2 of the 4 subunits (
SCNN1B
and
SCNN1D
) were also associated with estimated glomerular filtration rate (
P
<0.00625), but not with stroke.

Conclusions:
Our results suggest that variants in extrarenal ENaCs, in addition to ENaCs expressed in kidneys, influence blood pressure and kidney function.
First-Trimester Normotension Is a Weak Indicator of Normal Maternal Cardiovascular Function
Authors: Gyselaers Wilfried , Dreesen Pauline , Staelens Anneleen Simone , Tomsin Kathleen , Bruckers Liesbeth , Vonck Sharona 
Published: October 2022

Background:
As by definition, mean arterial pressure equals the product of cardiac output (CO) and total vascular resistance (TPR), we hypothesized that, irrespective of thresholds to define hypertension, a CO-TPR imbalance might exist in first-trimester normotensive pregnancies with altered risks for adverse gestational outcomes.

Methods:
A standard protocol was used for automated blood pressure measurement combined with impedance cardiography assessment of CO and TPR (NICCOMO). First-trimester normotensive pregnant women were categorized into 3 groups relative to the reference 75th percentile (P75) of CO and TPR: (1) normal CO and TPR, (2) high CO, and (3) high TPR. These subgroups were compared at blood pressure thresholds 140/90, 130/85, and 130/80 mmHg. The gestational outcome was categorized after birth according to International Society for Studies of Hypertension in Pregnancy criteria.

Results:

Compared with pregnancies with normal CO and TPR (≤P75), women with high TPR at blood pressure <140/90 mmHg are at risk for developing gestational hypertension (odds ratio, 3.795 [1.321–10.904];
P
<0.010), late-onset preeclampsia (odds ratio, 3.137 [1.060–9.287];
P
<0.050), and neonates small for gestational age (odds ratio, 1.780 [1.056–2.998];
P
<0.050).

Conclusions:
Cardiovascular imbalance can present in normotensive women in the first trimester and is associated with increased risks for adverse gestational outcomes. This study illustrates the relevance of CO and TPR assessments as an adjunct to blood pressure measurement and invites for further exploring their value in screening algorithms for gestational hypertensive disorders and/or small for gestational age.