bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variant reclassification and clinical implications
Authors: Walsh Nicola , Cooper Aislinn , Dockery Adrian , O'Byrne James J 
Published: January 2024

Genomic technologies have transformed clinical genetic testing, underlining the importance of accurate molecular genetic diagnoses. Variant classification, ranging from benign to pathogenic, is fundamental to these tests. However, variant reclassification, the process of reassigning the pathogenicity of variants over time, poses challenges to diagnostic legitimacy. This review explores the medical and scientific literature available on variant reclassification, focusing on its clinical implications.
Variant reclassification is driven by accruing evidence from diverse sources, leading to variant reclassification frequency ranging from 3.6% to 58.8%. Recent studies have shown that significant changes can occur when reviewing variant classifications within 1 year after initial classification, illustrating the importance of early, accurate variant assignation for clinical care.
Variants of uncertain significance (VUS) are particularly problematic. They lack clear categorisation but have influenced patient treatment despite recommendations against it. Addressing VUS reclassification is essential to enhance the credibility of genetic testing and the clinical impact. Factors affecting reclassification include standardised guidelines, clinical phenotype-genotype correlations through deep phenotyping and ancestry studies, large-scale databases and bioinformatics tools. As genomic databases grow and knowledge advances, reclassification rates are expected to change, reducing discordance in future classifications.
Variant reclassification affects patient diagnosis, precision therapy and family screening. The exact patient impact is yet unknown. Understanding influencing factors and adopting standardised guidelines are vital for precise molecular genetic diagnoses, ensuring optimal patient care and minimising clinical risk.
Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort
Authors: Yan Xiaohong , Wang Jing , Yang Wen , Li Linke , Shen Tian , Geng Jia , Zhang Qian , Zhong Mingjun , Xiong Wenyu , Bu Fengxiao , Lu Yu , Zhao Yu , Cheng Jing , Yuan Huijun 
Published: January 2024

BackgroundTownes-Brocks syndrome (TBS) is a rare genetic disorder characterised by multiple malformations. Due to its phenotypic heterogeneity and rarity, diagnosis and recognition of TBS can be challenging and there has been a lack of investigation of patients with atypical TBS in large cohorts and delineation of their phenotypic characteristics.MethodsWe screenedSALL1andDACT1variants using next-generation sequencing in the China Deafness Genetics Consortium (CDGC) cohort enrolling 20 666 unrelated hearing loss (HL) cases. Comprehensive clinical evaluations were conducted on seven members from a three-generation TBS family. Combining data from previously reported cases, we also provided a landscape of phenotypes and genotypes of patients with TBS.ResultsWe identified five novel and two reported pathogenic/likely pathogenic (P/LP)SALL1variants from seven families. Audiological features in patients differed in severity and binaural asymmetry. Moreover, previously undocumented malformations in the middle and inner ear were detected in one patient. By comprehensive clinical evaluations, we further provide evidence for the causal relationship betweenSALL1variation and certain endocrine abnormalities. Penetrance analysis within familial contexts revealed incomplete penetrance among first-generation patients with TBS and a higher disease burden among their affected offspring.ConclusionThis study presents the first insight of genetic screening for patients with TBS in a large HL cohort. We broadened the phenotypic-genotypic spectrum of TBS and our results supported an underestimated prevalence of TBS. Due to the rarity and phenotypic heterogeneity of rare diseases, broader spectrum molecular tests, especially whole genome sequencing, can improve the situation of underdiagnosis and provide effective recommendations for clinical management.
Increased vascular inflammation on PET/CT in psoriatic arthritis patients in comparison with controls
Authors: Kleinrensink Nienke J , Spierings Julia , Vonkeman Harald E , Seddiqi Negina , Herman Amin , Suijkerbuijk Karijn P M , Heijstek Marloes W , Jansen Mylène P , de Jong Pim A , Foppen Wouter 
Published: January 2024

BackgroundPatients with psoriatic arthritis (PsA) have an increased risk of cardiovascular disease, possibly due to a chronic inflammatory state.ObjectivesThe main objective of this study was to investigate the difference in vascular inflammation, measured with 18-fluorodeoxyglucose positron emission tomography/CT (PET/CT), in PsA patients and controls. We conducted a secondary analysis to assess the association between clinical parameters of disease activity with vascular inflammation in PsA.MethodsWe included a total of 75 PsA patients with active peripheral arthritis (defined as ≥2 tender and swollen joints) from an ongoing clinical trial (EudraCT 2017-003900-28) and a retrospective group of 40 controls diagnosed with melanoma, without distant metastases and not receiving immunotherapy. The main outcome measure was aortic vascular inflammation which was measured on PET/CT scans using target-to-background ratios. Clinical disease activity in PsA was assessed with joint counts, body surface area and the Disease Activity index for PsA. Laboratory assessments included C reactive protein and erythrocyte sedimentation rate.ResultsVascular inflammation was increased in patients with PsA in comparison with controls (mean target-to-background ratio for entire aorta, respectively, 1.63±0.17 vs 1.49±0.16; p=<0.001). This association remained significant after correction for gender, age, body mass index, mean arterial pressure and aortic calcification (p=0.002). Vascular inflammation was not associated with disease-related parameters.ConclusionsAortic vascular inflammation was significantly increased in patients with active PsA compared with controls. This evidence supports the theory that inflammation in PsA is not limited to the skin and joints but also involves the vascular system.
Delirium pathophysiology in cancer: neurofilament light chain biomarker – narrative review
Authors: Kruize Zita , van Campen Isa , Vermunt Lisa , Geerse Olaf , Stoffels Josephine , Teunissen Charlotte , van Zuylen Lia 
Published: January 2024

BackgroundDelirium is a debilitating disorder with high prevalence near the end of life, impacting quality of life of patients and their relatives. Timely recognition of delirium can lead to prevention and/or better treatment of delirium. According to current hypotheses delirium is thought to result from aberrant inflammation and neurotransmission, with a possible role for neuronal damage. Neurofilament light chain (NfL) is a protein biomarker in body fluids that is unique to neurons, with elevated levels when neurons are damaged, making NfL a viable biomarker for early detection of delirium. This narrative review summarises current research regarding the pathophysiology of delirium and the potential of NfL as a susceptibility biomarker for delirium and places this in the context of care for patients with advanced cancer.ResultsSix studies were conducted exclusively on NfL in patients with delirium. Three of these studies demonstrated that high plasma NfL levels preoperatively predict delirium in older adult patients postoperatively. Two studies demonstrated that high levels of NfL in intensive care unit (ICU) patients are correlated with delirium duration and severity. One study found that incident delirium in older adult patients was associated with increased median NfL levels during hospitalisation.ConclusionsTargeted studies are required to understand if NfL is a susceptibility biomarker for delirium in patients with advanced cancer. In this palliative care context, better accessible matrices, such as saliva or urine, would be helpful for repetitive testing. Improvement of biological measures for delirium can lead to improved early recognition and lay the groundwork for novel therapeutic strategies.
Outcomes associated to the time to treatment with intravenous tenecteplase for acute ischaemic stroke: subgroup analysis of the TRACE-2 randomised controlled clinical trial
Authors: Li Shuya , Wangqin Runqi , Pan Yuesong , Jin Aoming , Li Hao , Schwamm Lee H , Fisher Marc , Campbell Bruce C V , Parsons Mark W , Wang Ziran , Dai Hongguo , Li Deyang , Li Runhui , Wang Junhai , Wang David , Wang Yilong , Zhao Xingquan , Li Zixiao , Zheng Huaguang , Xiong Yunyun , Meng Xia , Wang Yongjun 
Published: January 2024

BackgroundThe benefit of intravenous alteplase in acute ischaemic stroke (AIS) is time-dependent. Tenecteplase is non-inferior to alteplase among patients with AIS. We aimed to delineate the association of the stroke onset to treatment time (OTT) with tenecteplase compared with alteplase on therapeutic benefit and clinical risks.MethodsThis is a post hoc analysis of the Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-2 an open-label, randomised, controlled, non-inferior trial. A total of 1430 AIS within 4.5 hours onset at 53 sites in China from 12 June 2021 to 29 May 2022 were randomly assigned (1:1) to receive either tenecteplase 0.25 mg/kg or alteplase 0.9 mg/kg. The primary efficacy outcome was the proportion of participants with a modified Rankin Scale score of 0–1 at 90 days. A post hoc subgroup analysis was conducted with the OTT divided into three intervals (0–90 min, 91–180 min and 181–270 min). The primary safety outcome was symptomatic intracranial haemorrhage within 36 hours post-thrombolytic treatment.ResultsTreatment was initiated within 270 min of stroke onset in 1412 patients who were randomly allocated to either tenecteplase (n=707) or alteplase (n=705). The OR of primary efficacy outcome was similar as OTT increased (p=0.84). Adjusted odds of an excellent functional outcome were 0.99 (95% CI 0.37 to 2.67) for 0–90 min, 1.23 (95% CI 0.88 to 1.71) for 91–180 min and 1.21 (95% CI 0.88 to 1.65) for 181–270 min. All were in favour of the tenecteplase group. Meta-analysis of 2949 patients yielded a pooled risk difference of 5.54 (95% CI −0.18 to 11.26; p=0.82) in favour of tenecteplase for more than 180 min and 1.77 (95% CI −2.66 to 6.20; p=0.58) for 0–180 min.ConclusionsIn AIS patients who were treated with either tenecteplase or alteplase within 4.5 hours onset, there was no difference observed in the efficacy and safety between the two groups at the three different OTT time intervals.
Prevalence and Correlates of Post-Diagnosis Alcohol Use among Cancer Survivors
Authors: Heffner Jaimee L. , Ton Mimi , Jones Salene M.W. , Malen Rachel C. , Cohen Stacey A. , Newcomb Polly A. 
Published: January 2024

Abstract

Background:
Alcohol is a risk factor for cancer and may pose unique risks for cancer survivors. Population-based studies of confirmed cancer cases are needed to estimate the extent of drinking among cancer survivors and to understand which survivors are most at risk of alcohol-related health problems.

Methods:
Cancer survivors who resided in the Puget Sound Surveillance, Epidemiology, and End Results (SEER) region, were ages 21 to 74 years at diagnosis, and were 6 to 17 months post-diagnosis at the start of the recruitment period (April 2020–December 2020) were sent a survey that included demographics, substance use, mental health, and cancer-related items. Data from returned surveys (n = 1,488) were weighted to represent the characteristics of the Puget Sound SEER region. We estimated the prevalence of post-diagnosis alcohol use as well as demographic, behavioral, and clinical correlates of three levels of drinking: any drinking, drinking exceeding cancer prevention guidelines, and hazardous drinking.

Results:
The weighted prevalence of any drinking, drinking exceeding cancer prevention guidelines, and hazardous drinking was 71%, 46.2%, and 31.6%, respectively. Higher income and cannabis use were associated with increased odds of all three drinking levels. Lower physical health quality of life, having non-colorectal gastrointestinal cancer, and receiving chemotherapy within the last month were associated with decreased odds of all three drinking levels.

Conclusions:
The prevalence of any drinking and at-risk drinking was higher than in previous studies and differed based on sociodemographic, substance use, and cancer-related factors.

Impact:
Findings highlight the importance of identifying and addressing risky alcohol use in cancer care settings.
Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams–Beuren Syndrome
Authors: Liu Delong , Billington Charles J. , Raja Neelam , Wong Zoe C. , Levin Mark D. , Resch Wulfgang , Alba Camille , Hupalo Daniel N. , Biamino Elisa , Bedeschi Maria Francesca , Digilio Maria Cristina , Squeo Gabriella Maria , Villa Roberta , Parrish Pheobe C. R. , Knutsen Russell H. , Osgood Sharon , Freeman Joy A. , Dalgard Clifton L. , Merla Giuseppe , Pober Barbara R. , Mervis Carolyn B. , Roberts Amy E. , Morris Colleen A. , Osborne Lucy R. , Kozel Beth A. 
Published: January 2024

Background
Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams–Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams–Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability.

Methods and Results

We performed genome sequencing on 473 individuals with Williams–Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway‐level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome‐wide association studies. We show that SVAS severity in Williams–Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (
ACAN
and
LTBP4
) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome‐wide association studies for aneurysm, bicuspid aortic valve, or aortic size.

Conclusions
Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta‐focused genome‐wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.
Impact of Cardiac Rehabilitation Health Insurance Coverage on Cardiac Rehabilitation Use in Korea Using an Interrupted Time Series
Authors: Park Yu Shin , Song In Sun , Jang Suk‐Yong , Nam Chung Mo , Park Eun‐Cheol 
Published: January 2024

Background
Since 2017, the cardiac rehabilitation (CR) program in Korea has been included in the coverage provided by the National Health Insurance to alleviate financial burden. Our study aimed to identify changes in the CR program use according to the implementation of CR coverage.

Methods and Results
We obtained data from the electronic medical records of a tertiary hospital in Seoul, Korea from January 2014 to February 2020. Data from 2988 patients with acute coronary syndrome who underwent percutaneous coronary intervention were included. To examine the CR use trend among patients undergoing percutaneous coronary intervention, the electronic medical records data of the patients were aggregated quarterly, resulting in a maximum of 24 repeated measures for each patient. Segmented regression is often used to estimate the effects of interventions in an interrupted time series. Policy implementation led to a prompt increase in the probability of CR use (odds ratio [OR], 3.99 [95% CI, 2.89–5.51]). After the implementation of CR coverage, no significant change in CR use (OR, 0.97 [95% CI, 0.92–1.01]) was observed. After percutaneous coronary intervention, more patients opted for CR, especially those receiving education compared with exercise (education: OR, 87.44 [95% CI, 36.79–207.83] versus exercise: OR, 1.99 [95% CI, 1.43–2.76]).

Conclusions
The implementation of CR coverage resulted in a rapid increase in the probability of CR use. Use of the educational program was higher than that of the exercise program. Given the persistently low use of CR, it is imperative to stimulate its adoption by increasing its availability.
Treatment of Acute Myocardial Infarction and Cardiogenic Shock: Outcomes of the RECOVER III Postapproval Study by Society of Cardiovascular Angiography and Interventions Shock Stage
Authors: Hanson Ivan D. , Rusia Akash , Palomo Andres , Tawney Adam , Pow Timothy , Dixon Simon R. , Meraj Perwaiz , Sievers Eric , Johnson Michael , Wohns David , Ali Omar , Kapur Navin K. , Grines Cindy , Burkhoff Daniel , Anderson Mark , Lansky Alexandra , Naidu Srihari S. , Basir Mir B. , O'Neill William 
Published: January 2024

Background
The Society for Cardiovascular Angiography and Interventions proposed a staging system (A–E) to predict prognosis in cardiogenic shock. Herein, we report clinical outcomes of the RECOVER III study for the first time, according to Society for Cardiovascular Angiography and Interventions shock classification.

Methods and Results

The RECOVER III study is an observational, prospective, multicenter, single‐arm, postapproval study of patients with acute myocardial infarction with cardiogenic shock undergoing percutaneous coronary intervention with Impella support. Patients enrolled in the RECOVER III study were assigned a baseline Society for Cardiovascular Angiography and Interventions shock stage. Staging was then repeated within 24 hours after initiation of Impella. Kaplan‐Meier survival curve analyses were conducted to assess survival across Society for Cardiovascular Angiography and Interventions shock stages at both time points. At baseline assessment, 16.5%, 11.4%, and 72.2% were classified as stage C, D, and E, respectively. At ≤24‐hour assessment, 26.4%, 33.2%, and 40.0% were classified as stage C, D, and E, respectively. Thirty‐day survival among patients with stage C, D, and E shock at baseline was 59.7%, 56.5%, and 42.9%, respectively (
P
=0.003). Survival among patients with stage C, D, and E shock at ≤24 hours was 65.7%, 52.1%, and 29.5%, respectively (
P
<0.001). After multivariable analysis of impact of shock stage classifications at baseline and ≤24 hours, only stage E classification at ≤24 hours was a significant predictor of mortality (odds ratio, 4.8;
P
<0.001).

Conclusions
In a real‐world cohort of patients with acute myocardial infarction with cardiogenic shock undergoing percutaneous coronary intervention with Impella support, only stage E classification at ≤24 hours was significantly predictive of mortality, suggesting that response to therapy may be more important than clinical severity of shock at presentation.
Longitudinal Lipidomic Signature of Coronary Heart Disease in American Indian People
Authors: Miao Guanhong , Pechlaner Raimund , Fiehn Oliver , Malloy Kimberly M. , Zhang Ying , Umans Jason G. , Mayr Manuel , Willeit Johann , Kiechl Stefan , Zhao Jinying 
Published: January 2024

Background
Dyslipidemia is an independent risk factor for coronary heart disease (CHD). Standard lipid panel cannot capture the complexity of the blood lipidome (ie, all molecular lipids in the blood). To date, very few large‐scale epidemiological studies have assessed the full spectrum of the blood lipidome on risk of CHD, especially in a longitudinal setting.

Methods and Results
Using an untargeted liquid chromatography–mass spectrometry, we repeatedly measured 1542 lipid species from 1835 unique American Indian participants who attended 2 clinical visits (≈5.5 years apart) and followed up to 17.8 years in the Strong Heart Family Study (SHFS). We first identified baseline lipid species associated with risk of CHD, followed by replication in a European population. The model adjusted for age, sex, body mass index, smoking, hypertension, diabetes, low‐density lipoprotein cholesterol, estimated glomerular filtration rate, education, and physical activity at baseline. We then examined the longitudinal association between changes in lipid species and changes in cardiovascular risk factors during follow‐up. Multiple testing was controlled by the false discovery rate. We found that baseline levels of multiple lipid species (eg, phosphatidylcholines, phosphatidylethanolamines, and ceramides) were associated with the risk of CHD and improved the prediction accuracy over conventional risk factors in American Indian people. Some identified lipids in American Indian people were replicated in European people. Longitudinal changes in multiple lipid species (eg, acylcarnitines, phosphatidylcholines, and triacylglycerols) were associated with changes in cardiovascular risk factors.

Conclusions
Baseline plasma lipids and their longitudinal changes over time are associated with risk of CHD. These findings provide novel insights into the role of dyslipidemia in CHD.
Associations of Lifelong Exercise Characteristics With Valvular Function and Aortic Diameters in Patients With a Bicuspid Aortic Valve
Authors: Schreurs Bibi A. , Hopman Maria T. E. , Bakker Chantal M. , Duijnhouwer Anthonie L. , van Royen Niels , Thompson Paul D. , van Kimmenade Roland R. J. , Eijsvogels Thijs M. H. 
Published: January 2024

Background
The potential impact of exercise on valvular function and aortic diameters in patients with a bicuspid aortic valve remains unclear. Therefore, we assessed the association between lifelong exercise characteristics, valvular dysfunction, and aortic dilatation in patients with a bicuspid aortic valve.

Methods and Results

In this cross‐sectional study, exercise volume (metabolic equivalent of task minutes per week), exercise intensity, and sport type were determined from the age of 12 years to participation using a validated questionnaire. Echocardiography was used to assess aortic stenosis or aortic regurgitation and to measure diameters at the sinuses of Valsalva and ascending aorta. Aortic dilatation was defined as a
Z
‐score ≥2. Four hundred and seven patients (42±17 years, 60% men) were included, of which 133 were sedentary (<500 metabolic equivalent of task minutes per week), 94 active (500–1000 metabolic equivalent of task minutes per week), and 180 highly active (≥1000 metabolic equivalent of task minutes per week). Moderate‐to‐severe aortic stenosis or aortic regurgitation was present in 23.7% and 20.0%, respectively. Sinuses of Valsalva and ascending aorta diameters were 34.8±6.6 and 36.5±8.1 mm, whereas aortic dilatation was found in 21.6% and 53.4%, respectively. Exercise volume was not associated with valve dysfunction or aortic dilatation. Vigorous intensity and mixed sports were associated with a lower prevalence of aortic stenosis (adjusted odds ratios, 0.43 [0.20–0.94] and adjusted odds ratios, 0.47 [0.23–0.95]). Exercise intensity and sport type were not associated with aortic regurgitation and aortic dilatation.

Conclusions
We found no deleterious associations between lifelong exercise characteristics, valvular dysfunction, and aortic dilatation in patients with a bicuspid aortic valve. Vigorous intensity and exercise in mixed sports were associated with a lower prevalence of moderate‐to‐severe aortic stenosis. These observations suggest that lifelong exercise does not appear to induce adverse cardiovascular effects in patients with a bicuspid aortic valve.