bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loeys-Dietz and Shprintzen-Goldberg syndromes: analysis of TGF-β-opathies with craniofacial manifestations using an innovative multimodality method
Authors: Almpani Konstantinia , Liberton Denise K. , Jani Priyam , Keyvanfar Cyrus , Mishra Rashmi , Curry Natasha , Orzechowski Pamela , Frischmeyer-Guerrerio Pamela A. , Lee Janice S. 
Published: December 2021

BackgroundElevated transforming growth factor-beta (TGF-β) signalling has been implicated in the pathogenesis of Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS). In this study, we provide a qualitative and quantitative analysis of the craniofacial and functional features among the LDS subtypes and SGS.MethodsWe explore the variability within and across a cohort of 44 patients through deep clinical phenotyping, three-dimensional (3D) facial photo surface analysis, cephalometric and geometric morphometric analyses of cone-beam CT scans.ResultsThe most common craniofacial features detected in this cohort include mandibular retrognathism (84%), flat midface projection (84%), abnormal eye shape (73%), low-set ears (73%), abnormal nose (66%) and lip shape (64%), hypertelorism (41%) and a relatively high prevalence of nystagmus/strabismus (43%), temporomandibular joint disorders (38%) and obstructive sleep apnoea (23%). 3D cephalometric analysis demonstrated an increased cranial base angle with shortened anterior cranial base and underdevelopment of the maxilla and mandible, with evidence of a reduced pharyngeal airway in 55% of those analysed. Geometric morphometric analysis confirmed that the greatest craniofacial shape variation was among patients with LDS type 2, with distinct clustering of patients with SGS.ConclusionsThis comprehensive phenotypic approach identifies developmental abnormalities that segregate to mutation variants along the TGF-β signalling pathway, with a particularly severe phenotype associated with TGFBR2 and SKI mutations. Multimodality assessment of craniofacial anomalies objectively reveals the impact of mutations of the TGF-β pathway with perturbations associated with the cranium and cranial base with severe downstream effects on the orbit, maxilla and mandible with the resultant clinical phenotypes.
Impact of pathogenicFBN1variant types on the development of severe scoliosis in patients with Marfan syndrome
Authors: Taniguchi Yuki , Takeda Norifumi , Inuzuka Ryo , Matsubayashi Yoshitaka , Kato So , Doi Toru , Yagi Hiroki , Yamauchi Haruo , Ando Masahiko , Oshima Yasushi , Tanaka Sakae 
Published: December 2021

BackgroundAmong the several musculoskeletal manifestations in patients with Marfan syndrome, spinal deformity causes pain and respiratory impairment and is a great hindrance to patients’ daily activities. The present study elucidates the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome.MethodsWe retrospectively evaluated 278 patients with pathogenic or likely pathogenicFBN1variants. The patients were divided into those with (n=57) or without (n=221) severe scoliosis. Severe scoliosis was defined as (1) patients undergoing surgery before 50 years of age or (2) patients with a Cobb angle exceeding 50° before 50 years of age. The variants were classified as protein-truncating variants (PTVs), which included variants creating premature termination codons and inframe exon-skipping, or non-PTVs, based on their location and predicted amino acid alterations, and the effect of theFBN1genotype on the development of severe scoliosis was examined. The impact of location ofFBN1variants on the development of severe scoliosis was also investigated.ResultsUnivariate and multivariate analyses revealed that female sex, PTVs ofFBN1and variants in the neonatal region (exons 25–33) were all independent significant predictive factors for the development of severe scoliosis. Furthermore, these factors were identified as predictors of progression of existing scoliosis into severe state.ConclusionsWe elucidated the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome. Patients harbouring pathogenicFBN1variants with these genetic risk factors should be monitored carefully for scoliosis progression.
Clinical characteristics and risk factors for survival in affected offspring of von Hippel-Lindau disease patients
Authors: Zhang Kenan , Qiu Jianhui , Yang Wuping , Ma Kaifang , Li Lei , Xie Haibiao , Xu Yawei , Gong Yanqing , Zhou Jingcheng , Cai Lin , Gong Kan 
Published: December 2021

BackgroundVon Hippel-Lindau (VHL) disease is an autosomal dominant genetic tumour syndrome with poor prognosis. The clinical manifestation was found to be more serious in affected offspring of patients with VHL disease, but the risk factors and survival for them have never been reported before. We aimed to explore how these patients were influenced by genetic and clinical factors.MethodsIn this retrospective study, we collected 372 affected offspring of VHL patients from 118 unrelated VHL families. Patients were stratified into different groups based on sets of variables. The age-related risk, overall survival and central nervous systemhaemangioblastoma (CHB)-specific survival were analysed between different groups using Kaplan-Meier survival analysis and Cox regression analysis.ResultsThe estimated median life expectancy and median age of onset for affected offspring of VHL patients were 66 years and 28 years, respectively. The later generation and patients with mutations in exon 3 had an earlier onset age. The first presenting symptom was the only independent risk factor influencing overall survival and CHB-specific survival. Patients that the first presenting symptom is central nervous system (CNS) significantly had a lower life expectancy both in overall survival and CHB-specific survival analysis than abdominal lesions group.ConclusionThis study indicated that affected offspring of VHL patients with CNS as the first presenting symptom was an independent risk factor for overall survival and CHB-specific survival. Generation and mutation region only had an effect on the onset age, which is helpful to clinical decision-making and generate a more precise surveillance protocol.
Integrating vocational rehabilitation and mental healthcare to improve the return-to-work process for people on sick leave with depression or anxiety: results from a three-arm, parallel randomised trial
Authors: Hoff Andreas , Poulsen Rie Mandrup , Fisker Jonas , Hjorthøj Carsten , Rosenberg Nicole , Nordentoft Merete , Bojesen Anders Bo , Eplov Lene Falgaard 
Published: December 2021

ObjectiveThe aim of this study was to investigate an integrated mental healthcare and vocational rehabilitation intervention to improve and hasten the process of return-to-work of people on sick leave with anxiety and depression.MethodsIn this three-arm, randomised trial, participants were assigned to (1) integrated intervention (INT), (2) improved mental healthcare (MHC) or (3) service as usual (SAU). The primary outcome was time to return-to-work measured at 12-month follow-up. The secondary outcomes were time to return-to-work measured at 6-month follow-up; levels of anxiety, depression, stress symptoms, and social and occupational functioning at 6 months; and return-to-work measured as proportion in work at 12 months.Results631 individuals were randomised. INT yielded a higher proportion in work compared with both MHC (56.2% vs 43.7%, p=0.012) and SAU (56.2% vs 45%, p=0.029) at 12-month follow-up. We found no differences in return-to-work in terms of sick leave duration at either 6-month or 12-month follow-up, with the latter being the primary outcome. No differences in anxiety, depression or functioning between INT, MHC and SAU were identified, but INT and MHC showed lower scores on Cohen’s Perceived Stress Scale compared with SAU at 6-month follow-up.ConclusionsAlthough INT did not hasten the process of return-to-work, it yielded better outcome with regard to proportion in work compared with MHC and SAU. The findings suggest that INT compared with SAU is associated with a few, minor health benefits. Overall, INT yielded slightly better vocational and health outcomes, but the clinical significance of the health advantage is questionable.Trial registration numberNCT02872051.
Purely leptonic decays of the ground charged vector mesons
Authors: Yang Yueling , Li Zhenglin , Li Kang , Huang Jinshu , Sun Junfeng 
Published: December 2021

AbstractThe study of the purely leptonic decays of the ground charged vector mesons is very interesting and significant in determining the CKM matrix elements, obtaining the decay constant of vector mesons, examining the lepton flavor universality, and searching for new physics beyond the standard model. These purely leptonic decays of the ground charged vector mesons are induced by the weak interactions within the standard model, and usually have very small branching ratios, $$\mathcal{B}({\rho }^{-}{\rightarrow }{\ell }^{-}{\nu }_{\ell })$$

B
(

ρ

-

→

ℓ

-

ν
ℓ

)

$${\sim }$$
∼
$$\mathcal{O}(10^{-13})$$

O
(

10

-
13

)

, $${{{\mathcal {B}}}}(K^{{*}-}{\rightarrow }{\ell }^{-}{\nu }_{\ell })$$

B
(

K

∗

-

→

ℓ

-

ν
ℓ

)

$${\sim }$$
∼
$${{{\mathcal {O}}}}(10^{-13})$$

O
(

10

-
13

)

, $$\mathcal{B}(D_{d}^{{*}-}{\rightarrow }{\ell }^{-}{\nu }_{\ell })$$

B
(

D

d

∗

-

→

ℓ

-

ν
ℓ

)

$${\sim }$$
∼
$$\mathcal{O}(10^{-10})$$

O
(

10

-
10

)

, $$\mathcal{B}(B_{u}^{{*}-}{\rightarrow }{\ell }^{-}{\nu }_{\ell })$$

B
(

B

u

∗

-

→

ℓ

-

ν
ℓ

)

$${\sim }$$
∼
$$\mathcal{O}(10^{-10})$$

O
(

10

-
10

)

, $$\mathcal{B}(D_{s}^{{*}-}{\rightarrow }{\ell }^{-}{\nu }_{\ell })$$

B
(

D

s

∗

-

→

ℓ

-

ν
ℓ

)

$${\sim }$$
∼
$$\mathcal{O}(10^{-6})$$

O
(

10

-
6

)

and $$\mathcal{B}(B_{c}^{{*}-}{\rightarrow }{\ell }^{-}{\nu }_{\ell })$$

B
(

B

c

∗

-

→

ℓ

-

ν
ℓ

)

$${\sim }$$
∼
$$\mathcal{O}(10^{-6})$$

O
(

10

-
6

)

. Inspired by the potential prospects of LHCb, Belle-II, STCF, CEPC and FCC-ee experiments, we discussed the probabilities of experimental investigation on these purely leptonic decays. It is found that the measurements of these decays might be possible and feasible with the improvement of data statistics, analytical technique, and measurement precision in the future. (1) With the hadron-hadron collisions, the purely leptonic decays of $${\rho }^{-}$$

ρ

-

, $$K^{{*}-}$$

K

∗

-

, $$D_{d,s}^{{*}-}$$

D

d
,
s

∗

-

and $$B_{u,c}^{{*}-}$$

B

u
,
c

∗

-

mesons might be accessible at LHC experiments. (2) With the $$e^{+}e^{-}$$

e
+

e
-

collisions, the purely leptonic decays of $$D_{d,s}^{{*}-}$$

D

d
,
s

∗

-

and $$B_{u,c}^{{*}-}$$

B

u
,
c

∗

-

mesons might be measurable with over $$10^{12}$$

10
12

$$Z^{0}$$

Z
0

bosons available at CEPC and FCC-ee experiments. In addition, the $$D_{d,s}^{{*}-}$$

D

d
,
s

∗

-

$${\rightarrow }$$
→
$${\ell }^{-}{\nu }_{\ell }$$

ℓ

-

ν
ℓ

decays could also be studied at Belle-II and SCTF experiments.
Global mass-preserving solutions to a chemotaxis-fluid model involving Dirichlet boundary conditions for the signal
Authors: Wang Yulan , Winkler Michael , Xiang Zhaoyin 
Published: December 2021

The chemotaxis-Stokes system [Formula: see text] is considered subject to the boundary condition [Formula: see text] with [Formula: see text] and a given nonnegative function [Formula: see text].In contrast to the well-studied case when the second requirement herein is replaced by a homogeneous Neumann boundary condition for [Formula: see text], the Dirichlet condition imposed here seems to destroy a natural energy-like property that has formed a core ingredient in the literature by providing comprehensive regularity features of the latter problem. This paper attempts to suitably cope with accordingly poor regularity information in order to nevertheless derive a statement on global existence within a generalized framework of solvability which involves appropriately mild requirements on regularity, but which maintains mass conservation in the first component as a key solution property.
Nobiletin Prevents High-Fat Diet-Induced Dysregulation of Intestinal Lipid Metabolism and Attenuates Postprandial Lipemia
Authors: Morrow Nadya M. , Trzaskalski Natasha A. , Hanson Antonio A. , Fadzeyeva Evgenia , Telford Dawn E. , Chhoker Sanjiv S. , Sutherland Brian G. , Edwards Jane Y. , Huff Murray W. , Mulvihill Erin E. 
Published: December 2021

Objective:
Nobiletin is a dietary flavonoid that improves insulin resistance and atherosclerosis in mice with metabolic dysfunction. Dysregulation of intestinal lipoprotein metabolism contributes to atherogenesis. The objective of the study was to determine if nobiletin targets the intestine to improve metabolic dysregulation in both male and female mice.

Approach and Results:

Triglyceride-rich lipoprotein (TRL) secretion, intracellular triglyceride kinetics, and intestinal morphology were determined in male and female LDL (low-density lipoprotein) receptor knockout (

Ldlr
–/–

), and male wild-type mice fed a standard laboratory diet or high-fat, high-cholesterol (HFHC) diet ± nobiletin using an olive oil gavage, radiotracers, and electron microscopy. Nobiletin attenuated postprandial TRL levels in plasma and enhanced TRL clearance. Nobiletin reduced fasting jejunal triglyceride accumulation through accelerated TRL secretion and lower jejunal fatty acid synthesis with no impact on fatty acid oxidation. Fasting-refeeding experiments revealed that nobiletin led to higher levels of phosphorylated AKT (protein kinase B) and FoxO1 (forkhead box O1) and normal Srebf1c expression indicating increased insulin sensitivity. Intestinal length and weight were diminished by HFHC feeding and restored by nobiletin. Both fasting and postprandial plasma GLP-1 (glucagon-like peptide-1; and likely GLP-2) were elevated in response to nobiletin. Treatment with a GLP-2 receptor antagonist, GLP-2(3-33), reduced villus length in HFHC-fed mice but did not impact TRL secretion in any diet group. In contrast to males, nobiletin did not improve postprandial lipid parameters in female mice.

Conclusions:
Nobiletin opposed the effects of the HFHC diet by normalizing intestinal de novo lipogenesis through improved insulin sensitivity. Nobiletin prevents postprandial lipemia because the enhanced TRL clearance more than compensates for increased TRL secretion.
Detection of Left Atrial Myopathy Using Artificial Intelligence–Enabled Electrocardiography
Authors: Verbrugge Frederik H. , Reddy Yogesh N.V. , Attia Zachi I. , Friedman Paul A. , Noseworthy Peter A. , Lopez-Jimenez Francisco , Kapa Suraj , Borlaug Barry A. 
Published: December 2021

Background:
Left atrial (LA) myopathy is common in patients with heart failure and preserved ejection fraction and leads to the development of atrial fibrillation (AF). We investigated whether the likelihood of LA remodeling, LA dysfunction, altered hemodynamics, and risk for incident AF could be identified from a single 12-lead ECG using a novel artificial intelligence (AI)-enabled ECG analysis.

Methods:
Patients with heart failure and preserved ejection fraction (n=613) underwent AI-enabled ECG analysis, echocardiography, and cardiac catheterization. Individuals were grouped by AI-enabled ECG probability of contemporaneous AF, taken as an indicator of underlying LA myopathy.

Results:

Structural heart disease was more severe in patients with higher AI-probability of AF, with more left ventricular hypertrophy, larger LA volumes, and lower LA reservoir and booster strain. Cardiac filling pressures and pulmonary artery pressures were higher in patients with higher AI-probability, while cardiac output reserve was more impaired during exercise. Among patients with sinus rhythm and no prior AF, each 10% increase in AI-probability was associated with a 31% greater risk of developing new-onset AF (hazard ratio, 1.31 [95% CI, 1.20–1.42];
P
<0.001). In the population as a whole, each 10% increase in AI-probability was associated with a 12% greater risk of death (hazard ratio, 1.12 [95% CI, 1.08–1.17];
P
<0.001) during long-term follow-up, which was no longer significant after adjustments for baseline characteristics.

Conclusions:
A novel AI-enabled score derived from a single 12-lead ECG identifies the presence of underlying LA myopathy in patients with heart failure and preserved ejection fraction as evidenced by structural, functional, and hemodynamic abnormalities, as well as long-term risk for incident AF. Further research is required to determine the role of the AI-enabled ECG in the evaluation and care of patients with heart failure and preserved ejection fraction.
DREAM-ICD-II Study
Authors: Steinberg Christian , Dognin Nicolas , Sodhi Amit , Champagne Catherine , Staples John A. , Champagne Jean , Laksman Zachary W. , Sarrazin Jean-François , Bennett Matthew T. , Plourde Benoit , Deyell Marc W. , Andrade Jason G. , Roy Karine , Yeung-Lai-Wah John A. , Hawkins Nathaniel M. , Mondésert Blandine , Blier Louis , Nault Isabelle , O’Hara Gilles , Krahn Andrew D. , Philippon François , Chakrabarti Santabhanu 
Published: December 2021

Background:
Regulatory authorities of most industrialized countries recommend 6 months of private driving restriction after implantation of a secondary prevention implantable cardioverter-defibrillator (ICD). These driving restrictions result in significant inconvenience and social implications. This study aimed to assess the incidence rate of appropriate device therapies in contemporary recipients of a secondary prevention ICD.

Methods:
This retrospective study at 3 Canadian tertiary care centers enrolled consecutive patients with new secondary prevention ICD implants between 2016 and 2020.

Results:

For a median of 760 days (324, 1190 days), 721 patients were followed up. The risk of recurrent ventricular arrhythmia was highest during the first 3 months after device insertion (34.4%) and decreased over time (10.6% between 3 and 6 months, 11.7% between 6 and 12 months). The corresponding incidence rate per 100 patient-days was 0.48 (95% CI, 0.35–0.64) at 90 days, 0.28 (95% CI, 0.17–0.45) at 180 days, and 0.21 (95% CI, 0.13–0.33) between 181 and 365 days after ICD insertion (
P
<0.001). The cumulative incidence of arrhythmic syncope resulting in sudden cardiac incapacitation was 1.8% within the first 90 days and subsequently dropped to 0.4% between 91 and 180 days (
P
<0.001) after ICD insertion.

Conclusions:
The incidence rate of appropriate therapies resulting in sudden cardiac incapacitation in contemporary recipients of a secondary prevention ICD is much lower than previously reported and declines significantly after the first 3 months. Lowering driving restrictions to 3 months after the index cardiac event seems safe, and revision of existing guidelines should be considered in countries still adhering to a 6-month period. Existing restrictions for private driving after implantation of a secondary prevention ICD should be reconsidered.
Familial Segregation of Venous Thromboembolism in Sweden: A Nationwide Family Study of Heritability and Complex Segregation Analysis
Authors: Zöller Bengt , Pirouzifard MirNabi , Svensson Peter J. , Holmquist Björn , Stenman Emelie , Elston Robert C. , Song Yeunjoo E. , Sundquist Jan , Sundquist Kristina 
Published: December 2021

Background
This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance.

Methods and Results
The Swedish Multi‐Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish‐born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64‐bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major‐type‐only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred.

Conclusions
This nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance.
Pragmatism and the Importance of Truth
Authors: Piacente Albert 
Published: December 2021

Abstract
This paper develops a position I call “apathetic pragmatism.” Apathetic pragmatism is a form of pragmatism that, through advocating “apathy” about the topic of truth, avoids the troubled identification of utility and truth found in classical and neo pragmatist theories of truth. Initially explored by Stephen Stich, I argue Stich’s case for apathetic pragmatism relies upon a theory of truth that causes vicious circularity. I then pursue a different route to apathetic pragmatism, one that sees apathetic pragmatism as a “paradigm shift” in relation to previous forms of pragmatism. It is a paradigm shift where pragmatism becomes a normative view concerning the questions that are necessary to ask, not an attempt to answer questions assumed necessary.
Evaluation of Imminent Take-Over Requests With Real Automation on a Test Track
Authors: Wintersberger Philipp , Schartmüller Clemens , Sadeghian Shadan , Frison Anna-Katharina , Riener Andreas 
Published: December 2021

Objective Investigating take-over, driving, non-driving related task (NDRT) performance, and trust of conditionally automated vehicles (AVs) in critical transitions on a test track. Background Most experimental results addressing driver take-over were obtained in simulators. The presented experiment aimed at validating relevant findings while uncovering potential effects of motion cues and real risk. Method Twenty-two participants responded to four critical transitions on a test track. Non-driving related task modality (reading on a handheld device vs. auditory) and take-over timing (cognitive load) were varied on two levels. We evaluated take-over and NDRT performance as well as gaze behavior. Further, trust and workload were assessed with scales and interviews. Results Reaction times were significantly faster than in simulator studies. Further, reaction times were only barely affected by varying visual, physical, or cognitive load. Post-take-over control was significantly degraded with the handheld device. Experiencing the system reduced participants’ distrust, and distrusting participants monitored the system longer and more frequently. NDRTs on a handheld device resulted in more safety-critical situations. Conclusion The results confirm that take-over performance is mainly influenced by visual-cognitive load, while physical load did not significantly affect responses. Future take-over request (TOR) studies may investigate situation awareness and post-take-over control rather than reaction times only. Trust and distrust can be considered as different dimensions in AV research. Application Conditionally AVs should offer dedicated interfaces for NDRTs to provide an alternative to using nomadic devices. These interfaces should be designed in a way to maintain drivers’ situation awareness. Précis This paper presents a test track experiment addressing conditionally automated driving systems. Twenty-two participants responded to critical TORs, where we varied NDRT modality and take-over timing. In addition, we assessed trust and workload with standardized scales and interviews.