bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in cerebellar output abnormally modulate cortical myoclonus sensorimotor hyperexcitability
Authors: Latorre Anna , Rocchi Lorenzo , Paparella Giulia , Manzo Nicoletta , Bhatia Kailash P , Rothwell John C 
Published: November 2023

Abstract
Cortical myoclonus is produced by abnormal neuronal discharges within the sensorimotor cortex, as demonstrated by electrophysiology. Our hypothesis is that the loss of cerebellar inhibitory control over the motor cortex, via cerebello-thalamo-cortical connections, could induce the increased sensorimotor cortical excitability that eventually causes cortical myoclonus. To explore this hypothesis, in the present study we applied anodal transcranial direct current stimulation over the cerebellum of patients affected by cortical myoclonus and healthy controls and assessed its effect on sensorimotor cortex excitability. We expected that anodal cerebellar transcranial direct current stimulation would increase the inhibitory cerebellar drive to the motor cortex and therefore reduce the sensorimotor cortex hyperexcitability observed in cortical myoclonus.
Ten patients affected by cortical myoclonus of various aetiology and 10 aged-matched healthy control subjects were included in the study. All participants underwent somatosensory evoked potentials, long-latency reflexes and short-interval intracortical inhibition recording at baseline and immediately after 20 min session of cerebellar anodal transcranial direct current stimulation. In patients, myoclonus was recorded by the means of surface EMG before and after the cerebellar stimulation.
Anodal cerebellar transcranial direct current stimulation did not change the above variables in healthy controls, while it significantly increased the amplitude of somatosensory evoked potential cortical components, long-latency reflexes and decreased short-interval intracortical inhibition in patients; alongside, a trend towards worsening of the myoclonus after the cerebellar stimulation was observed. Interestingly, when dividing patients in those with and without giant somatosensory evoked potentials, the increment of the somatosensory evoked potential cortical components was observed mainly in those with giant potentials.
Our data showed that anodal cerebellar transcranial direct current stimulation facilitates—and does not inhibit—sensorimotor cortex excitability in cortical myoclonus syndromes. This paradoxical response might be due to an abnormal homeostatic plasticity within the sensorimotor cortex, driven by dysfunctional cerebello-thalamo-cortical input to the motor cortex. We suggest that the cerebellum is implicated in the pathophysiology of cortical myoclonus and that these results could open the way to new forms of treatment or treatment targets.
The Steatosis-Associated Fibrosis Estimator (SAFE) score for assessing significant liver fibrosis in patients with psoriasis
Authors: Chularojanamontri Leena , Panjapakkul Waratchaya , Paringkarn Teerapat , Hutachoke Thrit , Chaiyabutr Chayada , Silpa-archa Narumol , Wongpraparut Chanisada , Bandidniyamanon Wimolrak , Charatcharoenwitthaya Phunchai 
Published: November 2023

Abstract

Background
There is an urgent need for noninvasive tests to identify patients with psoriasis at risk of significant liver fibrosis.

Objectives
To externally validate the ability of the Steatosis-Associated Fibrosis Estimator (SAFE) score to detect significant liver fibrosis in patients with psoriasis using transient elastography (TE) as a reference.

Methods
We analysed data from 75 patients with psoriasis, including TE, SAFE score, Fibrosis-4 Index (FIB-4) and Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS). Significant liver fibrosis was defined as TE values ≥ 7.1 kPa. Diagnostic accuracy was assessed using the area under the receiver operating characteristic curve (AUROC).

Results
Fifteen patients (20%) exhibited significant liver fibrosis. The AUROCs for the SAFE and FIB-4 scores were 0.82 [95% confidence interval (CI) 0.67–0.97] and 0.62 (95% CI 0.45–0.79), respectively. The SAFE score outperformed the FIB-4 Index (P = 0.01) but was comparable with the NFS (P = 0.05) in predicting significant fibrosis. Using thresholds of &lt; 0, 0 to &lt; 100 and ≥ 100, the SAFE score categorized 36, 24 and 15 patients into low, intermediate and high-risk groups for significant fibrosis, respectively. The negative predictive value for excluding significant fibrosis with a SAFE score of &lt; 0 was 94.4%, and the positive predictive value for diagnosing significant fibrosis with a SAFE score of &gt; 100 was 53.3%. The duration of psoriasis, joint involvement and methotrexate treatment did not affect the diagnostic ability of the SAFE score whereas age of the patient did.

Conclusions
The SAFE score demonstrated good accuracy in assessing clinically significant fibrosis among patients with psoriasis. This score should prove valuable for risk stratification and patient management in dermatology practice.
Neuromelanin-sensitive MRI of the substantia nigra distinguishes bipolar from unipolar depression
Authors: Kuai Xinping , Shao Dandan , Wang Shengyu , Wu Pu-Yeh , Wu Yan , Wang Xuexue 
Published: November 2023

Abstract
Depression in bipolar disorder (BD-II) is frequently misdiagnosed as unipolar depression (UD) leading to inappropriate treatment and downstream complications for many bipolar sufferers. In this study, we evaluated whether neuromelanin-MR signal and volume changes in the substantia nigra (SN) can be used as potential biomarkers to differentiate BD-II from UD. The signal intensities and volumes of the SN regions were measured, and contrast-to-noise ratio (CNR) to the decussation of the superior cerebellar peduncles were calculated and compared between healthy controls (HC), BD-II and UD subjects. Results showed that compare to HC, both BD-II and UD subjects had significantly decreased CNR and increased volume on the right and left sides. Moreover, the volume in BD-II group was significantly increased compared to UD group. The area under the receiver operating characteristic curve (AUC) for discriminating BD from HC was the largest for the Volume-L (AUC, 0.85; 95% confidence interval [CI]: 0.77, 0.93). The AUC for discriminating UD from HC was the largest for the Volume-L (AUC, 0.76; 95% CI: 0.65, 0.86). Furthermore, the AUC for discriminating BD from UD was the largest for the Volume-R (AUC, 0.73; 95% CI: 0.62, 0.84). Our findings suggest that neuromelanin-sensitive magnetic resonance imaging techniques can be used to differentiate BD-II from UD.
STREI: a new index of right heart function in isolated severe tricuspid regurgitation by speckle-tracking echocardiography
Authors: Hinojar Rocio , Fernández-Golfín Covadonga , González Gómez Ariana , García-Martin Ana , Monteagudo Juan Manuel , García Lunar Inés , García Sebastian Cristina , Pardo Ana , Sanchez Recalde Angel , Zamorano Jose Luis 
Published: November 2023

Abstract

Aims
Right ventricular (RV) performance determines clinical management in severe tricuspid regurgitation (TR). Right atrial (RA) function complements RV assessment in TR. This study aimed to design a novel index by speckle-tracking echocardiography (STREI index) integrating RA and RV strain information and to evaluate the clinical utility of combining RV and RA strain for prediction of cardiovascular (CV) outcomes.

Methods and results
Consecutive patients with at least (≥) severe TR evaluated in the Heart Valve Clinic (n = 300) were prospectively included. An additional independent TR cohort was included for external validation (n = 50). STREI index was developed with the formula: [2 ∗ RV-free wall longitudinal strain (RV-FWLS)] + reservoir RA strain (RASr). The composite endpoint included hospital admission due to heart failure and all-cause mortality. A total of 176 patients with ≥severe TR were finally included. STREI index identified a higher percentage of patients with RV dysfunction compared with conventional parameters. After a median follow-up of 2.2 years (interquartile range: 12–41 months), a total of 38% reached the composite endpoint. STREI values were predictors of outcomes independently of TR severity and RV dimensions. The combination of prognostic cut-off values of RASr (&lt;10%) and RV-FWLS (&gt;−20%) (STREI stratification) stratified four different groups of risk independently of TR severity, RV dimensions, and clinical status (adj HR per stratum 1.89 (1.4–2.34), P &lt; 0.001). Pre-defined cut-off values achieved similar prognostic performance in the validation cohort (n = 50).

Conclusion
STREI index is a novel parameter of RV performance that independently predicts CV events. The combination of RA and RV strain stratifies better patients’ risk, reflecting a broader effect of TR on right heart chambers.
A simple fragility fracture risk score for type 2 diabetes patients: a derivation, validation, comparison, and risk stratification study
Authors: Chuan Fengning , Gao Youyuan , Liao Kun , Ye Xin , Mei Mei , Tian Wenqing , Li Rong , Zhou Bo 
Published: November 2023

Abstract

Objectives
The aims of this study were to develop and validate 2 simple scores for stratification of the risks of (1) any fragility (AF) and (2) major osteoporotic fracture (MOF) in type 2 diabetes (T2D) patients; we also compared the performance of these scores with that of the Fracture Risk Assessment Tool (FRAX) and its adjustments.

Design and methods
In this longitudinal cohort study, 1855 patients with T2D were enrolled from January 2015 to August 2019. Cox proportional hazard regression was used to model the 5-year risk of AF and MOF. These scores were internally validated using a bootstrap resampling method of 1000.

Results
During a median follow-up of 5 years, 119 (6.42%) cases of AF and 92 (4.96%) cases of MOFs were identified. Both the concordance index (C-index) and calibration plots indicated improved identification performance using the newly established scores. Furthermore, these scores also showed improved outcomes regarding the decision curve analysis (DCA) and area under the curve (AUC) compared to the widely used FRAX and its derivatives. More importantly, these scores successfully separated T2D patients into risk groups according to significant differences in fracture incidence.

Conclusions
These novel scores enable simple and reliable fracture risk stratification in T2D patients. Future work is needed to validate these findings in external cohort(s).
Look left, look right: censoring in clinical research
Authors: Groenwold Rolf H H , Dekkers Olaf M 
Published: November 2023

Abstract
In this methodology editorial, the problem of censored survival (or time-to-event) data in clinical research is discussed. In case of censored observations, part of the observation time for some participants in a study is unobserved, which means that measures such as an average survival time cannot be calculated. Instead, censored survival time should explicitly be accounted for in the analysis of a study, for example using the Kaplan–Meier method. Implications of censoring and how to deal with it in the analysis of a study or when reading a research paper are discussed.
Dynamic electrocardiogram changes are a novel risk marker for sudden cardiac death
Authors: Pham Hoang Nhat , Holmstrom Lauri , Chugh Harpriya , Uy-Evanado Audrey , Nakamura Kotoka , Zhang Zijun , Salvucci Angelo , Jui Jonathan , Reinier Kyndaron , Chugh Sumeet S 
Published: November 2023

Abstract

Background and Aims
Electrocardiogram (ECG) abnormalities have been evaluated as static risk markers for sudden cardiac death (SCD), but the potential importance of dynamic ECG remodelling has not been investigated. In this study, the nature and prevalence of dynamic ECG remodelling were studied among individuals who eventually suffered SCD.

Methods
The study population was drawn from two prospective community-based SCD studies in Oregon (2002, discovery cohort) and California, USA (2015, validation cohort). For this present sub-study, 231 discovery cases (2015–17) and 203 validation cases (2015–21) with ≥2 archived pre-SCD ECGs were ascertained and were matched to 234 discovery and 203 validation controls based on age, sex, and duration between the ECGs. Dynamic ECG remodelling was measured as progression of a previously validated cumulative six-variable ECG electrical risk score.

Results
Oregon SCD cases displayed greater electrical risk score increase over time vs. controls [+1.06 (95% confidence interval +0.89 to +1.24) vs. −0.05 (−0.21 to +0.11); P &lt; .001]. These findings were successfully replicated in California [+0.87 (+0.7 to +1.04) vs. −0.11 (−0.27 to 0.05); P &lt; .001]. In multivariable models, abnormal dynamic ECG remodelling improved SCD prediction over baseline ECG, demographics, and clinical SCD risk factors in both Oregon [area under the receiver operating characteristic curve 0.770 (95% confidence interval 0.727–0.812) increased to area under the receiver operating characteristic curve 0.869 (95% confidence interval 0.837–0.902)] and California cohorts.

Conclusions
Dynamic ECG remodelling improved SCD risk prediction beyond clinical factors combined with the static ECG, with successful validation in a geographically distinct population. These findings introduce a novel concept of SCD dynamic risk and warrant further detailed investigation.
Has recombination changed during the recent evolution of the guppy Y chromosome?
Authors: Charlesworth Deborah , Qiu Suo , Bergero Roberta , Gardner Jim , Keegan Karen , Yong Lengxob , Hastings Abigail , Konczal Mateusz 
Published: November 2023

Abstract
Genome sequencing and genetic mapping of molecular markers have demonstrated nearly complete Y-linkage across much of the guppy (Poecilia reticulata) XY chromosome pair. Predominant Y-linkage of factors controlling visible male-specific coloration traits also suggested that these polymorphisms are sexually antagonistic (SA). However, occasional exchanges with the X are detected, and recombination patterns also appear to differ between natural guppy populations, suggesting ongoing evolution of recombination suppression under selection created by partially sex-linked SA polymorphisms. We used molecular markers to directly estimate genetic maps in sires from 4 guppy populations. The maps are very similar, suggesting that their crossover patterns have not recently changed. Our maps are consistent with population genomic results showing that variants within the terminal 5 Mb of the 26.5 Mb sex chromosome, chromosome 12, are most clearly associated with the maleness factor, albeit incompletely. We also confirmed occasional crossovers proximal to the male-determining region, defining a second, rarely recombining, pseudo-autosomal region, PAR2. This fish species may therefore have no completely male-specific region (MSY) more extensive than the male-determining factor. The positions of the few crossover events suggest a location for the male-determining factor within a physically small repetitive region. A sex-reversed XX male had few crossovers in PAR2, suggesting that this region's low crossover rate depends on the phenotypic, not the genetic, sex. Thus, rare individuals whose phenotypic and genetic sexes differ, and/or occasional PAR2 crossovers in males can explain the failure to detect fully Y-linked variants.
Glycosyltransferases as versatile tools to study the biology of glycans
Authors: Kofsky Joshua M , Babulic Jonathan L , Boddington Marie E , De León González Fabiola V , Capicciotti Chantelle J 
Published: November 2023

Abstract
All cells are decorated with complex carbohydrate structures called glycans that serve as ligands for glycan-binding proteins (GBPs) to mediate a wide range of biological processes. Understanding the specific functions of glycans is key to advancing an understanding of human health and disease. However, the lack of convenient and accessible tools to study glycan-based interactions has been a defining challenge in glycobiology. Thus, the development of chemical and biochemical strategies to address these limitations has been a rapidly growing area of research. In this review, we describe the use of glycosyltransferases (GTs) as versatile tools to facilitate a greater understanding of the biological roles of glycans. We highlight key examples of how GTs have streamlined the preparation of well-defined complex glycan structures through chemoenzymatic synthesis, with an emphasis on synthetic strategies allowing for site- and branch-specific display of glyco-epitopes. We also describe how GTs have facilitated expansion of glyco-engineering strategies, on both glycoproteins and cell surfaces. Coupled with advancements in bioorthogonal chemistry, GTs have enabled selective glyco-epitope editing of glycoproteins and cells, selective glycan subclass labeling, and the introduction of novel biomolecule functionalities onto cells, including defined oligosaccharides, antibodies, and other proteins. Collectively, these approaches have contributed great insight into the fundamental biological roles of glycans and are enabling their application in drug development and cellular therapies, leaving the field poised for rapid expansion.
Functional assay for assessment of pathogenicity of BAP1 variants
Authors: Repo Pauliina E , Backlund Michael P , Kivelä Tero T , Turunen Joni A 
Published: November 2023

Abstract

Background
Pathogenic germline variants in BRCA1-Associated Protein 1 (BAP1) cause BAP1 tumor predisposition syndrome (BAP1-TPDS). Carriers run especially a risk of uveal (UM) and cutaneous melanoma, malignant mesothelioma, and clear cell renal carcinoma. Approximately half of increasingly reported BAP1 variants lack accurate classification. Correct interpretation of pathogenicity can improve prognosis of the patients through tumor screening with better understanding of BAP1-TPDS.

Methods
We edited five rare BAP1 variants with differing functional characteristics identified from patients with UM in HAP1 cells using CRISPR-Cas9 and assayed their effect on cell adhesion/spreading (at 4 h) and proliferation (at 48 h), measured as cell index (CI), using xCELLigence real-time analysis system.

Results
In BAP1 knockout HAP1 cultures, cell number was half of wild type (WT) cultures at 48 h (p = 0.00021), reaching confluence later, and CI was 78% reduced (p &lt; 0.0001). BAP1-TPDS-associated null variants c.67+1G&gt;T and c.1780_1781insT, and a likely pathogenic missense variant c.281A&gt;G reduced adhesion (all p ≤ 0.015) and proliferation by 74%–83% (all p ≤ 0.032). Another likely pathogenic missense variant c.680G&gt;A reduced both by at least 50% (all p ≤ 0.032), whereas cells edited with likely benign one c.1526C&gt;T grew similarly to WT.

Conclusions
BAP1 is essential for optimal fitness of HAP1 cells. Pathogenic and likely pathogenic BAP1 variants reduced cell fitness, reflected in adhesion/spreading and proliferation properties. Further, moderate effects were quantifiable. Variant modelling in HAP1 with CRISPR-Cas9 enabled functional analysis of coding and non-coding region variants in an endogenous expression system.
Improving diagnostic precision in primary ovarian insufficiency using comprehensive genetic and autoantibody testing
Authors: Vogt Elinor Chelsom , Bratland Eirik , Berland Siren , Berentsen Ragnhild , Lund Agnethe , Björnsdottir Sigridur , Husebye Eystein , Øksnes Marianne 
Published: November 2023

STUDY QUESTION
Is it possible to find the cause of primary ovarian insufficiency (POI) in more women by extensive screening?

SUMMARY ANSWER
Adding next generation sequencing techniques including a POI-associated gene panel, extended whole exome sequencing data, as well as specific autoantibody assays to the recommended diagnostic investigations increased the determination of a potential etiological diagnosis of POI from 11% to 41%.

WHAT IS KNOWN ALREADY
POI affects ∼1% of women. Clinical presentations and pathogenic mechanisms are heterogeneous and include genetic, autoimmune, and environmental factors, but the underlying etiology remains unknown in the majority of cases.

STUDY DESIGN, SIZE, DURATION
Prospective cross-sectional study of 100 women with newly diagnosed POI of unknown cause consecutively referred to Haukeland University Hospital, Bergen, Norway, January 2019 to December 2021.

PARTICIPANTS/MATERIALS, SETTING, METHODS
In addition to standard recommended diagnostic investigations including screening for chromosomal anomalies and premutations in the fragile X mental retardation 1 gene (FMR1) we used whole exome sequencing, including targeted analysis of 103 ovarian-related genes, and assays of autoantibodies against steroid cell antigens.

MAIN RESULTS AND THE ROLE OF CHANCE
We identified chromosomal aberrations in 8%, FMR1 premutations in 3%, genetic variants related to POI in 16%, and autoimmune POI in 3%. Furthermore in 11% we identified POI associated genetic Variants of unknown signifcance (VUS). A homozygous pathogenic variant in the ZSWIM7 gene (NM_001042697.2) was found in two women, corroborating this as a novel cause of monogenic POI. No associations between phenotypes and genotypes were found.

LIMITATIONS, REASONS FOR CAUTION
Use of candidate genetic and autoimmune markers limit the possibility to discover new markers. To further investigate the genetic variants, family studies would have been useful. We found a relatively high proportion of genetic variants in women from Africa and lack of genetic diversity in the genomic databases can impact diagnostic accuracy.

WIDER IMPLICATIONS OF THE FINDINGS
Since no specific clinical or biochemical markers predicted the underlying cause of POI discussion of which tests should be part of diagnostic screening in clinical practice remains open. New technology has altered the availability and effectiveness of genetic testing, and cost-effectiveness analyses are required to aid sustainable diagnostics.

STUDY FUNDING/COMPETING INTEREST(S)
The study was supported by grants and fellowships from Stiftelsen Kristian Gerhard Jebsen, the Novonordisk Foundation, the Norwegian Research Council, University of Bergen, and the Regional Health Authorities of Western Norway. The authors declare no conflict of interest.

TRIAL REGISTRATION NUMBER
NCT04082169
Maybe it’s good to not have too much focus
Authors: Pechenik Jan A 
Published: November 2023

Abstract
I had no idea what I was getting into when I decided to go into marine biology as a graduate student. It has ended up being a wonderful career, with opportunities to work with wonderful people around the world, and to work with many wonderful students at a variety of grade levels. It has also opened up opportunities in completely unexpected directions and allowed me to explore a good variety of research questions, explore a variety of teaching methods at a variety of grade levels, write a few books, and even develop some games for middle-school students. Luck has certainly played a role in some of this, but my main advice is to always keep an eye open for opportunities of interest, within and outside of your normal field…and seize them if possible!
Uniqueness of Unbounded Component for Level Sets of Smooth Gaussian Fields
Authors: Severo Franco 
Published: November 2023

Abstract
For a large family of stationary continuous Gaussian fields $f$ on ${\mathbb {R}}^{d}$, including the Bargmann–Fock and Cauchy fields, we prove that there exists at most one unbounded connected component in the level set $\{f=\ell \}$ (as well as in the excursion set $\{f\geq \ell \}$) almost surely for every level $\ell \in {\mathbb {R}}$, thus proving a conjecture proposed by Duminil-Copin, Rivera, Rodriguez, and Vanneuville. As the fields considered are typically very rigid (e.g., analytic almost surely), there is no sort of finite energy property available and the classical approaches to prove uniqueness become difficult to implement. We bypass this difficulty using a soft shift argument based on the Cameron–Martin theorem.