bluuebunny/crossref_metadata_2025_split huggingface dataset:
Challenges in Obtaining Valid Causal Effect Estimates With Machine Learning Algorithms
Authors: Naimi Ashley I , Mishler Alan E , Kennedy Edward H 
Published: July 2021

Abstract
Unlike parametric regression, machine learning (ML) methods do not generally require precise knowledge of the true data-generating mechanisms. As such, numerous authors have advocated for ML methods to estimate causal effects. Unfortunately, ML algorithms can perform worse than parametric regression. We demonstrate the performance of ML-based singly and doubly robust estimators. We used 100 Monte Carlo samples with sample sizes of 200, 1,200, and 5,000 to investigate bias and confidence-interval coverage under several scenarios. In a simple confounding scenario, confounders were related to the treatment and the outcome via parametric models. In a complex confounding scenario, the simple confounders were transformed to induce complicated nonlinear relationships. In the simple scenario, when ML algorithms were used, double-robust estimators were superior to singly robust estimators. In the complex scenario, single-robust estimators with ML algorithms were at least as biased as estimators using misspecified parametric models. Doubly robust estimators were less biased, but coverage was well below nominal. The use of sample splitting, inclusion of confounder interactions, reliance on a richly specified ML algorithm, and use of doubly robust estimators was the only explored approach that yielded negligible bias and nominal coverage. Our results suggest that ML-based singly robust methods should be avoided.
Aperture: alignment-free detection of structural variations and viral integrations in circulating tumor DNA
Authors: Liu Hongchao , Yin Huihui , Li Guangyu , Li Junling , Wang Xiaoyue 
Published: July 2021

Abstract
The identification of structural variations (SVs) and viral integrations in circulating tumor DNA (ctDNA) is a key step in precision oncology that may assist clinicians in treatment selection and monitoring. However, due to the short fragment size of ctDNA, it is challenging to accurately detect low-frequency SVs or SVs involving complex junctions in ctDNA sequencing data. Here, we describe Aperture, a new fast SV caller that applies a unique strategy of $k$-mer-based searching, binary label–based breakpoint detection and candidate clustering to detect SVs and viral integrations with high sensitivity, especially when junctions span repetitive regions. Aperture also employs a barcode-based filter to ensure specificity. Compared with existing methods, Aperture exhibits superior sensitivity and specificity in simulated, reference and real data tests, especially at low dilutions. Additionally, Aperture is able to predict sites of viral integration and identify complex SVs involving novel insertions and repetitive sequences in real patient data. Aperture is freely available at https://github.com/liuhc8/Aperture.
In Their Own Words: Nalini Nadkarni
Authors: Verdier James M 
Published: July 2021

Abstract
In Their Own Words chronicles the stories of scientists who have made great contributions to their fields. These short histories provide our readers a way to learn from and share their experiences. We will publish the results of these conversations in the pages of BioScience and on our podcast, BioScience Talks (http://bioscienceaibs.libsyn.com). This history is with Nalini Nadkarni, professor of biology at the University of Utah.
Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe
Authors: Yushkevich Paul A , Muñoz López Mónica , Iñiguez de Onzoño Martin María Mercedes , Ittyerah Ranjit , Lim Sydney , Ravikumar Sadhana , Bedard Madigan L , Pickup Stephen , Liu Weixia , Wang Jiancong , Hung Ling Yu , Lasserve Jade , Vergnet Nicolas , Xie Long , Dong Mengjin , Cui Salena , McCollum Lauren , Robinson John L , Schuck Theresa , de Flores Robin , Grossman Murray , Tisdall M Dylan , Prabhakaran Karthik , Mizsei Gabor , Das Sandhitsu R , Artacho-Pérula Emilio , Arroyo Jiménez Marı’a del Mar , Marcos Raba Marı’a Pilar , Molina Romero Francisco Javier , Cebada Sánchez Sandra , Delgado González José Carlos , de la Rosa-Prieto Carlos , Córcoles Parada Marta , Lee Edward B , Trojanowski John Q , Ohm Daniel T , Wisse Laura E M , Wolk David A , Irwin David J , Insausti Ricardo 
Published: July 2021

Abstract
Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer’s disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer’s disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely.
To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template.
Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields.
Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer’s disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.
CSF-resident CD4+ T-cells display a distinct gene expression profile with relevance to immune surveillance and multiple sclerosis
Authors: Hrastelj James , Andrews Robert , Loveless Samantha , Morgan Joanne , Bishop Stefan Mark , Bray Nicholas J , Williams Nigel M , Robertson Neil P 
Published: July 2021

Abstract
The CNS has traditionally been considered an immune privileged site, but is now understood to have a system of immune surveillance, predominantly involving CD4+ T-cells. Identifying functional differences between CNS and blood CD4+ T-cells, therefore, have relevance to CNS immune surveillance as well as to neurological conditions, such as multiple sclerosis, in which CD4+ T-cells play a central role. Here, CD4+ T-cells were purified from CSF and blood from 21 patients with newly diagnosed treatment-naïve multiple sclerosis and 20 individuals with non-inflammatory disorders using fluorescence-activated cell sorting, and their transcriptomes were profiled by RNA sequencing. Paired comparisons between CD4+ T-cells from CSF and blood identified 5156 differentially expressed genes in controls and 4263 differentially expressed in multiple sclerosis patients at false discovery rate &lt;5%. Differential expression analysis of CD4+ T-cells collected from the CSF highlighted genes involved in migration, activation, cholesterol biosynthesis and signalling, including those with known relevance to multiple sclerosis pathogenesis and treatment. Expression of markers of CD4+ T-cell subtypes suggested an increased proportion of Th1 and Th17 cells in CSF. Gene ontology terms significant only in multiple sclerosis were predominantly those involved in cellular proliferation. A two-way comparison of CSF versus blood CD4+ T-cells in multiple sclerosis compared with non-inflammatory disorder controls identified four significant genes at false discovery rate &lt;5% (CYP51A1, LRRD1, YES1 and PASK), further implicating cholesterol biosynthesis and migration mechanisms. Analysis of CSF CD4+ T-cells in an extended cohort of multiple sclerosis cases (total N = 41) compared with non-inflammatory disorder controls (total N = 38) identified 140 differentially expressed genes at false discovery rate &lt; 5%, many of which have known relevance to multiple sclerosis, including XBP1, BHLHE40, CD40LG, DPP4 and ITGB1. This study provides the largest transcriptomic analysis of purified cell subpopulations in CSF to date and has relevance for the understanding of CNS immune surveillance, as well as multiple sclerosis pathogenesis and treatment discovery.
Transmission of Antimicrobial Resistant Yersinia pestis During a Pneumonic Plague Outbreak
Authors: Andrianaivoarimanana Voahangy , Wagner David M , Birdsell Dawn N , Nikolay Birgit , Rakotoarimanana Faniry , Randriantseheno Lovasoa N , Vogler Amy J , Sahl Jason W , Hall Carina M , Somprasong Nawarat , Cauchemez Simon , Schweizer Herbert P , Razafimandimby Harimahefa , Rogier Christophe , Rajerison Minoarisoa 
Published: July 2021

Abstract

Background
Pneumonic plague (PP), caused by Yersinia pestis, is the most feared clinical form of plague due to its rapid lethality and potential to cause outbreaks. PP outbreaks are now rare due to antimicrobial therapy.

Methods
A PP outbreak in Madagascar involving transmission of a Y. pestis strain resistant to streptomycin, the current recommended first-line treatment in Madagascar, was retrospectively characterized using epidemiology, clinical diagnostics, molecular characterization, and animal studies.

Results
The outbreak occurred in February 2013 in the Faratsiho district of Madagascar and involved 22 cases, including 3 untreated fatalities. The 19 other cases participated in funeral practices for the fatal cases and fully recovered after combination antimicrobial therapy: intramuscular streptomycin followed by oral co-trimoxazole. The Y. pestis strain that circulated during this outbreak is resistant to streptomycin resulting from a spontaneous point mutation in the 30S ribosomal protein S12 (rpsL) gene. This same mutation causes streptomycin resistance in 2 unrelated Y. pestis strains, one isolated from a fatal PP case in a different region of Madagascar in 1987 and another isolated from a fatal PP case in China in 1996, documenting this mutation has occurred independently at least 3 times in Y. pestis. Laboratory experiments revealed this mutation has no detectable impact on fitness or virulence, and revertants to wild-type are rare in other species containing it, suggesting Y. pestis strains containing it could persist in the environment.

Conclusions
Unique antimicrobial resistant (AMR) strains of Y. pestis continue to arise in Madagascar and can be transmitted during PP outbreaks.
Fecal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) RNA Is Associated With Decreased Coronavirus Disease 2019 (COVID-19) Survival
Authors: Das Adhikari Upasana , Eng George , Farcasanu Mara , Avena Laura E , Choudhary Manish C , Triant Virginia A , Flagg Meaghan , Schiff Abigail E , Gomez Isabella , Froehle Leah M , Diefenbach Thomas J , Ronsard Larance , Lingwood Daniel , Lee Grace C , Rabi Seyed Alireza , Erstad Derek , Velmahos George , Li Jonathan Z , Hodin Richard , Stone James R , Honko Anna N , Griffiths Anthony , Yilmaz Ömer H , Kwon Douglas S 
Published: July 2021

Abstract
The clinical significance of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) RNA in stool remains uncertain. We found that extrapulmonary dissemination of infection to the gastrointestinal tract, assessed by the presence of SARS-CoV-2 RNA in stool, is associated with decreased coronavirus disease 2019 (COVID-19) survival. Measurement of SARS-CoV-2 RNA in stool may have utility for clinical risk assessment.
Effects of force magnitude on dental arches in cervical headgear therapy
Authors: Talvitie Tuula , Helminen Mika , Karsila Susanna , Pirttiniemi Pertti , Signorelli Luca , Varho Reeta , Peltomäki Timo 
Published: July 2021

SummaryAimTo study the influence of different force magnitudes on dental arches in cervical headgear (CHG) treatment.Material and methodsIn this controlled clinical trial, patients (n = 40) were treated with CHG with light (L, 300 g, n = 22) or heavy force (H, 500 g, n = 18) magnitude. Subjects were asked to use CHG for 10 hours a day for 10 months. The outer bow of the CHG facebow was raised 10–20 degrees and the inner bow expanded 3–4 mm. Adherence to instructions and force magnitude were monitored with an electronic module (Smartgear, Swissorthodontics, Switzerland). Impressions for study models were taken before (T1) and after (T2) treatment and the study models were scanned into digital form (3Shape, R700 Scanner, Denmark). Measurements were made using the digital models (Planmeca Romexis, Model analyser, Finland).ResultsDuring the treatment (T1–T2) the upper inter-canine distance increased by 2.83 mm (P = 0.000) and 2.60 mm (P = 0.000) in the L and H force magnitude groups, respectively. Upper inter-molar width increased by 3.16 mm (P = 0.000) and 2.50 mm (P = 0.000) in the L and H groups, respectively. Maxillary total arch perimeter increased by 6.39 mm (P = 0.001) and 6.68 mm (P = 0.001) in the L and H groups, respectively. In the amount of change over time, T1–T2, in the upper arch measurements, no significant difference was found between the groups. Lower inter-canine width increased by 0.94 mm (P = 0.005) and 1.16 mm (P = 0.000) in the L and H groups, respectively; no difference between the groups. Lower inter-molar distance increased by 2.17 mm (P = 0.000) and 1.11 mm (P = 0.008) in the L and H groups, respectively. At the end of the study, upper and lower inter-molar width was larger in the L group than in the H group (P = 0.039 and P = 0.022, respectively).ConclusionCHG therapy is an effective method for expanding and releasing moderate crowding of the upper dental arch. The lower arch spontaneously follows the upper arch in widening effects, and minor expansion can also be seen on the lower arch. In the L group, larger inter-molar width was achieved on the upper and lower arch; probably due to better adherence to instructions. Light force is recommended for use in CHG therapy.
Handel’s harpsichords revisited Part II: Handel’s domestic harpsichords
Authors: Holman Peter 
Published: July 2021

Abstract
The harpsichords supposedly owned or played by Handel have long been the subject of scholarly enquiry, in recent years mainly to try to match their compasses and disposition to his solo music, a strategy also used, for instance, with instruments associated with J. S. Bach and Mozart. Similarly, Grant O’Brien, John Koster and others have tried to determine how Ruckers-family instruments might have been used to play early 17th-century keyboard music.
In Part I of this article (in the last Early Music) I discussed six Ruckers harpsichords associated with Handel and his followers in the 18th and 19th centuries, three of which can be identified with surviving instruments. I argued that Handel favoured them partly because they had a cachet equivalent to Amati violins, and partly because he used them for directing oratorios at Covent Garden, where a small instrument with a brilliant tone would have been an asset in a crowded performing area. In this second part I focus on five plucked instruments said to have been owned by Handel, and apparently used by him at home, for accompanying in small rehearsals, for performing solo music to his friends and for private practice. Not all the claims made for the total of eleven instruments associated with Handel stand up to scrutiny, as we shall see, but a surprising number of them can be traced back to his milieu, and I argue that the composer needed a large number of instruments for his varied activities as a composer, solo keyboard virtuoso, teacher and musical director.
Peripartum cardiomyopathy: from genetics to management
Authors: Sliwa Karen , Bauersachs Johann , Arany Zolt , Spracklen Timothy F , Hilfiker-Kleiner Denise 
Published: July 2021

Abstract
Peripartum cardiomyopathy (PPCM) is a disease that occurs globally in all ethnic groups and should be suspected in any peripartum women presenting with symptoms and signs of heart failure, towards the end of pregnancy or in the months following delivery, with confirmed left ventricular dysfunction. After good history taking, all women should be thoroughly assessed, and alternative causes should be excluded. Urgent cardiac investigations with electrocardiogram and natriuretic peptide measurement (if available) should be performed. Echocardiography follows as the next step in investigation. Patients with abnormal cardiac investigations should be urgently referred to a cardiology team for expert management. Referral for genetic work-up should be considered if there is a family history of cardiomyopathy or sudden death. PPCM is a disease with substantial maternal and neonatal morbidity and mortality. Maternal mortality rates range widely, from 0% to 30%, depending on the ethnic background and geographic region. Just under half of women experience myocardial recovery. Remarkable advances in the comprehension of the pathogenesis and in patient management and therapy have been achieved, largely due to team efforts and close collaboration between basic scientists, cardiologists, intensive care specialists, and obstetricians. This review summarizes current knowledge of PPCM genetics, pathophysiology, diagnostic approach, management, and outcome.
Reconstituting electrical conduction in soft tissue: the path to replace the ablationist
Authors: Post Allison D , Buchan Skylar , John Mathews , Safavi-Naeini Payam , Cosgriff-Hernández Elizabeth , Razavi Mehdi 
Published: July 2021

Abstract
Cardiac arrhythmias are a leading cause of morbidity and mortality in the developed world. A common mechanism underlying many of these arrhythmias is re-entry, which may occur when native conduction pathways are disrupted, often by myocardial infarction. Presently, re-entrant arrhythmias are most commonly treated with antiarrhythmic drugs and myocardial ablation, although both treatment methods are associated with adverse side effects and limited efficacy. In recent years, significant advancements in the field of biomaterials science have spurred increased interest in the development of novel therapies that enable restoration of native conduction in damaged or diseased myocardium. In this review, we assess the current landscape of materials-based approaches to eliminating re-entrant arrhythmias. These approaches potentially pave the way for the eventual replacement of myocardial ablation as a preferred therapy for such pathologies.
Has translational genomics come of age in Africa?
Authors: Kamp Michelle , Krause Amanda , Ramsay Michele 
Published: July 2021

Abstract
The rapid increase in genomics research in Africa and the growing promise of precision public health (PPH) begs the question of whether African genomics has come of age and is being translated into improved healthcare for Africans. An assessment of the continent’s readiness suggests that genetic service delivery remains limited and extremely fragile. The paucity of data on mutation profiles for monogenic disorders and lack of large genome-wide association cohorts for complex traits in African populations is a significant barrier, coupled with extreme genetic variation across different regions and ethnic groups. Data from many different populations are essential to developing appropriate genetic services. Of the proposed genetic service delivery models currently used in Africa—Uncharacterized, Limited, Disease-focused, Emerging and Established—the first three best describe the situation in most African countries. Implementation is fraught with difficulties related to the scarcity of an appropriately skilled medical genetic workforce, limited infrastructure and processes, insufficient health funding and lack of political support, and overstretched health systems. There is a strong nucleus of determined and optimistic clinicians and scientists with a clear vision, and there is a hope for innovative solutions and technological leapfrogging. However, a multi-dimensional approach with active interventions to stimulate genomic research, clinical genetics and overarching healthcare systems is needed to reduce genetic service inequalities and accelerate PPH on the continent. Human and infrastructure capacity development, dedicated funding, political will and supporting legislation, and public education and awareness, are critical elements for success. Africa-relevant genomic and related health economics research remains imperative with an overarching need to translate knowledge into improved healthcare. Given the limited data and genetic services across most of Africa, the continent has not yet come of ‘genomics’ age.
KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating
Authors: Zhang Yongqiang , Tachtsidis Georgios , Schob Claudia , Koko Mahmoud , Hedrich Ulrike B S , Lerche Holger , Lemke Johannes R , van Haeringen Arie , Ruivenkamp Claudia , Prescott Trine , Tveten Kristian , Gerstner Thorsten , Pruniski Brianna , DiTroia Stephanie , VanNoy Grace E , Rehm Heidi L , McLaughlin Heather , Bolz Hanno J , Zechner Ulrich , Bryant Emily , McDonough Tiffani , Kindler Stefan , Bähring Robert 
Published: July 2021

Abstract
Here, we report on six unrelated individuals, all presenting with early-onset global developmental delay, associated with impaired motor, speech and cognitive development, partly with developmental epileptic encephalopathy and physical dysmorphisms. All individuals carry heterozygous missense variants of KCND2, which encodes the voltage-gated potassium (Kv) channel α-subunit Kv4.2. The amino acid substitutions associated with the variants, p.(Glu323Lys) (E323K), p.(Pro403Ala) (P403A), p.(Val404Leu) (V404L) and p.(Val404Met) (V404M), affect sites known to be critical for channel gating. To unravel their likely pathogenicity, recombinant mutant channels were studied in the absence and presence of auxiliary β-subunits under two-electrode voltage clamp in Xenopus oocytes. All channel mutants exhibited slowed and incomplete macroscopic inactivation, and the P403A variant in addition slowed activation. Co-expression of KChIP2 or DPP6 augmented the functional expression of both wild-type and mutant channels; however, the auxiliary β-subunit-mediated gating modifications differed from wild type and among mutants. To simulate the putative setting in the affected individuals, heteromeric Kv4.2 channels (wild type + mutant) were studied as ternary complexes (containing both KChIP2 and DPP6). In the heteromeric ternary configuration, the E323K variant exhibited only marginal functional alterations compared to homomeric wild-type ternary, compatible with mild loss-of-function. By contrast, the P403A, V404L and V404M variants displayed strong gating impairment in the heteromeric ternary configuration, compatible with loss-of-function or gain-of-function. Our results support the etiological involvement of Kv4.2 channel gating impairment in early-onset monogenic global developmental delay. In addition, they suggest that gain-of-function mechanisms associated with a substitution of V404 increase epileptic seizure susceptibility.