bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Detection Rate of Copy Number Variations Using Capture Sequencing Data: A Retrospective Study
Authors: Sun Yu , Ye Xiantao , Fan Yanjie , Wang Lili , Luo Xiaomei , Liu Huili , Gao Xueren , Gong Zhuwen , Wang Yu , Qiu Wenjuan , Zhang Huiwen , Han Lianshu , Liang Lili , Ye Hui , Xiao Bing , Gu Xuefan , Yu Yongguo 
Published: January 2020

Abstract

Background
Capture sequencing (CS) is widely applied to detect small genetic variations such as single nucleotide variants or indels. Algorithms based on depth comparison are becoming available for detecting copy number variation (CNV) from CS data. However, a systematic evaluation with a large sample size has not been conducted to evaluate the efficacy of CS-based CNV detection in clinical diagnosis.

Methods
We retrospectively studied 3010 samples referred to our diagnostic laboratory for CS testing. We used 68 chromosomal microarray analysis–positive samples (true set [TS]) and 1520 reference samples to build a robust CS-CNV pipeline. The pipeline was used to detect candidate clinically relevant CNVs in 1422 undiagnosed samples (undiagnosed set [UDS]). The candidate CNVs were confirmed by an alternative method.

Results
The CS-CNV pipeline detected 78 of 79 clinically relevant CNVs in TS samples, with analytical sensitivity of 98.7% and positive predictive value of 49.4%. Candidate clinically relevant CNVs were identified in 106 UDS samples. CNVs were confirmed in 96 patients (90.6%). The diagnostic yield was 6.8%. The molecular etiology includes aneuploid (n = 7), microdeletion/microduplication syndrome (n = 40), and Mendelian disorders (n = 49).

Conclusions
These findings demonstrate the high yield of CS-based CNV. With further improvement of our CS-CNV pipeline, the method may have clinical utility for simultaneous evaluation of CNVs and small variations in samples referred for pre- or postnatal analysis.
Impact of sex hormone-binding globulin on the human phenome
Authors: Arathimos Ryan , Millard Louise A C , Bell Joshua A , Relton Caroline L , Suderman Matthew 
Published: January 2020

AbstractBackground: Sex hormone-binding globulin (SHBG) is a circulating glycoprotein and a regulator of sex hormone levels, which has been shown to influence various traits and diseases. The molecular nature of SHBG makes it a feasible target for preventative or therapeutic interventions. A systematic study of its effects across the human phenome may uncover novel associations. Methods: We used a Mendelian randomization phenome-wide association study (MR-pheWAS) approach to systematically appraise the potential functions of SHBG while reducing potential biases such as confounding and reverse causation common to the literature. We searched for potential causal effects of SHBG in UK Biobank (N = 334 977) and followed-up our top findings using two-sample MR analyses to evaluate whether estimates may be biased due to horizontal pleiotropy. Results: Results of the MR-pheWAS across over 21 000 outcome phenotypes identified 12 phenotypes associated with genetically elevated SHBG after Bonferroni correction for multiple testing. Follow-up analysis using two-sample MR indicated the associations of increased natural log SHBG with higher impedance of the arms and whole body, lower pulse rate, lower bone density, higher odds of hip replacement, lower odds of high cholesterol or cholesterol medication use and higher odds of gallbladder removal. Conclusions: Our systematic MR-pheWAS of SHBG, which was comprehensive to the range of phenotypes available in UK Biobank, suggested that higher circulating SHBG affects the body impedance, bone density and cholesterol levels, among others. These phenotypes should be prioritized in future studies aiming to investigate the biological effects of SHBG or develop targets for therapeutic intervention.
Opioid Use and Chronic Infections: The Value of Addressing the Syndemic in Correctional Settings Via Telemedicine Guidance and Broader Use of Long-Acting Medications
Authors: Krsak Martin , Montague Brian T , Trowbridge Paul , Johnson Steven C , Binswanger Ingrid A 
Published: January 2020

AbstractIn the United States, we are experiencing linked epidemics (a syndemic) of substance use disorders (SUDs) and infections associated with drug use, including unsafe injecting and unsafe sex in exchange for drugs or money. Current drug laws, together with risk-taking behavior among persons with SUDs, contribute to disproportionately high prevalences of these conditions in correctional settings. Detection and treatment of diseases with a high impact on public health are best addressed in the settings where such conditions are most prevalent (ie, jails and prisons for SUDs and chronic infections). The effectiveness, safety, cost of care. and public health impact of these conditions can be improved by means of broader screening and expanded access to specialty consultations through telemedicine/telehealth, along with broader use of long-acting medications for the treatment of human immunodeficiency virus and SUDs. Expanding telemedicine/telehealth, first for specialties which do not require advanced technology (eg, infectious diseases, addictions), can eventually lead to further advancements in correctional healthcare.
Does BERT need domain adaptation for clinical negation detection?
Authors: Lin Chen , Bethard Steven , Dligach Dmitriy , Sadeque Farig , Savova Guergana , Miller Timothy A 
Published: January 2020

Abstract

Introduction
Classifying whether concepts in an unstructured clinical text are negated is an important unsolved task. New domain adaptation and transfer learning methods can potentially address this issue.

Objective
We examine neural unsupervised domain adaptation methods, introducing a novel combination of domain adaptation with transformer-based transfer learning methods to improve negation detection. We also want to better understand the interaction between the widely used bidirectional encoder representations from transformers (BERT) system and domain adaptation methods.

Materials and Methods
We use 4 clinical text datasets that are annotated with negation status. We evaluate a neural unsupervised domain adaptation algorithm and BERT, a transformer-based model that is pretrained on massive general text datasets. We develop an extension to BERT that uses domain adversarial training, a neural domain adaptation method that adds an objective to the negation task, that the classifier should not be able to distinguish between instances from 2 different domains.

Results
The domain adaptation methods we describe show positive results, but, on average, the best performance is obtained by plain BERT (without the extension). We provide evidence that the gains from BERT are likely not additive with the gains from domain adaptation.

Discussion
Our results suggest that, at least for the task of clinical negation detection, BERT subsumes domain adaptation, implying that BERT is already learning very general representations of negation phenomena such that fine-tuning even on a specific corpus does not lead to much overfitting.

Conclusion
Despite being trained on nonclinical text, the large training sets of models like BERT lead to large gains in performance for the clinical negation detection task.
The Optimal Treatment for Partial Thickness Burns: A Cost-Utility Analysis of Skin Allograft vs. Topical Silver Dressings
Authors: Sheckter Clifford C , Meyerkord Nickolas L , Sinskey Yunna L , Clark Pariss , Anderson Katarina , Van Vliet Michael 
Published: January 2020

Abstract

Introduction
Partial thickness burns not undergoing surgical excision are treated with topical silver products including silver sulfadiazine (SSD) and Mepilex Ag. Skin allograft is a more costly alternative that acts as definitive wound coverage until autogenous epithelialization. Economic constraints and the movement toward value-based care demand cost and outcome justification prior to adopting more costly products.

Methods
A cost-utility analysis was performed comparing skin allograft to SSD and Mepilex Ag using decision tree analysis. The base case modeled a superficial partial thickness 20% total body surface area burn. Utilities were derived from expert opinion on the basis of personal experience. Costs were derived from 2019 Medicare payments. Quality adjusted life years were calculated using rollback method assuming standard life expectancies in the United States. Probabilistic sensitivity analysis was performed to asses model robustness.

Results
The incremental costs of skin allograft to Mepilex Ag and SSD were $907.71 and $1257.86, respectively. The incremental quality adjusted life year (QALY) gains from allograft over Mepilex Ag and SSD were 0.011 and 0.016. This yielded an incremental cost-utility ratio for allograft vs. Mepilex Ag of $84,189.29/QALY compared with an incremental cost-utility ratio of $79,684.63/QALY for allograft vs. SSD. Assuming willingness-to-pay thresholds of $100,000/QALY, probabilistic sensitivity analysis demonstrated that allograft was cost effective to Mepilex Ag in 62.1% of scenarios, and cost effective to SSD in 64.9% of simulations.

Conclusion
Skin allograft showed greater QALYs compared with topical silver dressings at a higher cost. Depending on willingness-to-pay thresholds, skin allograft may be a considered a cost-effective treatment of partial-thickness burns.
The Molecular Analysis for Therapy Choice (NCI-MATCH) Trial: Lessons for Genomic Trial Design
Authors: Flaherty Keith T , Gray Robert , Chen Alice , Li Shuli , Patton David , Hamilton Stanley R , Williams Paul M , Mitchell Edith P , Iafrate A John , Sklar Jeffrey , Harris Lyndsay N , McShane Lisa M , Rubinstein Larry V , Sims David J , Routbort Mark , Coffey Brent , Fu Tony , Zwiebel James A , Little Richard F , Marinucci Donna , Catalano Robert , Magnan Rick , Kibbe Warren , Weil Carol , Tricoli James V , Alexander Brian , Kumar Shaji , Schwartz Gary K , Meric-Bernstam Funda , Lih Chih-Jian , McCaskill-Stevens Worta , Caimi Paolo , Takebe Naoko , Datta Vivekananda , Arteaga Carlos L , Abrams Jeffrey S , Comis Robert , O’Dwyer Peter J , Conley Barbara A ,   for the NCI-MATCH Team
Published: January 2020

Abstract

Background
The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology.

Methods
Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA–targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial.

Results
At interim analysis, accrual was robust, tumor biopsies were safe (&lt;1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround).

Conclusions
The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.
The continuing arc toward phototropic enlightenment
Authors: Liscum Emmanuel , Nittler Patrick , Koskie Katelynn 
Published: January 2020

Abstract
Phototropism represents a simple physiological mechanism—differential growth across the growing organ of a plant—to respond to gradients of light and maximize photosynthetic light capture (in aerial tissues) and water/nutrient acquisition (in roots). The phototropin blue light receptors, phot1 and phot2, have been identified as the essential sensors for phototropism. Additionally, several downstream signal/response components have been identified, including the phot-interacting proteins NON-PHOTOTROPIC HYPOCOTYL 3 (NPH3) and PHYTOCHROME SUBSTRATE 4 (PKS4). While the structural and photochemical properties of the phots are quite well understood, much less is known about how the phots signal through downstream regulators. Recent advances have, however, provided some intriguing clues. It appears that inactive receptor phot1 is found dispersed in a monomeric form at the plasma membrane in darkness. Upon light absorption dimerizes and clusters in sterol-rich microdomains where it is signal active. Additional studies showed that the phot-regulated phosphorylation status of both NPH3 and PKS4 is linked to phototropic responsiveness. While PKS4 can function as both a positive (in low light) and a negative (in high light) regulator of phototropism, NPH3 appears to function solely as a key positive regulator. Ultimately, it is the subcellular localization of NPH3 that appears crucial, an aspect regulated by its phosphorylation status. While phot1 activation promotes dephosphorylation of NPH3 and its movement from the plasma membrane to cytoplasmic foci, phot2 appears to modulate relocalization back to the plasma membrane. Together these findings are beginning to illuminate the complex biochemical and cellular events, involved in adaptively modifying phototropic responsiveness under a wide varying range of light conditions.
Lower bounds for the state complexity of probabilistic languages and the language of prime numbers
Authors: Fijalkow NathanaËl 
Published: January 2020

Abstract
This paper studies the complexity of languages of finite words using automata theory. To go beyond the class of regular languages, we consider infinite automata and the notion of state complexity defined by Karp. Motivated by the seminal paper of Rabin from 1963 introducing probabilistic automata, we study the (deterministic) state complexity of probabilistic languages and prove that probabilistic languages can have arbitrarily high deterministic state complexity. We then look at alternating automata as introduced by Chandra, Kozen and Stockmeyer: such machines run independent computations on the word and gather their answers through boolean combinations. We devise a lower bound technique relying on boundedly generated lattices of languages, and give two applications of this technique. The first is a hierarchy theorem, stating that there are languages of arbitrarily high polynomial alternating state complexity, and the second is a linear lower bound on the alternating state complexity of the prime numbers written in binary. This second result strengthens a result of Hartmanis and Shank from 1968, which implies an exponentially worse lower bound for the same model.
Power Kripke–Platek set theory and the axiom of choice
Authors: Rathjen Michael 
Published: January 2020

Abstract
While power Kripke–Platek set theory, ${\textbf{KP}}({\mathcal{P}})$, shares many properties with ordinary Kripke–Platek set theory, ${\textbf{KP}}$, in several ways it behaves quite differently from ${\textbf{KP}}$. This is perhaps most strikingly demonstrated by a result, due to Mathias, to the effect that adding the axiom of constructibility to ${\textbf{KP}}({\mathcal{P}})$ gives rise to a much stronger theory, whereas in the case of ${\textbf{KP}}$, the constructible hierarchy provides an inner model, so that ${\textbf{KP}}$ and ${\textbf{KP}}+V=L$ have the same strength.
This paper will be concerned with the relationship between ${\textbf{KP}}({\mathcal{P}})$ and ${\textbf{KP}}({\mathcal{P}})$ plus the axiom of choice or even the global axiom of choice, $\textbf{AC}_{\tiny {global}}$. Since $L$ is the standard vehicle to furnish a model in which this axiom holds, the usual argument for demonstrating that the addition of ${\textbf{AC}}$ or $\textbf{AC}_{\tiny {global}}$ to ${\textbf{KP}}({\mathcal{P}})$ does not increase proof-theoretic strength does not apply in any obvious way. Among other tools, the paper uses techniques from ordinal analysis to show that ${\textbf{KP}}({\mathcal{P}})+\textbf{AC}_{\tiny {global}}$ has the same strength as ${\textbf{KP}}({\mathcal{P}})$, thereby answering a question of Mathias. Moreover, it is shown that ${\textbf{KP}}({\mathcal{P}})+\textbf{AC}_{\tiny {global}}$ is conservative over ${\textbf{KP}}({\mathcal{P}})$ for $\varPi ^1_4$ statements of analysis.
The method of ordinal analysis for theories with power set was developed in an earlier paper. The technique allows one to compute witnessing information from infinitary proofs, providing bounds for the transfinite iterations of the power set operation that are provable in a theory.
As the theory ${\textbf{KP}}({\mathcal{P}})+\textbf{AC}_{\tiny {global}}$ provides a very useful tool for defining models and realizability models of other theories that are hard to construct without access to a uniform selection mechanism, it is desirable to determine its exact proof-theoretic strength. This knowledge can for instance be used to determine the strength of Feferman’s operational set theory with power set operation as well as constructive Zermelo–Fraenkel set theory with the axiom of choice.
Melatonin protects the mouse testis against heat-induced damage
Authors: Zhang Pengfei , Zheng Yi , Lv Yinghua , Li Fuyuan , Su Lihong , Qin Yuwei , Zeng Wenxian 
Published: January 2020

AbstractSpermatogenesis, an intricate process occurring in the testis, is responsible for ongoing production of spermatozoa and thus the cornerstone of lifelong male fertility. In the testis, spermatogenesis occurs optimally at a temperature 2–4°C lower than that of the core body. Increased scrotal temperature generates testicular heat stress and later causes testicular atrophy and spermatogenic arrest, resulting in a lower sperm yield and therefore impaired male fertility. Melatonin (N-acetyl-5-methoxytryptamine), a small neuro-hormone synthesized and secreted by the pineal gland and the testis, is widely known as a potent free-radical scavenger; it has been reported that melatonin protects the testis against inflammation and reactive oxygen species generation thereby playing anti-inflammatory, -oxidative and -apoptotic roles in the testis. Nevertheless, the role of melatonin in the testicular response to heat stress has not been studied. Here, by employing a mouse model of testicular hyperthermia, we systematically investigated the testicular response to heat stress as well as the occurrence of autophagy, apoptosis and oxidative stress in the testis. Importantly, we found that pre-treatment with melatonin attenuated heat-induced apoptosis and oxidative stress in the testis. Also, post-treatment with melatonin promoted recovery of the testes from heat-induced damage, probably by maintaining the integrity of the Sertoli cell tight-junction. Thus, we for the first time provide the proof of concept that melatonin can protect the testis against heat-induced damage, supporting the potential future use of melatonin as a therapeutic drug in men for sub/infertility incurred by various testicular hyperthermia factors.
VERIFICATION AND OPTIMISATION OF PRESELECTED EXPOSURE PARAMETERS IN SCREENING MAMMOGRAPHY: A CENTRAL COMPOSITE DESIGN METHODOLOGY
Authors: Acho Sussan N , Stofile Caroline , Moller Mia , Morphis Michaella 
Published: January 2020

Abstract
In screening mammography, the automatic exposure control (AEC) device selects the optimum exposure parameters for each patient exposure. In practice, this device is calibrated to deliver an optimum figure of merit (FOM) for each set of exposure parameters. This study utilises the central composite design methodology to verify the operating level of the AEC performance for polymethyl methacrylate (PMMA) thicknesses of 4 and 5 cm. Quadratic surface plots reveal that the exposure parameters of the default AEC mode are optimised for the 4-cm thickness of the PMMA. However, the exposure parameters of the 5-cm thickness of PMMA need fine-tuning to obtain a maximum value for the FOM.
Multivariate neural signatures for health neuroscience: assessing spontaneous regulation during food choice
Authors: Cosme Danielle , Zeithamova Dagmar , Stice Eric , Berkman Elliot T 
Published: January 2020

Abstract
Establishing links between neural systems and health can be challenging since there is not a one-to-one mapping between brain regions and psychological states. Building sensitive and specific predictive models of health-relevant constructs using multivariate activation patterns of brain activation is a promising new direction. We illustrate the potential of this approach by building two ‘neural signatures’ of food craving regulation (CR) using multivariate machine learning and, for comparison, a univariate contrast. We applied the signatures to two large validation samples of overweight adults who completed tasks measuring CR ability and valuation during food choice. Across these samples, the machine learning signature was more reliable. This signature decoded CR from food viewing and higher signature expression was associated with less craving. During food choice, expression of the regulation signature was stronger for unhealthy foods and inversely related to subjective value, indicating that participants engaged in CR despite never being instructed to control their cravings. Neural signatures thus have the potential to measure spontaneous engagement of mental processes in the absence of explicit instruction, affording greater ecological validity. We close by discussing the opportunities and challenges of this approach, emphasizing what machine learning tools bring to the field of health neuroscience.
Exchange of information: the challenge ahead—Bermuda International Academy of Estate and Trust Law Tokyo May 2019
Authors: Robinson Keith 
Published: January 2020

Abstract
Bermuda has been engaging in tax information exchange with other jurisdictions since the 1980s. This article, which is based upon a paper presented at the annual meeting of the International Academy of Estate and Trusts Law in Tokyo, Japan in May 2019, looks at the historical trend towards information exchange. The article considers in detail the system now in place under Bermuda law for the production of information pursuant to tax information exchange agreements (TIEAs). This requires a court order and the reported case law dealing with challenges to these TIEA orders provides a useful insight into the nature and range of the requests being made by foreign tax authorities.