bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sinus headache: changing the treatment paradigm
Authors: Jang David W. , Godley Frederick A. , Hachem Ralph Abi 
Published: December 2021

Purpose of review
Although the majority of patients with sinus headache do not have rhinosinusitis, many patients will unnecessarily undergo work-up and treatment for rhinosinusitis. This leads to a significant cost burden to the healthcare system. In the era of value-based care, more effective management paradigms need to be developed for sinus headache.

Recent findings
Recent efforts to classify nonrhinogenic headache, namely the International Classification of Orofacial Pain, have served as an important step in advancing our understanding of this heterogeneous condition. In addition, a review of the literature points to certain clinical features that may allow for the identification of nonrhinogenic headache based on history.

Summary
A greater understanding of nonrhinogenic headache as well as innovative tools to differentiate rhinogenic from nonrhinogenic headache are needed to change the paradigm in the management of patients with sinus headache.
Tick Paralysis Case Series
Authors: Pontiff Kristen , Woodward Christopher , McMahon Pamela 
Published: December 2021

Objectives
The aims of the study were to identify and to describe cases of pediatric tick paralysis presenting to an emergency department in southern Louisiana during an 11-year period.

Methods
We conducted a retrospective chart review of patients aged 0 to 18 years with a diagnostic code of toxic effect of venom, tick-borne viral encephalitis, Guillain-Barré syndrome, acute infective polyneuritis, or abnormality of gait from July 2005 to June 2016. Data were collected on visit month, patient age, race and sex, tick's attachment site, location of tick removal, symptoms and length of symptoms, initial diagnosis, time to appropriate diagnosis, and hospital length of stay.

Results
Nine patients aged 2 to 10 years presented with lower limb weakness and varying degrees of upper extremity ataxia or paralysis, areflexia, dysarthria, diplopia, or petechia. Five cases were accurately and rapidly diagnosed; 4 cases involved a delay in accurate diagnosis. Treatment of the misdiagnosed cases ranged from septic workup to neurologic workup, including magnetic resonance imaging. The tick was discovered by the patients' relative in 4 cases, by a primary care or emergency care physician at another facility in 3 cases, and by 1 of our emergency care physicians in 2 patients.

Conclusions
The incidence of tick paralysis in southern Louisiana is unknown. However, our case series indicates that it is likely higher than expected. Although most cases in our facility were quickly diagnosed and treated through tick removal, delayed diagnosis results in unnecessary tests, procedures, and medical costs. All of our cases fully recovered after tick removal.
Impact of CYP2B6 genotype, tuberculosis therapy, and formulation on efavirenz pharmacokinetics in infants and children under 40 months of age
Authors: Nikanjam Mina , Tran Lana , Chadwick Ellen G. , Bwakura-Dangarembizi Mutsa , Bolton Moore Carolyn , Samson Pearl , Spector Stephen A. , Chakhtoura Nahida , Jean-Philippe Patrick , Frenkel Lisa , Zimmer Bonnie , Benns Alex , Libous Jennifer , Capparelli Edmund V. 
Published: December 2021

Objective:
Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics with tuberculosis (TB) therapy, formulation, age, and CYP2B6 genotype.

Design:
Pharmacokinetic data from three IMPAACT/PACTG studies (P382, P1021, and P1070) for children initiating therapy less than 40 months of age were evaluated.

Methods:
Pharmacokinetic data were combined in a population pharmacokinetic model. Exposure from the 2-week pharmacokinetic visit was compared with changes in viral RNA between the Week 0 and Week 4 visits.

Results:
The model included 103 participants (19 on TB therapy). CYP2B6 516 genotype information was available for 82 participants (TT: 15, GT: 28, GG: 39). Median age at the first pharmacokinetic visit was 17.0 months (range: 2.0–39.0 months). Liquid formulation led to a 42% decrease in bioavailability compared with opened capsules. TB therapy (isoniazid and rifampin) led to a 29% decreased clearance, however Monte Carlo simulations demonstrated the majority of participants on TB therapy receiving standard EFV dosing to be in the target area under the curve range. Clearance was 5.3-fold higher for GG than TT genotype and 3.3-fold higher for GT than TT genotype. Age did not have a significant effect on clearance in the final model. Initial viral RNA decay was lower for patients in the lowest quartile of exposures (area under the curves) than for higher quartiles (P = 0.013).

Conclusion:
EFV dosing should account for CYP2B6 516 genotype and formulation, but does not require adjustment for concurrent TB therapy.
Surgical Guides and Prebent Titanium Improve the Planning for the Treatment of Dentofacial Deformities Secondary to Condylar Osteochondroma
Authors: Zhu Zhaokun , He Ze , Tai Yue , Liu Yao , Liu Hanghang , Luo En 
Published: December 2021

Purpose:
To investigate current Computer-Aided Design and Computer-Aided Manufacturing (CAD/CAM) technologies applied in the treatment of dentofacial deformities secondary to condylar osteochondroma and introduce a modified method with additional pre-bent titanium miniplates to improve the accuracy of operation.

Methods:
Literature review about the application of CAD/CAM in the treatment of condylar osteochondroma and secondary dentofacial deformities was conducted. And 8 patients with condylar osteochondroma and secondary dentofacial deformities were treated by the CAD/CAM cutting and drilling surgical guides as well as pre-bent titanium miniplates. Pre- and post-operative 3D-cephalometric measurement were recorded and the difference between virtual simulation and postoperative modeling images was measured. Follow-up and radiographic examinations were performed.

Results:
A total of 17 studies (including 216 patients) about the application of CAD/CAM in the treatment of dentofacial deformities secondary to condylar osteochondroma have been reported since 2010, including the 8 present patients. In our study, all patients were satisfied with the surgical outcome, without obvious relapse or evidence of temporomandibular joint disorder or other complications during follow-up; all patients avoided condylar reconstruction and sagittal split of ramus osteotomy on the ipsilateral mandible side. Comparison between simulated plans and actual postoperative outcomes showed surgical simulation plan was accurately transferred to the actual surgery.

Conclusions:
The application of CAD/CAM cutting and drilling guides as well as pre-bent titanium plates could achieve more accurate and favorable outcomes, improving the clinical planning and surgical execution for patients with condylar osteochondroma and secondary dentofacial deformities.
Socioeconomic Factors Impact the Timing of Surgical Repair for Craniosynostosis - A Regional and National Assessment
Authors: Keyho Ryan J. , Cepeda Alfredo , Greives Matthew R. , Nguyen Phuong D. 
Published: December 2021

Introduction:
Timing of repair for patients with craniosynostosis are usually categorized into early “minimally invasive” surgeries such as strip craniotomy (SC), whereas those presenting later undergoing traditional cranial vault remolding (CVR). The impact that sociodemographic and socioeconomic disparities have on time to presentation for craniosynostosis and treatment is unknown. Herein, we examined sociodemographic and socioeconomic factors among a heterogenous patient population at a single institution who underwent craniosynostosis repair and compared this cohort to a national database.

Methods:
A retrospective review of patients at UTHealth who underwent craniosynostosis repair from 2016 to 2020 was performed. The patients were divided into cohorts based on type of operation: SC or cranial vault remolding. The Kid inpatient Database (KiD) database was used to assess sociodemographic factors in relation to craniosynostosis. Univariate and multivariate logistic regression were used to determine significant predictors and differences.

Results:
Single Institution (Regional): Compared with nonHispanic white (NHW) patients, Hispanic (OR 0.11), and NonHispanic Black (NHB) (OR 0.14) had lower odds of undergoing SC. Compared to those on private insurance, patients on Medicaid (OR 0.36) had lower odds of undergoing SC. Using zip code median income levels, patients with a higher median income level had slightly higher odds of undergoing SC compared to patients with a lower median income (OR 1.000025).

KIDS (National):
Compared with non-Hispanic white patients, NHB (OR 0.32) and Asian (OR 0.47) patients had lower odds of undergoing repair before the age of 1. Compared to patients with private insurance, those with Medicaid (OR 0.67) and self-pay (OR 0.58) had lower odds of undergoing repair before the age of 1. Patients in the lowest income quartile (OR 0.68) and second lowest income quartile (OR 0.71) had lower odds of undergoing repair before the age of 1 compared to the highest quartile.

Conclusions:
Our findings indicate that sociodemographic and socioeconomic factors may play a role in diagnosis of craniosynostosis and access to care. Patients of NHB and Hispanic race, lower income quartiles by zip code, and those that use public insurance are less likely to undergo early repair, both nationally and at our institution. Further research is needed to delineate the casualty of this disparity in presentation and timing of surgery.
Characteristics and data reporting of rare disease clinical trials: Getting better but still room for improvement
Authors: Mair Nina K. , Gottowik Jürgen , Rodriguez-Esteban Raul , Seabrook Timothy J. 
Published: December 2021

ABSTRACTBackgroundIt is estimated that there are more than 7,000 rare diseases (RDs) worldwide, impacting the lives of approximately 400 million people and only 5% have an approved therapy. Facing special challenges, including patient scarceness, incomplete knowledge of the natural history and only few specialized clinical sites, clinical trials (CT) are limited, making the data from trials critical for research and clinical care. Despite the introduction of the U.S. Food and Drug Administration Amendment Act (FDAAA) in 2007 requiring certain CTs to post results on the registry ClinicalTrials.gov within 12 months following completion, compliance has been reportedly poor. Here, we describe general characteristics of RD CTs, identify trends, and evaluate result reporting practices under the FDAAA aiming to draw awareness to the problem of non-compliance.MethodsCTs conducted between 2008 and 2015 were extracted from the public U.S. trial registry ClinicalTrials.gov using the text mining software I2E (Linguamatics). Disease names were matched with rare disease names from the Orphanet Rare Disease Ontology (ORDO, v2.5, Orphanet). Statistical analyses and data visualization were performed using GraphPad Prism 7 and R (v3.5). The Student’s t-test was employed to calculate significance using p-value cut-offs of <0.05 or <0.001.ResultsWe analyzed 1,056 RD CTs of which 55.7% were phase 2, 7.7% phase 2/3 and 36.7% phase 3 trials. The studies were mostly one- and two-armed experimental CTs with the majority (60.2%) being funded by industry. Cystic fibrosis and sickle cell disease represented the most frequently investigated diseases (25.0% and 16.5%). Industry-led phase 2 RD CTs were significantly (p<0.0001) shorter than their equivalent led by academia/non-profit (22 vs. 33 months). Screening CTs completed before the end of 2015, we found that of the 725 analyzed studies, 55.2% predominantly phase 2 CTs, did not report results. Taking their potential applicability to the FDAAA into account, 25.2% industry-funded and 28.0% academia/non-profit-funded trials failed to disclose results on ClinicalTrial.gov.ConclusionRD CTs tend to be comparatively small, industry-funded studies focusing on genetic and neurologic conditions. Sponsor-related differences in study design, duration, and enrollment were observed. There are still substantial shortcomings when it comes to result publication.
Understanding Psychiatric Illness Through Natural Language Processing (UNDERPIN): Rationale, Design, and Methodology
Authors: Kishimoto Taishiro , Nakamura Hironobu , Kano Yoshinobu , Eguchi Yoko , Kitazawa Momoko , Liang Kuo-ching , Kudo Koki , Sento Ayako , Takamiya Akihiro , Horigome Toshiro , Yamasaki Toshihiko , Sunami Yuki , Kikuchi Toshiaki , Nakajima Kazuki , Tomita Masayuki , Bun Shogyoku , Momota Yuki , Sawada Kyosuke , Murakami Junichi , Takahashi Hidehiko , Mimura Masaru 
Published: December 2021

AbstractIntroductionPsychiatric disorders are diagnosed according to diagnostic criteria such as the DSM-5 and ICD-11. Basically, psychiatrists extract symptoms and make a diagnosis by conversing with patients. However, such processes often lack objectivity. In contrast, specific linguistic features can be observed in some psychiatric disorders, such as a loosening of associations in schizophrenia. The purposes of the present study are to quantify the language features of psychiatric disorders and neurocognitive disorders using natural language processing and to identify features that differentiate disorders from one another and from healthy subjects.MethodsThis study will have a multi-center prospective design. Major depressive disorder, bipolar disorder, schizophrenia, anxiety disorder including obsessive compulsive disorder and, major and minor neurocognitive disorders, as well as healthy subjects will be recruited. A psychiatrist or psychologist will conduct 30-to-60-min interviews with each participant and these interviews will be recorded using a microphone headset. In addition, the severity of disorders will be assessed using clinical rating scales. Data will be collected from each participant at least twice during the study period and up to a maximum of five times.DiscussionThe overall goal of this proposed study, the Understanding Psychiatric Illness Through Natural Language Processing (UNDERPIN), is to develop objective and easy-to-use biomarkers for diagnosing and assessing the severity of each psychiatric disorder using natural language processing. As of August 2021, we have collected a total of >900 datasets from >350 participants. To the best of our knowledge, this data sample is one of the largest in this field.Trial registrationUMIN000032141, University Hospital Medical Information Network (UMIN).
The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: the case of the spike A222V mutation
Authors: Ginex Tiziana , Marco-Marín Clara , Wieczór Miłosz , Mata Carlos P. , Krieger James , López-Redondo Maria Luisa , Francés-Gómez Clara , Ruiz-Rodriguez Paula , Melero Roberto , Sánchez-Sorzano Carlos Óscar , Martínez Marta , Gougeard Nadine , Forcada-Nadal Alicia , Zamora-Caballero Sara , Gozalbo-Rovira Roberto , Sanz-Frasquet Carla , Bravo Jeronimo , Rubio Vicente , Marina Alberto ,   The IBV-Covid19-Pipeline, Geller Ron , Comas Iñaki , Gil Carmen , Coscolla Mireia , Orozco Modesto , Llácer José Luis , Carazo José-Maria 
Published: December 2021

AbstractThe S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has now reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness.
Decrowding Expansion Pathology: Unmasking Previously Invisible Nanostructures and Cells in Intact Human Brain Pathology Specimens
Authors: Valdes Pablo A. , Yu Chih-Chieh (Jay) , Aronson Jenna , Zhao Yongxin , Bernstock Joshua D. , Bhere Deepak , An Bobae , Viapiano Mariano S. , Shah Khalid , Chiocca E. Antonio , Boyden Edward S. 
Published: December 2021

AbstractProteins are densely packed in cells and tissues, where they form complex nanostructures. Expansion microscopy (ExM) variants have been used to separate proteins from each other in preserved biospecimens, improving antibody access to epitopes. Here we present an ExM variant, decrowding expansion pathology (dExPath), which can expand proteins away from each other in human brain pathology specimens, including formalin-fixed paraffin-embedded (FFPE) clinical specimens. Immunostaining of dExPath-expanded specimens reveals, with nanoscale precision, previously unobserved cellular structures, as well as more continuous patterns of staining. This enhanced molecular staining results in observation of previously invisible disease marker-positive cell populations in human glioma specimens, with potential implications for tumor aggressiveness. dExPath results in improved fluorescence signals even as it eliminates lipofuscin-associated autofluorescence. Thus, this form of expansion-mediated protein decrowding may, through improved epitope access for antibodies, render immunohistochemistry more powerful in clinical science and diagnosis.
NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease
Authors: Myakala Komuraiah , Wang Xiaoxin X , Shults Nataliia V. , Jones Bryce A. , Yang Xiaoping , Rosenberg Avi Z , Ginley Brandon , Sarder Pinaki , Brodsky Leonid , Jang Yura , Na Chan Hyun , Qi Yue , Zhang Xu , Guha Udayan , Wu Ci , Bansal Shivani , Ma Junfeng , Cheema Amrita , Albanese Chris , Hirschey Matthew D , Yoshida Teruhiko , Kopp Jeffrey B. , Panov Julia , Levi Moshe 
Published: December 2021

ABSTRACTDiabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. In spite of the beneficial interventions available for patients with diabetes, there remains a need for additional therapeutic targets and therapies in diabetic kidney disease (DKD). Inflammation and oxidative stress are increasingly recognized as important causes of renal diseases. Inflammation is closely associated with mitochondrial damage. The molecular connection between inflammation and mitochondrial metabolism remains to be elucidated. Recently, nicotinamide adenine nucleotide (NAD+) metabolism has been found to regulate immune function and inflammation. In the present studies we tested the hypothesis that enhancing NAD metabolism could prevent inflammation in and progression of DKD. We found that treatment ofdb/dbmice with type 2 diabetes with nicotinamide riboside (NR) prevented several manifestations of kidney dysfunction (i.e., albuminuria, increased urinary kidney injury marker-1 (KIM1) excretion and pathologic changes). These effects were associated with decreased inflammation, at least in part via inhibiting the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. An antagonist of the serum stimulator of interferon genes (STING) and whole-body STING deletion in diabetic mice showed similar renoprotection. Further analysis found that NR increased SIRT3 activity and improved mitochondrial function, which led to decreased mitochondrial DNA damage, a trigger for mitochondrial DNA leakage which activates the cGAS-STING pathway. Overall, these data show that NR supplementation boosted NAD metabolism to augment mitochondrial function, reducing inflammation and thereby preventing progression of diabetic kidney disease.
Mathematical expressions describing enzyme velocity and inhibition at high enzyme concentration
Authors: Hernandez Agustin 
Published: December 2021

ABSTRACTEnzyme behaviour is typically characterised in the laboratory using very diluted solutions of enzyme. However, in vivo processes usually occur at [ST] ≈ [ET] ≈ Km. Furthermore, the study of enzyme action usually involves analysis and characterisation of inhibitors and their mechanisms. However, to date, there have been no reports proposing mathematical expressions that can be used to describe enzyme activity at high enzyme concentration apart from the simplest single substrate, irreversible case. Using a continued fraction approach, equations can be easily derived to apply to the most common cases in monosubstrate reactions, such as irreversible or reversible reactions and small molecule (inhibitor or activator) kinetic interactions. These expressions are simple and can be understood as an extension of the classical Michaelis-Menten equations. A first analysis of these expressions permits to deduce some differences at high vs low enzyme concentration, such as the greater effectiveness of allosteric inhibitors compared to catalytic ones. Also, they can be used to understand catalyst saturation in a reaction. Although they can be linearised following classical approaches, these equations also show some differences that need to be taken into account. The most important one may be the different meaning of line intersection points in Dixon plots. All in all, these expressions may be useful tools for the translation in vivo of in vitro experimental data or for modelling in vivo and biotechnological processes.
Quantitative genetic analysis of interactions in the pepper-Phytophthora capsici pathosystem
Authors: Vogel Gregory , Giles Garrett , Robbins Kelly R. , Gore Michael A. , Smart Christine D. 
Published: December 2021

ABSTRACTThe development of pepper cultivars with durable resistance to the oomycete Phytophthora capsici has been challenging due to differential interactions between the species that allow certain pathogen isolates to cause disease on otherwise resistant host genotypes. Currently, little is known about the pathogen genes that are involved in these interactions. To investigate the genetic basis of P. capsici virulence on individual pepper genotypes, we inoculated sixteen pepper accessions – representing commercial varieties, sources of resistance, and host differentials – with 117 isolates of P. capsici, for a total of 1,864 host-pathogen combinations. Analysis of disease outcomes revealed a significant effect of inter-species genotype-by-genotype interactions, although these interactions were quantitative rather than qualitative in scale. Isolates were classified into five pathogen subpopulations, as determined by their genotypes at over 60,000 single-nucleotide polymorphisms (SNPs). While absolute virulence levels on certain pepper accessions significantly differed between subpopulations, a multivariate phenotype reflecting relative virulence levels on certain pepper genotypes compared to others showed the strongest association with pathogen subpopulation. A genome-wide association study (GWAS) identified four pathogen loci significantly associated with virulence, two of which colocalized with putative RXLR effector genes and another with a polygalacturonase gene cluster. All four loci appeared to represent broad-spectrum virulence genes, as significant SNPs demonstrated consistent effects regardless of the host genotype tested. Host genotype-specific virulence variants in P. capsici may be difficult to map via GWAS, perhaps controlled by many genes of small effect or by multiple alleles that have arisen independently at the same loci.