bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic therapy in an RNA toxicity mouse model with an antisense oligonucleotide therapy targeting a non-CUG sequence within the DMPK 3′UTR RNA
Authors: Yadava Ramesh S , Yu Qing , Mandal Mahua , Rigo Frank , Bennett C Frank , Mahadevan Mani S 
Published: March 2020

Abstract
Myotonic dystrophy type 1 (DM1), the most common adult muscular dystrophy, is an autosomal dominant disorder caused by an expansion of a (CTG)n tract within the 3′ untranslated region (3′UTR) of the dystrophia myotonica protein kinase (DMPK) gene. Mutant DMPK mRNAs are toxic, present in nuclear RNA foci and correlated with a plethora of RNA splicing defects. Cardinal features of DM1 are myotonia and cardiac conduction abnormalities. Using transgenic mice, we have demonstrated that expression of the mutant DMPK 3′UTR is sufficient to elicit these features of DM1. Here, using these mice, we present a study of systemic treatment with an antisense oligonucleotide (ASO) (ISIS 486178) targeted to a non-CUG sequence within the 3′UTR of DMPK. RNA foci and DMPK 3′UTR mRNA levels were reduced in both the heart and skeletal muscles. This correlated with improvements in several splicing defects in skeletal and cardiac muscles. The treatment reduced myotonia and this correlated with increased Clcn1 expression. Furthermore, functional testing showed improvements in treadmill running. Of note, we demonstrate that the ASO treatment reversed the cardiac conduction abnormalities, and this correlated with restoration of Gja5 (connexin 40) expression in the heart. This is the first time that an ASO targeting a non-CUG sequence within the DMPK 3′UTR has demonstrated benefit on the key DM1 phenotypes of myotonia and cardiac conduction defects. Our data also shows for the first time that ASOs may be a viable option for treating cardiac pathology in DM1.
Resolution of Inflammation and Gut Repair in IBD: Translational Steps Towards Complete Mucosal Healing
Authors: Ho Gwo-tzer , Cartwright Jennifer A , Thompson Emily J , Bain Calum C , Rossi Adriano G 
Published: March 2020

Abstract
Despite significant recent therapeutic advances, complete mucosal healing remains a difficult treatment target for many patients with inflammatory bowel diseases (IBD) to achieve. Our review focuses on the translational concept of promoting resolution of inflammation and repair as a necessary adjunctive step to reach this goal. We explore the roles of inflammatory cell apoptosis and efferocytosis to promote resolution, the new knowledge of gut monocyte-macrophage populations and their secreted prorepair mediators, and the processes of gut epithelial repair and regeneration to bridge this gap. We discuss the need and rationale for this vision and the tangible steps toward integrating proresolution therapies in IBD.
A close look at the contingencies of founders’ effect on venture performance
Authors: Grilli Luca , Jensen Paul H , Murtinu Samuele , Park Haemin Dennis 
Published: March 2020

AbstractStudies show that founders’ industry-specific experience is beneficial to venture performance. However, we know little on the contingencies associated with such an effect. Using a panel dataset of 338 Italian high-tech ventures, we find that founders’ industry-specific experience positively affects venture performance. However, changes in the top management team (TMT) during the initial phases of the venture’s life weaken the positive relationship between founders’ industry-specific experience and venture performance, whereas founders’ functional heterogeneity does not. We further find evidence of substitution effects between founders’ human and social capital affecting venture performance, such that the effect of founders’ industry-specific experience on venture performance is attenuated when a subset of founders had common background prior to founding their venture.
Myectomy versus alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy
Authors: Afanasyev Alexander V , Bogachev-Prokophiev Alexander V , Kashtanov Maxim G , Astapov Dmitriy A , Zalesov Anton S , Budagaev Sergei A , Sharifulin Ravil M , Idov Eduard M , Zheleznev Sergei I 
Published: March 2020

Abstract

OBJECTIVES
There is very little evidence comparing the safety and efficacy of alcohol septal ablation versus septal myectomy for a septal reduction in patients with hypertrophic obstructive cardiomyopathy. This study aimed to compare the immediate and long-term outcomes of these procedures.

METHODS
Following propensity score matching, we retrospectively analysed outcomes in 105 patients who underwent myectomy and 105 who underwent septal ablation between 2011 and 2017 at 2 reference centres.

RESULTS
The mean age was 51.9 ± 14.3 and 52.2 ± 14.3 years in the myectomy and ablation groups, respectively (P = 0.855), and postoperative left ventricular outflow tract gradients were 13 (10–19) mmHg vs 16 (12–26) mmHg; P = 0.025. The 1-year prevalence of the New York Heart Association class III–IV was higher in the ablation group (none vs 6.4%; P = 0.041). The 5-year overall survival rate [96.8% (86.3–99.3) after myectomy and 93.5% (85.9–97.1) after ablation; P = 0.103] and cumulative incidence of sudden cardiac death [0% and 1.9% (0.5–7.5), respectively P = 0.797] did not differ between the groups. The cumulative reoperation rate within 5 years was lower after myectomy than after ablation [2.0% (0.5–7.6) vs 14.6% (8.6–24.1); P = 0.003]. Ablation was associated with a higher reoperation risk (subdistributional hazard ratio = 5.9; 95% confidence interval 1.3–26.3, P = 0.020). At follow-up, left ventricular outflow tract gradient [16 (11–20) vs 23 (15–59) mmHg; P &lt; 0.001] and prevalence of 2+ mitral regurgitation (1.1% vs 10.6%; P = 0.016) were lower after myectomy than after ablation.

CONCLUSIONS
Both procedures improved functional capacity; however, myectomy better-resolved classes III–IV of heart failure. Septal ablation was associated with higher reoperation rates. Myectomy demonstrated benefits in gradient relief and mitral regurgitation elimination. The results suggest that decreasing rates of myectomy procedures need to be investigated and reconsidered.
A Critical Analysis of the Literature on Time-to-Antibiotics in Suspected Sepsis
Authors: Weinberger Jeremy , Rhee Chanu , Klompas Michael 
Published: March 2020

Abstract
The Surviving Sepsis Campaign recommends immediate antibiotics for all patients with suspected sepsis and septic shock, ideally within 1 hour of recognition. Immediate antibiotic treatment is lifesaving for some patients, but a substantial fraction of patients initially diagnosed with sepsis have noninfectious conditions. Aggressive time-to-antibiotic targets risk promoting antibiotic overuse and antibiotic-associated harms for this subset of the population. An accurate understanding of the precise relationship between time-to-antibiotics and mortality for patients with possible sepsis is therefore critical to finding the best balance between assuring immediate antibiotics for those patients who truly need them versus allowing clinicians some time for rapid investigation to minimize the risk of overtreatment and antibiotic-associated harms for patients who are not infected. More than 30 papers have been published assessing the relationship between time-to-antibiotics and outcomes, almost all of which are observational cohort studies. Most report significant associations but all have important limitations. Key limitations include focusing just on the sickest subset of patients (only patients requiring intensive care and/or patients with septic shock), blending together mortality estimates from patients with very long intervals until antibiotics with patients with shorter intervals and reporting a single blended (and thus inflated) estimate for the average increase in mortality associated with each hour until antibiotics, and failure to control for large potential confounders including patients’ presenting signs and symptoms and granular measures of comorbidities and severity of illness. In this study, we elaborate on these potential sources of bias and try to distill a better understanding of what the true relationship between time-to-antibiotics and mortality may be for patients with suspected sepsis or septic shock.
Human Challenge Studies to Accelerate Coronavirus Vaccine Licensure
Authors: Eyal Nir , Lipsitch Marc , Smith Peter G 
Published: March 2020

AbstractControlled human challenge trials of SARS-CoV-2 vaccine candidates could accelerate the testing and potential rollout of efficacious vaccines. By replacing conventional phase 3 testing of vaccine candidates, such trials may subtract many months from the licensure process, making efficacious vaccines available more quickly. Obviously, challenging volunteers with this live virus risks inducing severe disease and possibly even death. However, we argue that such studies, by accelerating vaccine evaluation, could reduce the global burden of coronavirus-related mortality and morbidity. Volunteers in such studies could autonomously authorize the risks to themselves, and their net risk could be acceptable if participants comprise healthy young adults, who are at relatively low risk of serious disease following natural infection, if they have a high baseline risk of natural infection, and if during the trial they receive frequent monitoring and, following any infection, the best available care.
Inclusion, Diversity, Access, and Equity (IDA&E) Roadmap: Infectious Diseases Society of America’s Commitment to the Future
Authors: Desruisseaux Mahalia S , Tan Tina Q 
Published: March 2020

Abstract
This article identifies the major elements of the strategic road map for the Infectious Diseases Society of America’s (IDSA) Inclusion, Diversity, Access, and Equity (IDA&E) initiative and discusses the long-term goals and the proposed steps needed to achieve these goals.
Structure, dynamics and function of the evolutionarily changing biliverdin reductase B family
Authors: Duff Michael R , Redzic Jasmina S , Ryan Lucas P , Paukovich Natasia , Zhao Rui , Nix Jay C , Pitts Todd M , Agarwal Pratul , Eisenmesser Elan Zohar 
Published: March 2020

Abstract
Biliverdin reductase B (BLVRB) family members are general flavin reductases critical in maintaining cellular redox with recent findings revealing that BLVRB alone can dictate cellular fate. However, as opposed to most enzymes, the BLVRB family remains enigmatic with an evolutionarily changing active site and unknown structural and functional consequences. Here, we applied a multi-faceted approach that combines X-ray crystallography, NMR and kinetics methods to elucidate the structural and functional basis of the evolutionarily changing BLVRB active site. Using a panel of three BLVRB isoforms (human, lemur and hyrax) and multiple human BLVRB mutants, our studies reveal a novel evolutionary mechanism where coenzyme ‘clamps’ formed by arginine side chains at two co-evolving positions within the active site serve to slow coenzyme release (Positions 14 and 78). We find that coenzyme release is further slowed by the weaker binding substrate, resulting in relatively slow turnover numbers. However, different BLVRB active sites imposed by either evolution or mutagenesis exhibit a surprising inverse relationship between coenzyme release and substrate turnover that is independent of the faster chemical step of hydride transfer also measured here. Collectively, our studies have elucidated the role of the evolutionarily changing BLVRB active site that serves to modulate coenzyme release and has revealed that coenzyme release is coupled to substrate turnover.
Concordance between treatment recommendations provided by IBM Watson for Oncology and a multidisciplinary tumor board for breast cancer in China
Authors: Zhao Xiaoyao , Zhang Yinbin , Ma Xingcong , Chen Yinxi , Xi Junfeng , Yin Xiaoran , Kang Huafeng , Guan Haitao , Dai Zijun , Liu Di , Zhao Fang , Sun Chu , Li Zongfang , Zhang Shuqun 
Published: March 2020

AbstractObjectiveWatson for Oncology (WFO), an artificial intelligence from IBM Corporation, can provide a treatment plan by analyzing patient’s disease characteristics. The present study was performed to examine the concordance between treatment recommendations proposed by WFO and the multidisciplinary tumor board at our center. The aim was to explore the feasibility of using WFO for breast cancer cases in China and to ascertain the ways to make WFO more suitable for Chinese patients with breast cancer.MethodsData from 302 breast cancer patients treated at the Second Affiliated Hospital of Xi’an Jiaotong University between October 2016 and February 2018 was retrieved and retrospectively analyzed by WFO. The recommendations were divided into ‘recommended’, ‘considered’ and ‘not recommended’ groups. Results were considered concordant when oncologists’ recommendations were categorized as ‘recommended’ or ‘for consideration’ by WFO.ResultsThe concordance rate of 200 subjects with postoperative adjuvant therapy was 77%. However, the rate was 27.5% in the remaining 102 cases with metastatic disease receiving either first-line or no treatment. Further analysis demonstrated that inconsistencies were mainly due to different choices of chemotherapy regimens. Subgroup study indicates that tumor stage, receptor status and age also had influences at the concordance rate.ConclusionThe results of this study suggest that WFO is a promising artificial intelligence system for the treatment of breast cancer. These findings can also serve as a reference framework for the inclusion of artificial intelligence in the ongoing medical reform in China.
Diagnostic Yield of Initial and Consecutive Blood Cultures in Children With Cancer and Febrile Neutropenia
Authors: Haeusler Gabrielle M , De Abreu Lourenco Richard , Clark Hannah , Thursky Karin A , Slavin Monica A , Babl Franz E , Mechinaud Francoise , Alvaro Frank , Clark Julia , Padhye Bhavna , Phillips Marianne , Super Leanne , Tapp Heather , Walwyn Thomas , Ziegler David , Phillips Robert , Worth Leon J 
Published: March 2020

Abstract

Background
The timing and necessity of repeated blood cultures (BCs) in children with cancer and febrile neutropenia (FN) are unknown. We evaluated the diagnostic yield of BCs collected pre- and post-empiric FN antibiotics.

Methods
Data collected prospectively from the Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study were used. Diagnostic yield was calculated as the number of FN episodes with a true bloodstream infection (BSI) detected divided by the number of FN episodes that had a BC taken.

Results
A BSI was identified in 13% of 858 FN episodes. The diagnostic yield of pre-antibiotic BCs was higher than of post-antibiotic cultures (12.3% vs 4.4%, P &lt; .001). Two-thirds of the post-antibiotic BSIs were associated with a new episode of fever or clinical instability, and only 2 new BSIs were identified after 48 hours of empiric antibiotics and persistent fever. A contaminated BC was identified more frequently in post-antibiotic cultures.

Conclusions
In the absence of new fever or clinical instability, BCs beyond 48 hours of persistent fever have limited yield. Opportunity exists to optimize BC collection in this population and reduce the burden of unnecessary tests on patients, healthcare workers, and hospitals.
Incidental finding of adenocarcinoma in a gallbladder lumen with no wall involvement
Authors: Pinheiro Rodrigo Nascimento , Fontoura Renata P , Rodrigues Letícia L P , Netto José Donato S , Sarmento Bruno José Q 
Published: March 2020

Abstract
Gallbladder cancer (GBC) is a rare disease characterized by its aggressiveness. Resection with free tumour margins is the sole curative treatment and, in incidental findings, surgical reapproach is recommended for segmentectomy IVb and V or wedge resection of the gallbladder fossa and lymphadenectomy. Here we report a case of gallbladder adenocarcinoma as an incidental finding in a fragment in its lumen with no wall involvement evidentiated. The patient was reoperated for resection of the gallbladder bed with hepatic hilum and cystic duct lymphadenectomy, later evidentiated as free of residual disease. The normality of the bile ducts evidenced by imaging studies, in addition to signs of chronic cholecystitis corroborate to GBC diagnosis. We suspect that the fragment was detached gallbladder polypoid neoplastic lesion. Despite the lack of clinical manifestations, the fast surgical interventions and the histopathological analysis of the material was probably a prognostic determinant for the patient.
Luminosity–duration relations and luminosity functions of repeating and non-repeating fast radio bursts
Authors: Hashimoto Tetsuya , Goto Tomotsugu , Wang Ting-Wen , Kim Seong Jin , Ho Simon C-C , On Alvina Y L , Lu Ting-Yi , Santos Daryl Joe D 
Published: March 2020

ABSTRACT
Fast radio bursts (FRBs) are mysterious radio bursts with a time-scale of approximately milliseconds. Two populations of FRB, namely repeating and non-repeating FRBs, are observationally identified. However, the differences between these two and their origins are still cloaked in mystery. Here we show the time-integrated luminosity–duration (Lν–wint, rest) relations and luminosity functions (LFs) of repeating and non-repeating FRBs in the FRB Catalogue project. These two populations are obviously separated in the Lν-wint, rest plane with distinct LFs, i.e. repeating FRBs have relatively fainter Lν and longer wint, rest with a much lower LF. In contrast with non-repeating FRBs, repeating FRBs do not show any clear correlation between Lν and wint, rest. These results suggest essentially different physical origins of the two. The faint ends of the LFs of repeating and non-repeating FRBs are higher than volumetric occurrence rates of neutron star (NS) mergers and accretion-induced collapse (AIC) of white dwarfs (WDs), and are consistent with those of soft gamma-ray repeaters (SGRs), Type Ia supernovae (SNe Ia), magnetars, and WD mergers. This indicates two possibilities: either (i) faint non-repeating FRBs originate in NS mergers or AIC and are actually repeating during the lifetime of the progenitor, or (ii) faint non-repeating FRBs originate in any of SGRs, SNe Ia, magnetars, and WD mergers. The bright ends of LFs of repeating and non-repeating FRBs are lower than any candidates of progenitors, suggesting that bright FRBs are produced from a very small fraction of the progenitors regardless of the repetition. Otherwise, they might originate in unknown progenitors.
Fetal antisense oligonucleotide therapy for congenital deafness and vestibular dysfunction
Authors: Wang Lingyan , Kempton J Beth , Jiang Han , Jodelka Francine M , Brigande Alev M , Dumont Rachel A , Rigo Frank , Lentz Jennifer J , Hastings Michelle L , Brigande John V 
Published: March 2020

AbstractDisabling hearing loss impacts ∼466 million individuals worldwide with 34 million children affected. Gene and pharmacotherapeutic strategies to rescue auditory function in mouse models of human deafness are most effective when administered before hearing onset, after which therapeutic efficacy is significantly diminished or lost. We hypothesize that preemptive correction of a mutation in the fetal inner ear prior to maturation of the sensory epithelium will optimally restore sensory function. We previously demonstrated that transuterine microinjection of a splice-switching antisense oligonucleotide (ASO) into the amniotic cavity immediately surrounding the embryo on embryonic day 13–13.5 (E13–13.5) corrected pre-mRNA splicing in the juvenile Usher syndrome type 1c (Ush1c) mouse mutant. Here, we show that this strategy only marginally rescues hearing and partially rescues vestibular function. To improve therapeutic outcomes, we microinjected ASO directly into the E12.5 inner ear. A single intra-otic dose of ASO corrects harmonin RNA splicing, restores harmonin protein expression in sensory hair cell bundles, prevents hair cell loss, improves hearing sensitivity, and ameliorates vestibular dysfunction. Improvements in auditory and vestibular function were sustained well into adulthood. Our results demonstrate that an ASO pharmacotherapeutic administered to a developing organ system in utero preemptively corrects pre-mRNA splicing to abrogate the disease phenotype.
Association of metabolic syndrome with glioblastoma: a retrospective cohort study and review
Authors: Rogers Lisa R , Ostrom Quinn T , Schroer Julia , Vengoechea Jaime , Li Li , Gerson Stanton , Nock Charles J , Machtay Mitchell , Selman Warren , Lo Simon , Sloan Andrew E , Barnholtz-Sloan Jill S 
Published: March 2020

Abstract

Background
Metabolic syndrome is identified as a risk factor for the development of several systemic cancers, but its frequency among patients with glioblastoma and its association with clinical outcomes have yet to be determined. The aim of this study was to investigate metabolic syndrome as a risk factor for and affecting survival in glioblastoma patients.

Methods
A retrospective cohort study, consisting of patients with diagnoses at a single institution between 2007 and 2013, was conducted. Clinical records were reviewed, and clinical and laboratory data pertaining to 5 metabolic criteria were extrapolated. Overall survival was determined by time from initial surgical diagnosis to date of death or last follow-up.

Results
The frequency of metabolic syndrome among patients diagnosed with glioblastoma was slightly greater than the frequency of metabolic syndrome among the general population. Within a subset of patients (n = 91) receiving the full schedule of concurrent radiation and temozolomide and adjuvant temozolomide, median overall survival was significantly shorter for patients with metabolic syndrome compared with those without. In addition, the presence of all 5 elements of the metabolic syndrome resulted in significantly decreased median survival in these patients.

Conclusions
We identified the metabolic syndrome at a slightly higher frequency in patients with diagnosed glioblastoma compared with the general population. In addition, metabolic syndrome with each of its individual components is associated with an overall worse prognosis in patients receiving the standard schedule of radiation and temozolomide after adjustment for age.
Concomitant Pulmonary Cystic Echinococcosis and Aspergillosis in a Male Child
Authors: Aboksari Maryam Safari , Safavi Moeinadin 
Published: March 2020

Abstract
Co-infection of cystic echinococcosis and aspergillosis is a rare finding. The patient was a 10-year-old boy complaining of chest pain and malaise with a cyst in the right lung who underwent surgical resection of the cyst. Medical therapy with albendazole was started for the patient with the initial clinical impression of cystic echinococcosis. Later, the microscopic evaluation revealed a laminated layer of cystic echinococcosis involved by acute angle branching hyaline hyphae with septate. Thus, the diagnosis of a cystic echinococcosis and aspergillosis co-infection was established. Surgery is the mainstay of treatment along with anthelminthic and anti-fungal therapy, especially in immunocompromised patients.
Reduction of Surgical Smoke in the Operating Room
Authors: Tagle Melissa 
Published: March 2020

Abstract
In the operating room, the surgical team faces a wide range of occupational hazards, one of which is the exposure to surgical smoke. The team is regularly exposed to surgical smoke that is generated by the thermal destruction of tissue from the use of electrocautery or heat-generating devices. There has been a growing interest in the potential health hazard that exposure to surgical smoke poses, subsequently generating the need for a more robust safety practice by the surgical team. The necessity to gather evidence to support the implementation of strategies that promote adoption of a smoke-free operating room is the aim of this research. Exposure to surgical fumes can potentially have a detrimental impact on an individual's personal and professional life; thus, it is important to take measures to reduce the risk.