bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-Reported Outcomes from a 1-Year, Real-World, Head-to-Head Comparison of OnabotulinumtoxinA and Topiramate for Headache Prevention in Adults With Chronic Migraine
Authors: Blumenfeld Andrew M. , Patel Atul T. , Turner Ira M. , Mullin Kathleen B. , Manack Adams Aubrey , Rothrock John F. 
Published: September 2020

Introduction/Objective: Chronic migraine (CM) is associated with impaired health-related quality of life and substantial socioeconomic burden, but many people with CM are underdiagnosed and do not receive appropriate preventive treatment. OnabotulinumtoxinA and topiramate have demonstrated efficacy (treatment benefit under ideal conditions) for the prevention of headaches in people with CM in clinical trials, but real-world studies suggest markedly different clinical effectiveness (treatment benefit based on a blend of efficacy and tolerability). This study sought to evaluate patient-reported outcomes (PROs) of onabotulinumtoxinA versus topiramate immediate release for people with CM. Methods: FORWARD was a prospective, multicenter, randomized, parallel-group, open-label, phase 4 study comparing onabotulinumtoxinA 155 U every 12 weeks with topiramate 50 to 100 mg/day for ≤36 weeks in people with CM. PROs measured included the Headache Impact Test (HIT-6), 9-item Patient Health Questionnaire Quick Depression Assessment (PHQ-9), Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP), and Functional Impact of Migraine Questionnaire (FIMQ). Results: A total of 282 patients were randomized and treated with onabotulinumtoxinA (n = 140) or topiramate (n = 142). From baseline to week 30, mean HIT-6 test scores improved significantly in patients taking onabotulinumtoxinA compared with topiramate ( P < .001). Improvements in depression over time were observed via larger changes in PHQ-9 scores with onabotulinumtoxinA than topiramate ( P < .001). Work productivity assessed via WPAI:SHP scores revealed significant improvements with onabotulinumtoxinA versus topiramate in Work Productivity Loss ( P = .024) and Activity Impairment ( P < .001) domains. Results from the FIMQ also revealed a larger reduction from baseline with onabotulinumtoxinA vs topiramate ( P < .0001). Conclusion: OnabotulinumtoxinA treatment had more favorable real-world effectiveness than topiramate on depression, headache impact, functioning and daily living, activity, and work productivity. The overall study results suggest that the beneficial effects on a range of PROs are the result of improved effectiveness when onabotulinumtoxinA is used as preventive treatment for CM. Trial Registration: ClinicalTrials.gov: NCT02191579; https://clinicaltrials.gov/ct2/show/NCT02191579
Characteristics of US Adults Delaying Dental Care Due to the COVID-19 Pandemic
Authors: Kranz A.M. , Gahlon G. , Dick A.W. , Stein B.D. 
Published: September 2020

Background: Coronavirus disease 2019 (COVID-19) has disrupted the delivery of health care services, including dental care. The objective of this study was to quantify and describe US adults who delayed dental care due to the COVID-19 pandemic. Methods: We analyzed cross-sectional responses collected from a nationally representative and long-running panel survey of US adults conducted in late May and early June 2020 (response rate = 70%). The survey included questions about dental care delayed due to the COVID-19 pandemic, purpose of the delayed dental visits, timing of future dental visits, and demographic information. Pearson’s chi-square tests were used to determine if rates of delayed dental care varied by subgroup. A multivariable regression model, adjusted for age, race, Hispanic ethnicity, census division, and rurality, was estimated to predict the odds of reporting delayed dental care. Results: Nearly half of respondents (46.7%) reported delaying going to the dentist or receiving dental care due to the COVID-19 pandemic. Among adults who reported delaying dental care due to the pandemic, 74.7% reported delaying a checkup, 12.4% reported delaying care to address something that was bothering them, and 10.5% reported delaying care to get planned treatment. About 44.4% of adults reported that they planned to visit the dentist within the next 3 mo. In the multivariable regression model, only living in an urban (vs. rural) area was associated with significantly higher odds of delayed dental care due to the pandemic (odds ratio: 1.5; 95% confidence interval: 1.1, 2.1). Conclusions: Nearly half of US adults reported delaying dental care due to the COVID-19 pandemic during the spring of 2020. Our results offer insight into the experiences of patients seeking dental care this spring and the economic challenges faced by dental providers due to the pandemic. Knowledge Transfer Statement: This article describes US adults who delayed dental care due to the COVID-19 pandemic. Results can be used by clinicians and policymakers to understand delayed care during the pandemic.
The combination of inspiratory muscle training and high-flow nasal cannula oxygen therapy for promoting weaning outcomes in difficult-to-wean patients: protocol for a randomised controlled trial
Authors: Patsaki Irini , Christakou Anna , Papadopoulos Emmanouel , Katartzi Martha , Kouvarakos Alexandros , Siempos Ilias , Tsimouris Dimitris , Skoura Anastasia , Xatzimina Antonina , Malachias Sotirios , Koulouris Νikolaos , Grammatopoulou Eirini , Zakinthinos Spiros , Ischaki Eleni 
Published: September 2020

BackgroundAccording to the literature, 20–30% of intubated patients are difficult to wean off mechanical ventilation and have a prolonged intensive care unit (ICU) stay with detrimental effects on muscle strength, functional ability and quality of life. Inspiratory muscle training (IMT)viaa threshold device has been proposed as an effective exercise for minimising the effects of mechanical ventilation on respiratory muscles of critically ill patients with prolonged weaning. In addition, high-flow nasal cannula (HFNC) oxygen has been proved to provide efficient support for both high- and low-risk patients after extubation, thus preventing re-intubation.Material and methodsA randomised controlled trial was designed to assess the efficacy of combining IMT and HFNC as therapeutic strategies for patients with high risk for weaning failure. Once patients with prognostic factors of difficult weaning are awake, ventilated with support settings and cooperative, they will be randomised to one of the two following study groups: intervention group (IMT and HFNC) and control group (IMT and Venturi mask). IMT will start as soon as possible. Each allocated oxygen delivery device will be applied immediately after extubation. IMT intervention will continue until patients' discharge from ICU. The primary outcome is the rate of weaning failure. Secondary outcomes are maximal inspiratory and expiratory strength, endurance of respiratory muscles, global muscle strength, functional ability and quality of life along with duration of ventilation (days) and ICU and hospital length of stay.ConclusionThe present study could significantly contribute to knowledge of how best to treat patients with difficult weaning and high risk of re-intubation.
Deficits in skilled motor and auditory learning in a rat model of Rett syndrome
Authors: Adcock Katherine S. , Blount Abigail E. , Morrison Robert A. , Alvarez-Dieppa Amanda , Kilgard Michael P. , Engineer Crystal T. , Hays Seth A. 
Published: September 2020

Abstract
Background
Rett syndrome is an X-linked neurodevelopmental disorder caused by a mutation in the gene MECP2. Individuals with Rett syndrome display developmental regression at an early age, and develop a range of motor, auditory, cognitive, and social impairments. Several studies have successfully modeled some aspects of dysfunction and Rett syndrome-like phenotypes in transgenic mouse and rat models bearing mutations in the MECP2 gene. Here, we sought to extend these findings and characterize skilled learning, a more complex behavior known to be altered in Rett syndrome.

Methods
We evaluated the acquisition and performance of auditory and motor function on two complex tasks in heterozygous female Mecp2 rats. Animals were trained to perform a speech discrimination task or a skilled forelimb reaching task.

Results
Our results reveal that Mecp2 rats display slower acquisition and reduced performance on an auditory discrimination task than wild-type (WT) littermates. Similarly, Mecp2 rats exhibit impaired learning rates and worse performance on a skilled forelimb motor task compared to WT.

Conclusions
Together, these findings illustrate novel deficits in skilled learning consistent with clinical manifestation of Rett syndrome and provide a framework for development of therapeutic strategies to improve these complex behaviors.
Single-cell transcriptome analysis of tumor and stromal compartments of pancreatic ductal adenocarcinoma primary tumors and metastatic lesions
Authors: Lin Wei , Noel Pawan , Borazanci Erkut H. , Lee Jeeyun , Amini Albert , Han In Woong , Heo Jin Seok , Jameson Gayle S. , Fraser Cory , Steinbach Margaux , Woo Yanghee , Fong Yuman , Cridebring Derek , Von Hoff Daniel D. , Park Joon Oh , Han Haiyong 
Published: September 2020

Abstract
Background
Solid tumors such as pancreatic ductal adenocarcinoma (PDAC) comprise not just tumor cells but also a microenvironment with which the tumor cells constantly interact. Detailed characterization of the cellular composition of the tumor microenvironment is critical to the understanding of the disease and treatment of the patient. Single-cell transcriptomics has been used to study the cellular composition of different solid tumor types including PDAC. However, almost all of those studies used primary tumor tissues.

Methods
In this study, we employed a single-cell RNA sequencing technology to profile the transcriptomes of individual cells from dissociated primary tumors or metastatic biopsies obtained from patients with PDAC. Unsupervised clustering analysis as well as a new supervised classification algorithm, SuperCT, was used to identify the different cell types within the tumor tissues. The expression signatures of the different cell types were then compared between primary tumors and metastatic biopsies. The expressions of the cell type-specific signature genes were also correlated with patient survival using public datasets.

Results
Our single-cell RNA sequencing analysis revealed distinct cell types in primary and metastatic PDAC tissues including tumor cells, endothelial cells, cancer-associated fibroblasts (CAFs), and immune cells. The cancer cells showed high inter-patient heterogeneity, whereas the stromal cells were more homogenous across patients. Immune infiltration varies significantly from patient to patient with majority of the immune cells being macrophages and exhausted lymphocytes. We found that the tumor cellular composition was an important factor in defining the PDAC subtypes. Furthermore, the expression levels of cell type-specific markers for EMT+ cancer cells, activated CAFs, and endothelial cells significantly associated with patient survival.

Conclusions
Taken together, our work identifies significant heterogeneity in cellular compositions of PDAC tumors and between primary tumors and metastatic lesions. Furthermore, the cellular composition was an important factor in defining PDAC subtypes and significantly correlated with patient outcome. These findings provide valuable insights on the PDAC microenvironment and could potentially inform the management of PDAC patients.
Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs
Authors: Castellani Christina A. , Longchamps Ryan J. , Sumpter Jason A. , Newcomb Charles E. , Lane John A. , Grove Megan L. , Bressler Jan , Brody Jennifer A. , Floyd James S. , Bartz Traci M. , Taylor Kent D. , Wang Penglong , Tin Adrienne , Coresh Josef , Pankow James S. , Fornage Myriam , Guallar Eliseo , O’Rourke Brian , Pankratz Nathan , Liu Chunyu , Levy Daniel , Sotoodehnia Nona , Boerwinkle Eric , Arking Dan E. 
Published: September 2020

AbstractBackgroundMitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.MethodsTo investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout ofTFAM, a regulator of mtDNA replication, via CRISPR-Cas9.ResultsThirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10− 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10− 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the “neuroactive ligand receptor interaction” KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10− 12), as well as theTFAMknockout methylation (P = 4.41 × 10− 4) and expression (P = 4.30 × 10− 4) studies.ConclusionsThese results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.
Accelerated long-term forgetting in healthy older adults predicts cognitive decline over 1 year
Authors: Wearn Alfie R. , Saunders-Jennings Esther , Nurdal Volkan , Hadley Emma , Knight Michael J. , Newson Margaret , Kauppinen Risto A. , Coulthard Elizabeth J. 
Published: September 2020

Abstract
Background
Here, we address a pivotal factor in Alzheimer’s prevention—identifying those at risk early, when dementia can still be avoided. Recent research highlights an accelerated forgetting phenotype as a risk factor for Alzheimer’s disease. We hypothesized that delayed recall over 4 weeks would predict cognitive decline over 1 year better than 30-min delayed recall, the current gold standard for detecting episodic memory problems which could be an early clinical manifestation of incipient Alzheimer’s disease. We also expected hippocampal subfield volumes to improve predictive accuracy.

Methods
Forty-six cognitively healthy older people (mean age 70.7 ± 7.97, 21/46 female), recruited from databases such as Join Dementia Research, or a local database of volunteers, performed 3 memory tasks on which delayed recall was tested after 30 min and 4 weeks, as well as Addenbrooke’s Cognitive Examination III (ACE-III) and CANTAB Paired Associates Learning. Medial temporal lobe subregion volumes were automatically measured using high-resolution 3T MRI. The ACE-III was repeated after 12 months to assess the change in cognitive ability. We used univariate linear regressions and ROC curves to assess the ability of tests of delayed recall to predict cognitive decline on ACE-III over the 12 months.

Results
Fifteen of the 46 participants declined over the year (≥ 3 points lost on ACE-III). Four-week verbal memory predicted cognitive decline in healthy older people better than clinical gold standard memory tests and hippocampal MRI. The best single-test predictor of cognitive decline was the 4-week delayed recall on the world list (R2 = .123, p = .018, β = .418). Combined with hippocampal subfield volumetry, 4-week verbal recall identifies those at risk of cognitive decline with 93% sensitivity and 86% specificity (AUC = .918, p < .0001).

Conclusions
We show that a test of accelerated long-term forgetting over 4 weeks can predict cognitive decline in healthy older people where traditional tests of delayed recall cannot. Accelerated long-term forgetting is a sensitive, easy-to-test predictor of cognitive decline in healthy older people. Used alone or with hippocampal MRI, accelerated forgetting probes functionally relevant Alzheimer’s-related change. Accelerated forgetting will identify early-stage impairment, helping to target more invasive and expensive molecular biomarker testing.
Production of probiotic Mozzarella cheese by incorporating locally isolated Lactobacillus acidophilus
Authors: Mukhtar Hamid , Yaqub Saima , Haq Ikram ul 
Published: September 2020

Abstract
Purpose
The present study was conducted to isolate and screen the potential probiotic strains for incorporation in Mozzarella cheese.

Methods
Probiotic cultures were isolated from different randomly purchased yogurt samples and were identified as Lactobacillus sp., Bifidobacteria sp., and Pediococcus sp. after morphological and biochemical characterization. Heat tolerance of isolates was tested at 55 °C and 65 °C to determine the survival of isolates in conditions similar to commercial cheese production. Lactobacillus acidophilus (S2) showed remarkable heat tolerance among all strains and was therefore selected to assess the probiotic potential. It showed good survival at acidic pH values (2–3). Moreover, it also showed > 50% tolerance to bile salt and was resistant to antibiotics, chloramphenicol, tetracycline, gentamycin, and vancomycin and also exhibited anti-microbial activity against Salmonella typhimurium, Escherichia coli, and Staphylococcus aureus. Thus, heat-tolerant Lactobacillus acidophilus (S2) isolate was an ideal strain for incorporation in Mozzarella cheese as probiotics. Three types of cheeses viz., cheese A with free cells of Lactobacillus acidophilus (S2), cheese B with encapsulated cells of Lactobacillus acidophilus (S2), and control cheese having no probiotics, were made.

Result
Microbiological analysis of prepared cheese revealed lesser loss of Lactobacillus acidophilus (S2) from encapsulated form (3.41 × 108 CFU/mL) compared to free cells of Lactobacillus acidophilus (S2) (1.10 × 107 CFU/mL). Coliforms were observed in control cheese after 10 days of storage, whereas no coliforms were observed in cheese A and cheese B even after 15 days of storage. Organoleptic properties of cheese A and cheese B were almost the same with an acceptability score of 2.7 ± 0.1 and 2.65 ± 0.1, respectively. Control cheese got the lowest scores after 15 days of storage.

Conclusion
The addition of probiotics in cheese not only prolongs the shelf-life of cheese but also increases the organoleptic properties of the cheese, making cheese a good delivery system for probiotics.
Early experiences of radiographers in Ireland during the COVID-19 crisis
Authors: Foley Shane J. , O’Loughlin Anne , Creedon Jill 
Published: September 2020

Abstract
Background
Imaging is crucial for assessing the severity and progression of COVID-19. Radiographers are amongst the first-line health professionals that may be exposed to infected persons. This work describes the early experience of radiographers in Ireland to the impact of COVID-19 using two electronic surveys distributed 6 weeks apart. Results were analysed using descriptive statistics and thematic analysis.

Results
A total of 370 responded to the first survey and 276 the second, with all six Irish health regions represented. Three quarters of radiographers (77%) reported having adequate personal protective equipment (PPE) available to them. However, almost half of the radiographers were inadvertently exposed to COVID-19-positive patients without appropriate PPE, largely attributed to poor communication and testing. Anxiety levels while initially high, reduced substantially 6 weeks into the crisis period. However, obvious distress was noted amongst some respondents. Forty percent of radiographers reported burnout symptoms due to the COVID-19 crisis and 30% reported considering changing jobs or retiring since the COVID-19 outbreak.

Conclusion
Clear communication regarding changing protocols and importantly patients’ infectious status are essential to safeguard healthcare workers and to minimise unnecessary anxiety and distress. Attention is required to staff mental health including the identification of burnout symptoms to prevent long-term negative consequences of the pandemic on radiography services.
Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE
Authors: Kurte Mónica , Vega-Letter Ana María , Luz-Crawford Patricia , Djouad Farida , Noël Danièle , Khoury Maroun , Carrión Flavio 
Published: September 2020

Abstract
Background
Mesenchymal stem cells (MSCs) have been recognized for their regenerative and anti-inflammatory capacity which makes them very attractive to cell therapy, especially those ones to treat inflammatory and autoimmune disease. Two different immune-phenotypes have been described for MSCs depending on which Toll-like receptor (TLR) is activated. MSC1 is endowed with a pro-inflammatory phenotype following TLR4 activation with LPS. On the other hand, anti-inflammatory MSC2 is induced by the activation of TLR3 with Poly(I:C). High immunoplasticity of MSCs is a matter of concern in cell-based therapies. In this study, we investigated whether a single stimulus can induce both types of MSCs through a differential activation of TLR4 with LPS.

Methods
MSCs were activated with LPS following a short exposure of 1-h (MSCs-LPS1h) or long-time exposure for 48 h (MSCs-LPS48h), and then, we evaluated the biological response in vitro, the immunosuppressive capacity of MSCs in vitro, and the therapeutic potential of MSCs in an experimental autoimmune encephalomyelitis (EAE) mouse model.

Results
Our results showed that 1-h LPS exposure induced a MSC1 phenotype. Indeed, MSCs-LPS1h expressed low levels of NO/iNOS and decreased immunosuppressive capacity in vitro without therapeutic effect in the EAE model. In contrast, MSCs-LPS48h achieved a MSC2-like phenotype with significant increase in the immunosuppressive capacity on T cell proliferation in vitro, together with an improved in the therapeutic effect and higher Treg, compared to unstimulated MSCs. Furthermore, we determine through the MSCs-TLR4KO that the expression of TLR4 receptor is essential for MSCs’ suppressive activity since TLR4 deletion was associated with a diminished suppressive effect in vitro and a loss of therapeutic effect in vivo.

Conclusions
We demonstrate that MSCs display a high immunoplasticity commanded by a single stimulus, where LPS exposure time regulated the MSC suppressive effect leading into either an enhanced or an impairment therapeutic activity. Our results underscore the importance of phenotype conversion probably related to the TLR4 expression and activation, in the design of future clinical protocols to treat patients with inflammatory and autoimmune diseases.