Miracle-dz/UniFAR-FTUs huggingface dataset:
A Cyclin A—Myb-MuvB—Aurora B network regulates the choice between mitotic cycles and polyploid endoreplication cycles

Cells switch to polyploid endoreplication cycles during development, wound healing, and cancer. We used integrated approaches in Drosophila to determine how mitotic cycles are remodeled into endoreplication cycles, and how similar this remodeling is between developmental and induced endoreplicating cells (devECs and iECs). We found that while only devECs had a dampened E2F1 transcriptome, repression of a Cyclin A - Myb-MuvB - Aurora B mitotic network promoted endoreplication in both devECs and iECs. Cyclin A associated with and activated Myb-MuvB to induce transcription of mitotic genes, with expression of one, Aurora B, being key for mitotic commitment. Knockdown of Cyclin A, Myb, Aurora B, or downstream cytokinetic proteins induced distinct types of endoreplication, suggesting that repression of different mitotic network steps may explain the known diversity of polyploid cycles. These findings reveal how remodeling of a mitotic network promotes polyploid cycles that contribute to development, wound healing, and cancer.
Botulinum toxin type A injection increases range of motion in hip, knee and ankle joint contractures of children with cerebral palsy.

OBJECTIVES This study aims to evaluate the clinical outcomes of children with spastic type cerebral palsy (CP) treated with botulinum toxin type A (BoNT-A) injection for lower limb contracture and the influence of age, gender, functional level and degree of initial contracture on treatment outcomes. PATIENTS AND METHODS Clinical records at pre-BoNT-A injection and post-BoNT-A injections of 153 sessions of a total of 118 consecutive children (67 boys, 51 girls; mean age 5.9±2.6 years; range, 2.5-16 years) were retrospectively evaluated. Degrees of pre- and post-injection contracture were evaluated. Post-injection supplemental casting for 10 days was recorded in all cases. Less than 20° of hip flexion contracture, more than 30° of hip abduction, a negative prone Ely test, less than 50° of popliteal angle and at least 5° of ankle dorsiflexion values at post-injection were accepted as sufficient clinical improvement. RESULTS Sufficient post-injection range of motion (ROM) was observed in 80% of cases with hip flexion contracture, in 45% of cases with hip adduction contracture, in 84% of cases with knee flexion contracture and in 77% of cases with ankle equinus contracture. Prone Ely test that was positive in 60% of cases with knee extension contracture was negative at post-injection. Improvement in contractures were prominent in children with lesser degree initial contractures. CONCLUSION Botulinum toxin type A injection increases ROM in hip, knee and ankle joint contractures in CP. Although age, gender and functional level may influence the clinical outcomes, pre-treatment level of contracture is the main determinant in improvement in ROM at post-injection.
Comparison of T2*GRE and DSC-PWI for hemorrhage detection in acute ischemic stroke patients: Pooled analysis of the EPITHET, DEFUSE 2, and SENSE 3 stroke studies

Aims The objective of this study was to compare the diagnostic performance of the baseline pre-contrast images of dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) with conventional T2*gradient recalled echo (GRE) imaging for detection of hemorrhage in acute ischemic stroke patients. Material and methods T2*GRE and DSC-PWI from 393 magnetic resonance imaging scans from 221 patients enrolled in three prospective stroke studies were independently evaluated by two readers blinded to clinical and other imaging data. Agreement between T2*GRE and DSC-PWI for the presence of hemorrhage, and acute hemorrhagic transformation, was assessed using the kappa statistic. Inter-reader agreement was also assessed using the kappa statistic. Results Agreement between the baseline images of DSC-PWI and T2*GRE regarding the presence of hemorrhage was almost perfect (kreader 1 : 0.90, 95% confidence interval 0.86–0.95 and kreader 2 : 0.91, 95% confidence interval 0.87–0.96). Agreement between the sequences was still higher for detection of acute hemorrhagic transformation (kreader 1 : 0.94, 95% confidence interval 0.91–0.98 and kreader 2 : 0.95, 95% confidence interval 0.92–0.98). Inter-reader agreement for detection of hemorrhage was also almost perfect for both T2*GRE (k: 0.95, 95% confidence interval 0.91–0.98) and DSC-PWI (k: 0.96, 95% confidence interval 0.93–0.99). Acute hemorrhagic transformation detected on T2*GRE was missed on DSC-PWI by one or both readers in 5/393 (1.3%) scans. Conclusion The almost perfect statistical agreement between DSC-PWI and conventional T2*GRE suggests that DSC-PWI is sufficient for hemorrhage screening prior to thrombolysis in stroke patients. T2*GRE can therefore be omitted when DSC-PWI is included, thereby shortening the acute ischemic stroke magnetic resonance imaging protocol and expediting treatment. Trial registration: ClinicalTrials.gov Identifier: NCT02586415.
Comparison of survival rate and risk of revision for mobile-bearing and fixed-bearing total knee replacements.

OBJECTIVES This study aims to determine whether there is a difference in the rate of survival and risk of revision for mobile-bearing (MB) compared with fixed-bearing (FB) total knee replacements (TKRs). PATIENTS AND METHODS This prospective observational study included 1,571 cemented non-posterior-stabilized TKRs without patellar resurfacing with the subsequent revision surgery in 63 patients (23 males, 40 females; mean age 69.7 years; range, 46.5 to 85.5 years). The group of FB TKRs consisted of 756 non-revised and 31 revised implants. The group of MB TKRs included 752 non-revised and 32 revised knees. We determined the survival rate of TKR with Kaplan-Meier method and the relative risk (RR) of the revision in relation to the type of the insert. The analysis of the RR was divided into subgroups based on the time to revision and the reason for revision. RESULTS No significant difference was found between FB and MB TKRs regarding the cumulative survival rate and the RR of total revision for any reasons. In the subgroup of early revisions for any reason, 2.22-fold increased risk of revision was found in the MB (p=0.02). The risk of late revisions for any reason in MB was lower than the risk in FB (RR 0.27; p=0.009). Higher risk of revision for instability was found in the subgroup of early revisions in MB (RR 23.8; p=0.03). MB was associated with significantly lower risk of total (RR 0.46; p=0.049) and late revisions for aseptic loosening (RR 0.14; p=0.008). CONCLUSION No differences were found in the cumulative survival rates between MB and FB TKRs. MB TKRs were associated with a lower risk of revision due to aseptic loosening in comparison with FB TKRs. MB inserts represented a significant risk factor only for early revisions due to instability.
Plasmodium vivax and Plasmodium falciparum infection in Neotropical primates in the western Amazon, Brazil

The Brazilian Amazon is endemic for malaria and natural infections by Plasmodium spp. have been detected in Neotropical primates. Despite the diversity of primate species in the region, studies on infections by these agents are limited. The aim of the present study was to investigate the frequency of infection by Plasmodium vivax and P. falciparum in free‐born primates that were kept in captivity, in the western Amazon, Brazil. Blood samples were collected from 98 Neotropical primates. Detection of P. vivax and P. falciparum DNA was performed using a semi‐nested PCR, and the amplified products were sequenced. Plasmodium spp. DNA was detected in 6.12% (6/98) of the primates. P. vivax, and P. falciparum DNA was detected in 2.04% (2/98) and 4.08% (4/98) of these mammals, respectively. Sequencing and phylogenetic analysis confirmed the results obtained from the semi‐nested PCR. The presence of infected non‐human primates (NHP) can be auxiliary in the maintenance of P. falciparum and P. vivax and may have implications for the malaria surveillance and control in the Brazilian Amazon. It is necessary to structure an efficient surveillance system for the aetiological agents of malaria that infect NHP and humans to reduce the risk of Plasmodium spp. introduction into new areas, to protect all susceptible species.
phz1 contributes much more to phenazine‐1‐carboxylic acid biosynthesis than phz2 in Pseudomonas aeruginosa rpoS mutant

Pseudomonas aeruginosa PAO1, a common opportunistic bacterial pathogen, contains two phenazine‐biosynthetic operons, phz1 (phzA1B1C1D1E1F1G1) and phz2 (phzA2B2C2D2E2F2G2). Each of two operons can independently encode a set of enzymes involving in the biosynthesis of phenazine‐1‐carboxylic acid. As a global transcriptional regulator, RpoS mediates a lot of genes involving secondary metabolites biosynthesis in many bacteria. In an other previous study, it was reported that RpoS deficiency caused overproduction of pyocyanin, a derivative of phenazine‐1‐carboxylic acid in P. aeruginosa PAO1. But it is not known how RpoS mediates the expression of each of two phz operons and modulates phenazine‐1‐carboxylic acid biosynthesis in detail. In this study, by deleting the rpoS gene in the mutant PNΔphz1 and the mutant PNΔphz2, we found that the phz1 operon contributes much more to phenazine‐1‐carboxylic acid biosynthesis than the phz2 operon in the absence of RpoS. With the construction of the translational and transcriptional fusion vectors with the truncated lacZ reporter gene, we demonstrated that RpoS negatively regulates the expression of phz1 and positively controls the expression of phz2, and the regulation of phenazine‐1‐carboxylic acid biosynthesis mediated by RopS occurs at the posttranscriptional level, not at the transcriptional level. Obviously, two copies of phz operons and their differential expression mediated by RpoS might help P. aeruginosa adapt to its diverse environments and establish infection in its hosts.
Dosage reduction and discontinuation of biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis: protocol for a pragmatic, randomised controlled trial (the BIOlogical Dose OPTimisation (BIODOPT) trial)

Introduction The The BIOlogical Dose OPTimisation (BIODOPT) trial is a pragmatic, multicentre, randomised controlled, open-label, parallel-group, equivalence study designed to evaluate tapering of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) in sustained clinical remission or low disease activity (LDA). Traditionally, these patients maintain standard dosage of bDMARD lifelong; however, recent studies indicate that a significant proportion of patients in sustained remission or LDA can taper their bDMARD and maintain stable disease activity. Thus, this trial aims to evaluate whether a disease activity-guided tapering strategy for bDMARDs will enable a significant dosage reduction while maintaining disease activity compared with usual care. From the individual patient’s standpoint as well as from a societal perspective, it would be advantageous if bDMARDs could be reduced or even discontinued while maintaining disease activity. Methods and analysis A total of 180 patients with RA, PsA or axSpA treated with bDMARDs and in clinical remission/LDA during the past 12 months will be enrolled from four centres in Denmark. Patients will be randomised in a ratio of 2:1 to either disease activity-guided tapering of bDMARDs (intervention group) or continuation of bDMARDs as usual care (control group). The primary objective is the difference between the two groups in the proportion of patients who have reduced their inclusion dosage of bDMARDs to 50% or less while maintaining stable disease activity at 18 months follow-up. Ethics and dissemination The study is approved by the ethics committee of Northern Jutland, Denmark (N-20170073) and by the Danish Medicine Agency. Patient research partner KHH contributed to refinement of the protocol and approved the final manuscript. Results will be disseminated through publication in international peer-reviewed journals. Trial registration number 2017-001970-41; Pre-results.
Associations between Polymorphisms in the Solute Carrier Family 6 Member 3 and the Myelin Basic Protein Gene and Posttraumatic Stress Disorder.

BACKGROUND Previous research showed inconsistent results concerning a possible association between solute carrier family 6 member 3 (SLC6A3) gene polymorphisms and dopamine symptoms of posttraumatic stress disorder (PTSD). Several studies also indicate that the myelin basic protein (MBP) gene is of importance in the etiology of several psychiatric disorders. The aim of this study was to investigate the relation of distinct SLC6A3 and MBP gene polymorphisms with PTSD and whether SLC6A3 and MBP genotypes contribute to PTSD symptom severity. SUBJECTS AND METHODS The study included 719 individuals who had experienced war trauma in the South Eastern Europe (SEE). Genotypes of variable number tandem repeat (VNTR) polymorphism within the SLC6A3 gene were assessed in 696 participants, and the single nucleotide polymorphism (SNP) rs12458282 located within the MBP gene region was genotyped in a total of 703 subjects. The Mini International Neuropsychiatric Interview, the Clinical Administrated PTSD Scale (CAPS) and Brief Symptom Inventory (BSI), were used for data collection. RESULTS No significant differences concerning the investigated SLC6A3 and MBP polymorphisms was identifiable between PTSD and non PTSD participants. Also we could not detect significant influence of these distinct SLC6A3 and MBP alleles on the severity of PTSD symptoms (CAPS) or BSI scores. However, the results of MBP rs12458282 within the patients with lifetime PTSD may point to a possible correlation of the major allele (T) with elevated CAPS scores. CONCLUSIONS Our results do not support an association of the analysed SLC6A3 and MBP gene polymorphisms with PTSD in war traumatized individuals. We found that there is a possibility for a correlation of the T allele rs12458282 within the MBP gene with higher CAPS scores in lifetime PTSD patients which would need to be tested in a sample providing more statistical power.
Cassie-Baxter Surfaces for Reversible, Barrier-Free Integration of Microfluidics and 3D Cell Culture.

3D cell culture and microfluidics both represent powerful tools for replicating critical components of the cell microenvironment; however, challenges involved in integration of the two and compatibility with standard tissue culture protocols still represent a steep barrier to widespread adoption. Here we demonstrate the use of engineered surface roughness in the form of microfluidic channels to integrate 3D cell-laden hydrogels and microfluidic fluid delivery. When a liquid hydrogel precursor solution is pipetted onto a surface containing open microfluidic channels, the solid/liquid/air interface becomes pinned at sharp edges such that the hydrogel forms the "fourth wall" of the channels upon solidification. We designed Cassie-Baxter microfluidic surfaces that leverage this phenomenon, making it possible to have barrier-free diffusion between the channels and hydrogel; in addition, sealing is robust enough to prevent leakage between the two components during fluid flow, but the sealing can also be reversed to facilitate recovery of the cell/hydrogel material after culture. This method was used to culture MDA-MB-231 cells in collagen, which remained viable and proliferated while receiving media exclusively through the microfluidic channels over the course of several days.
Osteosarcoma cell-derived exosomes affect tumor microenvironment by specific packaging of microRNAs.

Bone microenvironment provides growth and survival signals essential for osteosarcoma (OS) initiation and progression. OS cells regulate communications inside tumor microenvironment through different ways and, among all, tumor-derived exosomes support cancer progression and metastasis. To define the contribution of OS-derived exosomes inside the microenvironment, we investigated the effects induced in bone remodelling mechanism and tumor angiogenesis. We demonstrated that exosomes promoted osteoclasts differentiation and bone resorption activity. Furthermore, exosomes potentiated tube formation of endothelial cells and increased angiogenic markers expression. We therefore investigated the miRNA cargo from exosomes and their parental cells by performing small RNA sequencing through NGS Illumina platform. Hierarchical clustering highlighted a unique molecular profile of exosomal miRNA; bioinformatic analysis by DIANA-mirPath revealed that miRNAs identified take part in various biological processes and carcinogenesis. Among these miRNAs, some were already known for their involvement in the tumor microenvironment establishment, as miR-148a and miR-21-5p. Enforced expression of miR-148a and miR-21-5p in Raw264.7 and Huvec cells recapitulated the effects induced by exosomes. Overall, our study highlighted the importance of OS exosomes in tumor microenvironment, also by a specific packaging of miRNAs.
The CiTAS scale for evaluating taste alteration induced by chemotherapy: state of the art on its clinical use

Background: Cancer is the leading cause of death worldwide. Of the various therapeutic approaches, chemotherapy is the most widely used treatment. Among the various side effects associated with this treatment, taste alterations (TAs) have received little attention, even though they have a serious impact on the nutritional aspect and quality of life (QoL) of patients. TAs concern 75% of the patients receiving chemotherapy, and this figure is still considered to be underestimatedbeacuse could be due both to inadequate attention and to the absence of specific subjective tools able to fully evaluate TAs in patients undergoing chemotherapy. Methods: A review by querying CINAHL, PubMed, Scopus and Google Scholar databases about the current status of use of the CiTAS self-evaluation scale, was performed. Results: From critical reading of the selected reports, it can be said that until now CiTAS has not been used to a large extent for evaluating taste, even at a late stage in patients undergoing chemotherapy. However, the results and the selected reports seem to indicate hope for its wider use. Conclusions: In literature, CITAS scale has been used on very heterogeneous populations and not adequately studied in specific care settings, its use within controlled trials could implement its spread. Correct and subjective evaluation of TAs would allow the planning of specific and personalized interventions aimed at providing adequate nutrition to support the maintenance and/or achievement of a correct body mass index. All this could contribute significantly to a better perception of QoL in patients undergoing chemotherapy. (www.actabiomedica.it)
Variability in catheter-associated asymptomatic bacteriuria rates among individual nurses in intensive care units: An observational cross-sectional study

Catheter-associated asymptomatic bacteriuria (CAABU) is frequent in intensive care units (ICUs) and contributes to the routine use of antibiotics and to antibiotic-resistant infections. While nurses are responsible for the implementation of CAABU-prevention guidelines, variability in how individual nurses contribute to CAABU-free rates in ICUs has not been previously explored. This study’s objective was to examine the variability in CAABU-free outcomes of individual ICU nurses. This observational cross-sectional study used shift-level nurse-patient data from the electronic health records from two ICUs in a tertiary medical center in the US between July 2015 and June 2016. We included all adult (18+) catheterized patients with no prior CAABU during the hospital encounter and nurses who provided their care. The CAABU-free outcome was defined as a 0/1 indicator identifying shifts where a previously CAABU-free patient remained CAABU-free (absence of a confirmed urine sample) 24–48 hours following end of shift. The analytical approach used Value-Added Modeling and a split-sample design to estimate and validate nurse-level CAABU-free rates while adjusting for patient characteristics, shift, and ICU type. The sample included 94 nurses, 2,150 patients with 256 confirmed CAABU cases, and 21,729 patient shifts. Patients were 55% male, average age was 60 years. CAABU-free rates of individual nurses varied between 94 and 100 per 100 shifts (Wald test: 227.88, P<0.001) and were robust in cross-validation analyses (correlation coefficient: 0.66, P<0.001). Learning and disseminating effective CAABU-avoidance strategies from top-performers throughout the nursing teams could improve quality of care in ICUs.
Enhancing Quality of Service metrics for high fan-in Node.js applications by optimising the network stack : Leveraging IX: The Dataplane Operating System

This thesis investigates the feasibility of porting Node.js, a JavaScript web application framework and server, to IX, a dataplane operating system specifically developed to meet the needs of high performance microsecond-computing type of applications in a datacentre setting. We show that porting requires extensions to the IX kernel to support UDS polling, which we implement. We develop a distributed load generator to benchmark the framework. The results show that running Node.js on IX improves throughput by up to 20.6\%, latency by up to 5.23×, and tail latency by up to 5.68× compared to a Linux baseline.We show how server side request level reordering affect the latency distribution, predominantly in cases where the server is load saturated.Finally, due to various limitations of IX, we are unable at this time to recommend running Node.js on IX in a production environment, despite improved metrics in all test cases. However, the limitations are not fundamental, and could be resolved in future work.
Design and Preclinical Development of TransCon PTH, an Investigational Sustained‐Release PTH Replacement Therapy for Hypoparathyroidism

Hypoparathyroidism (HP) is a condition of parathyroid hormone (PTH) deficiency leading to abnormal calcium and phosphate metabolism. The mainstay of therapy consists of vitamin D and calcium supplements, as well as adjunct Natpara (PTH(1‐84)). However, neither therapy optimally controls urinary calcium (uCa) or significantly reduces the incidence of hypercalcemia and hypocalcemia. TransCon PTH, a sustained‐release prodrug of PTH(1‐34) in development for the treatment of HP, was designed to overcome these limitations. To determine the pharmacokinetics and pharmacodynamics of TransCon PTH, single and repeat s.c. dose studies were performed in rats and monkeys. TransCon PTH demonstrated a half‐life of 28 and 34 hours in rats and monkeys, respectively. After repeated dosing, an infusion‐like profile of the released PTH, characterized by low peak‐to‐trough levels, was obtained in both species. In intact rats and monkeys, daily subcutaneous administration of TransCon PTH was associated with increases in serum calcium (sCa) levels and decreases in serum phosphate levels (sP). In monkeys, at a single dose of TransCon PTH that increased sCa levels within the normal range, a concurrent decrease in uCa excretion was observed. In 4‐week repeat‐dose studies in intact rats and monkeys, uCa excretion was comparable to controls across all dose levels despite increases in sCa levels. Further, in a rat model of HP, TransCon PTH normalized sCa and sP levels 24 hours per day. This was in contrast to only transient trends toward normalization of sCa and sP levels with an up to 6‐fold higher molar dose of PTH(1‐84). After repeated dosing to HP rats, uCa excretion transiently increased, corresponding to increases in sCa above normal range, but at the end of the treatment period, uCa excretion was generally comparable to sham controls. TransCon PTH was well tolerated and the observed pharmacokinetics and pharmacodynamics were in line with the expected action of physiological replacement of PTH. © 2019 American Society for Bone and Mineral Research.