Miracle-dz/UniFAR-FTUs huggingface dataset:
Nuclear magnetic resonance (NMR)-based metabolome profile evaluation in dairy cows with and without displaced abomasum

Abstract Background Displaced abomasum (DA) is a condition of dairy cows that severely impacts animal welfare and causes huge economic losses. Objective To assess the metabolic status of the disease using metabolomics in serum, urine and liver samples aimed at both water soluble and lipid soluble fractions. Methods Fifty Holstein multiparous cows with DA (42 left, 8 right) and 20 clinically healthy Holstein multiparous cows were used. Left DA was associated with concomitant ketosis in 19 animals and right in two. NMR-based metabolomics approach and hematological and biochemical analyses were performed. Statistical analysis was carried out on 1H-NMR data after they have been normalized using PQN method. Results Contrary to generated PCA score plots the OPLS-supervised method revealed differences between healthy animals and diseased ones based on serum water-soluble samples. While water and lipid soluble metabolites decreased in serum samples, fatty acid fractions and cholesterol were increased in liver samples in DA affected cows. The metabolomic and chemical profiles clearly revealed that cows with DA (especially with LDA) were at risk of ketosis and fatty liver. Serum hippuric acid concentration was significantly higher in healthy cows in comparison with LDA, whereas serum glycine concentration was reported higher for healthy when compared to RDA affected animals. Conclusion A biochemical network and pathway mapping revealed ‘valine, leucine and isoleucine biosynthesis’ and ‘phenylalanine, tyrosine and tryptophan biosynthesis’ as the most probable altered metabolic pathway in DA condition. Serum was advocated as the optimal biological matrix for the 1H-NMR analysis.
Prediction of dolutegravir pharmacokinetics and dose optimization in neonates via physiologically based pharmacokinetic (PBPK) modelling.

BACKGROUND Only a few antiretroviral drugs (ARVs) are recommended for use during the neonatal period and there is a need for more to be approved to increase treatment and prophylaxis strategies. Dolutegravir, a selective integrase inhibitor, has potential for treatment of HIV infection and prophylaxis of transmission in neonates. OBJECTIVES To model the pharmacokinetics of dolutegravir in neonates and to simulate a theoretical optimal dosing regimen. METHODS The physiologically based pharmacokinetic (PBPK) model was built incorporating the age-related changes observed in neonates. Virtual neonates between 0 and 28 days were simulated. The model was validated against observed clinical data for raltegravir and midazolam in neonates, prior to the prediction of dolutegravir pharmacokinetics. RESULTS Both raltegravir and midazolam passed the criteria for model qualification, with simulated data within 1.8-fold of clinical data. The qualified model predicted the pharmacokinetics for several multidose regimens of dolutegravir. Regimen 6 involved 5 mg doses with a 48 h interval from Day 1-20, increasing to 5 mg once daily on Week 3, yielding AUC and Ctrough values of 37.2 mg·h/L and 1.3 mg/L, respectively. These exposures are consistent with those observed in paediatric patients receiving dolutegravir. CONCLUSIONS Dolutegravir pharmacokinetics were successfully simulated in the neonatal PBPK model. The predictions suggest that during the first 3 weeks of life a 5 mg dose administered every 48 h may achieve plasma exposures needed for therapy and prophylaxis.
Adults’ Preferences for Behavior Change Techniques and Engagement Features in a Mobile App to Promote 24-Hour Movement Behaviors: Cross-Sectional Survey Study

Background There is a limited understanding of components that should be included in digital interventions for 24-hour movement behaviors (physical activity [PA], sleep, and sedentary behavior [SB]). For intervention effectiveness, user engagement is important. This can be enhanced by a user-centered design to, for example, explore and integrate user preferences for intervention techniques and features. Objective This study aimed to examine adult users’ preferences for techniques and features in mobile apps for 24-hour movement behaviors. Methods A total of 86 participants (mean age 37.4 years [SD 9.2]; 49/86, 57% female) completed a Web-based survey. Behavior change techniques (BCTs) were based on a validated taxonomy v2 by Abraham and Michie, and engagement features were based on a list extracted from the literature. Behavioral data were collected using Fitbit trackers. Correlations, (repeated measures) analysis of variance, and independent sample t tests were used to examine associations and differences between and within users by the type of health domain and users’ behavioral intention and adoption. Results Preferences were generally the highest for information on the health consequences of movement behavior self-monitoring, behavioral feedback, insight into healthy lifestyles, and tips and instructions. Although the same ranking was found for techniques across behaviors, preferences were stronger for all but one BCT for PA in comparison to the other two health behaviors. Although techniques fit user preferences for addressing PA well, supplemental techniques may be able to address preferences for sleep and SB in a better manner. In addition to what is commonly included in apps, sleep apps should consider providing tips for sleep. SB apps may wish to include more self-regulation and goal-setting techniques. Few differences were found by users’ intentions or adoption to change a particular behavior. Apps should provide more self-monitoring (P=.03), information on behavior health outcome (P=.048), and feedback (P=.04) and incorporate social support (P=.048) to help those who are further removed from healthy sleep. A virtual coach (P<.001) and video modeling (P=.004) may provide appreciated support to those who are physically less active. PA self-monitoring appealed more to those with an intention to change PA (P=.03). Social comparison and support features are not high on users’ agenda and may not be needed from an engagement point of view. Engagement features may not be very relevant for user engagement but should be examined in future research with a less reflective method. Conclusions The findings of this study provide guidance for the design of digital 24-hour movement behavior interventions. As 24-hour movement guidelines are increasingly being adopted in several countries, our study findings are timely to support the design of interventions to meet these guidelines.
Common and Challenging Behaviors Among Individuals on Long-term Opioid Therapy.

OBJECTIVE Long-term opioid therapy (LTOT) is commonly prescribed for chronic pain, despite risks such as opioid use disorder (OUD) and overdose. Caring for patients on LTOT can be difficult, given lack of evidence about assessment of challenging behaviors among patients on LTOT. To develop this evidence, a critical first step is to systematically identify the common and challenging behaviors that primary care providers encounter among patients on LTOT, and also to highlight to diverse range of behaviors encountered. METHOD We conducted a Delphi study in 42 chronic pain experts to determine consensus on how to address the top common and challenging behaviors. This paper reports on the first round of the study, which elicited a range of behaviors. We conducted thematic analysis of the behaviors and also used the Diagnostic and Statistical Manual (DSM)-5 criteria for OUD as a priori codes. RESULTS In all, 124 unique behaviors were identified by participants and coded into 4 thematic categories: concerning behaviors that map onto DSM-5 criteria for OUD, and those that do not which were: behaviors that suggest deception, signs of diversion, and nonadherence to treatment plan. Those behaviors that fell outside of OUD criteria we identified as "gray zone" behaviors. CONCLUSIONS While some of these challenging behaviors fall under the criteria for an OUD, many fall outside of this framework, making diagnosis and treatment difficult, and consensus on how to deal with these "gray zone" behaviors is vital. Future research should explore how these "gray zone" behaviors can best be assessed and managed in a primary care setting.
Children’s reliance on the non-verbal cues of a robot versus a human

Robots are used for language tutoring increasingly often, and commonly programmed to display non-verbal communicative cues such as eye gaze and pointing during robot-child interactions. With a human speaker, children rely more strongly on non-verbal cues (pointing) than on verbal cues (labeling) if these cues are in conflict. However, we do not know how children weigh the non-verbal cues of a robot. Here, we assessed whether four- to six-year-old children (i) differed in their weighing of non-verbal cues (pointing, eye gaze) and verbal cues provided by a robot versus a human; (ii) weighed non-verbal cues differently depending on whether these contrasted with a novel or familiar label; and (iii) relied differently on a robot’s non-verbal cues depending on the degree to which they attributed human-like properties to the robot. The results showed that children generally followed pointing over labeling, in line with earlier research. Children did not rely more strongly on the non-verbal cues of a robot versus those of a human. Regarding pointing, children who perceived the robot as more human-like relied on pointing more strongly when it contrasted with a novel label versus a familiar label, but children who perceived the robot as less human-like did not show this difference. Regarding eye gaze, children relied more strongly on the gaze cue when it contrasted with a novel versus a familiar label, and no effect of anthropomorphism was found. Taken together, these results show no difference in the degree to which children rely on non-verbal cues of a robot versus those of a human and provide preliminary evidence that differences in anthropomorphism may interact with children’s reliance on a robot’s non-verbal behaviors.
Data mining analysis of the PP2A cell cycle axis in mesothelioma patients

Mesothelioma is an aggressive tumor that affects thousands of people every year. The therapeutic options for patients are limited; hence, a better understanding of mesothelioma biology is crucial to improve patient survival. To find new molecular targets and therapeutic strategies related to the protein phosphatase 2A (PP2A) network, we analyzed the gene expression of known PP2A inhibitors in mesothelioma patient samples. Our analysis disclosed a general overexpression of all PP2A‐negative regulators in mesothelioma patients. Moreover, the expression of ANP32E and CIP2A genes, increased in 16% and 11% of cases, positively correlates with the ones of all the other PP2A regulators and the ones of the main cyclins and CDKs, suggesting the existence of a feed‐forward loop that might contribute to the mesothelioma progression via PP2A inactivation. Overall, our study indicates the existence of a strategic and targetable axis between PP2A inhibitors (ANP32E and CIP2A) and cell cycle regulators (cyclin B2/CDK1) and provides a valuable rationale for using a personalized combinational therapy approach to improve mesothelioma patient survival.
Transcutaneous Spinal Cord Stimulation and Motor Rehabilitation in Spinal Cord Injury: A Systematic Review

Background. Epidural spinal electrical stimulation at the lumbar spinal level evokes rhythmic muscle activation of lower-limb antagonists, attributed to the central pattern generator. However, the efficacy of noninvasive spinal stimulation for the activation of lower-limb muscles is not yet clear. This review aimed to analyze the feasibility and efficacy of noninvasive transcutaneous spinal cord stimulation (tSCS) on motor function in individuals with spinal cord injury. Methods. A search for tSCS studies was made of the following databases: PubMed; Cochrane Registry; and Physiotherapy Evidence Database (PEDro). In addition, an inverse manual search of the references cited by the identified articles was carried out. The keywords transcutaneous, non-invasive, electrical stimulation, spinal cord stimulation [Mesh term], and spinal cord injury were used. Results. A total of 352 articles were initially screened, of which 13 studies met the inclusion criteria for systematic review. The total participant sample comprised 55 persons with spinal cord injury. All studies with tSCS provided evidence of induced muscle activation in the lower and upper limbs, and applied stimulation at the level of the T11-T12 and C4-C7 interspinous space, respectively. All studies reported an increase in motor response measured by recording surface electromyography, voluntary movement, muscle strength, or function. Conclusions. Although this review highlights tSCS as a feasible therapeutic neuromodulatory strategy to enhance voluntary movement, muscle strength, and function in patients with chronic spinal cord injury, the clinical impact and efficacy of electrode location and current intensity need to be characterized in statistically powered and controlled clinical trials.
Reduced cerebral blood flow in an α-synuclein transgenic mouse model of Parkinson’s disease

There is increasing evidence that widespread cortical cerebral blood flow deficits occur early in the course of Parkinson’s disease. Although cerebral blood flow measurement has been suggested as a potential biomarker for early diagnosis of Parkinson’s disease, as well as a means for tracking response to treatment, the relationship of cerebral blood flow to α-synucleinopathy, a major pathological hallmark of Parkinson’s disease, remains unclear. Therefore, we performed arterial spin-labeling magnetic resonance imaging and diffusion tensor imaging on transgenic mice overexpressing human wild-type α-synuclein and age-matched controls to measure cerebral blood flow and degenerative changes. As reported for early-stage Parkinson’s disease, α-synuclein mice exhibited a significant reduction in cortical cerebral blood flow, which was accompanied by motor coordination deficits and olfactory dysfunction. Although no overt degenerative changes were apparent in diffusion tensor imaging images, magnetic resonance imaging volumetric analysis revealed a significant reduction in olfactory bulb volume, similar to that seen in Parkinson’s disease patients. Our data, representing the first report of cerebral blood flow deficit in an animal model of Parkinson’s disease, suggest a causative role for α-synucleinopathy in cerebral blood flow deficits in Parkinson’s disease. Thus, α-synuclein transgenic mice comprise a promising model to study Parkinson’s disease-related mechanisms of cerebral blood flow deficits and to investigate further its utility as a potential biomarker for Parkinson’s disease.
Progressive Therapeutic Exercise Program for Successful Treatment of a Postpartum Woman With a Severe Diastasis Recti Abdominis

Background:Pregnancy is the most common cause of a diastasis recti abdominis (DRA), usually occurring during the third trimester. An abnormally wide interrecti distance (IRD) from a DRA can persist up to 1 year postpartum or longer. Although some women can fully recover function with an abnormally widened IRD, in others impaired muscle contractility of the abdominals decreases trunk stability and strength during load transfer activities of daily living. Diastasis recti abdominis has also been correlated with support-related pelvic floor impairments persisting years after delivery. There is a paucity of research describing conservative interventions for DRA, and no existing clinical protocols for best practice patterns at present to guide the physical therapist. This case report describes physical therapy intervention for a postpartum patient with a large DRA. Study Design:Case study with review of the literature. Case Description:This report describes physical therapy intervention for a 32-year-old gravida 2, para 2 (G2P2) woman referred at 7 weeks postpartum with a DRA measuring 11.5 cm IRD at the umbilicus and extending more than 9 cm vertically along the linea alba. Outcome:The patient attended 18 sessions from evaluation to discharge over a 4-month period. Interrecti distance was reduced to 2.0 cm at the widest point of separation. She regained functional strength and achieved all goals for load transfer activities: standing, walking, lifting and carrying her child, and light jogging. Discussion:The patient in this case report demonstrated successful reduction of IRD of a large DRA and restoration of functional strength with physical therapy intervention. Physical therapists play an important role in identifying and treating patients with significant DRAs. However, guidelines are currently not available in the literature identifying how large of a diastasis can be conservatively treated with exercise. Interventions should include patient education on precautions with DRA, therapeutic progressive exercise with abdominal muscle retraining, and recommendations for support garments or self-bracing of recti muscles during trunk flexion.
Influence of technique on upper body force and power production during medicine ball throws

ABSTRACT This project examined the interrelationships between power production and upper body kinematics during a series of medicine ball push-press (MBP-P) throws. Twenty-five regular weight trainers (body mass = 86 ± 10 kg) performed a series of ballistic vertical MBP-P throws at loads representing 5% and 10% of their assessed 5RM bench press. Throws were performed lying supine on a force platform (1 kHz) with upper body kinematics assessed using standard infra-red motion capture techniques (0.5 kHz). Gross measures of performance and power production such as peak vertical ball velocity (Velpeak), peak force (Fpeak) and power (Ppeak) were recorded during the propulsive phase of the movement. Comparative analyses indicated that despite significant reductions in Velpeak from the 5% to 10% loads (P < 0.001), Fpeak remained largely unchanged (P = 0.167). Analysis of inter-trial variability showed that the gross measures of performance and power were relatively stable (Coefficient of Variation [CV%] <13%), while most upper limb segmental kinematics varied considerably between trials (CV% up to 70%). This project highlights the complexity of the relationships between power production and upper body kinematics during light load ballistic MBP-P throwing. Additionally, it shows how trained athletes can achieve similar outcomes during ballistic movements using a variety of movement strategies.
Dual role of a GTPase conformational switch for membrane fusion by mitofusin ubiquitylation

Mitochondrial fusion requires a conformational change in α4 of the GTPase domain, followed by AAA-ATPase regulation, thus revealing striking mechanistic similarities between small and large GTPases. Mitochondria are essential organelles whose function is upheld by their dynamic nature. This plasticity is mediated by large dynamin-related GTPases, called mitofusins in the case of fusion between two mitochondrial outer membranes. Fusion requires ubiquitylation, attached to K398 in the yeast mitofusin Fzo1, occurring in atypical and conserved forms. Here, modelling located ubiquitylation to α4 of the GTPase domain, a critical helix in Ras-mediated events. Structure-driven analysis revealed a dual role of K398. First, it is required for GTP-dependent dynamic changes of α4. Indeed, mutations designed to restore the conformational switch, in the absence of K398, rescued wild-type-like ubiquitylation on Fzo1 and allowed fusion. Second, K398 is needed for Fzo1 recognition by the pro-fusion factors Cdc48 and Ubp2. Finally, the atypical ubiquitylation pattern is stringently required bilaterally on both involved mitochondria. In contrast, exchange of the conserved pattern with conventional ubiquitin chains was not sufficient for fusion. In sum, α4 lysines from both small and large GTPases could generally have an electrostatic function for membrane interaction, followed by posttranslational modifications, thus driving membrane fusion events.
TGFβ1‐induced beta‐site APP‐cleaving enzyme 2 upregulation promotes tumorigenesis through the NF‐κB signalling pathway in human gliomas

Gliomas are the most common primary malignant tumours of the central nervous system, and new molecular biomarkers are urgently needed for diagnosis and targeted therapy. Here, we report that increased beta‐site APP‐cleaving enzyme 2 (BACE2) expression is associated with increases in the grade of human glioma, the incidence of the mesenchymal molecular glioblastoma multiforme subtype and the likelihood of poor prognoses for patients. BACE2 knockdown suppressed cell invasion, cell migration and tumour growth both in vitro and in vivo, while BACE2 overexpression promoted the mesenchymal transition and cell proliferation. Furthermore, TGFβ1 stimulated BACE2 expression through Smad‐dependent signalling, which modulated TNF‐α‐induced NF‐κB activity through the PP1A/IKK pathway to promote tumorigenesis in both U87MG and U251 cells. Our study indicated that BACE2 plays a significant role in glioma development. Therefore, BACE2 is a potential therapeutic target for human gliomas due to its function and ability to be regulated.
Regional citrate versus systemic heparin anticoagulation for continuous renal replacement therapy in critically ill children

Objectives: Anticoagulation is used to prevent filter clotting in patients undergoing continuous renal replacement therapy. Regional citrate anticoagulation is associated with lower rates of bleeding complications and prolongs the filter life span; however, a number of metabolic side effects had been associated with this therapy. The aim of this study was to evaluate the effect and safety of citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill children. Methods: A retrospective comparative cohort study. Department of Pediatric Intensive Care, Acibadem Mehmet Ali Aydınlar University School of Medicine. Results: From August 2016 to August 2018, 45 patients (19 in the citrate group and 26 in the heparin group) were included. A total of 101 hemofilters were used in all therapies: 44 in the citrate group (total continuous renal replacement therapy time: 2699 h) and 57 in the heparin group (total continuous renal replacement therapy time: 2383 h). The median circuit lifetime was significantly longer for regional citrate anticoagulation (53.0; interquartile range, 40–70 h) than for heparin anticoagulation (40.25; interquartile range, 22.75–53.5 h; p = 0.025). Mortality rates were similar in both groups (31.58% vs 30.77%). The most common indication for dialysis was hypervolemia in both groups. Transfusion rates were 1.65 units (interquartile range, 0.5–2.38) with heparin and 0.8 units (interquartile range, 0.3–2.0) with citrate (p = 0.32). Clotting-related hemofilter failure occurred in 11.36% of filters in the citrate group compared with 26.31% of filters in the heparin group. Conclusion: Our study showed that citrate is superior in terms of safety and efficacy, with longer filter life span. Regional citrate should be considered as a better anticoagulation method than heparin for continuous renal replacement therapy in critically ill children.