Miracle-dz/UniFAR-FTUs huggingface dataset:
Inherited disorders of cobalamin metabolism disrupt nucleocytoplasmic transport of mRNA through impaired methylation/phosphorylation of ELAVL1/HuR

Abstract The molecular mechanisms that underlie the neurological manifestations of patients with inherited diseases of vitamin B12 (cobalamin) metabolism remain to date obscure. We observed transcriptomic changes of genes involved in RNA metabolism and endoplasmic reticulum stress in a neuronal cell model with impaired cobalamin metabolism. These changes were related to the subcellular mislocalization of several RNA binding proteins, including the ELAVL1/HuR protein implicated in neuronal stress, in this cell model and in patient fibroblasts with inborn errors of cobalamin metabolism and Cd320 knockout mice. The decreased interaction of ELAVL1/HuR with the CRM1/exportin protein of the nuclear pore complex and its subsequent mislocalization resulted from hypomethylation at R-217 produced by decreased S-adenosylmethionine and protein methyl transferase CARM1 and dephosphorylation at S221 by increased protein phosphatase PP2A. The mislocalization of ELAVL1/HuR triggered the decreased expression of SIRT1 deacetylase and genes involved in brain development, neuroplasticity, myelin formation, and brain aging. The mislocalization was reversible upon treatment with siPpp2ca, cobalamin, S-adenosylmethionine, or PP2A inhibitor okadaic acid. In conclusion, our data highlight the key role of the disruption of ELAVL1/HuR nuclear export, with genomic changes consistent with the effects of inborn errors of Cbl metabolisms on brain development, neuroplasticity and myelin formation.
Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer

Abstract Background We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28–18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76–21.25). Discussion In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration ClinicialTrials.gov identifier: CNCT02193633
Age, Daily Stress Processes, and Allostatic Load: A Longitudinal Study

Objective: The present study examined age differences in the association between daily stressors and allostatic load. Method: Participants consisted of 317 adults (34-84 years) who participated in Waves 1 (1996-1997) and 2 (between 2005 and 2009) of the Midlife Development in the United States Survey. During Wave 1, participants reported the stressors they encountered across eight consecutive days. Within-person affective reactivity slopes indexing change in negative affect from a nonstressor day to a stressor day were calculated for each participant. Affective reactivity and stressor exposure scores at Wave 1 were used to predict allostatic load at Wave 2. Results: Heightened levels of affective reactivity at Wave 1 predicted elevated levels of allostatic load at Wave 2 but only among older adults who also reported high levels of stressor exposure. No significant associations emerged for younger adults. Discussion: Daily stress processes may be one pathway through which age-related physical health declines occur.
Amplitude-Based Filtering for Video Magnification in Presence of Large Motion

Video magnification reveals important and informative subtle variations in the world. These signals are often combined with large motions which result in significant blurring artifacts and haloes when conventional video magnification approaches are used. To counter these issues, this paper presents an amplitude-based filtering algorithm that can magnify small changes in video in presence of large motions. We seek to understand the amplitude characteristic of small changes and large motions with the goal of extracting accurate signals for visualization. Based on spectrum amplitude filtering, the large motions can be removed while small changes can still be magnified by Eulerian approach. An advantage of this algorithm is that it can handle large motions, whether they are linear or nonlinear. Our experimental results show that the proposed method can amplify subtle variations in the presence of large motion, as well as significantly reduce artifacts. We demonstrate the presented algorithm by comparing to the state-of-the-art and provide subjective and objective evidence for the proposed method.
High Gut Microbiota Diversity Provides Lower Resistance against Infection by an Intestinal Parasite in Bumblebees

The microbiome, especially the gut flora, is known to affect the interaction between parasites and their hosts. In this context, a parasitic infection can be viewed as an invasion into the preexisting microbial ecological community. Hence, in addition to the intrinsic defense mechanisms of the host itself, infection success depends on the colonization resistance of the microbiota. In the bumblebee Bombus terrestris, the microbiota provides resistance to the intestinal parasite Crithidia bombi, yet which properties actually provide protection remains largely unknown. Here, we show that the community structure of the gut microbiota—in terms of bacterial operational taxonomic units (OTUs) of 16S ribosomal RNA gene sequences—before parasite exposure can be informative of the eventual infection outcome. Specifically, higher microbiota OTU diversity is associated with less resistance. However, the microbial community structure does not differ between infected and noninfected individuals or between infected individuals of varying susceptibility. This suggests that parasite infection success depends on the microbiota composition but that subsequent changes occur, although the exact alteration that occurs remains elusive. In fact, the bumblebee microbiota is surprisingly unaffected by parasite exposure and infection. Rather, the microbiota-host interaction before parasite exposure seems to be a key mechanism regulating resistance to infection.
Improving the handover and transport of critically ill pediatric patients

AIMS AND OBJECTIVES The aims of this project were to (a) determine barriers to current handover and transport process, (b) develop a new protocol and process for team-to-team handover, and (c) evaluate staff satisfaction with the new process. BACKGROUND The handover and transport of critically ill patients from the paediatric emergency department to the paediatric intensive care unit is a period of vulnerability associated with adverse events. DESIGN A mixed-methods study using a quasi-experimental design and qualitative approach. METHODS Focus groups were conducted to determine the barriers and facilitators of the current handover and transport process. Using these themes, a multidisciplinary team developed and implemented a new process including establishment of eight patient criteria for specialised transport and a standardised, interdisciplinary handover tool for team-to-team handover. Staff satisfaction was examined pre- and postintervention. RESULTS Content analysis of focus groups revealed five categories: need for improved communication, cultural dissonance among units, defects in system and processes, need for standardisation and ambiguity between providers regarding acuity. Staff members reported improvements in their perceptions of satisfaction, safety, communication and role understanding associated with the new process. CONCLUSIONS Standardisation through the establishment of severity of illness criteria and communication tools creates shared mental models and decreases risks to safety. A paradigm shift of team-to-team handover and transport is recommended. RELEVANCE TO CLINICAL PRACTICE This paper suggests the importance of improving communication during the handover and transport process through establishing standardised patient severity of illness criteria, use of standardised tools and team-to-team handover processes.
Community outbreak of serogroup B invasive meningococcal disease in Beaujolais, France, February to June 2016: from alert to targeted vaccination

In February and March 2016, four cases of serogroup B invasive meningococcal disease (IMD) occurred over 3 weeks in a small area north of Lyon in the Auvergne-Rhône-Alpes region, France. There were no deaths but two cases had sequelae. This community outbreak was caused by a rare meningococcal strain of the clonal complex ST-32, covered by the 4CMenB/Bexsero vaccine. The incidence rate for serogroup B IMD in this area was 22.5 per 100,000 inhabitants, which is above the epidemic threshold (10/100,000). The number of cases observed was significantly higher than expected in the age group of 0–24 year-olds (standardised incidence ratio: 96). These results suggested the potential emergence of this invasive strain in this sub-population. In accordance with French recommendations, it was decided to vaccinate the population aged between 2 months and 24 years, living, working or studying in the epidemic area. The vaccination campaign took place from April to September 2016. Vaccination coverage was estimated at 47% for one dose and 40% for two doses. The lowest coverage estimations were observed for the age groups younger than 3 and 15–19 years. Enhanced epidemiological and microbiological surveillance reported a fifth case in June 2016, outside the epidemic area.
The Association of Maternal Thyroid Autoimmunity During Pregnancy With Child IQ

Context Thyroperoxidase antibody (TPOAb) positivity is a major risk factor for gestational thyroid dysfunction. During the first 18 to 20 weeks of pregnancy, high concentrations of human chorionic gonadotropin (hCG) stimulate the thyroid to ensure adequate thyroid hormone availability for the developing fetus. However, TPOAb-positive women have an impaired thyroidal response to hCG stimulation. Objective To study the association of maternal TPOAb positivity during pregnancy with child IQ. Design, Setting, and Participants This study was embedded in two prospective birth cohorts: Generation R (Rotterdam, the Netherlands) and Avon Longitudinal Study of Parents and Children (ALSPAC; United Kingdom). Mother-child pairs with available data on early pregnancy TPOAb (≤18 weeks of gestation) and offspring IQ were included (n = 3637 for Generation R and n = 2396 for ALSPAC). Main Outcome Measures Child IQ at 5 to 10 years of age. Results In Generation R, TPOAb positivity was associated with a 2.0 ± 0.9-point lower mean child IQ (P = 0.03). Sensitivity analyses showed negative effect estimates already from TPOAb concentrations considerably lower than currently used manufacturer cutoffs. In ALSPAC, neither TPOAb positivity nor TPOAb concentrations below manufacturer cutoffs were associated with child IQ (TPOAb positivity: 0.7 ± 1.0; P = 0.45). Adjustment for maternal TSH or free T4 concentrations or urinary iodine/creatinine ratio did not change the results. Conclusion TPOAb positivity during pregnancy was associated with lower child IQ in Generation R but not in ALSPAC. Further studies are needed to elucidate whether differences between the study populations, such as maternal iodine status, could be the underlying cause for these differences.
Preparation of palladized carbon nanotubes encapsulated iron composites: highly efficient dechlorination for trichloroethylene and low corrosion of nanoiron

A method developed based on the capillary effect and capillary condensation theory was used to synthesize an innovative Fe/C/Pd composite in this study. This composite (Fe@CNTs@Pd) consists of carbon nanotubes (CNTs) with nanoscale zerovalent iron (NZVI) on the inner surface and palladium nanoparticles supported on the outer surface of CNTs. This structure successfully addresses the problems of high iron corrosion rate and lower utilization rate of hydrogen in the application of bimetal nanoparticles for trichloroethylene (TCE) removal. TCE degradation experiments and electrochemical tests were conducted to investigate the material properties and reaction mechanisms of the composite. It is found that the prepared composite material contribute a high level of TCE dechlorination rate and substantially reduced hydrogen production during iron corrosion in water compared with the conventional CNTs-supported bimetal materials (Fe/Pd@CNTs). Hydrogen spillover effect helps the reactivity of Fe@CNTs@Pd for TCE degradation and suppressed the galvanic cell effect, which results in a stronger resistance to corrosion. Although the Kobs of Fe@CNTs@Pd was 16.87% lower than that of Fe/Pd@CNTs, the hydrogen production rate of Fe@CNTs@Pd was 10 times slower than that of Fe/Pd@CNTs. Therefore, Fe@CNTs@Pd shows a significant reduction in the corrosion rate at a cost of slightly slower degradation of TCE. In sum, the prepared composites demonstrate important characteristics, including alleviating NZVI agglomeration, maintaining high TCE removal efficiency and reducing the corrosion of NZVI.
Outcomes of cementless joint prosthesis versus tendon interposition for trapeziometacarpal osteoarthritis: a prospective study

We compared 84 patients with the Ivory trapeziometacarpal prosthesis versus 62 with ligament reconstruction and tendon interposition arthroplasty performed for osteoarthritis. There were 134 women and 12 men with a mean age of 60 years. Prospective clinical assessment was made using the Quick Disability of the Arm, Shoulder and Hand (DASH) questionnaire, visual analogue scale for pain, range of motion, and grip and pinch strength. The mean follow-up was 4 years (range 2–5). Prosthetic replacement provided significantly better thumb abduction, adduction, pinch strength, QuickDASH, pain relief, satisfaction and a faster return to daily activities and previous work. Revision surgery was required for two patients in the prosthesis group, two for dislocation and one cup loosening, while in the ligament reconstruction group there were no revisions. We conclude that trapeziometacarpal prosthesis provides better mid-term results in terms of function compared with ligament reconstruction and tendon interposition for patients with Stages 2 and 3 osteoarthritis of the trapeziometacarpal joint. Level of evidence: II
Does the Post-Feeding Position Affect Gastric Residue in Preterm Infants?

BACKGROUND Body position affects the gastric emptying rate and hence the amount of gastric residue. OBJECTIVE This study aims to analyze the effect of the post-feeding position of preterm infants on gastric residue. MATERIALS AND METHODS This experimental study was conducted in the neonatal intensive care unit (NICU) of a university hospital (İnönü University Turgut Özal Medical Center) in Eastern Turkey. The study included 40 preterm infants weighing less than 2,000 g, who were fed orogastrically. The preterm infants were sequentially placed in four positions and were fed before each change of position. The infants were sequentially placed in the right lateral, left lateral, supine, and prone positions; their gastric residues were measured with a nasogastric tube. The gastric residue was recorded in percentages at 30, 60, 120, and 180 minutes. Ethical principles were applied in all phases of the study. RESULTS The lowest mean gastric residue level was observed in the right lateral position at 30 minutes (58.16 ± 12.71%) and 60 minutes (33.97 ± 15.00%). The prone position showed the lowest mean gastric residue level (1.74 ± 1.08%), followed by the right lateral (3.06 ± 1.97%), supine (3.53 ± 2.18%), and left lateral position (5.14 ± 1.85%) at 120 minutes. The final measurements were taken at 180 minutes with the right lateral position showing the lowest mean gastric residue level (0.38 ± 0.34%). CONCLUSION The premature infants had similar lower levels of gastric residue in the right lateral and prone positions and higher levels of gastric residue in left lateral and supine positions. The gastric emptying rate was found to be highest in the right lateral position at 30, 60, and 180 minutes and in the prone position at 120 minutes.
The Unexpected Effects of L-Carnitine Supplementation on Lipid Metabolism in Hemodialysis Patients

Background/Aims: There is a growing body of evidence that the long-term hemodialysis (HD) treatment leads to disturbances of carnitine homeostasis but the results of L-carnitine supplementation in HD patients have been conflicting. In the present prospective study, we investigated the effectiveness of intravenous L-carnitine in mitigating dialysis-related protein-energy wasting (PEW) based on pre-treatment albumin levels. Methods: Fifty patients (46% male, mean age 63±18.28 years, HD vintage 37.5 (7-288) months) received 1 g L-carnitine intravenously at the end of every HD session for 12 months. Clinical data were obtained from the medical records and charts. Intradialytic hypotension periods (defined as a decrease of systolic blood pressure by ≥ 20 mmHg) were recorded. Dietary habits were evaluated using a self-administered questionnaire prior to L-carnitine supplementation. Laboratory parameters were measured prior to the supplementation and controlled in 6-months intervals. Anthropometric measurements were performed prior to HD session, including „dry“ body weight and height, body mass index (BMI), and body composition analysis using bioimpedance spectroscopy. Malnutrition-inflammation score (MIS) was used as a scoring system representing the severity of PEW and an indicator of general functional capacity. Results: A significant increase in total cholesterol, predominantly on the account of LDL was found (p=0.005). Simultaneously, HDL decreased (p=0.001) while triglyceride levels remained unchanged. Although the rise in serum prealbumin could be observed, lean tissue index (LTI) decreased and fat tissue index (FTI) increased which resulted in reduction of the LTI/FTI ratio (p=0.002). When divided into two groups according to the pre-treatment albumin values (< 35 g/L or ≥35 g/L), patients from the higher albumin group showed significant increase in prealbumin (p=0.005), and improved MIS (p=0.03). Multivariate regression analysis showed that higher FTI after introduction of L-carnitine led to greater hemodynamic stability (OR 1.709, 95% CI 1.006-2.905, p=0.048). As there was no differences in HD treatment characteristics, primery kidney disease or residual diuresis we could conclude that positive energy balance (with an increase in prealbumin and FTI) eventually led to better hemodynamic stability. Conclusion: Our results show significant effects of L-carnitine supplementation on lipid metabolism. Further clinical trials, as well as experimental research are needed to define the role of lipid metabolism in CKD population. Significant benefits of L-carnitine supplementation in patients with better initial serum albumin levels suggest that this therapy should not be restricted to patients with the worst nutritional and overall status.
Evaluation of Preanalytical Conditions and Implementation of Quality Control Steps for Reliable Gene Expression and DNA Methylation Analyses in Liquid Biopsies.

BACKGROUND Liquid biopsy provides important information for the prognosis and treatment of cancer patients. In this study, we evaluated the effects of preanalytical conditions on gene expression and DNA methylation analyses in liquid biopsies. METHODS We tested the stability of circulating tumor cell (CTC) messenger RNA by spiking MCF-7 cells in healthy donor peripheral blood (PB) drawn into 6 collection-tube types with various storage conditions. CTCs were enriched based on epithelial cell adhesion molecule positivity, and RNA was isolated followed by cDNA synthesis. Gene expression was quantified using RT-quantitative PCR for CK19 and B2M. We evaluated the stability of DNA methylation in plasma under different storage conditions by spiking DNA isolated from MCF-7 cells in healthy donor plasma. Two commercially available sodium bisulfite (SB)-conversion kits were compared, in combination with whole genome amplification (WGA), to evaluate the stability of SB-converted DNA. SB-converted DNA samples were analyzed by real-time methylation-specific PCR (MSP) for ACTB, SOX17, and BRMS1. Quality control was assessed using Levey-Jennings graphs. RESULTS RNA-based analysis in CTCs is severely impeded by the preservatives used in many PB collection tubes (except for EDTA), as well as by time to analysis. Plasma and SB-converted DNA samples are stable and can be used safely for MSP when kept at -80 °C. Downstream WGA of SB-converted DNA compensated for the limited amount of available sample in liquid biopsies. CONCLUSIONS Standardization of preanalytical conditions and implementation of quality control steps is extremely important for reliable liquid biopsy analysis, and a prerequisite for routine applications in the clinic.
Withdrawal Symptoms after Serotonin-Noradrenaline Reuptake Inhibitor Discontinuation: Systematic Review

Background: Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim of this paper is to identify the occurrence, frequency, and features of withdrawal symptoms after SNRI discontinuation. Methods: PRISMA guidelines were followed to conduct a systematic review. Electronic databases included PubMed, the Cochrane Library, Web of Science, and MEDLINE from the inception of each database to June 2017. Titles, abstracts, and topics were searched using a combination of the following terms: “duloxetine” OR “venlafaxine” OR “desvenlafaxine” OR “milnacipran” OR “levomilnacipran” OR “SNRI” OR “second generation antidepressant” OR “serotonin norepinephrine reuptake inhibitor” AND “discontinuation” OR “withdrawal” OR “rebound. ” Only published trials in the English language were included. Results: Sixty-one reports met the criteria for inclusion. There were 22 double-blind randomized controlled trials, 6 studies where patients were treated in an open fashion and then randomized to a double-blind controlled phase, 8 open trials, 1 prospective naturalistic study, 1 retrospective study, and 23 case reports. Withdrawal symptoms occurred after discontinuation of any type of SNRI. The prevalence of withdrawal symptoms varied across reports and appeared to be higher with venlafaxine. Symptoms typically ensued within a few days from discontinuation and lasted a few weeks, also with gradual tapering. Late onset and/or a longer persistence of disturbances occurred as well. Conclusions: Clinicians need to add SNRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with other types of psychotropic drugs. The results of this study challenge the use of SNRI as first-line treatment for mood and anxiety disorders.