Miracle-dz/UniFAR-FTUs huggingface dataset:
An e-Delphi study generates expert consensus on the trends in future continuing medical education engagement by resident, practicing, and expert surgeons

Abstract Background: The Delphi method is a demonstrated way to gather structured expert opinions to forecast, plan, and prioritize around a given topic. It builds consensus through iterative rounds. Aims: The goal of this study was to build consensus-based predictions for the year 2022 about: future trends in surgeon continuing medical education (CME); the role of technology in learning for surgeons of different experience levels (trainee/resident, practicing, expert); and CME funding models. Methods: A three round e-Delphi method was employed for this study. Panelist identities were anonymized, and controlled feedback and consensus rules were employed. Fifteen international expert panelists’ input was collected via electronically distributed, open-ended questionnaire (Round 1) and 5-point Likert scale ranking surveys (Rounds 2 and 3), in a series of nine questions (Round 1) and 26 and 25 summary statements (Rounds 2 and 3, respectively). Summary statements were collated via key words and ideas collected from panelist’s input. Mean, median, standard deviation, and 95% confidence intervals were calculated. Results: Response rate was 100% for each round. Consensus in Round 2 was 61% and 88% in Round 3. Seven key finding statements with supporting background information was the result. Discussion: Reliable, affordable internet access was identified as a likely barrier to education for certain regions, even in 5 years’ time. The use of similar educational resources were identified for all levels of surgeon, what varied was the reliance on a particular resource by each level of surgeon. Conclusion: Institutes of employment were predicted to have ended CME funding for expert surgeons by 2022. Industry sponsored CME was predicted to have a continued role for trainee/residents and practicing surgeons.
Behavioural evaluation of analgesic efficacy for pain mitigation in lame sows.

Lameness in breeding swine has a large negative economic impact and is a welfare concern. Pain-related behaviour, such as postural changes, may be used to evaluate the presence and severity of pain in animals. The objective of this work was to determine the effects of flunixin meglumine (FM) and meloxicam (M) on postural changes in lame sows. Lameness was induced in 24 mature sows (Sus scrofa) using a chemical synovitis model. Three treatments were compared: FM (2.2 mg kg; n = 24, intramuscular [IM]), M (1.0 mg kg; n = 24, by mouth [PO]) and sterile saline (equivalent volume to FM; n = 24 [IM]), administered approximately 28 and 52 h after lameness induction. Behavioural data were collected in the home pen during 12-h periods and quantified using 15-min scan sampling on the day prior to (–24 h; Day –1) through +168 h post lameness induction. Frequency of behaviour was analysed by day using generalised linear mixed model methods. The frequency of standing postures significantly decreased and lying postures increased 24–72 h post lameness induction relative to baseline day. All postures returned to baseline frequencies by +168 h. Meloxicam-treated sows demonstrated lower frequencies of lying postures +48 and +72 h after lameness induction compared to saline-treated sows. Flunixin-treated sows did not differ in lying behaviours compared to saline-treated sows. No differences were noted in standing or sitting postures between treatments. The results of this study suggest that meloxicam mitigates pain sensitivity as demonstrated by higher frequency of standing and lower frequency of lying compared to saline-treated sows.
Oscillatory cAMP signaling rapidly alters H3K4 methylation

This work explores how GPCR-cAMP signaling dynamically influences histone methylation by altering intracellular labile Fe(II) levels and subsequently modulating histone demethylase activity. Epigenetic variation reflects the impact of a dynamic environment on chromatin. However, it remains elusive how environmental factors influence epigenetic events. Here, we show that G protein–coupled receptors (GPCRs) alter H3K4 methylation via oscillatory intracellular cAMP. Activation of Gs-coupled receptors caused a rapid decrease of H3K4me3 by elevating cAMP, whereas stimulation of Gi-coupled receptors increased H3K4me3 by diminishing cAMP. H3K4me3 gradually recovered towards baseline levels after the removal of GPCR ligands, indicating that H3K4me3 oscillates in tandem with GPCR activation. cAMP increased intracellular labile Fe(II), the cofactor for histone demethylases, through a non-canonical cAMP target—Rap guanine nucleotide exchange factor-2 (RapGEF2), which subsequently enhanced endosome acidification and Fe(II) release from the endosome via vacuolar H+-ATPase assembly. Removing Fe(III) from the media blocked intracellular Fe(II) elevation after stimulation of Gs-coupled receptors. Iron chelators and inhibition of KDM5 demethylases abolished cAMP-mediated H3K4me3 demethylation. Taken together, these results suggest a novel function of cAMP signaling in modulating histone demethylation through labile Fe(II).
Prevalence of low scores on language tests as a potential factor in misdiagnosis of cognitive impairment in a Spanish-speaking adult population

Abstract Objective In this study, the prevalence of low scores for two neuropsychological tests of language has been determined. Methods In total, N = 5218 healthy adults from 11 countries in Latin America (LA) were administered the Boston Naming Test (BNT) and the Verbal Fluency Test (VFT) as part of a comprehensive neuropsychological evaluation. Z-scores were calculated for BNT Total score, and phonological (letters F, A, S, M) and semantic (Animals, Fruits). Scores were adjusted for age, age2, sex, education, and interaction variables if significant for the given country. Each Z-score was converted to a percentile for each of the seven test-scores. Each participant was categorized based on his/her number of low scoring tests in specific percentile cutoff groups (25th, 16th, 10th, 5th, and 2nd). Results Between 53% (Paraguay) and 71% (Mexico) of the sample had at least 1-score below the 25th percentile, and between 41% (Paraguay) and 55% (Cuba) scored below the 16th percentile. Between 27% (Paraguay) and 39% (Peru) scored below the 10th percentile on at least 1-score, and between 17% (Chile) and 23% (Argentina) scored below the 5th percentile. Conclusions Clinicians should use these data to reduce false-positive diagnoses and to improve the neuropsychological assessments in Spanish-speaking individuals from LA countries.
Unique white matter structural connectivity in early-stage drug-naive Parkinson disease

Objective To investigate the topographic arrangement and strength of whole-brain white matter (WM) structural connectivity in patients with early-stage drug-naive Parkinson disease (PD). Methods We employed a model-free data-driven approach for computing whole-brain WM topologic arrangement and connectivity strength between brain regions by utilizing diffusion MRI of 70 participants with early-stage drug-naive PD and 41 healthy controls. Subsequently, we generated a novel group-specific WM anatomical network by minimizing variance in anatomical connectivity of each group. Global WM connectivity strength and network measures were computed on this group-specific WM anatomical network and were compared between the groups. We tested correlations of these network measures with clinical measures in PD to assess their pathophysiologic relevance. Results PD-relevant cortical and subcortical regions were identified in the novel PD-specific WM anatomical network. Impaired modular organization accompanied by a correlation of network measures with multiple clinical variables in early PD were revealed. Furthermore, disease duration was negatively correlated with global connectivity strength of the PD-specific WM anatomical network. Conclusion By minimizing variance in anatomical connectivity, this study found the presence of a novel WM structural connectome in early PD that correlated with clinical symptoms, despite the lack of a priori analytic assumptions. This included the novel finding of increased structural connectivity between known PD-relevant brain regions. The current study provides a framework for further investigation of WM structural changes underlying the clinical and pathologic heterogeneity of PD.
Synaptonemal Complex-Deficient Drosophila melanogaster Females Exhibit Rare DSB Repair Events, Recurrent Copy-Number Variation, and an Increased Rate of de Novo Transposable Element Movement

Genetic stability depends on the maintenance of a variety of chromosome structures and the precise repair of DNA breaks. During meiosis, programmed double-strand breaks (DSBs) made in prophase I are normally repaired as gene conversions or crossovers. DSBs can also be made by other mechanisms, such as the movement of transposable elements (TEs), which must also be resolved. Incorrect repair of these DNA lesions can lead to mutations, copy-number changes, translocations, and/or aneuploid gametes. In Drosophila melanogaster, as in most organisms, meiotic DSB repair occurs in the presence of a rapidly evolving multiprotein structure called the synaptonemal complex (SC). Here, whole-genome sequencing is used to investigate the fate of meiotic DSBs in D. melanogaster mutant females lacking functional SC, to assay for de novo CNV formation, and to examine the role of the SC in transposable element movement in flies. The data indicate that, in the absence of SC, copy-number variation still occurs and meiotic DSB repair by gene conversion occurs infrequently. Remarkably, an 856-kilobase de novo CNV was observed in two unrelated individuals of different genetic backgrounds and was identical to a CNV recovered in a previous wild-type study, suggesting that recurrent formation of large CNVs occurs in Drosophila. In addition, the rate of novel TE insertion was markedly higher than wild type in one of two SC mutants tested, suggesting that SC proteins may contribute to the regulation of TE movement and insertion in the genome. Overall, this study provides novel insight into the role that the SC plays in genome stability and provides clues as to why the sequence, but not structure, of SC proteins is rapidly evolving.
Pulmonary surfactant lipids inhibit infections with the pandemic H1N1 influenza virus in several animal models

The influenza A (H1N1)pdm09 outbreak in 2009 exemplified the problems accompanying the emergence of novel influenza A virus (IAV) strains and their unanticipated virulence in populations with no pre-existing immunity. Neuraminidase inhibitors (NAIs) are currently the drugs of choice for intervention against IAV outbreaks, but there are concerns that NAI-resistant viruses can transmit to high-risk populations. These issues highlight the need for new approaches that address the annual influenza burden. In this study, we examined whether palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI) effectively antagonize (H1N1)pdm09 infection. POPG and PI markedly suppressed cytopathic effects and attenuated viral gene expression in (H1N1)pdm09-infected Madin-Darby canine kidney cells. POPG and PI bound to (H1N1)pdm09 with high affinity and disrupted viral spread from infected to noninfected cells in tissue culture and also reduced (H1N1)pdm09 propagation by a factor of 102 after viral infection was established in vitro. In a mouse infection model of (H1N1)pdm09, POPG and PI significantly reduced lung inflammation and viral burden. Of note, when mice were challenged with a typically lethal dose of 1000 plaque-forming units of (H1N1)pdm09, survival after 10 days was 100% (14 of 14 mice) with the POPG treatment compared with 0% (0 of 14 mice) without this treatment. POPG also significantly reduced inflammatory infiltrates and the viral burden induced by (H1N1)pdm09 infection in a ferret model. These findings indicate that anionic phospholipids potently and efficiently disrupt influenza infections in animal models.
Association of mRNA Levels of IL6, MMP-8, GSS in Saliva and Pyelonephritis in Children

Nowadays, saliva is a subject of growing scientific interest because of its definite advantages as diagnostic medium. The aim of our study was to investigate the diagnostic potential and reliability of messenger RNAs (mRNAs) of selected genes—interleukin-6 (IL-6), matrix metalloproteinase-8 (MMP-8) and glutathione synthetase (GSS)—as salivary markers in children with diagnosed pyelonephritis and to correlate their levels with typical urine para-clinical indicators of the disease. Analysis of the mRNA levels for IL-6, MMP-8 and GSS in 28 children hospitalized with the diagnosis of pyelonephritis was conducted applying the method of quantitative reverse transcription polymerase chain reaction (RT-qPCR). In the study group (n = 28), IL-6 mRNA levels demonstrated 64-fold increase (p < 0.001). MMP-8 and GSS mRNA levels were increased in 12 samples in patients with pyelonephritis 3.27 (p < 0.01) and 1.94 (p < 0.001) times, respectively. We found a strong and significant correlation (p < 0.001) between the investigated mRNA for IL-6 and MMP-8, IL-6 and GSS, MMP-8 and GSS. Moderate degree of correlation was established between IL-6 and the typical para-clinical indicator of leucocytes (0.43, p < 0.05) and between GSS and leucocytes (0.54, p < 0.01). Salivary IL-6, MMP-8 and GSS mRNA levels in combination with urine test analysis could be useful diagnostic tool for the very distributed disorder of pyelonephritis in childhood.
Vitamin E TPGS based transferosomes augmented TAT as a promising delivery system for improved transdermal delivery of raloxifene

Raloxifene is commonly used for breast cancer protection. The low bioavailability of raloxifene (2%) is the result of its low solubility and intestinal glucuronidation. The nano-lipid carriers are characterized by small particle size, biocompatibility, and sustainable properties that improve cellular uptake of the loaded drug. The aim of this study was the improvement of raloxifene bioavailability by enhancing its solubility and cellular penetration through formulation of D-α-tocopheryl polyethylene glycol 1000 succinate based transferosomes and augmenting their effect with the cationic cell-penetrating peptide transactivator of transcription of the human immunodeficiency virus. Particle size, zeta potential, and transmission electron microscope investigation of the formed nanocarriers were carried out. Ex vivo raloxifene permeation through rat skin and cell viability studies was investigated. The results of D-α-tocopheryl polyethylene glycol 1000 succinate- transactivator of transcription of the human immunodeficiency virus transferosomes showed an average vesicle size of 96.05 nm with positively charged vesicles 39.4 mV of zeta potential value. The results revealed significant (p < 0.05) enhancement of raloxifene permeation from raloxifene transferosomes- loaded film when compared with raw raloxifene film. IC50 results showed significant improvement of formulated raloxifene cytotoxicity by 1.42-fold in comparison with raw raloxifene against MCF-7 cell lines. The developed raloxifene—transferosomes are considered promising nano-lipid carriers for the enhancement delivery of raloxifene.
Significant others' perceptions of being taken seriously by the Swedish Ambulance Service when the patient is assessed as nonurgent.

BACKGROUND At least 50% of all ambulance assignments are deemed nonurgent, while 47-96% are initiated by someone other than the patient. Previous research has highlighted the importance of being taken seriously. However, additional knowledge of how significant others experience the situation when a patient is assessed as nonurgent is needed. OBJECTIVE The aim of this study was to explore the person-centred climate in the Ambulance Service from the perspective of significant others by means of the Person-centred Climate Questionnaire - Family version (PCQ-F), to psychometrically investigate the construct validity of additional items intended to measure perceptions of being taken seriously and to explore possible relationships between the person-centred climate and these additional items. METHODS A retrospective, explorative, cross-sectional survey design was employed. In total, 241 questionnaires were distributed. Descriptive and comparative statistics and a factor analysis of eight items possibly constructing person-centredness are presented. RESULTS The 100 respondents experienced the climate as very person-centred. Relationships were found between the items that might constitute person-centredness and the PCQ-F. The PCQ-F can explain perceived person-centredness through the additional items that may constitute person-centredness in the Ambulance Service context. CONCLUSION Significant others consider eight aspects of being taken seriously as the core of person-centredness in nonurgent Ambulance Service assignments. There is a relationship between the psychosocial climate and the additional items that might constitute person-centredness.
The role of endobronchial ultrasound‐guided transbronchial needle aspiration liquid‐based cytology in the diagnosis of mediastinal lymphadenopathy

Endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) is a minimally invasive, reliable technique for sampling mediastinal lymph nodes (LNs). Liquid‐based cytology (LBC) is widely used for cervical cancer screening because it provides reliable and feasible results. The present study aimed to evaluate effectiveness of the combination of EBUS‐TBNA and LBC in the diagnosis of mediastinal lymphadenopathy.
Unexpected Roles of Triethanolamine in the Photochemical Reduction of CO2 to Formate by Ruthenium Complexes.

A series of 4,4'-dimethyl-2,2'-bipyridyl ruthenium complexes with carbonyl ligands were prepared and studied using a combination of electrochemical and spectroscopic methods with infrared detection to provide structural information on reaction intermediates in the photochemical reduction of CO2 to formate in acetonitrile (CH3CN). An unsaturated 5-coordinate intermediate was characterized, and the hydride transfer step to CO2 from a singly-reduced metal hydride complex was observed with kinetic resolution. While triethanolamine (TEOA) was expected to act as a proton acceptor to ensure the sacrificial behavior of 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzo[d]imidazole (BIH) as an electron donor, time-resolved infrared (TRIR) measurements revealed that about 90% of the photogenerated one-electron reduced complexes undergo unproductive back electron-transfer. Furthermore, TEOA showed the ability to capture CO2 from CH3CN solutions to form a Zwitterionic alkylcarbonate adduct, and was actively engaged in key catalytic steps such as the metal hydride formation, the hydride transfer to CO2 to form the bound formate intermediate and the dissociation of formate ion product. Collectively, the data provide an overview on transient intermediates of Ru(II) carbonyl complexes, and emphasize the importance of considering the participation of TEOA when investigating and proposing catalytic pathways.
MicroRNA‐mediated suppression of P‐glycoprotein by quantum dots in lung cancer cells

The interactions between adenosine triphosphate‐binding cassette (ABC) transporters and nano‐sized materials are attracting increasing attention, due to their great potential in overcoming the multidrug resistance (MDR) phenomena in cancer treatment. However, the inner mechanisms involved in the interactions are largely unknown. In this study, two commercial quantum dots (QDs), CdSe/ZnS‐MPA and CdSe/ZnS‐GSH, were tested for their interactions with P‐glycoprotein (P‐gp), as well as the relating mechanisms in lung cancer (A549) cells. Both QDs significantly suppressed the gene and protein expressions of P‐gp in A549 cells. To explain this, the gene expressions of nine relating microRNAs (miRNAs) were evaluated. The results indicated a shared up‐regulation of miR‐34b and miR‐185 by both QDs. Furthermore, mimics and inhibitors of miR‐34b and miR‐185 significantly enhanced and suppressed the gene and protein expressions of P‐gp, respectively, confirming the modulatory function of these two miRNAs on P‐gp. Interestingly, expressions of both miRNAs were suppressed during treatment with Cd2+ and doxorubicin, which induced the expression of P‐gp, indicating the universality of these miRNAs‐related mechanisms. Thus, as miR‐34b and miR‐185 participated in the suppression of P‐gp functions in A549 cells they could be interesting targets for the treatment of lung cancer.
Interplay of Placental DNA Methylation and Maternal Insulin Sensitivity in Pregnancy

The placenta participates in maternal insulin sensitivity changes during pregnancy; however, mechanisms remain unclear. We investigated associations between maternal insulin sensitivity and placental DNA methylation markers across the genome. We analyzed data from 430 mother-offspring dyads in the Gen3G cohort. All women underwent 75-g oral glucose tolerance tests at ∼26 weeks of gestation; we used glucose and insulin measures to estimate insulin sensitivity (Matsuda index). At delivery, we collected samples from placenta (fetal side) and measured DNA methylation using Illumina EPIC arrays. Using linear regression models to quantify associations at 720,077 cytosine-guanine dinucleotides (CpGs), with adjustment for maternal age, gravidity, smoking, BMI, child sex, and gestational age at delivery, we identified 188 CpG sites where placental DNA methylation was associated with Matsuda index (P < 6.94 × 10−8). Among genes annotated to these 188 CpGs, we found enrichment in targets for miRNAs, in histone modifications, and in parent-of-origin DNA methylation including the H19/MIR675 locus (paternally imprinted). We identified 12 known placenta imprinted genes, including KCNQ1. Mendelian randomization analyses revealed five loci where placenta DNA methylation may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2. Our results suggest that placental DNA methylation is fundamentally linked to the regulation of maternal insulin sensitivity in pregnancy.
Neurons differentiate magnitude and location of mechanical stimuli

Significance Our study provides a quantitative and morphological framework for mechanical neuromodulation. We report that mechanical stimuli at subtraumatic forces and pressures can evoke neuronal calcium responses. Cultured cortex and hippocampus neurons respond to both global and local mechanical forces and pressures delivered by shear stress and indentation, respectively, and show either short-lived or sustained responses, depending on the magnitude and location of the applied stimulus. Chemical perturbation experiments suggest that ion channel activity is modulated by forces and pressures acting on neurons. Our insights contribute to the understanding of how neurons respond to mechanical stimuli and may guide future studies to mechanically control neurons by, for example, electromagnetic forces or ultrasound. Neuronal activity can be modulated by mechanical stimuli. To study this phenomenon quantitatively, we mechanically stimulated rat cortical neurons by shear stress and local indentation. Neurons show 2 distinct responses, classified as transient and sustained. Transient responses display fast kinetics, similar to spontaneous neuronal activity, whereas sustained responses last several minutes before returning to baseline. Local soma stimulations with micrometer-sized beads evoke transient responses at low forces of ∼220 nN and pressures of ∼5.6 kPa and sustained responses at higher forces of ∼360 nN and pressures of ∼9.2 kPa. Among the neuronal compartments, axons are highly susceptible to mechanical stimulation and predominantly show sustained responses, whereas the less susceptible dendrites predominantly respond transiently. Chemical perturbation experiments suggest that mechanically evoked responses require the influx of extracellular calcium through ion channels. We propose that subtraumatic forces/pressures applied to neurons evoke neuronal responses via nonspecific gating of ion channels.