Miracle-dz/UniFAR-FTUs huggingface dataset:
Antimicrobial Drug Interactions: Systematic Evaluation of Protein and Nucleic Acid Synthesis Inhibitors

Antimicrobial multidrug resistance and its transmission among strains are serious problems. Success rate is decreased and treatment options are narrowed due to increasing bacterial multidrug resistance. On the other hand, the need for long-term efforts to discover new antibiotics and difficulties finding new treatment protocols make this problem more complex. Combination therapy, especially with synergistic use of antimicrobials is a rational treatment option with huge benefits. Thus, screening antibiotic interactions is crucial for finding better treatment options. Clinicians currently use combinatorial antibiotic treatment as an effective treatment option. However, antibiotics can show synergistic or antagonistic interactions when used together. In our study, we aimed to investigate interactions of antibiotics with different mechanisms of action. Antibiotics, which act as protein synthesis inhibitors (P) and nucleic acid synthesis inhibitors (N) were used in our study. We tested 66 (PN), 15 (NN), and 55 (PP) drug pairs on the Escherichia coli strain. The Loewe additivity model was used and alpha scores were calculated for analysis of interactions of drug combinations. Drug interactions were categorized as synergistic or antagonistic. Accordingly, pairwise combinations of protein synthesis inhibitors (PP) showed stronger synergistic interactions than those of nucleic acid synthesis inhibitors (NN) and nucleic acid synthesis–protein synthesis inhibitors (PN). As a result, the importance of mechanisms of action of drugs is emphasized in the selection of synergistic drug combinations.
Parechovirus A Infections in Healthy Australian Children During the First 2 Years of Life: A Community-based Longitudinal Birth Cohort Study

Abstract Background Hospital-based studies identify parechovirus (PeV), primarily PeV-A3, as an important cause of severe infections in young children. However, few community-based studies have been published and the true PeV infection burden is unknown. We investigated PeV epidemiology in healthy children participating in a community-based, longitudinal birth cohort study. Methods Australian children (n = 158) enrolled in the Observational Research in Childhood Infectious Diseases (ORChID) study were followed from birth until their second birthday. Weekly stool and nasal swabs and daily symptom diaries were collected. Swabs were tested for PeV by reverse-transcription polymerase chain reaction and genotypes determined by subgenomic sequencing. Incidence rate, infection characteristics, clinical associations, and virus codetections were investigated. Results PeV was detected in 1423 of 11 124 (12.8%) and 17 of 8100 (0.2%) stool and nasal swabs, respectively. Major genotypes among the 306 infection episodes identified were PeV-A1 (47.9%), PeV-A6 (20.1%), and PeV-A3 (18.3%). The incidence rate was 144 episodes (95% confidence interval, 128–160) per 100 child-years. First infections appeared at a median age of 8 (interquartile range, 6.0–11.7) months. Annual seasonal peaks changing from PeV-A1 to PeV-A3 were observed. Infection was positively associated with age ≥6 months, summer season, nonexclusive breastfeeding at age <3 months, and formal childcare attendance before age 12 months. Sole PeV infections were either asymptomatic (38.4%) or mild (32.7%), while codetection with other viruses in stool swabs was common (64.4%). Conclusions In contrast with hospital-based studies, this study showed that diverse and dynamically changing PeV genotypes circulate in the community causing mild or subclinical infections in children. Parechovirus can cause severe illnesses in children. However, studies focus mainly on hospitalized populations. True disease burden in the community remains largely unknown. From our community-based cohort, we found diverse parechovirus genotypes in the community, causing mild or subclinical infections in children.
Lay People Training in CPR and in the Use of an Automated External Defibrillator, and Its Social Impact: A Community Health Study

Out-of-hospital cardiac arrest (OHCA) mortality remains high. The best survival rates are achieved when trained people provide OHCA victims with cardiopulmonary resuscitation (CPR); however, it is estimated that only 25% of victims receive CPR. This community health study aims to evaluate the effectiveness of a training programme in basic CPR and in the use of an automatic external defibrillator (AED) on knowledge and skills for lay people, and its social impact. The training courses were based on Catalan Council of Resuscitation guidelines. Data were collected on sociodemographic characteristics, evaluation of knowledge and practical skills at baseline and at the end of the training courses, and also on the social impact of the programme. A total of 36 training courses with 482 participants were carried out, and most participants achieved a qualification of suitable. The mean score in knowledge was 3.1 ± 1.1 at baseline and 3.8 ± 1.2 (p = 0.001) at the end of the programme. Participants rated the training courses as very satisfactory, considered the training useful, and felt more qualified to respond to an emergency. This study shows that a high percentage of participants acquired skills in basic CPR and use of an AED, which confirms the usefulness and effectiveness of training courses and its important social impact.
Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study

Background: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after (cid:2) 36-month follow-up for all living patients. 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and < 3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial obser-vations, and no new safety signals were detected with long-term use. Conclusions: These data demonstrate that durable ( (cid:2) 3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.
Influence of excess weight on lower-extremity vertical stiffness and metabolic cost of walking

ABSTRACT The purpose was to test whether lower-extremity vertical stiffness and gait mechanics explain differences in energy cost of walking (Cw) between individuals with normal weight (NW) and obesity (OB). Ten OB (33.1 ± 2.0 kg m−2) and 10 NW (24.2 ± 1.3 kg m−2) walked for six minutes on an instrumented treadmill at 1.25 m s−1 while Cw, lower-extremity kinematics, and vertical stiffness (K vert) were measured. NW completed another trial with a loaded vest (NWL) to simulate the BMI of the obese group. Cw was 24% greater in OB (277.5 ± 45.3 J m−1) and 23% greater in NWL (272.7 ± 35.7 J m−1) than NW (211.0 ± 27.0 J m−1, P < 0.005). Mass-specific Cw (Cwkg) wasn’t different between conditions (P = 0.085). Lower-extremity K vert was 40% higher in OB (32.7 ± 5.2 kN m−1) than NW (23.3 ± 4.7 kN m−1, P < 0.001), but neither was different from NWL (27.5 ± 3.4 kN m−1, P > 0.05). Mass-specific K vert (P = 0.081) was similar across conditions. K vert was related to Cw (r = 0.55, P = 0.001). Cwkg wasn’t different between NW or OB, but there was a negative correlation between BMI and Cwkg driven by lower Cwkg in NWL. Cw and K vert covaried in proportion to body mass, but mass-specific K vert was unrelated to Cwkg. Mass-specific K vert was lower in NWL than OB due to NWL’s greater angle of attack, center of mass displacement, and joint range of motion.
Somatosensory neurons integrate the geometry of skin deformation and mechanotransduction channels to shape touch sensing

Touch sensation hinges on force transfer across the skin and activation of mechanosensitive ion channels along the somatosensory neurons that invade the skin. This skin-nerve sensory system demands a quantitative model that spans the application of mechanical loads to channel activation. Unlike prior models of the dynamic responses of touch receptor neurons in Caenorhabditis elegans (Eastwood et al., 2015), which substituted a single effective channel for the ensemble along the TRNs, this study integrates body mechanics and the spatial recruitment of the various channels. We demonstrate that this model captures mechanical properties of the worm’s body and accurately reproduces neural responses to simple stimuli. It also captures responses to complex stimuli featuring non-trivial spatial patterns, like extended or multiple contacts that could not be addressed otherwise. We illustrate the importance of these effects with new experiments revealing that skin-neuron composites respond to pre-indentation with increased currents rather than adapting to persistent stimulation.
Profiling and Bioinformatic Analysis of Differentially Expressed Cytokines in Aqueous Humor of High Myopic Eyes – Clues for Anti-VEGF Injections

ABSTRACT Purpose To investigate the aqueous humor growth factor profile in high myopic eyes and analyze the interaction of differentially expressed cytokines. Methods A case–control study including aqueous humor samples from 36 high myopic patients and 32 controls was conducted. Quantibody® Human Growth Factor Array was used to screen the presence of 40 growth factors in aqueous humor. Expressions of differential growth factors were validated by Bio-Plex ProTM multiplex bead-based immunoassay. Protein–protein interaction (PPI) and gene ontology (GO) analyses were performed. Results Growth differentiation factor 15 (GDF-15), hepatocyte growth factor (HGF), and platelet-derived growth factor (PDGF)-AA were found to be significantly higher and vascular endothelial growth factor (VEGF) was detected to be lower in high myopic eyes (all P = .03). Multi-plex bead-based assay further validated the differential expressions of four growth factors and all of them were significantly correlated with axial length (P < .001). Twenty-six proteins were mapped into PPI network and positive regulation of cell migration, cellular component movement, and cell motility were the most enriched biological processes based on GO analysis. Conclusions Differential expressed cytokines that indicates a distinctive intraocular microenvironment in high myopic eyes might provide clues for pathological changes within high myopic eyes after anti-VEGF injections.
Invalid Baseline Testing with ImPACT: Does Sandbagging Occur with High School Athletes?

Abstract The aim of this large-scale research was to determine the frequency of valid, invalid, and sandbagging results in ImPACT baseline testing of high school athletes. This retrospective study identified valid, invalid (identified by five embedded Invalidity Indicators), and sandbagging (identified by three “red flags”) results in the ImPACT baseline test scores of 6,346 high school athletes. In addition, the ImPACT postconcussion scores of 266 athletes who sustained a concussion during the school year were evaluated to compare the baseline-to-postconcussion changes of valid versus a combined group of invalid and sandbagging scorers. There were 3,299 (51.99%) athletes who had valid baseline scores, 269 (4.24%) had invalid scores, and 3,009 (47.42%) had sandbagging scores. (There were 231 who obtained both invalidity and sandbagging scores.) The overall difference in baseline-to-postconcussion changes between the valid scorers and the combined group of invalid and sandbagging scorers was statistically significant. The high rate of athletes who had invalid and sandbagging scores raised concern that the underperformance of baseline testing occurs more commonly than is probably realized by those who utilize computerized neuropsychological testing with high school athletes. Accordingly, efforts are needed to improve test administration procedures so that maximal attention and effort can be maintained among the test takers. In the meantime, increased caution is called for in employing the baseline-to-postconcussion paradigm when return-to-play decisions are made.
Characterization of Vibrio cholerae O1 isolates responsible for cholera outbreaks in Kenya between 1975 and 2017

Kenya is endemic for cholera with different waves of outbreaks having been documented since 1971. In recent years, new variants of Vibrio cholerae O1 have emerged and have replaced most of the traditional El Tor biotype globally. These strains also appear to have increased virulence, and it is important to describe and document their phenotypic and genotypic traits. This study characterized 146 V. cholerae O1 isolates from cholera outbreaks that occurred in Kenya between 1975 and 2017. Our study reports that the 1975–1984 strains had typical classical or El Tor biotype characters. New variants of V. cholerae O1 having traits of both classical and El Tor biotypes were observed from 2007 with all strains isolated between 2015 and 2017 being sensitive to polymyxin B and carrying both classical and El Tor type ctxB. All strains were resistant to Phage IV and harbored rstR, rtxC, hlyA, rtxA and tcpA genes specific for El Tor biotype indicating that the strains had an El Tor backbone. Pulsed field gel electrophoresis (PFGE) genotyping differentiated the isolates into 14 pulsotypes. The clustering also corresponded with the year of isolation signifying that the cholera outbreaks occurred as separate waves of different genetic fingerprints exhibiting different genotypic and phenotypic characteristics. The emergence and prevalence of V. cholerae O1 strains carrying El Tor type and classical type ctxB in Kenya are reported. These strains have replaced the typical El Tor biotype in Kenya and are potentially more virulent and easily transmitted within the population.
Silencing of lncRNA SNHG20 delays the progression of nonalcoholic fatty liver disease to hepatocellular carcinoma via regulating liver Kupffer cells polarization

This study aims to investigate the role of long noncoding RNA SNHG20 in the progression of nonalcoholic fatty liver disease (NALFD) to hepatocellular carcinoma (HCC), and to elucidate whether polarization of Kupffer cells (KCs, liver macrophages) was involved in this process. Mouse NALFD was induced by 16 weeks of high‐fat diet (HFD) feeding. Mouse NALFD‐HCC was induced by 36 weeks of HFD feeding (from 1 week to 36 weeks) and 20 weeks of diethyl nitrosamine (DEN) administration (from 17 weeks to 36 weeks). The LV‐shRNA‐ and LV‐sh‐SNHG20‐infected RAW264.7 cells were injected into the NALFD mice followed by DEN treatment to evaluate the role of SNHG20 in regulating the progression of NALFD to HCC in mice. The proportion of M1 and M2 macrophages was determined by flow cytometry. The levels of M1‐related inducible nitric oxide synthase (iNOS) and tumor necrosis factor‐α and M2‐related Arg‐1 and interleukin (IL)‐10 were also examined. SNHG20 expression was decreased in NALFD but increased in NALFD‐HCC, both in human and experimental mouse livers. Furthermore, human and mouse NALFD‐HCC KCs displayed decreased M1/M2 ratio compared with NALFD KCs. Moreover, SNHG20 overexpression induced M2 polarization through activating STAT6, whereas SNHG20 silencing suppressed M1 polarization in RAW264.7 macrophages and delayed the progression of NALFD to HCC in mice. SNHG20 may facilitate the progression of NALFD to HCC via inducing liver KCs M2 polarization via STAT6 activation.
Blood pressure measurement in atrial fibrillation: review and meta-analysis of evidence on accuracy and clinical relevance.

: Atrial fibrillation (AF) often coexists with hypertension in the elderly and multiplies the risk of stroke and death. Blood pressure (BP) measurement in patients with AF is difficult and uncertain and has been a classic exclusion criterion in hypertension clinical trials leading to limited research data. This article reviews the evidence on the accuracy of BP measurement in AF performed using different methods (office, ambulatory, home) and devices (auscultatory, oscillometric) and its clinical relevance in predicting cardiovascular damage. The current evidence suggests the following: (i) Interobserver and intra-observer variation in auscultatory BP measurement is increased in AF because of increased beat-to-beat BP variability and triplicate measurement is required; (ii) The evidence from validation studies of automated electronic BP monitors in AF is limited and methodologically heterogeneous and suggests reasonable accuracy in measuring SBP and a small yet consistent overestimation of DBP; (iii) 24-h ambulatory BP monitoring is feasible in AF, with similar proportion of errors as in individuals without AF; (iv) both auscultatory and automated oscillometric BP measurements appear to be clinically relevant in AF, providing similar associations with intra-arterial BP measurements and with indices of preclinical cardiac damage as in patients without AF, and predict cardiovascular events and death; (v) Screening for AF in the elderly using an AF-specific algorithm during routine automated office, home or ambulatory BP measurement has high diagnostic accuracy. In conclusion, in AF patients, BP measurement is important, reliable, and clinically relevant and should not be neglected in clinical research and in practice.
MiR‐203a‐3p inhibits retinal angiogenesis and alleviates proliferative diabetic retinopathy in oxygen‐induced retinopathy (OIR) rat model via targeting VEGFA and HIF‐1α

Proliferative diabetic retinopathy (PDR) is a common complication of diabetes mellitus, characterized by abnormal retinal angiogenesis. MicroRNA‐203‐3p (miR‐203‐3p) was found to be down‐regulated in a murine model of proliferative retinopathy. This study was performed to explore the role of miR‐203a‐3p in retinal angiogenesis of PDR. Firstly, a rat OIR model, which was used to mimic PDR, was established and the OIR rats were treated with scrambled control or miR‐203a‐3p agomir by intravitreal injection. The results showed that the level of miR‐203a‐3p was decreased in OIR rats, and forced over‐expression of miR‐203a‐3p inhibited OIR‐induced retinal angiogenesis as evidenced by reduced blood vessel profiles and CD31 expression. OIR‐induced up‐regulation of VEGFA, HIF‐α, PCNA, and MMPs in the retina was also counteracted by miR‐203a‐3p. Additionally, high glucose (HG)‐induced proliferation, migration and tube formation of human retinal microvascular endothelial cells (HRMECs) were also dampened by the up‐regulation of miR‐203a‐3p. Dual‐luciferase reporter assay showed that miR‐203a‐3p could specifically bind to the 3′UTR of VEGFA and HIF‐1α. Over‐expression of VEGFA or HIF‐1α restored the tube formation activity of HRMECs suppressed by miR‐203a‐3p. In conclusion, our findings demonstrate that up‐regulation of miR‐203a‐3p might inhibit pathological retinal angiogenesis of PDR by targeting VEGFA and HIF‐1α.
Dietary resveratrol supplementation inhibits heat stress-induced high-activated innate immunity and inflammatory response in spleen of yellow-feather broilers

The aim of this study was to investigate the effect of dietary resveratrol supplementation on innate immunity and inflammatory responses in the spleen of yellow-feather broilers under heat stress. A total of 288 yellow-feather broilers of 28-day-old were randomly assigned to 3 treatment groups with 6 replicates. A thermo-neutral group (TN) (24 ± 2°C) received a basal diet and another 2 heat-stressed groups (37 ± 2°C for 8 h/D and 24 ± 2°C for the remaining time) were fed the basal diet (HT) or basal diet with 500 mg/kg resveratrol (HT+Res) for 14 consecutive days. The results showed that heat stress decreased (P < 0.05) the growth index of thymus, spleen, and bursa of Fabricius, reduced (P < 0.05) the levels of complement C3 and C4 in serum. Heat stress also caused activation of inflammatory immune responses evidenced by increased (P < 0.05) the mRNA abundance of HSP (heat shock protein) 70, toll-like receptor (TLR)1, TLR4, TLR5, myeloid differentiation factor-88 (MyD88), nucleotide-binding oligomerization domain 1 (NOD1), Dectin-1, transforming growth factor-β-activated kinase 1 (TAK1), interleukin (IL)-1, IL-4, IL-6, and tumor necrosis factor (TNF)-α, but decreased the mRNA abundance of interferon (IFN)-γ, activated nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPK), and phosphoinositide-3 kinases-protein kinase B (PI3K/AKT) signaling pathways. Dietary supplementation with resveratrol improved (P < 0.05) the growth index of thymus, spleen and bursa Fabricius, and increased (P < 0.05) the serum level of complement C3 under heat stress. In addition, resveratrol reduced (P < 0.05) the mRNA abundance of HSP70, TLR4, TLR5, NOD1, Dectin-1, and TAK1, and inhibited the NF-κB, MAPK and PI3K/AKT signaling pathway via down-regulated the phosphorylation of p65, extracellular signal-regulated kinases 1/2, c-Jun N-terminal protein kinase and AKT, as well as decreased the inflammatory cytokines expression, including IL-1, IL-4, IL-6, and TNF-α in the spleen under heat stress. Collectively, dietary resveratrol could have beneficial effects to regulate innate immunity and inflammatory response, via inhibiting the activation of NF-κB, MAPK, and PI3K/AKT signaling pathways induced by heat stress in the spleen.
Does closed incision negative wound pressure therapy in non‐traumatic major lower‐extremity amputations improve survival rates?

Closed incision negative pressure wound therapy (CINPWT) has been shown to be clinically effective compared with the traditional gauze dressing, reducing surgical site infections and wound complications. We evaluated the effect of CINPWT compared with gauze dressing on the need for revision surgery and survival after non‐traumatic major lower amputation. We included 309 patients undergoing 403 major lower amputations in a retrospective study from January 1, 2010 to November 23, 2017. A total of 139 patients received CINPWT, and 170 patients received stump bandage. There was no statistically significant difference between the two groups regarding the need for revision surgery (P = .45). Fourteen stump bandage patients and 15 CINPWT patients died in hospital (P = .57). One year after amputation, 55 CINPWT patients and 66 stump bandage patients had died (P = .82). Survival probabilities adjusted for age and gender 2 years after amputation were . 52 (.43‐.61) and . 49 (.42‐.58), respectively, and 3 years after amputation were . 36 (.25‐.50) and . 39 (.32‐.47), respectively. We also found no significant difference in the need for revision surgery in survival probabilities up till 3 years after amputation between patients treated with CINPWT and patients treated with gauze bandage postoperatively.