Miracle-dz/UniFAR-FTUs huggingface dataset:
Increasing age- and gender-specific burden and complexity of multimorbidity in Taiwan, 2003–2013: a cross-sectional study based on nationwide claims data

Objective Although there is accumulating evidence regarding multimorbidity in Western countries, this information is very limited in Asian countries. This study aimed to estimate population-based, age-specific and gender-specific prevalence and trends of multimorbidity in the Taiwanese population. Design This was a cross-sectional study based on claims data (National Health Insurance Research Database, Taiwan). Participants The participants included a subset of the National Health Insurance Research Database, which contains claims data for two million randomly selected beneficiaries (~10% of the total population) under Taiwan’s mandatory National Health Insurance system. Outcome measurements The prevalence of multimorbidity in different age groups and in both sexes in 2003 and 2013 was reported. We analysed data on the prevalence of 20 common diseases in each age group and for both sexes. To investigate the clustering effect, we used graphical displays to analyse the likelihood of co-occurrence with one, two, three, and four or more other diseases for each selected disease in 2003 and 2013. Results The prevalence of multimorbidity (two or more diseases) was 20.07% in 2003 and 30.44% in 2013. In 2013, the prevalence varied between 5.21% in patients aged 20–29 years and 80.96% in those aged 80–89 years. In patients aged 50–79 years, the prevalence of multimorbidity was higher in women than in men. In men, the prevalence of chronic pulmonary disease and cardiovascular-related diseases was predominant, while in women the prevalence of osteoporosis, arthritis, cancer and psychosomatic disorders was predominant. Co-occurring diseases varied across different age and gender groups. Conclusions The burden of multimorbidity is increasing and becoming more complex in Taiwan, and it was found to vary across different age and gender groups. Fulfilling the needs of individuals with multimorbidity requires collaborative work between healthcare providers and needs to take the age and gender disparities of multimorbidity into account.
Safety and Efficacy of Low Dose Domperidone for Treating Nausea and Vomiting Due to Acute Gastroenteritis in Children.

BACKGROUND This study was conducted based on a request from the European Medicines Agency to generate robust data on domperidone efficacy in children in the relief of symptoms of nausea and vomiting by assessing the effect of a low-dose and short treatment duration. METHODS In this randomized, double-blind, phase 3 study, children aged 6-months to 12-years with acute gastroenteritis randomly (1:1) received oral domperidone 0.25-mg/kg plus oral rehydration therapy (ORT) or matching placebo thrice-daily for 2-7 days. The proportion of patients with no vomiting episodes (primary endpoint) and patients aged ≥4 years with no nausea episodes (key secondary endpoint) within 48-hours of first treatment administration were evaluated. RESULTS The study was terminated early following futility analysis. At early termination, 292 patients randomly received domperidone (n = 147) or placebo (n = 145). The proportion of patients with no vomiting episodes within 48-hours of first treatment administration was similar between domperidone (32.0%) and placebo groups (33.8%). Similarly, there was no significant difference in proportion of patients aged ≥4 years with no nausea episodes within 48-hours of first treatment administration between domperidone (35.7%) and placebo (38.6%). Total 13 patients (domperidone, 3.4% [5/147] versus placebo, 5.5% [8/145]) reported ≥1 treatment-emergent adverse events. No deaths or adverse events of special interest (extrapyramidal symptoms and QT prolongation) were reported. CONCLUSION Low-dose of domperidone plus ORT did not significantly differ from placebo in reducing vomiting and nausea episodes in pediatric patients with AG, and the safety profile was similar between both groups.
Participation of the Serine Protease Jonah66Ci in the Drosophila Antinematode Immune Response

Serine proteases and serine protease homologs form the second largest gene family in the Drosophila melanogaster genome. Certain genes in the Jonah multigene family encoding serine proteases have been implicated in the fly antiviral immune response. Here, we report the involvement of Jonah66Ci in the Drosophila immune defense against Steinernema carpocapsae nematode infection. ABSTRACT Serine proteases and serine protease homologs form the second largest gene family in the Drosophila melanogaster genome. Certain genes in the Jonah multigene family encoding serine proteases have been implicated in the fly antiviral immune response. Here, we report the involvement of Jonah66Ci in the Drosophila immune defense against Steinernema carpocapsae nematode infection. We find that Drosophila Jonah66Ci is upregulated in response to symbiotic (carrying the mutualistic bacterium Xenorhabdus nematophila) or axenic (lacking Xenorhabdus) Steinernema nematodes and is expressed exclusively in the gut of Drosophila larvae. Inactivation of Jonah66Ci provides a survival advantage to larvae against axenic nematodes and results in differential expression of Toll and Imd pathway effector genes, specifically in the gut. Also, inactivation of Jonah66Ci increases the numbers of enteroendocrine and mitotic cells in the gut of uninfected larvae, and infection with Steinernema nematodes reduces their numbers, whereas the numbers of intestinal stem cells are unaffected by nematode infection. Jonah66Ci knockdown further reduces nitric oxide levels in response to infection with symbiotic Steinernema nematodes. Finally, we show that Jonah66Ci knockdown does not alter the feeding rates of uninfected Drosophila larvae; however, infection with axenic Steinernema nematodes lowers larval feeding. In conclusion, we report that Jonah66Ci participates in maintaining homeostasis of certain physiological processes in Drosophila larvae in the context of Steinernema nematode infection. Similar findings will take us a step further toward understanding the molecular and physiological mechanisms that take place during parasitic nematode infection in insects.
A Revised Species Concept for Opportunistic Mucor Species Reveals Species-Specific Antifungal Susceptibility Profiles

Recently, the species concept of opportunistic Mucor circinelloides and its relatives has been revised, resulting in the recognition of its classical formae as independent species and the description of new species. In this study, we used isolates of all clinically relevant Mucor species and performed susceptibility testing using the EUCAST reference method to identify potential species-specific susceptibility patterns. ABSTRACT Recently, the species concept of opportunistic Mucor circinelloides and its relatives has been revised, resulting in the recognition of its classical formae as independent species and the description of new species. In this study, we used isolates of all clinically relevant Mucor species and performed susceptibility testing using the EUCAST reference method to identify potential species-specific susceptibility patterns. In vitro susceptibility profiles of 101 mucoralean strains belonging to the genus Mucor (72), the closely related species Cokeromyces recurvatus (3), Rhizopus (12), Lichtheimia (10), and Rhizomucor (4) to six antifungals (amphotericin B, natamycin, terbinaﬁne, isavuconazole, itraconazole, and posaconazole) were determined. The most active drug for all Mucorales was amphotericin B. Antifungal susceptibility profiles of pathogenic Mucor species were specific for isavuconazole, itraconazole, and posaconazole. The species formerly united in M. circinelloides showed clear differences in their antifungal susceptibilities. Cokeromyces recurvatus, Mucor ardhlaengiktus, Mucor lusitanicus (M. circinelloides f. lusitanicus), and Mucor ramosissimus exhibited high MICs to all azoles tested. Mucor indicus presented high MICs for isavuconazole and posaconazole, and Mucor amphibiorum and Mucor irregularis showed high MICs for isavuconazole. MIC values of Mucor spp. for posaconazole, isavuconazole, and itraconazole were high compared to those for Rhizopus and the Lichtheimiaceae (Lichtheimia and Rhizomucor). Molecular identification combined with in vitro susceptibility testing is recommended for Mucor species, especially if azoles are applied in treatment.
An Fc-Optimized CD133 Antibody for Induction of Natural Killer Cell Reactivity Against Colorectal Cancer

The introduction of monoclonal antibodies (mAbs) has largely improved treatment options for cancer patients. The ability of antitumor mAbs to elicit antibody-dependent cellular cytotoxicity (ADCC) contributes to a large extent to their therapeutic efficacy. Many efforts accordingly aim to improve this important function by engineering mAbs with Fc parts that display enhanced affinity to the Fc receptor CD16 expressed, e.g., on natural killer (NK) cells. Here we characterized the CD133 mAb 293C3-SDIE that contains an engineered Fc part modified by the amino acid exchanges S239D/I332E—that reportedly increase the affinity to CD16—with regard to its ability to induce NK reactivity against colorectal cancer (CRC). 293C3-SDIE was found to be a stable protein with favorable binding characteristics achieving saturating binding to CRC cells at concentrations of approximately 1 µg/mL. While not directly affecting CRC cell growth and viability, 293C3-SDIE potently induced NK cell activation, degranulation, secretion of Interferon-γ, as well as ADCC resulting in potent lysis of CRC cell lines. Based on the preclinical characterization presented in this study and the available data indicating that CD133 is broadly expressed in CRC and represents a negative prognostic marker, we conclude that 293C3-SDIE constitutes a promising therapeutic agent for the treatment of CRC and thus warrants clinical evaluation.
Relationship between the shift of socioeconomic status and cardiovascular mortality

Background The aim of this study is to investigate whether upward or downward shifts in socioeconomic status have an effect on cardiovascular mortality. Design A retrospective cohort study. Methods Among the Korean National Health Insurance Service National Sample Cohort, 178,812 subjects were selected who were over 20 years of age as of 2002, with available data on routine health check and free of a diagnosis of ischaemic heart disease, stroke, heart failure or cancer at baseline. Cause of death was identified by the death certificate. Stratification of socioeconomic status was done by income as low (lower 30th percentile), high (higher 30th percentile) and middle, which was reclassified annually. Shift in socioeconomic status was defined as any change in the income class from baseline. Results During the follow-up of a median 10 years, cardiovascular mortality was significantly higher among middle and low socioeconomic status groups (hazard ratio and 95% confidence interval for middle 1.92 (1.68–2.19) and low 1.73 (1.50–2.00)) compared to the high socioeconomic status group after adjustment for age, gender, residence, blood pressure, fasting glucose, smoking and medications (statins and antiplatelet agents). In the same regression model, an upward shift of socioeconomic status was associated with a lower risk of cardiovascular death (hazard ratio 0.46, 95% confidence interval 0.40–0.52), while a downward shift was not a significant predictor. Conclusion An upward shift of socioeconomic status was associated with a lower risk of cardiovascular mortality after adjustment for baseline socioeconomic status, conventional risk factors and risk-reducing pharmacological treatments.
Transcriptomic Analysis Identifies New Non-Target Site Glyphosate-Resistance Genes in Conyza bonariensis

Conyza bonariensis (hairy fleabane) is one of the most problematic and widespread glyphosate-resistant weeds in the world. This highly competitive weed species significantly interferes with crop growth and substantially decreases crop yield. Despite its agricultural importance, the molecular mechanisms of glyphosate resistance are still unknown. The present RNA-Seq study was performed with the goal of identifying differentially expressed candidate transcripts (genes) related to metabolism-based non-target site glyphosate resistance in C. bonariensis. The whole-transcriptome was de novo assembled from glyphosate-resistant and -sensitive biotypes of C. bonariensis from Southern Brazil. The RNA was extracted from untreated and glyphosate-treated plants at several timepoints up to 288 h after treatment in both biotypes. The transcriptome assembly produced 90,124 contigs with an average length of 777 bp and N50 of 1118 bp. In response to glyphosate treatment, differential gene expression analysis was performed on glyphosate-resistant and -sensitive biotypes. A total of 9622 genes were differentially expressed as a response to glyphosate treatment in both biotypes, 4297 (44.6%) being up- and 5325 (55.4%) down-regulated. The resistant biotype presented 1770 up- and 2333 down-regulated genes while the sensitive biotype had 2335 and 2800 up- and down-regulated genes, respectively. Among them, 974 up- and 1290 down-regulated genes were co-expressed in both biotypes. In the present work, we identified 41 new candidate target genes from five families related to herbicide transport and metabolism: 19 ABC transporters, 10 CYP450s, one glutathione S-transferase (GST), five glycosyltransferases (GT), and six genes related to antioxidant enzyme catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD). The candidate genes may participate in metabolic-based glyphosate resistance via oxidation, conjugation, transport, and degradation, plus antioxidation. One or more of these genes might ‘rescue’ resistant plants from irreversible damage after glyphosate treatment. The 41 target genes we report in the present study may inform further functional genomics studies, including gene editing approaches to elucidate glyphosate-resistance mechanisms in C. bonariensis.
Treatment of cervical cancer with electronic brachytherapy

Abstract Purpose We report the first cervical cancer cases treated with interstitial electronic brachytherapy (eBT) at our hospital and compare them with plans made with high‐dose‐rate interstitial brachytherapy based on Ir192 (HDR‐BT). Materials and methods Eight patients with cervical cancer were treated with the Axxent eBT device (Xoft, Inc.). Planning was with magnetic resonance imaging and computed tomography following the recommendations of the EMBRACE protocol. The dosimetry parameters of organs at risk (OAR) were evaluated for the bladder, rectum, and sigmoid colon (D2cc, D1cc, and D0.1cc). In addition, the V150 and V200 of irradiated tissue were compared for both eBT and HDR‐BT. All patients received intensity‐modulated external beam radiation therapy with a regimen of 23 sessions of 2 Gy followed by four sessions of 7 Gy of eBT performed over 2 weeks (two sessions followed by another two sessions a week later) following the EMBRACE recommendations. Each of the eight patients was followed to assess acute toxicity associated with treatment. Results The doses reaching OAR for eBT plans were lower than for HDR‐BT plans. As for acute toxicity associated with eBT, very few cases of mucositis were detected. No cases of rectal toxicity and one case with grade 1 urinary toxicity were detected. The results at 1 month are equally good, and no relapses have occurred to date. Conclusions The first results of treatment with the Axxent eBT device are promising, as no recurrences have been observed and toxicity is very low. eBT is a good alternative for treating cervical cancer in centers without access to conventional HDR.
Modulated electro‐hyperthermia induced p53 driven apoptosis and cell cycle arrest additively support doxorubicin chemotherapy of colorectal cancer in vitro

Modulated electro‐hyperthermia (mEHT), a noninvasive complementary treatment of human chemo‐ and radiotherapy, can generate selective ~42°C heat in cancer due to elevated glycolysis (Warburg‐effect) and electric conductivity in malignant tissues. Here we tested the molecular background of mEHT and its combination with doxorubicin chemotherapy using an in vitro model.
Obesity and the Mediterranean Diet: A Review of Evidence of the Role and Sustainability of the Mediterranean Diet

Several different socio-economic factors have caused a large portion of the population to adopt unhealthy eating habits that can undermine healthcare systems, unless current trends are inverted towards more sustainable lifestyle models. Even though a dietary plan inspired by the principles of the Mediterranean Diet is associated with numerous health benefits and has been demonstrated to exert a preventive effect towards numerous pathologies, including obesity, its use is decreasing and it is now being supplanted by different nutritional models that are often generated by cultural and social changes. Directing governments’ political actions towards spreading adherence to the Mediterranean Diet’s principles as much as possible among the population could help to tackle the obesity epidemic, especially in childhood. This document intends to reiterate the importance of acting in certain age groups to stop the spread of obesity and proceeds with a critical review of the regulatory instruments used so far, bearing in mind the importance of the scientific evidence that led to the consideration of the Mediterranean Diet as not just a food model, but also as the most appropriate regime for disease prevention, a sort of complete lifestyle plan for the pursuit of healthcare sustainability.
Mechanistic study on the use of the L-type amino acid transporter 1 for brain intracellular delivery of ketoprofen via prodrug: a novel approach supporting the development of prodrugs for intracellular targets.

L-type amino acid transporter 1 (LAT1), selectively expressed at the blood-brain barrier (BBB) and brain parenchymal cells, mediates brain delivery of drugs and prodrugs such as L-dopa and gabapentin. Although knowledge about BBB transport of LAT1-utilizing prodrugs is available, there is a lack of quantitative information about brain intracellular delivery and influence of prodrugs on the transporter's physiological state. We studied the LAT1-mediated intra-brain distribution of a recently developed prodrug of the cyclooxygenase inhibitor ketoprofen as well as its impact on transporter protein expression and function (i.e. amino acid exchange) using brain slice method in mice and rats. The intra-brain distribution of the prodrug was 16 times higher than that of ketoprofen. LAT1 involvement in brain cellular barrier uptake of the prodrug was confirmed, reflected by a higher unbound brain intracellular compared to brain extracellular fluid concentration. The prodrug did not alter LAT1 protein expression and amino acid exchange. Integration of derived parameters with previously performed in vivo pharmacokinetic study using the Combinatory Mapping Approach allowed to estimate the brain extra- and intra-cellular levels of unbound ketoprofen, prodrug and released parent drug. The overall efficiency of plasma to brain intracellular delivery of prodrug-released ketoprofen was 11 times higher than after ketoprofen dosing. In summary, this study provides quantitative information supporting the use of the LAT1-mediated prodrug approach for enhanced brain delivery of drugs with intracellular targets.
Efficacy of Xenogeneic Collagen Matrix to Augment Peri-Implant Soft Tissue Thickness Compared to Autogenous Connective Tissue Graft: A Systematic Review and Meta-Analysis.

PURPOSE Several approaches for increasing peri-implant mucosal thickness have been proposed, including autogenous, allogeneic, and xenogeneic grafts. The objective of this meta-analysis was to analyze whether xenogeneic matrices are viable alternatives to autogenous soft tissue grafts in peri-implant soft tissue augmentation. MATERIALS AND METHODS A systematic search was performed to select randomized clinical trials that compared connective tissue grafts and xenogeneic collagen matrices. The primary outcomes were the mucosal thickness and keratinized mucosa changes, while the secondary outcomes were patient morbidity, painkiller consumption, and surgical time required for the procedure. RESULTS Seven randomized clinical trials were included for the final evaluation with a total number of 218 implant sites (108 in the connective tissue graft group, 110 in the collagen matrix group) with 3 to 12 months (mean: 6 months) follow-up period. Results showed mucosal thickness increase in both buccal and crestal sites, but it did not yield statistical significance. The keratinized mucosa gain difference was only -0.06 mm (95% CI [-30.0, 0.18]) between the treatments. The postsurgical discomfort, increased consumption of painkillers, and reduction of treatment time (15.46 minutes less) differed significantly in favor of the collagen matrix group. CONCLUSION Within the limits of this study, it can be concluded that collagen matrix and connective tissue graft are equivalent in peri-implant soft tissue augmentation.
Impact of well-controlled type 2 diabetes mellitus on implant stability and bone biomarkers.

PURPOSE To evaluate initial implant stability and initial healing around newly placed dental implants in well-controlled type 2 diabetes patients. MATERIALS AND METHODS Forty patients requiring implant therapy comprising 15 nondiabetic and 25 diabetic patients were recruited for this prospective study. Implant stability quotient and bone biomarkers such as osteopontin, receptor activator of nuclear factor-kB ligand, and interleukin 8 were evaluated at baseline and 1 and 3 months using Osstell Mentor and enzyme-linked immunosorbent assay, respectively. RESULTS Mean implant stability quotient values showed a statistically significant difference at each interval in both of the groups except between 1 and 3 months in the diabetic group. The percentage increase in implant stability quotient values was more in the nondiabetic (14.2%) than in the diabetic group (6.03%) from 1 to 3 months. Significant variations were observed in all three bone biomarkers between baseline and 3 months at P < . 002 in both groups. In the diabetic group, receptor activator of nuclear factor-kB ligand showed a higher reduction from baseline to 3 months, whereas interleukin 8 showed a less significant decrease between baseline and 1 month. Changes in correlation between implant stability and bone biomarkers were noted in the initial period of healing between the two groups. CONCLUSION Variations in the pattern of response of osteopontin, receptor activator of nuclear factor-kB ligand, interleukin 8, and initial implant stability are noted in well-controlled diabetic individuals.