Miracle-dz/UniFAR-FTUs huggingface dataset:
Dried blood spot-based metabolomic profiling in adults with cystic fibrosis.

Mucoviscidosis of the respiratory, gastrointestinal and genitourinary tracts is the major pathology in patients with cystic fibrosis (CF), a lethal monogeneic pan-ethnic and multi-systemic disease most commonlyidentified in Caucasians. Currently, the measurement of Immuno Reactive Trypsinogen (IRT) in dry blood spots (DBS) is the gold-standard method for initial newborn screening for CF, followed by targeted CFTR mutation analysis, and ultimate confirmation with abnormally elevatedsweat chloride. Previous metabolomics studies in patients with CF reported on different biomarkers such as breath 2-aminoacetophenone produced during acute and chronic infection in human tissues, including the lungs of CF patients. Herein, we used liquid and gas chromatography-mass spectrometry-based targeted metabolomics profiling to identify potentiallyreliable, sensitive, and specific biomarkers in dry blood spots (DBS) collected from 69 young and adult people including CF patients (n= 39) and healthy control (n=30). A distinctive metabolic profile including 26 significantly differentially expressed metabolites involving the amino acids, glycolysis, mitochondrial and peroxisomal metabolism and sorbitol pathways was identified. Specifically, the osmolyte (sorbitol) was remarkably down-regulated in CF patients compared to healthy controls indicating perturbation in the sorbitol pathway which may be responsible for the mucoviscidosis seen in patients with CF. The significance of our findings is supported by the clinical utility of inhaled mannitol and hypertonic saline in patients with CF. The systemic administration of sorbitol in such patients may confer additional benefits beyond the respiratory system especially in those with misfolded CFTR proteins.
Low-cost, ultracompact handheld optical coherence tomography probe for in vivo oral maxillofacial tissue imaging

Abstract. Significance: Optical coherence tomography (OCT) has proven useful for detecting various oral maxillofacial abnormalities. To apply it to clinical applications including biopsy guidance and routine screening, a handheld imaging probe is indispensable. OCT probes reported for oral maxillofacial imaging were either based on a bulky galvanometric mirror pair (not compact or long enough) or a distal-end microelectromechanical systems (MEMS) scanner (raised safety concerns), or adapted from fiber-optic catheters (ill-suited for oral cavity geometry). Aim: To develop a handheld probe featuring great compactness and excellent maneuverability for oral maxillofacial tissue imaging. Approach: A dual-axis MEMS scanner was deployed at the proximal end of the probe and the scanned beam was relayed to the distal end through a 4f configuration. Such design provides both a perfect dual-axis telecentric scan and excellent compactness. Results: A handheld probe with a rigid part 70 mm in length and 7 mm in diameter and weighing 25 g in total was demonstrated through both ex vivo and in vivo experiments, including structural visualization of various oral maxillofacial tissues and monitoring the recovery process of an oral mucosa canker sore. Conclusions: The proposed probe exhibits excellent maneuverability and imaging performance showing great potential in clinical applications.
A glycosylated Fc‐fused glucagon‐like peptide‐1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide

To evaluate the pharmacokinetic and pharmacodynamic properties of a novel glycosylated Fc‐fused glucagon‐like peptide‐1(GLP‐1‐gFc) receptor agonist with distinctive receptor binding affinity, designed to improve in vivo stability and safety relative to the commercial GLP‐1 analogue dulaglutide, and assess its safety profile and pharmacokinetics in healthy humans.
Effect of binary combinations of solvent systems on permeability profiling of pure agomelatine across rat skin: a comparative study with statistically optimized polymeric nanoparticles

Abstract Objective: Agomelatine (AGM), an antidepressant drug has low biological half-life coupled with extensive hepatic first-pass metabolism. For effective treatment of depression, daily medication is required but irregular dose intake occurs due to psychological illness which can be overcome by development of transdermal drug delivery system. But for effective transdermal delivery permeation of AGM through stratum corneum is a crucial step. Thus present study was intended to formulate and optimize polymeric nanoparticles of agomelatine and to compare the effect of binary combinations of solvent system on permeability profiling of pure agomelatine with statistically optimized polymeric nanoparticles. Methods: Polymeric agomelatine nanoparticles (AGM-PNPs) were prepared by nano-precipitation method which was further optimized by experimental design and characterized by FTIR, DSC, XRD and SEM study while ex-vivo study was performed on adult male wistar rats. Results: The optimized formulation has particle size in nano range (107.64 nm) with low PDI (0.209), stable zeta potential (−15 mV) and high entrapment efficiency (81.91%). Ex-vivo analysis of optimized nanoparticles suggests that nanoparticles permeate faster compared to plain AGM, while, permeation profile of AGM was enhanced when combination of solvent systems were used. It was observed that among various solvent system 33% PG-ethanol showed maximum flux (148.48 ± 3.24 µg/cm2/h) and least lag time (4.04 ± 0.12 h). The flux was further enhanced (180.98 ± 2.54 µg/cm2/h) when 5%v/v transcutol-HP was added as penetration enhancer. Conclusion: The above observations concluded that binary combination of 33% PG-ethanol with 5 %v/v transcutol-HP can serve as a solvent system of choice for effective transdermal delivery of agomelatine via nanoparticulate system.
Prediction of Antibiotic Susceptibility for Urinary Tract Infection in a Hospital Setting

Empiric antibiotic prescribing can be supported by guidelines and/or local antibiograms, but these have limitations. We sought to use data from a comprehensive electronic health record to use statistical learning to develop predictive models for individual antibiotics that incorporate patient- and hospital-specific factors. This paper reports on the development and validation of these models with a large retrospective cohort. This was a retrospective cohort study including hospitalized patients with positive urine cultures in the first 48 h of hospitalization at a 1,500-bed tertiary-care hospital over a 4. ABSTRACT Empiric antibiotic prescribing can be supported by guidelines and/or local antibiograms, but these have limitations. We sought to use data from a comprehensive electronic health record to use statistical learning to develop predictive models for individual antibiotics that incorporate patient- and hospital-specific factors. This paper reports on the development and validation of these models with a large retrospective cohort. This was a retrospective cohort study including hospitalized patients with positive urine cultures in the first 48 h of hospitalization at a 1,500-bed tertiary-care hospital over a 4.5-year period. All first urine cultures with susceptibilities were included. Statistical learning techniques, including penalized logistic regression, were used to create predictive models for cefazolin, ceftriaxone, ciprofloxacin, cefepime, and piperacillin-tazobactam. These were validated on a held-out cohort. The final data set used for analysis included 6,366 patients. Final model covariates included demographics, comorbidity score, recent antibiotic use, recent antimicrobial resistance, and antibiotic allergies. Models had acceptable to good discrimination in the training data set and acceptable performance in the validation data set, with a point estimate for area under the receiver operating characteristic curve (AUC) that ranged from 0.65 for ceftriaxone to 0.69 for cefazolin. All models had excellent calibration. We used electronic health record data to create predictive models to estimate antibiotic susceptibilities for urinary tract infections in hospitalized patients. Our models had acceptable performance in a held-out validation cohort.
Epigenetic modulation of macrophage polarization prevents lumbar disc degeneration

Inflammation plays an essential role in the development of lumbar disc degeneration (LDD), although the exact effects of macrophage subtypes on LDD remain unclear. Based on previous studies, we hypothesized that M2-polarization of local macrophages and simultaneous suppression of their production of fibrotic transforming growth factor beta 1 (TGFβ1) could inhibit progression of LDD. Thus, we applied an orthotopic injection of adeno-associated virus (AAV) carrying shRNA for DNA Methyltransferase 1 (DNMT1) and/or shRNA for TGFβ1 under a macrophage-specific CD68 promoter to specifically target local macrophages in a mouse model for LDD. We found that shDNMT1 significantly reduced levels of the pro-inflammatory cytokines TNFα, IL-1β and IL-6, significantly increased levels of the anti-inflammatory cytokines IL-4 and IL-10, significantly increased M2 macrophage polarization, significantly reduced cell apoptosis in the disc degeneration zone and significantly reduced LDD-associated pain. The anti-apoptotic and anti-pain effects were further strengthened by co-application of shTGFβ1. Together, these data suggest that M2 polarization of macrophages induced by both epigenetic modulation and suppressed production and release of TGFβ1 from polarized M2 macrophages, may have a demonstrable therapeutic effect on LDD.
Moxibustion for the treatment of ankylosing spondylitis: a systematic review and meta-analysis.

BACKGROUND To systematically evaluate the efficacy of moxibustion in the treatment of ankylosing spondylitis (AS). METHODS Seven electronic databases were systematically searched for relevant studies for inclusion from databases inception to December 31, 2018. Randomized controlled trials investigating the efficacy of moxibustion for AS treatment versus Western medicine (Wm) treatment were included for systematic review and meta-analysis. Effect estimates were pooled using the fixed or random-effects models. Between-study heterogeneity and publication bias were also assessed. Stratification analyses were further performed based on the treatment plan of experimental groups. RESULTS Twenty-six studies were eligible for inclusion with a total of 1,944 AS patients. Meta-analysis showed that compared with those receiving Wm treatment alone, patients receiving moxibustion combined with Wm treatment or moxibustion alone had a higher clinical efficacy rate [odds ratio (OR) =4.21, 95% confidence interval (CI): 2.91 to 6.10, P<0.001 for moxibustion combined with Wm versus Wm; OR =2.43, 95% CI: 1.62 to 3.65, P<0.001 for moxibustion alone versus Wm]. In addition, patients receiving moxibustion combined with Wm treatment had lower levels of C-reactive protein [weighed-median difference (WMD) =-6.33, 95% CI: -9.64 to -3.01, P<0.001] and erythrocyte sedimentation rate (WMD =-7.86, 95% CI: -11.26 to -4.46, P<0.001) after treatment, respectively. Furthermore, moxibustion could also improve Schober test scores (WMD =0.85, 95% CI: 0.15 to 1.55, P=0.017), occipital-wall distances (WMD =-0.55, 95% CI: -0.92 to -0.19, P=0.003), and finger-ground distances (WMD =-3.64, 95% CI: -5.61 to -1.68, P<0.001) of AS patients. CONCLUSIONS This study suggests that moxibustion is an effective complementary treatment for AS patients. However, further large-scale multicenter clinical trials are needed to confirm these findings.
Application of microsatellite/SSR markers for the identification of peach rootstocks and chromosomal regions associated with the response to Peach Tree Short Life syndrome

ii DEDICATION . v ACKNOWLEDGMENTS . vi LIST OF TABLES . ix LIST OF FIGURES . xi CHAPTER 1. LITERATURE REVIEW . 1 Peach Industry Introduction . 1 Scions and Rootstocks . 2 Peach Rootstock Identification . 4 Molecular Markers and their Application in DNA Fingerprinting . 5 Isozymes . 6 Restriction Fragment Length Polymorphisms (RFLPs) . 7 Random Amplification of Polymorphic DNAs (RAPDs) . 8 Amplified Fragment Length Polymorphisms (AFLPs) . 9 Simple Sequence Repeats (SSRs)/Microsatellites . 11 Single Nucleotide Polymorphisms (SNPs) . 12 Peach Tree Short Life (PTSL) Syndrome . 14 Ring Nematode Parasitism . 15 Control Methods/Orchard Management . 17 Peach Rootstock Selection and Breeding for Tolerance to Ring Nematodes . 17 Genetic Mapping and its Development in Pru us . 19 Mapping Disease Resistance Genes in Prunus . 22 Project Overview . 24 References . 25
Slo2 potassium channel function depends on RNA editing-regulated expression of a SCYL1 protein

Slo2 potassium channels play important roles in neuronal function, and their mutations in humans may cause epilepsies and cognitive defects. However, it is largely unknown how Slo2 is regulated by other proteins. Here we show that the function of C. elegans Slo2 (SLO-2) depends on adr-1, a gene important to RNA editing. ADR-1 promotes SLO-2 function not by editing the transcripts of slo-2 but those of scyl-1, which encodes an orthologue of mammalian SCYL1. Transcripts of scyl-1 are greatly decreased in adr-1 mutants due to deficient RNA editing at a single adenosine in their 3’-UTR. SCYL-1 physically interacts with SLO-2 in neurons. Single-channel open probability (Po) of neuronal SLO-2 is ~50% lower in scyl-1 knockout mutant than wild type. Moreover, human Slo2.2/Slack Po is doubled by SCYL1 in a heterologous expression system. These results suggest that SCYL-1/SCYL1 is an evolutionarily conserved regulator of Slo2 channels.
The efficacy of transcranial alternating current stimulation for treating post-stroke depression

Abstract Background: The treatment of post-stroke depression (PSD) with anti-depressant drugs is partly practical. Transcranial alternating current stimulation (tACS) offers the potential for a novel treatment modality for adult patients with PSD. In this study, we will assess the efficacy and safety of tACS for treating PSD and explore its effect on gamma and beta-oscillations involving in emotional regulation. Methods: The prospective study is an 8-week, double-blind, randomized, placebo-controlled trial. Seventy eligible participants with mild to moderate PSD aged between 18 years and 70 years will be recruited and randomly assigned to either active tACS intervention group or sham group. Daily 40-minute, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas on weekdays for 4 consecutive weeks (week 4), and an additional 4-week observational period (week 8) will be followed up. The primary outcome is the proportion of participants having an improvement at week 8 according to the Hamilton Depression Rating Scale 17-Item (HAMD-17) score, including the proportion of participants having a decrease of ≥ 50% in HAMD-17 score or clinical recovery (HAMD-17 score ≤ 7). Secondary outcomes include neurological function, independence level, activities of daily living, disease severity, anxiety, and cognitive function. The exploratory outcomes are gamma and beta-oscillations assessed at baseline, week 4, and week 8. Data will be analyzed by logistical regression analyses and mixed-effects models. Discussion: The study will be the first randomized controlled trial to evaluate the efficacy and safety of tACS at a 77.5-Hz frequency and 15-mA current in reducing depressive severity in patients with PSD. The results of the study will present a base for future studies on the tACS in PSD and its possible mechanism. Trial registration number: NCT03903068, pre-results.
The Peripheral Peril: Injected Insulin Induces Insulin Insensitivity in Type 1 Diabetes

Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable consistency and considerable magnitude. Although therapeutic innovations are continuing to normalize dysglycemia, a sizable body of data suggests a second metabolic abnormality—iatrogenic hyperinsulinemia—principally drives insulin resistance and its consequences in this population and has not been addressed. We review this evidence to show that injecting insulin into the peripheral circulation bypasses first-pass hepatic insulin clearance, which leads to the unintended metabolic consequence of whole-body insulin resistance. We propose restructuring insulin therapy to restore the physiological insulin balance between the hepatic portal and peripheral circulations and thereby avoid the complications of life-long insulin resistance. As technology rapidly advances and our ability to ensure euglycemia improves, iatrogenic insulin resistance will become the final barrier to overcome to restore normal physiology, health, and life in type 1 diabetes.
Adipose Triglyceride Lipase Is a Key Lipase for the Mobilization of Lipid Droplets in Human β-Cells and Critical for the Maintenance of Syntaxin 1a Levels in β-Cells

Lipid droplets (LDs) are frequently increased when excessive lipid accumulation leads to cellular dysfunction. Distinct from mouse β-cells, LDs are prominent in human β-cells. However, the regulation of LD mobilization (lipolysis) in human β-cells remains unclear. We found that glucose increases lipolysis in nondiabetic human islets but not in islets in patients with type 2 diabetes (T2D), indicating dysregulation of lipolysis in T2D islets. Silencing adipose triglyceride lipase (ATGL) in human pseudoislets with shRNA targeting ATGL (shATGL) increased triglycerides (TGs) and the number and size of LDs, indicating that ATGL is the principal lipase in human β-cells. In shATGL pseudoislets, biphasic glucose-stimulated insulin secretion (GSIS), and insulin secretion to 3-isobutyl-1-methylxanthine and KCl were all reduced without altering oxygen consumption rate compared with scramble control. Like human islets, INS1 cells showed visible LDs, glucose-responsive lipolysis, and impairment of GSIS after ATGL silencing. ATGL-deficient INS1 cells and human pseudoislets showed reduced SNARE protein syntaxin 1a (STX1A), a key SNARE component. Proteasomal degradation of Stx1a was accelerated likely through reduced palmitoylation in ATGL-deficient INS1 cells. Therefore, ATGL is responsible for LD mobilization in human β-cells and supports insulin secretion by stabilizing STX1A. The dysregulated lipolysis may contribute to LD accumulation and β-cell dysfunction in T2D islets.
Life expectancy after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: a Swedish single-center study

Pulmonary endarterectomy is the guideline recommended treatment for chronic thromboembolic pulmonary hypertension, in addition to life-long anticoagulation therapy. The aim was to analyze long-term relative survival after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. We included all patients who underwent pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension at Karolinska University Hospital between 1997 and 2018 (n = 100). We obtained baseline characteristics and vital status from patient charts and national health-data registers. The expected survival from the general Swedish population matched by age, sex, and year of surgery was obtained from the Human Mortality Database. The relative survival was used as an estimate of cause-specific mortality. The mean age of the patients was 62 years and 39% were women. Most patients were severely symptomatic (95% in New York Heart Association functional class III–IV), and mean preoperative systolic/diastolic (mean) pulmonary artery pressure was 78/27 (45) mmHg. The mean and maximum follow-up time was 7.2 and 22.1 years, respectively. Early (30-day) mortality was 7%. The 15-year observed, expected, and relative survival was 55% (95% confidence interval, 40%–68%), 71%, and 77% (95% confidence interval, 56%–95%), respectively. The 15-year relative survival conditional on 30-day survival was 83% (95% confidence interval, 60%–100%). Although the life expectancy following pulmonary endarterectomy was shorter compared to the general population, the difference was small in those who survived the operation and the early postoperative period. Patients with chronic thromboembolic pulmonary hypertension who are surgical candidates should undergo pulmonary endarterectomy to improve prognosis.
Efficacy and safety of XEN®—Implantation vs. trabeculectomy: Data of a “real-world” setting

Objective To compare surgical success, postoperative intraocular pressure and complication rates between trabeculectomy and XEN gelstent surgery in a cohort of glaucoma patients in a typical clinical setting. Methods A retrospective cohort study of consecutive patients with refractory open-angle glaucoma including patients who underwent either stand-alone XEN gelstent insertion with Mitomycin C or trabeculectomy with Mitomycin C between 2016 and 2018 at the University Eye Hospital Mainz, Germany. Primary outcome measure was the proportion of surgical success 1 year after surgery. Patients with an IOP ≤18mmHg, an intraocular pressure reduction of >20% and in no need of revision surgery or topical medication were considered a complete surgical success. If topical therapy was necessary, they were considered a qualified success. Multivariable logistic regression analysis was carried out for the primary outcome including gender, age, preoperative intraocular pressure and number of medication classes used preoperatively as adjustment variables. Results 171 eyes of 144 patients were included, including 82 eyes of 58 patients in the XEN group and 89 eyes of 86 patients in the trabeculectomy group. The primary outcome defined as the proportion of surgical success after 1 year (mean 11.1 months ± 2.2) was similar for both groups. The complete success proportion was 65.5% (95%-CI: 55.6–75.9%) in the trabeculectomy group, and 58.5% (95%-CI: 47.6–69.4%) in the XEN group and not statistically different in our analysis model (crude OR = 0.61; 95%-CI: 0.31–1.22; adjusted OR = 0.66; 95%-CI: 0.32–1.37). The intraocular pressure reduction, as secondary outcome measure, was higher in the trabeculectomy group (10.5 mmHg) compared to the XEN group (7.2 mmHg; p = 0.003) at the 12-month follow-up. Conclusion Both XEN gelstent implantation and trabeculectomy show similar proportions of surgical success and of complications and are therefore both recommendable for clinical routine. However, trabeculectomy seems to be more effective in lowering intraocular pressure than the XEN implantation. A prospective randomized clinical trial is necessary to evaluate differences in the long-term clinical outcome.