Aims: To investigate the effects of ABCB1 DNA methylation in donors on individual differences in tacrolimus blood concentrations following liver transplantation. Methods: Twenty-three donor liver samples carrying the CYP3A5*3/*3 genotype were classified into two groups based on the initial tacrolimus concentration/dose (C0/D) ratio following liver transplantation. ABCB1 mRNA levels in liver tissues and HepG2 cells were determined by qRT-PCR. DNA methylation status in liver tissues and HepG2 cells was determined using Illumina 850 methylation chip sequencing technology and pyrosequencing. 5-Aza-2dC was used to reverse methylation in HepG2 cells. Intracellular tacrolimus concentrations were determined by liquid mass spectrometry. Results: Genome-wide methylation sequencing and pyrosequencing analyses showed that the methylation levels of three ABCB1 CpG sites (cg12501229, cg00634941, and cg05496710) were significantly different between groups with different tacrolimus C0/D ratios. ABCB1 mRNA expression in donor livers was found to be positively correlated with tacrolimus C0/D ratio (r = 0.458, P < 0.05). After treatment with 5-Aza-2-Dc, the methylation levels of the ABCB1 CpG sites in HepG2 cells significantly decreased, and this was confirmed by pyrosequencing; there was also a significant increase in ABCB1 transcription, and this most likely induced a decrease in intracellular tacrolimus concentrations. Conclusions: ABCB1 CpG site methylation affects tacrolimus metabolism in humans by regulating ABCB1 expression. Therefore, ABCB1 DNA methylation in donor livers might be an important epigenetic factor that affects tacrolimus blood concentrations following liver transplantation.

Another recent evidence of the clinical utility of the high-power, short-duration radiofrequency ablation strategyKoichiro Ejima, MD, PhD,1, 2 Kyoichiro Yazaki, MD,1 Morio Shoda, MD, PhD, 1, 2Nobuhisa Hagiwara, MD, PhD 11. Department of Cardiology, Tokyo Women’s Medical University2. Clinical Research Division for Heart Rhythm Management, Department of Cardiology, Tokyo Women’s Medical UniversityDepartment of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666 JapanFunding : (None)Disclosures : (None)Corresponding author : Koichiro EjimaE-mail address : koichiro@qf6.so-net.ne.jpDepartment of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666 JapanTel : +81-3-3353-8111 FAX : +81-3-3356-0441Winkle et al. reviewed the literature of the high-power, short-duration (HPSD) radiofrequency ablation strategy.1We appreciate that they included our study that compared an HPSD ablation with a low-power, long-duration (LPLD) ablation using unipolar signal modification (USM) as a local endpoint during atrial fibrillation (AF) ablation.2 This study included 32 patients (paroxysmal 22, persistent 10) who underwent AF ablation using the HPSD strategy and 32 using the LPLD, and the median follow-up period was 10 months. After that, we reported another study that compared the HPSD ablation with the LPLD ablation using the USM as a local endpoint during AF ablation, which included only patients with paroxysmal AF.3 The number of patients included in the study was larger (HPSD 60, LPLD 60), and the follow-up duration was longer (mean follow-up period of the HPSD group, 12.5 months) than that in our former study. In this study, the freedom from recurrence after a single ablation procedure without any antiarrhythmic drugs was higher in the HPSD group than LPLD group (88.3% vs. 73.3% at 12-months after the procedure, log-rank; P=0.0423). This article was electrically published on May 15, 2020, more than 6 months before Winkle’s review article was received by the editorial office of the Journal of Cardiovascular Electrophysiology (December 4, 2020).We believe that this study is also worth being included the Winkle’s review article and might contribute to future investigators.

Please let me know if it is necessary…we are working on a reply to a previous work

The iliopsoas muscle abscess is rare condition, with increasing recognition, that can be either primary, by hematological or lymphatic dissemination, or secondary to infections in the gastrointestinal, genitourinary tract or musculoskeletal system. Its early identification is highlighted, for an adequate therapeutic orientation, contributing to a good prognosis.

In this paper, we study Aronson-B\’{e}nilan gradient estimates for positive solutions of weighted porous medium equations $$\partial_{t}u(x,t)=\Delta_{\phi}u^{p}(x,t),\,\,\,\,(x,t)\in M\times[0,T]$$ coupled with the geometric flow $\frac{\partial g}{\partial t}=2h(t),\,\,\,\frac{\partial \phi}{\partial t}=\Delta \phi$ on a complete measure space $(M^{n},g,e^{-\phi}dv)$. As an application, by integrating the gradient estimates, we derive the corresponding Harnack inequalities.

A)The crises related to climate and the economy endanger future and current generations, but altering the small impact or minimal emissions of an individual person is-because of the failure of political coordination-not the best way to overcome these crises. B) When we act as individuals to act as stopgaps for policy to minimise the mountain of problems, the following applies: We should not waste our energies on limited involvements in small, primarily symbolic collaborations but should instead endeavour to make the biggest difference of which we are capable with regard to improving the world.C) We make the biggest difference when our limited budget for improving the world is used against poverty, for example, and combatting poverty is precisely what brings positive side effects with regard to human rights and the protection of the climate, animals and species. For example, support for poor farmers in rain forests can save those rain forests. Every CO2 calculator demonstrates that commitment to the Third World is up to 50 times more efficient than personal emissions reductions.

COVID-19 can cause pneumothorax but pneumothorax in COVID-19 patient associated with bronchopleural fistula is very rarely reported. We present this unusual case of Tension Pneumothorax in COVID -19 Patient associated with Bronchopleural Fistula.

Nasal schwannomas account for about 4% of head and neck schwannomas. We report a rare case of lateral nasal wall schwannoma presenting as a nasal mass in a 70-year-old man.

Microbial metabolism of specific dietary components, such as fiber, contribute to the sophisticated inter-kingdom dialogue in the gut that maintains a stable environment with important beneficial physiological, metabolic, and immunological effects on the host. Historical changes in fiber intake may be contributing to the increase of allergic and hypersensitivity disorders as fiber-derived metabolites are evolutionarily hardwired into the molecular circuitry governing immune cell decision making processes. In this review, we highlight the importance of fiber as a dietary ingredient, its effects on the microbiome, its effects on immune regulation, and potential mechanisms for dietary fibers in the prevention and management of allergic diseases. In addition, we review the human studies examining fiber or prebiotic interventions on asthma and respiratory outcomes, allergic rhinitis, atopic dermatitis, and overall risk of atopic disorders. While exposures, interventions and outcomes were too heterogeneous for meta-analysis, there is significant potential for using fiber in targeted manipulations of the gut microbiome and its metabolic functions in promoting immune health.

Listeria monocytogenes is a human pathogen. It is the causative agent of listeriosis, the leading cause of bacterial-linked foodborne mortality in Europe and elsewhere. Outbreaks of listeriosis have been associated with the consumption of fresh produce including vegetables and fruits. In this review we summarize current data providing direct or indirect evidence that plants can serve as habitat for L. monocytogenes, enabling this human pathogen to survive and grow. The current knowledge of the mechanisms involved in the interaction of this bacterium with plants is addressed, and whether this foodborne pathogen elicits an immune response in plants is discussed.

DWP16001 is a novel sodium-glucose cotransporter-2 (SGLT2) inhibitor under development for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of DWP16001 after single and multiple doses in healthy subjects. A randomized, double-blind, placebo- and active-controlled, single- and multiple-dose study was conducted. Twelve subjects in each dose group received a single dose (0.2, 0.5, 1.0, 2.0, or 5.0 mg) or multiple doses (0.1, 0.3, 0.5, 1.0, or 2.0 mg once daily for 15 consecutive days) of DWP16001, dapagliflozin 10 mg, or placebo, in a ratio of 8:2:2. Serial blood samples and interval urine samples were collected for PK and PD analyses. Safety and tolerability were assessed throughout the study period. A dose-dependent increase in urinary glucose excretion (UGE) was observed after a single dose, and the steady-state UGE was 50–60 g/day after multiple doses in the dose range of 0.3 – 2.0 mg. DWP16001 was rapidly absorbed with the time to peak plasma concentration of 1.0 – 3.0 hours, and eliminated with a mean elimination half-life of 13 - 29 hours. The systemic exposure of DWP16001 increased proportionally with the dose after multiple administrations in the range of 0.1 – 2.0 mg. DWP16001 was well tolerated in all dose groups. DWP16001 caused glucosuria in a dose-dependent manner, and systemic exposure was observed after multiple doses. DWP16001 was well tolerated up to 5.0 mg after a single oral dose and up to 2.0 mg after multiple oral administration

Although Streptococcus agalactiae periprosthetic joint infection (PJI) is not as prevalent as staphylococcal PJI, invasive S. agalactiae infection has recently increased in incidence. Here, RNA-Seq was used to perform transcriptomic analysis of S. agalactiae PJI using fluid derived from sonication of explanted arthroplasties of subjects with S. agalactiae PJI, with results compared to those of S. agalactiae strain NEM316 grown in vitro. 227 genes with outlier expression were found (164 up-regulated and 63 down-regulated) between PJI sonicate fluid and in vitro conditions. Functional enrichment analysis showed genes involved in mobilome and inorganic ion transport and metabolism to be most enriched. Genes involved in nickel, copper, and zinc transport, were upregulated. Among known virulence factors, cyl operon genes, encoding beta-hemolysin/cytolysin, were consistently highly expressed in PJI versus in vitro. The data presented provide insight into S. agalactiae PJI pathogenesis and may be a useful resource for the identification of novel PJI therapeutics or vaccines against invasive S. agalactiae infections.

Thermochemical conversions are pathways for the utilization of biomass to produce a variety of value-added energy and chemical products. For the development of novel thermochemical conversion technologies, an accurate understanding of the reaction performance and kinetics is essential. Given the diversity of the thermal analysis techniques, it is necessary to understand the features and limitations of the reactors, ensuring that the selected thermal analysis reactor meets the specific need for reaction characterization. This paper provides a critical overview of the thermal analysis reactors based on the following perspectives: 1) gas flow conditions in the reactor, 2) particle’s external and internal heat and mass transfer limitations, 3) heating rate, 4) temperature distribution, 5) nascent char production and reaction, 6) liquid feeding and atomization, 7) simultaneous sampling and analyzing of bed materials, and 8) reacting atmosphere change. Finally, prospects and future research directions in the development of thermal analysis techniques are proposed.

Nell'industria estrattiva di petrolio e gas, il trattamento di acqua di produzione rappresenta un problema di non poco conto, data l'alta concentrazione di sali ed oli. Esistono, ad oggi, diversi metodi atti alla rimozione degli oli, delle particelle in sospensione, del ferro ed alla dissalazione. Tra questi, l’impiego di membrane è sempre più diffuso. Le membrane ceramiche portano con sé diverse problematiche relative all'esiguo flusso d'acqua. Per ovviare a tale limitazione, sono state effettuati diversi studi per migliorarne le prestazioni. Questo articolo si focalizza sull’esporre le diverse prove effettuate per il miglioramento della tecnologia. Principalmente, le modifiche effettuate alle membrane sono di due tipologie: modifiche dei materiali utilizzati per la fabbricazione della membrana oppure modifiche tramite rivestimento in nanoparticelle a formare un materiale composito.

Coronavirus disease 2019 (COVID-19) is a viral disease caused by a novel coronavirus that can lead to severe acute respiratory failure. Recent studies have shown that aggravating factors in the etiology of COVID-19 disease include genetic defects and autoantibodies against type 1 interferon. Mycobacterium tuberculosis is an immobile aerobic bacillus that causes tuberculosis disease. SARS-CoV-2 infection and immunosuppressive drugs may temporarily inhibit immunologic system, then may lead to active tuberculosis by reactivation or infection of M. tuberculosis. We aimed to show that there is a relationship between covid-19 infection and an increase in the number of tuberculosis patients. Eight patients diagnosed with tuberculosis in the Pediatric Pulmonology and Pediatric Infectious Diseases Clinics of Necmettin Erbakan University, Meram Medical Faculty between March 2020 and May 2021 were enrolled in this study. The presence of COVID-19 infection was confirmed by COVID-19 antibody test and patient’s detailed medical history. The patient with negative antibody test was also included in the study if other family members confirmed for COVID-19 infection by RT-PCR. We evaluated demographic data, laboratory findings, imaging tests and pathology results of all patients. The remarkable increase in the number of tuberculosis activation in the recent year suggests the role of COVID-19 infection. The pathologic structure of the virus may be responsible of the increase, although the mechanism is not fully understood. Further research should be done on this topic.

In this paper we apply the Legendre wavelets basis to solve the linear weakly singular Volterra integral equation of the second kind. The basis is defined on [0,1) , and in this work we extend this interval to [0,n) for some positive integer n. For this aim we solve the problem on [0,1); then we apply the Legendre wavelets on [1,2) and use the lag solution on [0,1) to obtain the solution on [0,2) and continue this procedure. Convergence analysis of Legendre wavelets on [n,n+1), is considered in Section2. We give a convergence analysis for the proposed method, established on compactness of operators. In numerical results we give two sample problems from heat conduction. For this purpose, in Section 6 we give an equivalent theorem between the proposed heat conduction problem and an integral equation. Then we solve the equivalent integral equation by the proposed method on union of some interval and obtain the solution of the heat conduction problem. As Tables and Figures of two and three dimensional plots show, accuracy of the method is reasonable and there is not any propagation of error from lag intervals. The convergence analysis and these sample problems demonstrate the accuracy and applicability of the method.

Aim: Edoxaban is a non-vitamin K antagonist oral anticoagulant (NOAC) widely used for long-term stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Adherence to NOACs is unsatisfactory and decreases over time. The aim of this study was to explore appropriated remedial dosing regimens for non-adherent edoxaban-treated NVAF patients through the Monte Carlo simulation. Methods: Six proposed regimens were compared with the recommendations in the European Heart Rhythm Association (EHRA) guide regarding the trough total deviation time considering both edoxaban plasma concentration and inactive factor Xa activity. Monte Carlo simulations were performed using RxODE based on the published population pharmacokinetics/pharmacodynamics model. Results: The proposed remedial strategies were different from EHRA recommendations and were related to delay duration. The missed dose can be taken immediately if the delay time is within 11 h. When the delay period is between 12 and 19 h, a half dose followed by a regular dosing schedule is recommended. When the delay time exceeds 19 h, a full dose followed by a half dose is preferred compared to that recommended in the EHRA guide. Our proposed strategies resulted in a shorter total deviation time than EHRA guide. Conclusion: PK/PD modelling and simulation are effective in developing and evaluating the remedial strategies of edoxaban, which could help maximize its therapeutic effect.

Introduction: Youth diagnosed with sickle cell disease (SCD) often utilize the healthcare setting to manage disease-related symptoms, yet the connection between healthcare use and their overall wellbeing has been understudied. This study investigates whether healthcare utilization predicts the health-related quality of life (HRQOL) in youth with SCD. It is hypothesized that increased healthcare utilization will predict lower HRQOL in pediatric SCD. Methods: A total of 150 patients, ages 8-17 years old, were enrolled in this cross-sectional quantitative study. Patients completed the Pediatric Quality of Life (PedsQL) 3.0 SCD module, while the researcher conducted a retrospective chart review to gather patient characteristics such as emergency room (ER) and hospitalization occurrences over the past 12 months. Results: A higher frequency of ER visits (p < .05) and hospitalizations (p < .01) predicted lower HRQOL scores. Age (p < .05) also emerged as a significant predictor for both regression models. Discussion: As youth with SCD require ER treatment and/or hospital admission, they are at increased risk for lower HRQOL, specifically as they get older.

Background: Hepatic steatosis is associated with increased surgical complications in patients undergoing bariatric surgery. The aim of this study was to evaluate the effect of phentermine in reducing hepatic steatosis, adipose tissue and surgical complications in patients undergoing bariatric surgery. Methods: This study is a two-arm, double-blind, randomized, controlled pilot trial of 64 adult subjects with BMI >35 kg/m2 selected for bariatric surgery randomized to phentermine 15 mg once daily for 8 week or placebo. Both groups adhered to a hypocaloric diet and individualized exercise program. The primary end point was the reduce frequency of hepatic steatosis measured by ultrasound and the reduce adipose tissue through fat mass in total kilograms or percentage. Key secondary points were the prevalence of surgical complications. Baseline and final biochemical parameters and blood pressure too were assessments. Results: Phentermine group the frequency of hepatic steatosis decreased 19%, and the percentage of patients with a normal ultrasound increased from 9% to 20% (p= 0.053). Likewise, the decrease in fat mass in kilograms was greater in the phentermine group (56.1 kg vs. 51.8 kg, p=0.02), and a significant decrease in the HOMA-IR index was observed regardless of weight loss. No differences in surgical complications were observed between groups. Phentermine was well tolerated; no differences were observed in the frequency of adverse events between the groups. Conclusions: Phentermine decreased the proportion of individuals with hepatic steatosis by 19%, promoted a greater loss of fat mass in kilograms, and decreased insulin resistance among candidates for bariatric surgery.

Background: Patients with venoarterial extracorporeal membrane oxygenation (VA-ECMO) are at risk of cerebral reperfusion injury after prolonged hypoperfusion and immediate restoration of systemic blood flow. We aimed to examine the impact of mild hypothermia during the first 24 hours post-ECMO on neurological outcome in VA-ECMO patients. Methods: This was a retrospective study of adult VA-ECMO patients from a tertiary care center. Mild hypothermia was defined as 32-36°C during the first 24 hours post-ECMO. Primary outcome was good neurological function at discharge measured by a modified Rankin Scale ≤3. Multivariable logistic regression analysis was performed for primary outcome adjusting for pre-specified covariates. Results: Overall, 128 consecutive patients with VA-ECMO support (median age: 60 years and 63% males) were included. Within the first 24 hours of VA-ECMO cannulation, we found a median of 71 readings per patient (interquartile range 45-88). Eighty-eight patients (68.8%) experienced mild hypothermia within the first 24 hours while 18 of those 88 patients (14.2%) had a mean temperature<36°C. ECMO indications included post-cardiotomy shock (39.8%), cardiac arrest (29.7%), and cardiogenic shock (26.6%). Duration of mild hypothermia, but not mean temperature, was independently associated with increased odds of good neurological outcome at discharge (Odds Ratio [OR]=1.16, 95% Confidence Interval [CI]=1.04-1.31, p=0.01) after adjusting for age, severity of illness, post-ECMO systemic hemorrhage, post-cardiotomy shock, acute brain injury, and mean 24-hour PaO 2. Neither duration of mild hypothermia (OR=0.93, CI=0.84-1.03, p=0.17) nor mean temperature (OR=0.78, CI=0.29-2.08, p=0.62) was significantly associated with mortality. Similarly, duration of mild hypothermia (p=0.47) and mean 24-hour temperature (p=0.76) were not significantly associated with frequency of systemic hemorrhages. Conclusions: In this single center study, longer duration of mild hypothermia during the first 24 hours of ECMO support was significantly associated with improved neurological outcome. Mild hypothermia was not associated with an increased risk of systemic hemorrhage or improved survival.

Background and Purpose: The current study investigated whether the manipulation of gut microbiome through treatment with an antibiotic cocktail can alter the bioavailability of clopidogrel active metabolite (Clop-AM) in T2DM rats. Experimental Approach: Control and T2DM rats were orally administered with either vehicle or an antibiotic cocktail containing ampicillin, neomycin, metronidazole, and vancomycin for 5 consecutive days. The levels of clopidogrel (Clop) and its metabolites were measured by LC-MS/MS. Biochemical parameters, liver microsome metabolism, mRNA, protein or activity of Clop- metabolizing enzymes and transporter, and 16S rRNA sequence of fecal samples were analyzed to explain any altered pharmacokinetic profile of Clop-AM. Key Results: Antibiotic administration markedly alleviated T2DM rats’ phenotypes including hyperglycemia, hyperlipidemia, insulin resistance, liver dysfunction and inflammation. Meanwhile, the reduced systemic exposure of Clop-AM in T2DM rats as compared to control rats was significantly reversed after antibiotic treatment, accompanied with the decreased expression of P-glycoprotein (P-gp) in small intestine, suggesting P-gp-based Clop absorption might be promoted, consequently making more Clop available for Clop-AM formation. Interestingly, fecal microbiome analysis exhibited the reduced microbial amount and the altered microbial composition in antibiotic-treated T2DM rats. Especially, there was an inconsistent change of P-gp levels between T2DM rats and SW480 cells after antibiotic treatment, suggesting antibiotic-induced microbiome depletion, not the direct role of antibiotics is associated with the enhanced Clop-AM plasma exposure in T2DM rats. Conclusion and Implication: The findings show that gut microbiota modulation is an effective therapeutic strategy to enhance Clop-AM generation under T2DM conditions.

Osteopoikilosis(OPK) is one of the rare genetic musculoskeletal, non inflammatory disorders that we should increase awareness towards. We report a case of a patient diagnosed with psoriatic arthritis with incidental imaging findings of lesions suggestive of osteopoikilosis.

Cryoglobulinemia vasculitis (CV) is a rare, small vascular occlusive disease caused by cryoglobulin precipitation in the plasma. We report the case of a 61-year-old female suffering from pain in the toes of the left foot in autumn, who subsequently developed acute pain, during hospitalization.

Population dynamics are functions of several demographic processes including survival, reproduction, somatic growth, and maturation. The rates or probabilities for these processes can vary by time, by location, and by individual. These processes can co-vary and interact to varying degrees, e.g., an animal can only reproduce when it is in a particular maturation state. Population dynamics models that treat the processes as independent may yield somewhat biased or imprecise parameter estimates, as well as predictions of population abundances or densities. However, commonly used integral projection models (IPMs) typically assume independence across these demographic processes. We examine several approaches for modelling between process dependence in IPMs, and include cases where the processes co-vary as a function of time (temporal variation), co-vary within each individual (individual heterogeneity), and combinations of these (temporal variation and individual heterogeneity). We compare our methods to conventional IPMs, which treat vital rates independent, using simulations and a case study of Soay sheep (Ovis aries). In particular, our results indicate that correlation between vital rates can moderately affect variability of some population-level statistics. Therefore, including such dependent structures is generally advisable when fitting IPMs to ascertain whether or not such between vital rate dependencies exist, which in turn can have subsequent impact on population management or life-history evolution.