Aim: The aim of this study was to establish a population pharmacokinetic (PPK) model for rivaroxaban in Chinese elderly patients with NVAF to evaluate precision dosing regimens and analyze hemorrhagic risk after rivaroxaban treatment. Method: A population pharmacokinetic model was developed using the nonlinear mixed-effects model (NONMEM). The plasma concentration of rivaroxaban was detected by UPLC-MS/MS method and the gene polymorphisms were detected by Sanger dideoxy DNA sequencing method. A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates for the target range of therapeutic drug monitoring concentrations (Cmax,ss, Cmin,ss). Exposure of rivaroxaban was simulated and assessed in hemorrhagic risk evaluation. Results: Model-building dataset including 360 plasma concentrations from 180 Chinese elderly patients (median age 81year). A one-compartment population PK model with estimated glomerular filtration rate (eGFR), total bilirubin (TBIL) and ABCB1 rs1045642 as major covariates for apparent clearance were developed. The average probability of target attainment (PTA) of optimal dosing regimens with different covariates levels for targeted Cmax,ss and Cmin,ss were 29.35%-31.30% and 64.91%-65.80%, respectively. 10 mg of rivaroxaban in Chinese elderly patients with normal renal and liver function was appropriate. AUC24,ss was statistically significant associated with the increased risk of the bleeding events (OR 1.0006; 95%CL 1.0003-1.001; p<0.0001). Conclusion: Lower dose is recommended for older patients with renal impairment to avoid overexposure and bleeding events. The population pharmacokinetic model could inform individualized dosing for Chinese older NVAF patients with rivaroxaban anticoagulation therapy.

Objective: Evaluation of the inter-observer and intra-observer agreement for CTG interpretation by NICE guidelines 2017. Design: A hospital-based Prospective observational study. Setting: The study was conducted at a university teaching hospital Sample size: A total of 165 CTG tracings from 165 laboring women were included in the study for interpretation by 6 clinicians with varying levels of experience in the specialty. Methods: 6 clinicians (3 consultants & 3 residents in training) independently interpreted CTG traces using NICE 2017 guidelines twice with a locking period of 3 months between 2 interpretations. Main outcome measure: Fleiss’s kappa and Cohen’s kappa coefficient was employed for ascertaining interobserver and intraobserver agreement using SPSS statistical software. Results: Among all CTG parameters, observed agreement for baseline fetal heart was substantial [k=0.678(0.677-0.679), p<0.0001] but the congruence for variability was only slightly above the chance [0.185 (0.184-0.186), p<0.0001]. Overall kappa coefficient was 0.382 (0.381-0.383) with a p<0.0001 (moderate agreement) for classifying the CTG category. The intra-observer agreement of most senior consultant for baseline was nearly perfect (Kf=0.937) as compared to a kappa coefficient of 0.367 of the junior-most resident. Conclusions: Different CTG interpretation parameters were observed to have varying levels of agreement among clinicians. Where experience was witnessed to improve the agreement, the higher degree of non-congruence in certain CTG parameters like variability, and type of decelerations may perhaps point to the need for further objectivity in defining these parameters.

Objectives To study effects of physiotherapist-guided pelvic floor muscle training on pelvic organ prolapse (POP) early postpartum period. Design Assessor-blinded, randomized controlled trial. Setting Physiotherapy Clinic, Reykjavik. Sample Eighty-four primiparous women with a singleton delivery. Methods Participants were screened for eligibility 6-13 weeks postpartum. Women randomized to the training group conducted 12 weekly individual sessions with a physiotherapist, starting on average 9 weeks after childbirth. Outcomes were assessed after the last session (short-term) and at 12 months postpartum (long-term). The control group received no instructions after the initial assessment. Main outcome measures Self-evaluated POP symptoms by the Australian Pelvic Floor Questionnaire. Results Forty-one and 43 women were randomized to the training and control groups, respectively. At recruitment, 17 (42.5%) of the training and 15 (37%) of the control group reported prolapse symptoms (p=0.6). Five (13%) from the training and 9 (21%) controls were bothered by the symptoms (p=0.3). There was a gradual decrease in the number of women with symptoms and no significant short-term (p=0.08 at 6 months) or long-term (p=0.6 at 12 months) differences between the groups regarding rates of women with POP sympoms. No difference was between groups regarding bother in the short (p=0.3) or longer term (p=0.4). Repeated measure analyses using Proc Genmod in SAS did not indicate a significant effect of the intervention over time, p>0.05. Conclusions There was an overall decrease in postpartum symptoms of POP and bother during the first year. Physiotherapist-lead pelvic floor muscle training did not change the outcomes.

Invasive predatory species are frequently observed to cause evolutionary responses in prey phenotypes, which in turn may translate into evolution of the prey’s population dynamics. Research has provided a link between rates of predation and the evolution of prey population growth in the lab, but studies from natural populations are rare. Here we tested for evolutionary changes in population dynamics parameters of zooplankton Daphnia pulicaria following invasion by the predator Bythotrephes longimanus into Lake Kegonsa, Wisconsin, US. We used a resurrection ecological approach, whereby clones from pre- and post-invasive periods were hatched from eggs obtained in sediment cores and were used in a 3-month growth experiment. Based on these data we estimated intrinsic population growth rates (r) and carrying capacities (K) using theta-logistic models. We found that post-invasion Daphnia maintained a higher r and K under these controlled, predation-free laboratory conditions. Thus, whereas previous experimental evolution studies of predator-prey interactions have demonstrated that genotypes that have evolved under predation have inferior competitive ability when the predator is absent, this was not the case for the Daphnia. Given that our study was conducted in a laboratory environment and the possibility for genotype-by-environment interactions, extrapolating these apparent counterintuitive results to the wild should be done with caution. However, barring such complications, we discuss how selection for reduced predator exposure, either temporally or spatially, may have led to the observed changes. This scenario suggests that complexities in ecological interactions represents a challenge when predicting the evolutionary responses of population dynamics to changes in predation pressure in natural systems.

Pseudoaneurysm of ascending aorta following cardiac surgery is a very rare and life threatening entity due to risk of exsanguination from its rupture. This is a case report of a 39 year old male patient who presented with impending rupture of ascending aorta pseudoaneurysm following mitral valve replacement. He underwent urgent reoperation under femoro-femoral cardiopulmonary bypass and deep hypothermic circulatory arrest. The pseudoaneurysm was excised and repaired with pericardial patch. He was discharged after an uneventful postoperative course.

Background and Purpose: (S)-ketamine induced rapid-acting antidepressant effects have revolutionized pharmacotherapy of major depression, however this medication produces also psychotomimetic effects including timing distortion. In contrast, (R)-ketamine appears to produce less of dissociative effects, but its antidepressant actions were less studied. It has been suggested that opioid receptors are involved in the antidepressant effect of ketamine. In addition, recent report suggests that while (S)-ketamine induced time underestimation, the (R)-isomer did not affect timing. Experimental approach: (R)- and (S)-ketamine, and fluoxetine as a positive control were tested in the differential-reinforcement-of-low-rate (DRL) 72-s schedule of reinforcement in male rats following naloxone pretreatment. Several DRL classic metrics as well as peak deviation analyses served to determine antidepressant-like actions and those associated with timing. Key Results: Antidepressant-like effect of (S)-ketamine (30-60 mg/kg) resembled fluoxetine (2.5-10 mg/kg) actions. Fluoxetine and (S)-ketamine increased reinforcement rate and peak location, suggesting increased performance, reduced premature responses, suggesting time underestimation and decreased Weber’s fraction, suggesting increased timing precision. In contrast, (R)-ketamine (60 mg/kg) increased reinforcement rate and peak location without affecting premature responses. Only fluoxetine decreased burst responses, suggesting decreased impulsivity. Naloxone pretreatment did not block ketamine enantiomers’ actions, but unexpectedly, increased fluoxetine’ performance. Conclusions & Implications: Fluoxetine’ and (S)- but not (R)- ketamine induced time underestimation could be associated with their antidepressant effects. The potentiation of DRL performance of fluoxetine by naloxone was unexpected and warrants further clinical studies.

Background and Purpose: Anxiety disorders associated with pain are a common health problem. However, the underlying mechanisms remain poorly understood. We aimed to investigate the role of paraventricular nucleus (PVN)-central nucleus of the amygdala (CeA) oxytocinergic projections in anxiety-like behaviours induced by inflammatory pain. Experimental Approach: Complete Freund’s adjuvant (CFA)-induced inflammatory pain model was used to induce the anxiety-like behaviours. Chemogenetic, optogenetic and fibre photometry recordings were used to modulate and record the activity of the oxytocinergic projections of the PVN-CeA. Key Results: Inflammatory pain induced anxiety-like behaviours in mice accompanied by decreased activity of PVN oxytocin neurons. Chemogenetic activation of PVN oxytocin neurons prevented pain-related anxiety-like behaviours, whereas inhibition of PVN oxytocin neurons induced anxiety-like behaviours in naive mice. PVN oxytocin neurons projected directly to the CeA, and microinjection of oxytocin into the CeA blocked anxiety-like behaviours. Inflammatory pain also decreased the activity of CeA neurons, and optogenetic activation of PVNoxytocin -CeA circuits prevented anxiety-like behaviour in response to inflammatory pain. Conclusion and Implications: Our study suggests that oxytocin has anti-anxiety effects and provides novel insights into the role of PVN-CeA oxytocin projections in the regulation of anxiety-like behaviours induced by inflammatory pain.

Atrial dissection is an uncommon entity after cardiac surgery. There is not an extensive knowledge about pathophysiology, clinical presentation and management. We report the case of a 65 year-old male who after triple myocardial revascularization bypass suffered a left atrial dissecition. We chose a conservative manegement and close follow up.

Chimeric Antigen Receptor T-cells represent a breakthrough in personalized cancer therapy. In this strategy, synthetic receptors comprised of antigen recognition, signaling, and stimulatory domains are used to reprogram T-cells to target tumor cells for destruction. Despite the success of this approach in refractory B-cell malignancies, optimal potency of CAR T-cell therapy for many other cancers, particularly solid tumors, has not been achieved. NK cells are powerful cytotoxic lymphocytes specialized in recognizing and dispensing with changed cells, and in coordinating versatile anti-tumor immunity.NK cells are as a rule practically depleted within the tumor microenvironment. In like manner, current investigate endeavors center on exactness designing of CAR T-cells with routine CRISPR-Cas9 frameworks or novel editors that can introduce craved hereditary changes with or without presentation of a double-stranded break into the genome. These instruments and methodologies can be specifically connected to focusing on negative controllers of T-cell work, coordinating helpful transgenes to particular genomic loci, and producing reproducibly secure and powerful allogeneic widespread CAR T-cell items for on-demand cancer immunotherapy. The revelation and improvement of the CRISPR/Cas9 innovation offer an adaptable and proficient gene-editing capability in tweaking different pathways that intercede NK cell fatigue and in outfitting NK cells with novel chimeric antigen receptors to particularly target tumor cells. Despite the tall productivity in its gene-editing capability, trouble within the conveyance of the CRISPR/Cas9 framework remains a major bottleneck for its restorative applications, especially for NK cells.This review assesses a

This case report describes the multidisciplinary orthodontic treatment of an adult female with a skeletal Class III malocclusion, extensive root absorption in the incisors, and a mesially impacted and excessively rotated canine, treated using clear aligners without application of temporary anchorage devices.

Background: Increased liver stiffness can be result of increased liver iron concentration (LIC) which may not yet be reflected in the liver fibrotic status. The objective of our study was to examine relationship between hemochromatosis, liver stiffness, and serum ferritin level in transfusion-dependent patients. Methods: All transfusion-dependent patients aged between seven and 60 years referred for evaluating LIC status by magnetic resonance imaging (MRI) followed by two-dimensional ultrasonography shear wave elastography (2D-SWE) were included in this study. Results: The optimal cut point for prediction of severe hemochromatosis using median SWE (kPa) and SWV (m/s) was ≥ 7.0 kPa and ≥ 1.54 m/s, respectively, with sensitivity of 0.76 (95% confidence interval [CI] 0.55, 0.91) and, specificity of 0.69 (95%CI 0.53, 0.82). When combing the optimal cut point of SWE (kPa) at ≥ 7.0 and serum ferritin ≥ 4123 ng/mL, the sensitivity increased to 0.84 (95%CI 0.64, 0.95) with specificity of 0.67 (95%CI 0.50, 0.80), positive predictive value (PPV) of 0.60 (95%CI 0.42, 0.76), and negative predictive value (NPV) of 0.88 (95%CI 0.71, 0.96). Simultaneous tests of 2D-SWE and serum ferritin for prediction of severe hemochromatosis showed the highest sensitivity of 84% (95%CI 0.64-0.95), as compared to 2D-SWE alone at 76% (95%CI 0.55, 0.91) or serum ferritin alone at 44% (95%CI 0.24-0.65). Conclusions: We recommend measuring both 2D-SWE and serum ferritin in short interval follow up patients. Adding 2D-SWE to the management guideline will help in deciding if aggressive adjustments of iron chelating medication in indicated in patients suspicious for severe hemochromatosis.

A 23-year-old woman followed for adult-onset Still’s disease (AOSD) presented fever and chest pain. Clinical examination showed erythematous papules suggestive of flagellate dermatoses. Laboratory findings showed increased Cardiac troponin. Myocarditis due to AOSD was therefore suspected. The patient was treated with prednisone and methotrexate with significant clinical improvement.

MLL-rearranged (MLL-r) infant Acute lymphoblastic leukemia (ALL) is an aggressive leukemia with poor prognosis and poor response to conventional chemotherapy. Inotuzumab Ozogamicin (InO) is approved to treat relapsed ALL, typically as a bridge to more curative therapy. Here we present a case of prolonged MRD negative remission using Inotuzumab, in a patient with heavily treated, multiple relapsed, MLL-r infant ALL. InO should be considered as an alternative therapy for relapsed/refractory CD22+ infant ALL, either as a bridge to curative therapy, or as an option for life prolongation therapies.

Purpose : To determine whether extent of surgical resection of the primary tumour correlates with survival in patients with International Neuroblastoma Staging System (INSS) stage 4, high-risk neuroblastoma. Methods : Data were extracted for patients with newly diagnosed INSS stage 4, high-risk neuroblastoma between 2001-2019 from the national Cancer in Young People in Canada (CYPC) database. Complete resection was defined as gross total resection of primary tumour based on operative reports. Primary endpoints were 3 and 5-year event-free (EFS) and overall survival (OS). Survival analyses were completed using log-rank test and Cox proportional hazards regression including covariates of age, sex, decade of treatment (2001-2009 vs. 2010-2019), immunotherapy, and tandem stem-cell transplant (SCT). Results : One-hundred and forty patients with complete surgical data were included. On univariate analysis, 3-year EFS and OS for patients that had complete vs. incomplete resection was 71% (95% CI 57-80%) vs. 48% (36-60%) and 86% (75-93%) vs. 64% (51-74%), p=0.008 and p=0.002, respectively. 5-year EFS and OS for patients with complete resection also demonstrated significantly improved survival. On Cox Proportional Hazards models adjusted for age, immunotherapy, tandem SCT and surgical resection, only complete resection was associated with statistically significant improved 3 yr EFS and OS, HR=0.48 (0.29-0.81; p=0.006) and HR=0.42 (0.24-0.73; p=0.002). Conclusions : In a large Canadian INSS stage 4 high-risk neuroblastoma cohort, complete surgical resection was associated with increased EFS and OS. Within the constraints of a retrospective study, these results suggest that the ability to achieve primary tumor complete resection in patients with metastatic high-risk disease is associated with improved survival.

Introduction: Acute bronchiolitis (AB) is the main cause of hospitalization in children under two years of age, with a regular winter seasonality, mostly due to the respiratory syncytial virus (RSV). Objectives: To describe the epidemiology of bronchiolitis hospitalizations in our centre in the last twelve years, and analyse the changes in clinical characteristics, microbiology, and adverse outcomes during the SARS-CoV2 pandemic. Methods: Ambispective observational study including patients admitted for bronchiolitis between April 2010 and December 2021 in a Spanish tertiary paediatric hospital. Relevant demographic, clinical, microbiological, and adverse outcome variables were collected in an anonymized database. The pandemic period (April 2020 to December 2021) was compared to 2010-2015 seasons using appropriate statistical tests. Results: There were 2138 bronchiolitis admissions, with a mean of 195.6 per year between 2010-2019 and a 2–4-month peak between November and March. In the winter of 2020, there was a 94.4% reduction of bronchiolitis hospitalizations, with only eleven cases admitted in the first year of the pandemic. Bronchiolitis cases increased during the summer of 2021 in a six-month long peak, reaching a total of 171 cases. Length of stay was significantly shorter during the pandemic, but no differences were found in clinical and microbiological characteristics or other adverse outcomes. Conclusions: The SARS-CoV2 pandemic has modified the seasonality of bronchiolitis hospitalizations, with a dramatic decrease in cases during the winter of 2020-2021, and an extemporaneous summer-autumn peak in 2021 with longer duration but similar patient characteristics.

Respiratory syncytial virus (RSV) causes annual epidemics of acute respiratory disease in large part because antibody levels fall rapidly after infection. RSV is able to infect cultured dendritic cells (DCs) and persist in these cells. Given the importance of DCs in antigen presentation, RSV infection and persistence is likely to be an evolutionary adaptation that can subvert the host immune response. This study aimed to demonstrate infection and persistence of RSV in lung DCs using an in vivo model of RSV infection. Mice were infected with a modified strain of RSV which expresses a red fluorescent protein (RSV-RFP) when replicating. Clinical symptoms of infection were monitored using weight change and inflammatory cell counts from bronchoalveolar lavage, which were correlated to RSV viral titre (quantitative PCR). Lung tissues were collected at 3, 5, 7 and 21 days post-infection (dpi) to assess leukocyte populations by flow cytometry. Clinical symptoms and RSV viral load peaked at 5 dpi. RSV-RFP was most prevalent in macrophages at 3 dpi and observed in B cells and DCs. At 21 dpi, RSV-RFP remained evident in a subset of conventional DCs (CD103 +CD11b +) even though clinical symptoms and pulmonary inflammation had resolved. This data indicates that RSV infects, replicates in and persists in a sub-population of lung cDCs after resolution of symptoms and clearance of virus from the airways. Understanding the implications of this adaptation is likely to provide crucial insights into the virus’s ability to generate annual epidemics of respiratory disease.

Data from UNICEF on the percentage of pneumonia careseekers were subjected under descriptive and inferential statistical analysis to compare the percentage of pneumonia careseekers in rural and urban areas in developing countries. Prior to the two sample t-test, the data was first subjected to Levene’s test and found that equal variances cannot be assumed so Welch’s test was done. We reject the null hypothesis because the two areas, rural and urban, have a statistically significant difference in sample means, with t= -6.8227 and p = 0.00003858092. A comparison of the individual t-scores of careseekers in urban and rural areas worldwide reveals that more treatment was sought in urban areas compared to rural areas as the years progress. The data was also subjected to linear regression test and it was found that linear relationship exists between rural careseekers and time (p=0.001636), while there is no linear relationship between urban careseekers and time (p=0.07574). Linear relationship is also observed between rural and urban careseekers combined and the year (p=0.02349).

This case illustrates another promising example of the recent advances within pediatric interventional bronchoscopy. As innovative medical therapies continue to make their way into the pediatric realm (e.g. a 1.1-mm flexible cryoprobe has been recently developed by Erbe), opportunities for novel approaches and techniques will continue to present themselves.

Changes in the thermal structure of lake ecosystems have been documented as a precursor of climate change, but the dynamics of biomass distribution, which fundamentally determines species conservation, have been less studied. An interdisciplinary approach was used to demonstrate the influence of climate-driven changes on the biomass distribution of two species (Gymnogobius isaza and Palaemon paucidens) in Lake Biwa. In field surveys in 2016–2017 (full water circulation) and 2019 (partial water circulation), environmental DNA concentrations of these species were used as proxies for biomass to measure 43 and 47 sites sampled at the lake bottom, respectively. A structural equation model was used to estimate the correlation between species biomass and environmental parameters. The species-environment relationship was applied to species biomass distributions under existing and future environments calculated by the model. Differences between the species were found in their responses to climate change. The biomass distribution of G. isaza will benefit in the future if full water circulation occurs, although it appears to be independent of water circulation at present. Partial water circulation enlarges the distribution area of P. paucidens, but its biomass will be low in the future, regardless of the extent of water circulation. These findings advance the knowledge of how species respond to climate change and suggest special attention should be given to species such as P. paucidens, which is currently abundant but sensitive to climate change. Furthermore, they emphasize the potential application of interdisciplinary methodologies for improved species conservation.

We provide a generalization of Beurling's theorem for the Clifford- Fourier transform and we give some of its applications. Indeed, analogues of Hardy, Cowling-Price and Gelfand-Shilov theorems are obtained in the Clifford analysis setting.

The current research numerically investigates the Marangoni convection in a cylindrical annulus filled with hybrid nanofluid saturated porous media. The interior and exterior walls are subjected to spatially varying sinusoidal thermal distributions with various amplitude ratios and phase deviations. The limits at the top and bottom are adiabatic. To solve the system of non-dimensional governing equations, the finite difference approach is applied. The major goal of the ongoing study is to investigate the impact of the Marangoni convection, amplitude ratio and phase deviation on the fluid flow, thermal characteristics, local and average Nusselt numbers in the hybrid nanofluid filled vertical cylindrical annulus with magnetic effects. The findings indicate that the sinusoidal temperature promotes multicellular flow in the porous annular region. In the annulus with sinusoidal boundaries, the Marangoni number underperforms while the nanoparticle volume fraction outperforms.

In this article, we study the quasilinear Schr\”{o}dinger equation \begin{eqnarray*} \begin{array}{ll} \triangle{u}+V(x)u-\triangle(u^2)u=g(x,u), \ x\in\mathbb{R}^N, \end{array} \end{eqnarray*} where the potential $V(x)$ and the primitive of $g(x,u)$ is allowed to be sign-changing. Under more general superlinear conditions on $g$, we obtain the existence of infinitely many nontrivial solutions by using Mountain Pass Theorem. Recent results in the literature are significantly improved.

Abstract Background. Still now, COVID-19 is a public health concern in both developed and developing countries. Risk perception has been studied in different countries with different population groups. However, there have been few studies conducted risk perception on elderly people and there is no study on elderly people’ in Ethiopia including this study area.This study aimed to assess coronavirus disease low risk perception level and associated factors among the elderly. Methods. To carry out this study among elders in Areka town from 01 August 2021 to 30 August 2021, a community-based cross-sectional study was used. Multi-stage sampling method was applied to select study participants. The data were collected through a structured questionnaire with the mobile application of Open Data Kit mobile(ODK). Results. This study showed that individuals with age range of 65 to 74 [AOR= 4.76, 95% CI (2.35-9.64)], poor practice on preventing coronavirus disease [AOR= 2.39, 95% CI (1.51-3.78), low trust level in medical professionals [AOR=2.44, 95%CI (1.45-4.10)], no history of coronavirus disease [AOR=6.45, 95%CI (2.02-20.58)], poor perceived self-efficacy for preventive practice [AOR=2.25, 95% CI (1.43-3.54)] were identified as associated factors of low risk perception. Conclusions. In the current study area, the perception of risk of coronavirus disease was affected by age, perceived self-efficacy, trust in medical professionals, preventive practice, and history of coronavirus disease. Including Ethiopia, the findings of this study would help for developing countries to generate evidence-based policy decisions for elderly people during COVI-D-19 pandemic and future pandemic(s). Keywords: Associated factors, Coronavirus, Elderly, Ethiopia, Perception

The rheological properties of emulsions gradually change to non-Newtonian fluid characteristics as the dispersed phase volume fraction increase. In premix membrane emulsification, a microporous membrane is used to prepare emulsions at higher production rates and higher volume fractions. The droplet size and droplet size distribution (span) can be precisely controlled, thus easier to study the rheological properties of emulsions. The influence of volume fraction, dispersed phase viscosity, and surfactant concentration were investigated. When the droplet size and span were controlled in a narrow range, the emulsion viscosity increased with dispersed phase viscosity due to energy loss to friction as the droplets become more rigid and less deformable, while the surfactant concentration had no significant influence on the emulsion rheology showing that surfactants mainly affect emulsion rheology through reduction of droplet size.