Left bundle branch pacing (LBBP) is a new physiological pacing technique that provides new options for device treatment in patients with bradycardia and heart failure. Recent data have shown that this method was able to obtain a low and stable threshold compared to His bundle pacing 1. The Wenckebach phenomenon refers to a progressive lengthening of impulse conduction time, followed by a non-conducted impulse or dropped beat. We have observed a progressive prolongation of stimulus-ventricular (S-V) interval that was followed by ventricular depolarization in an intracardiac electrogram (EGM) of a patient. This process is defined as the Jiang’s phenomenon, which is different from the Wenckebach phenomenon. Some electrophysiological phenomena were also observed with the guidance of John Jiang’s connecting cable in LBBP 2. Unlike a traditional connecting cable, which has to be disconnected while the pacing lead is screwed into the septum, John Jiang’s connecting cable allows for simultaneous monitoring and recording of electrocardiogram (ECG) and intracardiac EGM during lead deployment.

Transcatheter pacing systems are self-contained, leadless, devices that offer the potential benefits of avoiding complications related to pectoral pocket and upper extremity vascular access. These systems in preapproval trials demonstrated excellent safety profile with the incidence of device related cardiac perforation as low as 1.6% with Micra TM (Medtronic, Minneapolis, MN) and 1.3% in Nanostim (Abbott, Abbott Park, IL). In post approval registry of Micra TM TPS the rate of major complications was even lower than in investigational study ranging from 0.63 to 0.77%. Recently, published report found a much higher rates of need for rescue surgery, shock, tamponade, and death among patients implanted with the Micra TM device when compared with transvenous devices. This case reports describes two cases of major right ventricular perforation requiring surgical intervention.

Objective: To assess the level of husband’s involvement in and the key factors associated with birth preparedness and complication readiness (BPCR) in urban slums of Mangaluru, Karnataka, India Design: Cross-sectional community-based study Setting: 21 urban slums in Mangaluru, India Population: Resident men in 21 urban slums (whose wife had childbirth/s within one year) selected by multi-stage random sampling. Methods: We interviewed eligible husbands using a semi-structured questionnaire to collect data on socio-demography, wife’s obstetric and antenatal care (ANC) details, and husband’s involvement in six key BPCR practices. Main Outcome Measure: Husband’s optimal BPCR involvement (i.e. followed minimum four of six practices). Results: Of the 214 eligible husbands, 207 participated (96.7%-response rate) and 50.2% (95%CI:43.3-57.2) displayed optimal BPCR involvement. 98.6% of wives had ≥4 ANC visits, and 91.8% of husbands escorted wives for ANC at least once. Literate wife (AdjOR:6.5; 95%CI:1.4-28.9), ANC in first trimester (AdjOR:7.8; 95%CI:1.01-61.1), and receiving adequate advice on BPCR (AdjOR:47.8; 95%CI:10.4-219.8) were associated with husband’s optimal BPCR involvement. Conclusions: Only half of the husbands showed optimal BPCR involvement, and it was associated with wife’s literacy, ANC in first trimester, and receiving adequate BPCR information. Although nine of 10 husbands escorted their wives for ANC at least once, only about one-fourth of them received adequate information on BPCR, emphasising missed opportunities for health education during ANC. Grassroots health workers should engage husbands during ANC and explain various BPCR practices. Further qualitative research may help develop socio-culturally contextualised strategies to enhance the husband’s role in BPCR.

There are different methods to separate Natural Gas Liquid (NGL) from natural gas. One of these methods is refrigeration. Temperature reduction occurs in the dew point adjustment part to condense the NGL. The aim of this paper is to present a methodology for optimizing the NGL production process by calculating the best quantity for some set-points (the temperature, pressure, and etc for some vessels or other equipment) and at the same time try to reduce the energy consumption. To do this, we use a hybrid algorithm including a Genetic Algorithm (NSGA II) and Artificial Neural Network system (ANN). Indeed, in this research, we define a multi-objective problem and try to investigate more solutions for finding the best pareto-front. Therefore, it needs more time for evaluating solutions, for this reason, by using learning methods such as ANN, the behavior of the system is learned. Using ANN for evaluating the solutions is faster than simulation methods. We solve the defined multi-objective problem by using of NSGAII. In order to design a tool that is a decision-helper for selecting the appropriate set-points, the ability of the ANN algorithm along with multi-objective optimization is evaluated. We implement our proposed algorithm on one of the Iranian chemical factories knowing as the NGL plant, which separates the Natural Gas Liquid (NGL) from natural gas as the case study of this article. We show the effectiveness of our proposed algorithm by using the nonparametric statistical Kruskal-Wallis.

Objective: To estimate risk of SARS-CoV-2 infection in pregnancy and assess adverse maternal and perinatal outcomes. Design: A population-based, retrospective cohort. Setting: Florida, USA. Population: All pregnancies with a live birth or fetal death from March 1, 2020 to April 30, 2021. Methods: COVID-19 case reports were matched to vital registries. Modified Poisson and multinomial logistic regression models were used to derive relative risk estimates. Main Outcome Measures: Infection in pregnancy, preterm birth, maternal or neonatal admission to and intensive care unit (ICU), fetal death. Results: Of 234,492 women with a live birth or fetal death during the study period, 12,976 (5.5%) were identified with COVID-19 during pregnancy. Risk factors for COVID-19 in pregnancy included Hispanic ethnicity (relative risk [RR]=1.89), Black race (RR=1.34), being unmarried (RR=1.04), and being overweight or obese pre-pregnancy (RR=1.08-1.32). COVID-19 during pregnancy was associated with preterm birth (RR=1.31), Cesarean delivery (RR=1.04), and neonatal (RR=1.17) and maternal (RR=3.10) ICU admission, but no association was found with increased risk of perinatal (RR=0.72) or fetal death (RR=0.86). Women infected during any trimester showed increased risk of preterm birth compared to women without COVID-19. Thirteen maternal deaths were identified among COVID-19 cases; of those who died, 11 were obese. The death rate was 20.53 per 10,000 among obese and 1.22 per 10,000 among non-obese gravida with COVID-19 during pregnancy (RR=16.88, P=0.001). Conclusions: Obesity is a risk factor for SARS-CoV-2 infection in pregnancy and for more severe COVID-19 illness among pregnant women. SARS-CoV-2 infection is associated with preterm birth.

Objectives: Primary ciliary dyskinesia (PCD) is a rare genetic disease mainly involved in lung dysfunction. PCD patient outcomes after azithromycin (AZM) treatment have rarely been reported. This study was aimed to assess AZM treatment effects on disease progression of pediatric PCD patients. Study design: This retrospective follow-up study involved PCD patients diagnosed from December 2009 to December 2020. Changes of clinical outcomes, pulmonary function, and chest computed tomography findings were compared between untreated and AZM-treated patients. Results: Of 63 enrolled patients (median follow-up duration of 3.1 years), 30 received AZM (AZM-treated group) and 33 received no AZM (AZM-untreated group). At diagnosis, no significant intergroup differences in age, sex, height, weight, respiratory infection frequency, and FEV1% and FVC% predicted values were found, although FEF25-75% predicted was lower in AZM group. Between treatment initiation and follow-up, patients in AZM-treated group had less respiratory infection frequency than that of controls (1.4 ± 0.8 VS 3.0 ± 2.1 times/year, respectively, P = 0.001) and fewer AZM-treated group patients exhibited exercise intolerance. Increases above baseline of AZM-treated group FEV1% and FVC% predicted values exceeded corresponding control increases, but intergroup differences were insignificant (FEV1% predicted: 5.3 (-13.4, 9.4) VS 1.8 (-12.1, 9.5), P = 0.477; FVC% predicted: 6.7 (-7.6, 18.8) VS 1.6 (-5.6, 7.6), P = 0·328). Conclusions: Long-term AZM treatment can reduce respiratory infection frequency and may maintain pulmonary diseases stable in pediatric PCD patients.

The rupture of gas-forming pyogenic liver abscess is a life-threatening complication especially in elderly patients. It's an unusual cause of pneumoperitoneum which most commonly occurs by perforation of a hollow viscus. Computed tomography is the key of accurate diagnosis. It may rule out differential diagnosis and helps guide percutaneous drainage.

In this paper, we establish Hermite-Hadamard type inequalities for Riemann-Liouville fractional integrals via strongly h-convex functions. Some midpoint type and trapezoid type estimates related to them for n-times differentiable functions are also obtained, which extend some known results.

An understanding of the quantitative relationship between bile canaliculus (BC) dynamics and the disruption of tight junctions (TJs) during drug-induced intrahepatic cholestasis may lead to new strategies aimed at drug development and toxicity testing. To investigate the relationship between BC dynamics and TJ disruption, we retrospectively analyzed the extent of TJ disruption in response to changes in the dynamics of BCs cultured with entacapone (ENT). Three hours after adding ENT, the ratio of surface areas of ZO-1-negative BCs became significantly higher (4.1-fold) than those of ZO-1-positive BCs. Based on these data, we calculated slopes of surface area changes, m, of each ZO-1-positive and ZO-1-negative BC and BCs with m ≤ 15 that fell within the 95% confidence interval of ZO-1-positive BCs were defined as ZO-1-positive BCs. To validate this method, we compared the frequency of ZO-1-positive BCs, FZ, with that of BCs with m ≤ 15, FT, in culture, using drugs that regulate TJ, or induce intrahepatic cholestasis. FT values were correlated with FZ under all culture conditions (R2 = 0.99). Our results indicated that the magnitude of BC surface area change was a factor affecting TJ disruption, suggesting that maintaining TJ integrity by slowing BC dilation inhibits cell death.

BACKGROUND AND PURPOSE The advanced human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CMs) technology provides a novel in vitro platform for identification of the patients at high risk of drug-induced cardiotoxicity. Purpose of the current study is to develop an in vitro to in vivo translational platform to predict the incidence of drug induced cardiac dysfunction in clinic with hiPSC-CMs based in vitro assessment. EXPERIMENTAL APPROACH Doxorubicin induced cardiotoxicity was tested in hiPSC-CMs with varied exposure levels and durations. A mechanistic toxicodynamic (TD) model was developed to describe the concentration-response relationship of doxorubicin induced contraction magnitude reduction. The TD model was then integrated into a previous developed QSP-PBPK-TD model to generate an in vitro to in vivo translational platform. Virtual clinical trials were conducted to predict the clinical incidence of doxorubicin-induced cardiotoxicity in sub-populations with different drug exposures, susceptibility of cardiomyocytes, or cardiovascular disease statuses. KEY RESULTS The developed TD model successfully captured the concentration-response relationship and identified the mechanism of doxorubicin induced cardiotoxicity. The full-scale in vitro to in vivo QSP-PBPK-TD translational platform accurately predicted the reduction of left ventricular ejection fraction (LVEF) in patients with different myocardial susceptibilities or accepting different doxorubicin dosing schedules. A recommended dose table has been generated for individualized dosing of doxorubicin based on patient-specific hiPSC-CMs readouts. CONCLUSION AND IMPLICATIONS A QSP-PBPK-TD model-based in vitro to in vivo translational platform incorporating hiPSC-CMs-based in vitro testing has been developed to predict drug-induced cardiotoxicity. This platform could potentially improve accuracy of safe dose prediction for individual patients.

Background and objectives: Cardiac rehabilitation program (CRP) is a multidisciplinary strategy to help cardiac patients override the complications associated with cardiac disease. Patients following Coronary Artery Bypass Graft (CABG) face a critical complication that may affect their health-related quality of life and physiological outcomes, and these programs provide a better and faster recovery from cardiac surgery within the first weeks after surgery. This study reviews the impact of cardiac rehabilitation programs on the specific outcomes among CABG patients. Methods: In this systematic review the PRISMA-2020 guideline was used. Assessment of quality of the chosen studies, using the “Consolidated Standards of Reporting Trial (CONSORT)” and Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) checklist. Eligible studies were finally included in the literature review were 8 out of the 45 records identified, (from 2010-2021). Results: The cardiac rehabilitation program showed a consistent enhancement in health-related quality of life as a primary outcome and in the physiological variables as a secondary outcome. This study of a systematic review of experimental and non-experimental studies highlights the positive impact of this type of program on health-related quality of life and physiological variables of CABG patients. Conclusion: The results have significant implications in nursing research and practice, as the data offered can be used by the stakeholders and administrators of health institutions to improve their awareness of joining CRP in the routine care of CABG patients. KEYWORDS: cardiac rehabilitation programs, experimental study, health-related quality of life, physiological variables, systematic review.

As agricultural production is reaching its limits regarding outputs and land use, the need to further improve crop yield is greater than ever. The limited translatability from in vitro lab results into more natural growth conditions in soil remains problematic. Although considerable progress has been made in developing soil-growth assays to tackle this bottleneck, the majority of these assays use pots or whole trays, making them not only space- and resource-intensive, but also hampering the individual treatment of plants. Therefore, we developed a flexible and compact screening system in which individual seedlings are grown in wells filled with soil. The combination of an insert plate, containing the wells, with an adapter plate, containing reservoirs, allows for single-plant irrigation, different liquid treatments and mimicking stress conditions. The system makes use of an automated image-analysis pipeline that extracts multiple growth parameters from individual seedlings over the time course of the experiment, including projected rosette area, relative growth rate, compactness, and stockiness. The system is also optimized for maize with results that are consistent with Arabidopsis while different in amplitude. We conclude that the PhenoWell® system enables the translation of results obtained from in vitro studies into useful applications in soil.

New pathologies are causing dramatic declines and extinctions of multiple amphibian species. In 2013, we found fire salamanders with undescribed cysts at the throat level in one population in Northern Italy, which existence is not reported in amphibians yet. With the aim of describing this novel phenomenon, we performed repeated surveys to assess the frequency of affected salamanders from 2014 to 2020, and integrated morphological, histological and molecular analyses. Cysts affected up to 22 % of salamanders of the study population and started spreading to nearby populations. Cysts are formed by mucus surrounding cells about 10 μm long, characterized by numerous undulipodia. Morphological and genetic analyses did not yield a clear match with any described organism or salamander cell. The occurrence of these cysts calls for more studies on the origin and impact on wild populations.

Objective To evaluate the population pharmacokinetics of voriconazole (VRC) and identify the factors affecting it in Chinese patients with Talaromyces marneffei infection. Based on the final model, the optimal dosing regimen was further investigated in these patients. Methods Patients with talaromycosis from two hospitals who met the inclusion criteria were enrolled. Patients’ demographic information, VRC medication history, concomitant medications and laboratory test information data were recorded. A population pharmacokinetic model was developed through from the nonlinear mixed-effects models (NONMEM). Monte Carlo Simulation was applied to optimize the initial dosing regimens. Results A total of 146 blood samples taken from 46 patients with talaromycosis were included in the study. A one-compartment model was used to characterize VRC pharmacokinetics. Population estimates of clearance (CL) and volume of distribution (V) were 2.19 L/h and 88.4L, respectively. VRC clearance was significantly associated with C-reactive protein (CRP) level, which causing individual pharmacokinetics variation. CYP2C19 polymorphisms had no effect on voriconazole pharmacokinetic parameters. Based on the dosing simulations with CRP level, the initial dosing regimens was recommended are as follows: loading dose 150mg q12h 1day followed by maintenance dose 100mg q12h intravenous for CRP< 40mg/L, and loading dose 75mg q12h followed by maintenance dose 50mg q12h intravenous for CRP ≥ 40mg/L. Conclusion A population pharmacokinetic model of VRC was successfully established in patients with Talaromyces marneffei infection. CRP was identified to significantly affect VRC plasma concentration. Optimizing initial dosing regimens according to the CRP level may be useful to guide VRC dosing in clinical practice.

In this article we elaborately study certain characteristics of the set of all $\mathcal{I}$-lacunary statistical convergence sequences over various sequence spaces. Earlier results of some authors were mainly concerned regarding the closeness property of the sets: set of all bounded statistically convergent sequences, set of all bounded statistically convergent sequences of order $\alpha,$ set of all bounded $\mathcal{I}$-convergent sequences over the space $\ell^\infty$ ($\ell^\infty$- endowed with the sup-norm). Our approach is to examine different behaviors of the set of all $\mathcal{I}$-lacunary statistical convergence sequences over different sequence spaces. Finally we are able to impose some condition(s) over sequence spaces that turn the set of all $\mathcal{I}$-lacunary statistical convergence sequences to be a closed set.

Introduction: While reliable  in vitro testing for sensitivity to common aeroallergens has been available for decades, if and how asthma might be predictably expressed in people matched for comparable multiple sensitizations is unknown.   Objective: Our aim is to develop an understanding of these relations, which are known as allergic poly-sensitizations (APS) using a machine learning approach. We performed an audit of adult urban patients with moderate to severe asthma who presented to an urban outpatient pulmonary clinic. Methods: We constructed a database of sensitizations to the 25 aeroallergens in the zone 1 ImmunoCAP® assay. We used the Scikit-Learn® machine learning library to perform model-based clustering to identify APS clusters. Subsequently, clusters were compared for differences in clinical markers of allergic asthma.  Results: The database consisted of 509 patients. Mixture modeling identified ten clusters of increasing APS of varying size (n = 1 to 339). There were significant increases in mean serum immunoglobulin E (p<.001), peripheral blood eosinophil count (p<.001), and D LCO (p=.02) with increasing APS. There was a significant decline in mean age at presentation (p<.001), FEV 1/FVC (p=.01), and FEF 25-75 (p=.002), but not FEV 1 (p=.29), nor RV/TLC (p=.14) with increasing APS by simple linear regression. Finally, we identified two apparent divergent paths for the poly-atopic march, one driven by perennial allergens and the other by seasonal allergens.  Conclusion: We provide the framework for a novel machine learning understanding and approach to the classification of APS and its heretofore under-appreciated potential influences on asthma cluster analyses. To our knowledge, this represents the first attempt to identify poly-sensitization patterns that have clinical implications.

Title pageTitle: Eosinophilic esophagitis and chronic cough originated beyond the respiratory treeBrief title : Eosinophilic esophagitis and chronic cough

In the quest of constructing a user-friendly handy algorithm for the numerical solutions of the modified Burgers equation an adaptive finite point method is carefully orchestrated without compromising on accuracy, stability and consistency. The proposed algorithm has been designed such that the local properties of the exact solution is innately inherited to the numerical solutions. Apart from being conditionally stable, consistent, converging and rapid the method above and beyond replicates the exact solutions on coarse meshes even when the kinematic viscosity close in to zero. To illustrate the applicability of the algorithm differing examples are taken into account. The numerical results obtained are in accordance with the exact physical behavior and with its friendly algorithm have outshined many of the existing sophisticated methods in literature.

The main purpose of this paper is to establish existence and multiplicity of positive solutions for a generalized p-Laplacian fractional differential equation with integral conditions: 8>>>>< >>>>: D 0+(ϕ(D 0+u(t))) + f(t; u(t)) = 0; t 2 [0; 1] u(0) = 0; u(1) = ∫ 1 0 u(s) dA(s): (ϕ(D 0+u(0)) = 0; (ϕ(D 0+u(1)) ′ = ∫ 1 0 ϕ(D 0+u(s)) dB(s): (0.1) where 1 < 2, 1 < 2, D 0+ and D 0+ are the standard Riemann-Liouville fractional derivatives, > 0 is a parameter. We derived explicit intervals of in which the uniqueness and multiplicity of solutions of problem are ensured. To prove our results, we used the strongly monotone operator principle and Guo-Krasnosel’skii xed-point theorem on cones. Four examples presented to illustrate our main results.

Background The spread of COVID-19 continues, the mutation of SARS-COV-2 is still difficult to control, and the need for antiviral drugs to treat COVID-19 remains urgent. The use of arbidol in the treatment of COVID-19 is limited and controversial. Methods To clarify the efficacy of arbidol on COVID-19, we collected 25 cases and 178 related studies. We analyzed the treatment information of arbidol based on the obtained cases, expanded the scope of the study, and collected current studies on the treatment of COVID-19 in various databases for in-depth analysis. Results History analysis showed that arbidol was effective (76% cure rate) compared with other drugs. However, compared with other antiviral drugs or standard therapy, the arbidol group had no significant advantage in reducing the time to negative virus transformation, length of hospital stays, or improvement in CT (MD=0.22, 95%CI -0.29-0.73; MD = 0.61, 95% CI 1.46 to 2.67; RR=1.15, 95%CI 0.88-1.50); Analysis of adverse events showed no significant difference between the arbidol group and the other groups (RR=0.82, 95%CI 0.25-2.71). Conclusion Our study showed that arbidol had no significant effect on COVID-19, but showed a slight advantage in CT improvement and adverse events. Our study objectively evaluated the efficacy of arbidol in the treatment of COVID-19 and provided some guidance for arbidol in the treatment of COVID-19.

Propagation of ion acoustic waves (IAWs) and collision of double-, triple-, and quadruple IAWs have been studied in a magnetized plasma system consisting of cold ions and degenerate electrons. It is considered that the ions are inertial and non-degenerate while the electrons are degenerate and non-inertial. The reductive perturbation method is used to derive Zakharov and Kuznetsov (ZK) equation. The multi-soliton solutions of ZK equation are derived using the Hirota bilinear method. The consequences of external periodic force and exchange-correlation potential on the propagation and overtaking collision of ion acoustic (IA) ZK-solitons are investigated taking into account the plasma parameters as observed in astrophysical objects. The considered quantum fluid model is valid for astrophysical conditions in non-relativistic degenerate plasmas where the plasma density and magnetic field strength are 〖10〗^26≤n_0≤〖10〗^29 cm^(-3) and 〖10〗^6≤B_0≤〖10〗^9 G, respectively. It is found that, the amplitude and width of theIAZK-solitons are modified due to the periodic force and exchange-correlation potential. It is also found that the large amplitude solitons always overtake the smaller one.

Objective To evaluate the methodological quality of Tuina clinical practice guidelines. Methods Computer searches of China National Knowledge Infrastructure (CNKI), Chinese Technical Periodicals (VIP), Wanfang Data Knowledge Service Platform, PubMed, Cochrane Library, Embase, and other databases were conducted to search for published guidelines on Tuina, with a search time frame from database creation to March 2021. Four evaluators independently used the Appraisal of Guidelines for Research and Evaluation II instrument to evaluate the quality of the included guidelines. Results Eight guidelines related to Tuina were included in this study. The quality of reporting was low in all included guidelines. The highest quality report had a total score of 404 and was rated as “highly recommended”. The worst guideline had a final score of 241 and was rated as “not recommended”. Overall, 25% of the included guidelines were recommended for clinical use, 37.5% were recommended after revision, and 37.5% were not recommended. Conclusion The number of existing Tuina clinical practice guidelines is limited. The methodological quality is low, far from the internationally accepted clinical practice guideline development and reporting norms. In the future, reporting specifications of guidelines and the methodology of guideline development, including the rigor of the guideline development process, the clarity, application, and independence of reporting, should be emphasized in the development of Tuina guidelines. These initiatives could improve the quality and applicability of clinical practice guidelines to guide and standardize the clinical practice of Tuina.

Rationale, aims and objectives: Iron sucrose remains a top expenditure in Fraser Health Authority. Audit data from an iron sucrose standardized order set (SSO) pilot coupled with the addition of iron isomaltoside to formulary resulted in the implementation of a regional SSO. Survey objectives were to clarify how iron infusion referrals are triaged, determine iron infusion wait times and identify what other services can impact wait times prior to regional SSO implementation. Method: Information was collected from a web-based survey sent to outpatient unit staff at all 11 sites within the health authority Results: Survey response rate was 73%. Urgent and non-urgent referral definitions varied and included laboratory parameters, prescriber specification, consideration of procedure dates and evidence of symptoms. Urgent referrals wait times are usually within the same week and non urgent wait times varied from same week booking to up to 3 months. Outpatient units provide a multitude of services that require urgent appointment times that may require scheduling ahead of non-urgent iron infusion referrals. Outpatient clinics deal with multiple other clinical reasons other than iron infusions which contribute complicate the triage and booking process and can lead to long wait times. Wait time reduction could be the result of utilizing a SSO that displayed all the information required by clinic staff and streamlined the booking process rather than the addition of iron isomaltoside to formulary. Conclusions: With the implementation of a regional SSO the iron infusion referral process may be simplified, thereby shortening appointment wait times. It is recommended that comparable information regarding iron infusion wait times be collected after these changes in practice.

Introduction A 54-year-old man with superior vena cava occlusion was referred to our institution for an upgrade to cardiac resynchronization therapy defibrillator. Methods and results Right ventricular lead extraction with modified venoplasty, rocket-shape crossing technique (RCT), was performed. In RCT, the integration of the inflated balloon, halfway inside the laser sheath, and the laser sheath are advanced through the occlusion like a “rocket-shape crossing”. Conclusion Modified venoplasty can be useful during device upgrades in patients with venous occlusion.