Some considerations on the dependence to numerical schemes of Lagrangian radionuclide transport models for the aquatic environment.

Lagrangian models present several advantages over Eulerian models to simulate the transport of radionuclides in the aquatic environment in emergency situations. A radionuclide release is simulated as a number of particles whose trajectories are calculated along time and thus these models do not require a spatial discretization (although it is always required in time). In this paper we investigate the dependence of a Lagrangian model output with the grid spacing which is used to calculate concentrations from the final distribution of particles, with the number of particles in the simulation and with the interpolation schemes which are required because of the discrete nature of the water circulation data used to feed the model. Also, a Lagrangian model may describe the exchanges of radionuclides between phases (liquid and solid), which is done in terms of transition probabilities. The dependence of these probabilities with time step is analyzed as well. It was found that the optimum grid size used to calculate concentrations should be carefully checked, and that temporal interpolation is more significant than spatial interpolation to obtain a more accurate solution. A method to estimate the number of particles required to have a certain accuracy level is proposed. Finally, it was found that for low sediment concentrations and small radionuclide kd, exact equations for the transition probabilities should be used; and that phase transitions introduce a stability condition as in Eulerian models.

Synergetic effect of high dose rate radiations (10× FFF/2400 MU/min/10 MV x-rays) and paclitaxel selectively eliminates melanoma cells.

BACKGROUND: Melanoma is one of the most aggressive cancers, with 1.6% of total cancer deaths in the United States. In recent years treatment options for metastatic melanoma have been improved by the FDA approval of new therapeutic agents. However, these inhibitors-based therapies are non-specific and have severe toxicities, including hyperkeratosis, photosensitivity, hepatitis, arthralgia, and fatigue. AIMS: The aim of this study is to determine the synthetic lethal effect (paclitaxel and radiations) on melanoma cells and reduce the total radiation doses by increasing the dose rates up to 2400 MU/min. METHODS AND RESULTS: We previously reported a radiation treatment (10 MV x-rays, 10X-FFF, dose rate 2400MU/min, low total dose 0.5 Gy) that kills melanoma cells with 80% survival of normal HEM in vitro. In this study, we extended the radiation cycle up to four and included paclitaxel treatment to study the synthetic lethal effect on melanoma and two other normal primary cells, HDF and HEK. Cells were treated with paclitaxel prior to the radiation at a dose rate of 400 and 2400 MU/min with a total radiation dose of only 0.5 Gy. Mitochondrial respiration assay, DNA damage assay, and colony formation assays were performed to study apoptosis and cell death induction. Four days of consequent radiation treatment with paclitaxel significantly reduces the survival of melanoma cells by inducing apoptosis and mitochondrial damage. After treatment, excessive DNA damage in melanoma cells leads to an increase in the expression of pro-apoptotic genes (Caspase-3) and a decrease in the expression of DNA repair gene (PARP1) and anti-apoptotic gene (Bcl-2) to activate the apoptosis pathway. The combination of paclitaxel and radiation reduces the survival of melanoma cells colonies compared to radiation alone. CONCLUSION: Our study indicates that radiations with paclitaxel have a potential synthetic lethal effect on melanoma cells and can be developed as a melanoma therapy without toxicities or harmful effects on normal primary skin cells.

Third international challenge to model the medium- to long-range transport of radioxenon to four Comprehensive Nuclear-Test-Ban Treaty monitoring stations.

In 2015 and 2016, atmospheric transport modeling challenges were conducted in the context of the Comprehensive Nuclear-Test-Ban Treaty (CTBT) verification, however, with a more limited scope with respect to emission inventories, simulation period and number of relevant samples (i.e., those above the Minimum Detectable Concentration (MDC)) involved. Therefore, a more comprehensive atmospheric transport modeling challenge was organized in 2019. Stack release data of Xe-133 were provided by the Institut National des Radioéléments/IRE (Belgium) and the Canadian Nuclear Laboratories/CNL (Canada) and accounted for in the simulations over a three (mandatory) or six (optional) months period. Best estimate emissions of additional facilities (radiopharmaceutical production and nuclear research facilities, commercial reactors or relevant research reactors) of the Northern Hemisphere were included as well. Model results were compared with observed atmospheric activity concentrations at four International Monitoring System (IMS) stations located in Europe and North America with overall considerable influence of IRE and/or CNL emissions for evaluation of the participants' runs. Participants were prompted to work with controlled and harmonized model set-ups to make runs more comparable, but also to increase diversity. It was found that using the stack emissions of IRE and CNL with daily resolution does not lead to better results than disaggregating annual emissions of these two facilities taken from the literature if an overall score for all stations covering all valid observed samples is considered. A moderate benefit of roughly 10% is visible in statistical scores for samples influenced by IRE and/or CNL to at least 50% and there can be considerable benefit for individual samples. Effects of transport errors, not properly characterized remaining emitters and long IMS sampling times (12-24 h) undoubtedly are in contrast to and reduce the benefit of high-quality IRE and CNL stack data. Complementary best estimates for remaining emitters push the scores up by 18% compared to just considering IRE and CNL emissions alone. Despite the efforts undertaken the full multi-model ensemble built is highly redundant. An ensemble based on a few arbitrary runs is sufficient to model the Xe-133 background at the stations investigated. The effective ensemble size is below five. An optimized ensemble at each station has on average slightly higher skill compared to the full ensemble. However, the improvement (maximum of 20% and minimum of 3% in RMSE) in skill is likely being too small for being exploited for an independent period.

The transport, effective half-lives and age distributions of radioactive releases in the northern Indian Ocean.

A Lagrangian model which describes radionuclide transport in the northern Indian Ocean is described. Water circulation is obtained from HYCOM ocean model for year 2017. The model includes advection by currents, turbulent mixing and radionuclide interactions between water and sediments, described in a dynamic way using kinetic transfer coefficients. Hypothetical releases from five coastal nuclear power plants operating in the northern Indian Ocean were simulated. Releases were supposed to start both during the winter and summer monsoons, to study reversing circulation effects. Age distributions of releases were calculated, which adds information about circulation and radionuclide pathways. It was found that, for some of the NPPs, radionuclide distributions resulting from releases starting in both seasons were not as different as could be expected from the opposed circulation schemes during each monsoon. Effective 137Cs half-lives in the ocean surface were calculated and results were two orders of magnitude below previous estimations.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with early breast cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.

In view of the planned new edition of the most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of primary breast cancer published in 2015, it was decided at the ESMO Asia Meeting in November 2018, by both the ESMO and the Korean Society of Medical Oncology (KSMO), to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the latest ESMO 2019 guidelines to take into account the ethnic and geographical differences associated with the treatment of early breast cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with early breast cancer representing the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO) Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices, and the drug availability and reimbursement situations, in the individual participating Asian countries.

Correction to: CD4 T cell count is positively associated with lumbar spine bone mass in HIV-infected men under the age of 50 years.

Two sentences in the Discussion section were incorrect.

De Novo Hepatitis B Virus Infection After Liver Transplantation in Hepatitis B Core-positive Recipients Using Hepatitis B Core-negative Grafts.

BACKGROUND: Hepatitis B core antibody-positive (HBcAb+) graft is known as a risk for de novo hepatitis B virus (HBV) infection in recipients after liver transplantation (LT). However, little is known about the possibility or incidence of de novo HBV infections after LT in hepatitis B surface antigen-negative (HBsAg-)/HBcAb+ recipients using HBsAg-/HBcAb- grafts. The study aimed to evaluate the prevalence of de novo HBV infection in HBsAg-/HBcAb+ recipients using HBsAg-/HBcAb- grafts. A retrospective review was performed with the records of 1129 adult patients who underwent primary LT at a single institution in an HBV endemic area between January 2000 and December 2013. A total of 78 patients (6.9%) were reviewed for de novo HBV infection after LT. De novo HBV infection was developed in 1 patient (1.28%). The patient was a 65-year-old woman who underwent LT due to alcoholic liver cirrhosis. De novo HBV was not related to graft loss or death and well treated with tenofovir. In conclusion, de novo HBV infections may occur in HBsAg-/HBcAb+ recipients using HBsAg-/HBcAb- grafts, and caution is needed in these patients.

CD4 T cell count is inversely associated with lumbar spine bone mass in HIV-infected men under the age of 50 years.

HIV-infected men under the age of 50 years had a lower bone mass compared to that of HIV-uninfected men. Lower CD4 T cell counts, independent of whether antiretroviral therapy (ART) was used, were associated with lower BMD. HIV-infected patients with low CD4 T cell counts may need follow-up and intervention regarding bone health, including younger patients. INTRODUCTION: HIV-infected patients have a low bone mineral density (BMD) owing to multifactorial interaction between common osteoporosis risk factors and HIV-related factors, including chronic inflammation and ART. Although HIV infection and ART might affect bone metabolism, little data is available for patients aged under 50 years. We aimed to investigate the association of HIV infection-induced low CD4 T cell counts and ART with BMD in men aged under 50 years. METHODS: We performed an age- and body mass index-matched case-control study. BMD values of HIV-infected and HIV-uninfected men (< 50 years) were compared, and HIV-infected men were stratified by CD4 T cell counts and ART use. RESULTS: After adjusting confounders, HIV-infected men with CD4 T cell counts ≥ 500 cells/µL (n = 28) and < 500 cells/µL (n = 139) had lower BMD at the femoral neck (FN, p < 0.001) and total hip (TH, p < 0.001) than HIV-uninfected men (n = 167). HIV-infected men with CD4 T cell counts < 500/µL had lower BMD at the lumbar spine (LS, p = 0.034) than those with counts of ≥ 500 cells/µL, but not at FN and TH. The CD4 T cell count (γ = 0.169, p = 0.031) was positively correlated with BMD at LS. There was no significant difference in the BMD (p = 0.499-> 0.999) between the ART-naïve (n = 75) and ART-user group (n = 92). CONCLUSIONS: Despite their relatively younger age, HIV-infected men had a lower BMD than HIV-uninfected men. Lower CD4 T cell counts, irrespective of ART, might result in lower bone mass.

Hospital-acquired Clostridium difficile infection: an institutional costing analysis.

BACKGROUND: Healthcare-acquired Clostridium difficile infection (HA-CDI) is a common infection and a financial burden on the healthcare system. AIM: To estimate the hospital-based financial costs of HA-CDI by comparing time-fixed statistical models that attribute cost to the entire hospital stay to time-varying statistical models that adjust for the time between admission, diagnosis of HA-CDI, and discharge and that only attribute HA-CDI costs post diagnosis. METHODS: A retrospective cohort study was conducted (April 2008 to March 2011) using clinical and administrative costing data of inpatients (≥15 years) who were admitted to The Ottawa Hospital with stays >72 h. Two time-fixed analyses, ordinary least square regression and generalized linear regression, were contrasted with two time-dependent approaches using Kaplan-Meier survival curve. FINDINGS: A total of 49,888 admissions were included and 366 (0.73%) patients developed HA-CDI. Estimated total costs (Canadian dollars) from time-fixed models were as high as $74,928 per patient compared to $28,089 using a time-varying model, and these were 1.47-fold higher compared to a patient without HA-CDI (incremental cost $8,997 per patient). The overall annual institutional cost at The Ottawa Hospital associated with HA-CDI was as high as $10.07 million using time-fixed models and $1.62 million using time-varying models. CONCLUSION: When calculating costs associated with HA-CDI, accounting for the time between admission, diagnosis, and discharge can substantially reduce the estimated institutional costs associated with HA-CDI.

Prioritizing research areas for antibiotic stewardship programmes in hospitals: a behavioural perspective consensus paper.

SCOPE: Antibiotic stewardship programmes (ASPs) are necessary in hospitals to improve the judicious use of antibiotics. While ASPs require complex change of key behaviours on individual, team organization and policy levels, evidence from the behavioural sciences is underutilized in antibiotic stewardship studies across the world, including high-income countries (HICs). A consensus procedure was performed to propose research priority areas for optimizing effective implementation of ASPs in hospital settings using a behavioural perspective. METHODS: A workgroup for behavioural approaches to ASPs was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). Eighteen clinical and academic specialists in antibiotic stewardship, implementation science and behaviour change from four HICs with publicly funded healthcare systems (e.g. Canada, Germany, Norway and the UK) met face-to-face to agree on broad research priority areas using a structured consensus method. Question addressed and recommendations: The consensus process assessing the ten identified research priority areas resulted in recommendations that need urgent scientific interest and funding to optimize effective implementation of ASPs for hospital inpatients in HICs with publicly funded healthcare systems. We suggest and detail behavioural science evidence-guided research efforts in the following areas: (a) comprehensively identifying barriers and facilitators to implementing ASPs and clinical recommendations intended to optimize antibiotic prescribing; (b) identifying actors ('who') and actions ('what needs to be done') of ASPs and clinical teams; (c) synthesizing available evidence to support future research and planning for ASPs; (d) specifying the activities in current ASPs with the purpose of defining a control group for comparison with new initiatives; (e) defining a balanced set of outcomes and measures to evaluate the effects of interventions focused on reducing unnecessary exposure to antibiotics; (f) conducting robust evaluations of ASPs with built-in process evaluations and fidelity assessments; (g) defining and designing ASPs; (h) establishing the evidence base for impact of ASPs on resistance; (i) investigating the role and impact of government and policy contexts on ASPs; and (j) understanding what matters to patients in ASPs in hospitals. CONCLUSIONS: Assessment, revisions and updates of our priority-setting exercise should be considered at intervals of 2 years. To propose research priority areas in low- and middle-income countries, the methodology reported here could be applied.

Fukushima 137Cs releases dispersion modelling over the Pacific Ocean. Comparisons of models with water, sediment and biota data.

A number of marine radionuclide dispersion models (both Eulerian and Lagrangian) were applied to simulate 137Cs releases from Fukushima Daiichi nuclear power plant accident in 2011 over the Pacific at oceanic scale. Simulations extended over two years and both direct releases into the ocean and deposition of atmospheric releases on the ocean surface were considered. Dispersion models included an embedded biological uptake model (BUM). Three types of BUMs were used: equilibrium, dynamic and allometric. Model results were compared with 137Cs measurements in water (surface, intermediate and deep layers), sediment and biota (zooplankton, non-piscivorous and piscivorous fish). A reasonable agreement in model/model and model/data comparisons was obtained.

Urinary Neutrophil Gelatinase-Associated Lipocalin as a Biomarker for Renal Injury in Liver Transplant Recipients Using Calcineurin Inhibitors.

BACKGROUND: Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is an early biomarker of renal injury. We examined the feasibility of using uNGAL as an early predictor of renal impairment in patients under calcineurin inhibitors in liver transplant recipients. METHODS: From urine samples obtained from liver transplant recipients, the glomerular filtration rate (GFR) at the time of urine sampling was compared with that at 5 to 7 months later. Patients were divided into 3 groups according to initial GFR and then divided into 2 groups according to the uNGAL level of 25 ng/mL. Progression of renal injury (PRI) was defined as a decrease in the GFR of more than 5 mL/min/1.73 m2 in the mild or moderate groups, or if a normal group patient shifted to the mild or moderate group. RESULTS: Fifty-one patients were enrolled. The mean uNGAL level was higher in the moderate group than in the normal and mild groups (18.38 ± 14.31 vs 7.74 ± 8.13; P < .01). A proportion of uNGAL-high was also higher in the moderate group than in the mild group (40% vs 5%; P = .03). uNGAL-high was a risk factor for 6-month PRI (odds ratio, 60.375; 95% confidence interval, 1.283-4088.25; P = .037) and 1-year PRI (odds ratio, 21.311; % confidence interval, 0.947-479.578; P = .054). CONCLUSIONS: A uNGAL of >25 ng/mg can be a marker for moderate renal impairment (GFR of 30-59 mL/min/1.73 m2) and a predictor of PRI at 6 months in patients using calcineurin inhibitors. Renal protection strategies should be considered in liver transplant recipients with a uNGAL of >25 ng/mg in spot urine sampling.

Challenging Alveolar Hemorrhage Complicating Pneumonia After Liver Transplantation: A Case Report.

Alveolar hemorrhage is a life-threatening clinical syndrome often initially thought to be atypical pneumonia. Association with hematopoietic stem cell transplantation is well studied, but not with solid organ transplantation. We report a case of a 54-year-old woman presented with fever and shortness of breath on the third posttransplant day after deceased donor liver transplantation. Imaging studies showed diffuse bilateral pulmonary infiltrates and a positive sequential bronchoalveolar lavage test was revealed during bronchoscopy. Cytomegalovirus antigenemia was present in 8/200,000 white blood cells; Aspergillus galactomannan and Pneumocystis jirovecii were also present. However, only Aspergillus hyphae were found in the sputum culture. Management strategy aimed to treat underlying infections, provide adequate respiratory support, and control inflammation. We proposed that diffuse alveolar hemorrhage should be considered as differential diagnosis in early pulmonary complications after liver transplantation. Early diagnosis and aggressive treatment protocol is the key for a good outcome.

Prolactin Induced Protein (PIP) is a potential biomarker for early stage and malignant breast cancer.

OBJECTIVES: Breast cancer (BC) is the second leading cause of cancer-related mortality in women. Bioinformatic analysis and expression screening showed that Prolactin Induced Protein (PIP) was differentially expressed in BC. The objective of this investigation was to characterize the expression pattern of PIP, an aspartyl proteinase, in malignant and non-malignant breast tissues. MATERIALS AND METHODS: Real time quantitative PCR was employed to analyze PIP and androgen receptor (AR) mRNA levels in BC cell lines and 190 normal tissues and tumor samples. The tumor specimens were categorized based on TNM classification, anatomic stage, histologic grade and molecular subtype and expression pattern evaluated. To detect protein levels, immunohistochemistry followed by semi quantitative scoring was employed in the examination of 517 normal, benign, and invasive BC tissues. RESULTS: We observed substantial downregulation of PIP transcription in cancer samples compared to normal breast tissue. mRNA levels were significantly downregulated (93 fold, P < 0.005) in advanced grades compared to lower grades. Transcript levels were also significantly lower (22 fold, P < 0.05) in triple negative tumors compared to hormone receptor positive tumors. Significant downregulation was observed in early stage samples of triple negative and hormone receptor positive tumors. Though PIP protein showed a wide range of expression levels in BC, early stage samples showed significant downregulation. CONCLUSIONS: PIP mRNA is significantly downregulated in early stage BC compared to normal breast tissue. Consequently, low PIP mRNA expression in BC tissues could potentially be used as a tissue based biomarker to assist pathologists in confirmation of early stage BC diagnosis.

Initial experience with purely laparoscopic living-donor right hepatectomy.

BACKGROUND: There may be concerns about purely laparoscopic donor right hepatectomy (PLDRH) compared with open donor right hepatectomy, especially when performed by surgeons accustomed to open surgery. This study aimed to describe technical tips and pitfalls in PLDRH. METHODS: Data from donors who underwent PLDRH at Seoul National University Hospital between December 2015 and July 2017 were analysed retrospectively. Endpoints analysed included intraoperative events and postoperative complications. All operations were performed by a single surgeon with considerable experience in open living donor hepatectomy. RESULTS: A total of 26 donors underwent purely laparoscopic right hepatectomy in the study interval. No donor required transfusion during surgery, whereas two underwent reoperation. In two donors, the dissection plane at the right upper deep portion of the midplane was not correct. One donor experienced portal vein injury during caudate lobe transection, and one developed remnant left hepatic duct stenosis. One donor experienced remnant portal vein angulation owing to a different approach angle, and one experienced arterial damage associated with the use of a laparoscopic energy device. One donor had postoperative bleeding due to masking of potential bleeding foci owing to intra-abdominal pressure during laparoscopy. Two donors experienced right liver surface damage caused by a xiphoid trocar. CONCLUSION: Purely laparoscopic donor hepatectomy differs from open donor hepatectomy in terms of angle and caudal view. Therefore, surgeons experienced in open donor hepatectomy must gain adequate experience in laparoscopic liver surgery and make adjustments when performing PLDRH.

Pure laparoscopic living donor hepatectomy: Focus on 55 donors undergoing right hepatectomy.

Although laparoscopic donor hepatectomy is increasingly common, few centers with substantial experience have reported the results of pure laparoscopic donor right hepatectomy (PLDRH). Here, we report the experiences of 60 consecutive liver donors undergoing pure laparoscopic donor hepatectomy (PLDH), with most undergoing right hepatectomy. None of the 60 donors who underwent PLDH had intraoperative complications and none required transfusions, reoperation, or conversion to open hepatectomy. Forty-five donors who underwent PLDRH between November 2015 and December 2016 were compared with 42 who underwent conventional donor right hepatectomy (CDRH) between May 2013 and February 2014. The total operation time was longer (330.7 vs 280.0 minutes; P < .001) and the percentage with multiple bile duct openings was higher (53.3% vs 26.2%; P = .010) in the PLDRH group. However, the length of postoperative hospital stay (8.4 vs 8.2 days; P = .495) and rate of complications (11.9% vs 8.9%; P = .733) and re-hospitalizations (4.8% vs 4.4%; P = 1.000) were similar in both groups. PLDH, including PLDRH, is feasible when performed by a highly experienced surgeon and transplant team. Further evaluation, including long-term results, may support these preliminary findings of comparative outcomes for donors undergoing PLDRH and CDRH.

Efficacy and Safety of Generic Mycophenolate Mofetil (My-rept) 500-Milligram Tablets in Primary Liver Transplant Recipients.

BACKGROUND: Generic immunosuppressants may be cost-effective if clinical outcomes are equivalent to the brand-name medications. Mycophenolate mofetil in the form of My-rept may be cost-effective being a generic immunosuppressant, which is available as a 500-mg tablet as well as a 250-mg capsule (Chong Kun Dang Pharmaceutical Corporation, Seoul, Korea). OBJECTIVE: This study aimed to evaluate the efficacy, safety, cost-effectiveness, and convenience of My-rept 500-mg tablets in liver transplant recipients. SETTING: The setting was an outpatient liver transplantation clinic of a tertiary hospital in Korea. METHOD: A phase 4, single-center, open-label, noncomparative study was undertaken. A total of 50 patients were recruited. Acute transplant rejection, changes in blood chemistry, white blood cell count, assessments of renal function, occurrence of adverse drug reactions, and other characteristics of the patients were recorded for 24 weeks. After study termination, a satisfaction survey was conducted. RESULTS: All enrolled patients and their liver grafts had survived for 24 weeks post-transplantation. No episodes of acute rejection were reported. Nine patients (18.8%) presented with adverse drug reactions that had been commonly reported with the use of other mycophenolate mofetil products, and no serious adverse drug reactions were reported. CONCLUSION: In conclusion, the My-rept 500-mg tablet appears to be feasible and convenient for administration to recipients of a liver transplant.

Primary Living-donor Liver Transplantation Is Not the Optimal Treatment Choice in Patients With Early Hepatocellular Carcinoma With Poor Tumor Biology.

OBJECTIVE: Liver resection (LR) and living-donor liver transplantation (LDLT) are considered the two potentially curative treatments for hepatocellular carcinoma (HCC). The aim of this study was to investigate whether there is a difference in the oncologic outcomes between LR and LDLT according to tumor biology. METHODS: Patients (137 LDLTs and 199 LRs) were stratified into four groups by tumor biology according to the number of risk factors for recurrence (preoperative alpha-fetoprotein >200 ng/mL, Edmonson grade 3 or 4, tumor size >3 cm, and presence of microvascular invasion). RESULTS: In the favorable tumor biology patients (groups I and II), there was a significantly worse recurrence-free survival rate in those patients who underwent LR compared to those who underwent LDLT (group I, P = .002; group II, P = .001). The overall survival rates in the LR and LDLT groups were not different (group I, P = .798; group II, P = .981). In the poor tumor biology patients (groups III and IV), there was no significant difference between the two groups in terms of recurrence-free survival rate (group III, P = .342; group IV, P = .616). The LDLT group showed a significantly lower overall survival rate (group III, P = .001; group IV, P = .025). CONCLUSIONS: Primary LDLT should not be recommended in early stage HCC patients with poor tumor biology because of lower survival rates and a high chance of HCC recurrence.