Economic Evaluation of anti-epileptic Medicines for Autistic Children with Epilepsy.

We examine the cost-effectiveness of treating epilepsy with anti-epileptic medicines in autistic children, looking at impacts on healthcare providers (in England, Ireland, Italy and Spain) and children's families (in Ireland). We find carbamazepine to be the most cost-effective drug to try first in children with newly diagnosed focal seizures. For England and Spain, oxcarbazepine is the most cost-effective treatment when taken as additional treatment for those children whose response to monotherapy is suboptimal. In Ireland and Italy, gabapentin is the most cost-effective option. Our additional scenario analysis presents the aggregate cost to families with autistic children who are being treated for epilepsy: this cost is considerably higher than healthcare provider expenditure.

Prevention of the spread of multidrug-resistant organisms in nursing homes.

The increase in the aged population led to a global rise in the demand for elderly healthcare services, such as long-term care facilities (LTCFs), nursing homes, residential homes. Unfortunately, the spread of multidrug-resistant organisms (MDROs) in these structures represent an urgent public health threat requiring immediate action. The aim of this review is to provide a practice guide for the prevention of infections in European LTCFs. A team of experts identify specific problems and proposed practical solutions for the management of colonized and infected patients residing in LTCFs. The heterogeneity of LTCF represents one of the main problems for the implementation of standardized surveillance and infection control programs. Crucial steps involved in the spread of infections among LTCF residents are represented by patient's accommodation, MDRO screening on admission, management of patients with rectal colonization by MDROs, management of patients at high risk of MDRO infections, MDRO transmission by staff and implementation of antimicrobial stewardship. Efforts to implement specific actions in each of these fields are required to reduce the infections in this setting.

Socioeconomic impact of restless legs syndrome and inadequate restless legs syndrome management across European settings.

Restless legs syndrome (RLS) is one of the most common neurological disorders. It describes an irresistible urge to move the legs, mostly manifested in the evening and at night, which can lead to severe sleep disturbance. As part of the European Brain Council (EBC)-led Value-of-Treatment project, this study aimed at capturing the socioeconomic impact of RLS related to the inadequate diagnosis and treatment across different European healthcare settings. The economic burden of RLS was estimated using the published EBC framework of analysis in three separate European Union healthcare systems (France, Germany, and Italy). The RLS care pathway was mapped to identify the unmet needs of patients. Based on specific patient stories, the economic impact of correctly diagnosing RLS and changing between inadequate and target treatment was calculated using appropriate scenario analysis. RLS proved to be a significant personal and social burden, when epidemiological data, high prevalence of RLS, and its need for treatment are combined. By looking at the savings emerging from the provision of optimal care management (timely and correct diagnosis, evidence-based therapy, avoidance of therapy-related complications such as augmentation), the authors foresee substantial economic savings with the achievement of adequate diagnosis and treatment of RLS. Education about RLS is urgently needed for all subspecialties involved in RLS patient care as well as the general public. Equally important, the search for new causal treatment strategies should be intensified to reduce suffering and substantial societal cost.

The economic benefit of timely, adequate, and adherence to Parkinson's disease treatment: the Value of Treatment Project 2.

BACKGROUND: Parkinson's disease (PD) is a chronic progressive neurological disorder with a high psychosocial and economic burden. As part of the European Brain Council (EBC)-led Value of Treatment project, this study aimed to capture the economic benefit of timely, adequate, and adherence to PD treatment. METHODS: The EBC Value of Treatment Initiative combined different stakeholders to identify unmet needs in the patients' journey according to Rotterdam methodology. The economic evaluation focused on three major topics identified as major gaps: start of treatment; best treatment for advanced disease; and adherence to treatment. Two separate healthcare systems (Germany and the UK) were chosen. Cost-effectiveness was determined by using decision-analytical modelling approaches. Effectiveness was expressed as quality-adjusted life-years (QALYs) gained and incremental cost-effectiveness ratio (ICER). RESULTS: Treatment intervention in PD was found to be cost-effective regardless of the initial health state of the patient receiving the treatment. Cost savings were between -€1000 and -€5400 with 0.10 QALY gain and -€1800 and -€7600 with 0.10 QALY gain for Germany and the UK, respectively. Treatment remains cost-effective within the National Institute for Health and Care Excellence thresholds. Availability of adequate treatment to more patients was also found to be cost-effective, with an ICER of €15,000-€32,600 across country settings. Achieving the target adherence to treatment would generate cost-savings of €239,000-€576,000 (Germany) and €917,000-€2,980.000 (UK) for every 1,000 patients treated adequately. CONCLUSIONS: The analyses confirmed that timely, adequate, and adherence to PD treatment will not only improve care of the patients but is also cost-effective across healthcare systems. Further studies with a distinct identification of gaps in care are necessary to develop better and affordable care.

Idiopathic normal-pressure hydrocephalus: the cost-effectiveness of delivering timely and adequate treatment in Germany.

BACKGROUND AND PURPOSE: Idiopathic normal-pressure hydrocephalus (iNPH) is a progressive, severe brain disorder, which mainly affects people above the age of 65 years. iNPH is characterized by the accumulation of excess cerebrospinal fluid in the brain's ventricles. In most cases, iNPH patients can be effectively treated with shunt surgery, which involves placing a tube into the brain to drain the excess fluid. As part of the European Brain Council-led Value of Treatment project, this study aimed to investigate the cost-effectiveness of delivering timely and adequate iNPH treatment in Germany. METHODS: The study identified treatment gaps that prevent iNPH patients from receiving adequate and timely treatment. The cost-effectiveness of delivering shunt surgery to iNPH-prevalent patients aged ≥65 years in Germany was calculated using decision-analytical modelling. The model compared two alternatives, current care (shunt surgery in 25% of iNPH cases) and target care (shunt surgery in 90% of iNPH cases), and looked at healthcare costs (diagnosis, shunt intervention and follow-up care) from the public health insurance perspective, as well as effectiveness outcomes in terms of lives saved and quality-adjusted life-years (QALYs) gained. RESULTS: Delivering timely and adequate iNPH treatment proved to be cost-effective. Cost per life saved varied between €27 921 at 5 years and €246 726 at 15 years. Cost-per-QALY estimates varied between €10 202 at 5 years and €35 128 at 15 years. CONCLUSIONS: Idiopathic normal-pressure hydrocephalus is a treatable but often not-treated disease, resulting in unnecessary and avoidable disease burden for the healthcare system. Actions required to close this treatment gap are straightforward and their implementation has been modelled with successful outcomes.

Predictors of mortality in nursing-home residents with pneumonia: a multicentre study.

OBJECTIVES: To evaluate predictors of mortality in patients residing in nursing-homes (NHs) or long-term care facilities (LTCFs) with diagnosis of NH-acquired pneumonia (NHAP). METHODS: We conducted an observational, prospective study (December 2013-December 2015) of patients residing in nine NHs/LTCFs of Central and Northern Italy with diagnosis of NHAP. Data on demographics, comorbidities, microbiology, and therapies were entered into an electronic database. To identify risk factors associated with 30-day mortality, we performed univariable and multivariable analyses, and predictors were internally validated using a bootstrap resampling procedure. We derived a prediction rule using the coefficients obtained from the multivariable logistic regression. The model obtained was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: Overall, 446 patients with NHAP were included in the final cohort. The median age was 80 (IQR 75-87) years. A definite aetiology was obtained in 120 (26.9%) patients; of these, 66 (55%) had a culture positive for a multidrug-resistant pathogen. The 30-day mortality was 28.7%. On multivariate analysis, malnutrition (OR 7.8; 95% CI 3-20.2, 2 points), bilateral pneumonia (OR 3.7; 95% CI 1.4-9.8, 1 point), acute mental status deterioration (OR 6.2; 95% CI 2.2-17.6, 2 points), hypotension (OR 7.7; 95% CI 2.3-24.9, 2 points), and PaO2/FiO2 ratio ≤250 (OR 7.4; 95% CI 2.2-24.2, 2 points) were independently associated with 30-day mortality. The derived prediction rule showed an AUROC of 0.83 (95% CI 0.78-0.87, p <0.001). CONCLUSIONS: NH residents with pneumonia have specific risk factors associated with 30-day mortality. Malnutrition and acute mental change appear as major determinants of death in this population.

Arthrodesis for septic arthritis of the ankle: risk factors and complications.

INTRODUCTION: Septic ankle joint arthrodesis is a good therapeutic option in cases of infection after trauma or orthopedic surgical procedures. Many different procedures have been described, but external fixation seems to be standard. Aim of this study is to identify risk factors for complications in septic ankle joint arthrodesis with the external AO frame fixator. MATERIALS AND METHODS: Patients who received septic ankle joint arthrodesis between January 2008 and December 2012 were included in this study. Patients were evaluated clinically and with radiographs or CT scans. RESULTS: Follow-up of 74 of 79 patients with an external AO frame fixator could be evaluated; follow-up was 411 days (105-991). The mean age at surgery was 57.7 years (19-87). At this time, complications occurred in 41 patients (52 %) with wound healing problems (17 patients, 22 %) and non-union (12 patients, 15 %), and some needed surgical revision. In our collective, men had a significant higher non-union rate (p = 0.031), age or BMI showed no difference. Patients with diabetes and alcohol consumption showed a higher risk for complications (p = 0.049 and p = 0.031, respectively). 62 % of primary arthrodesis showed union, whereas in the case of revision, arthrodesis only 39 % showed union. CONCLUSIONS: Septic ankle joint arthrodesis with the external AO frame fixator is a probable tool to achieve union. This study showed that there is a high complication rate and some risk factors for complications could be identified. A blinded and prospective study is needed to compare intramedullary nailing and external fixation to evaluate the possible advantage of intramedullary devices in septic ankle arthrodesis.

Correct positioning of pedicle screws with a percutaneous minimal invasive system in spine trauma.

BACKGROUND: When performing minimally invasive spine surgery in trauma patients, a short operation time and a perfect positioning of pedicle screws are demanded. In this study, we show that a Minimally Invasive Pedicle Screw System allows both. METHODS: One hundred and twenty-one patients (131 fractures) with fractures between Th 3 and L 5 were treated. The most common fracture type was A3. We treated 52 females and 69 men with a mean age of 56.7 years. In 72% of the cases, the procedure was performed by two experienced spine surgeons. Postoperatively, all patients were examined using a CT-scan. In 61 patients, an anterior stabilization was additionally performed in 33 patients, vertebroplasty or cyphoplasty was performed. Fifteen patients underwent laminectomy. RESULTS: No patient postoperatively developed any additional neurological compromise. In total, 682 screws were placed. In the postoperative CT-scan, we found 16 screws (2.2%) in suboptimal position, 8 with medial and 8 with lateral deviation. DISCUSSION: With the Minimally Invasive Pedicle Screw System used in this study, spinal fractures can be treated in a short operation time with percutaneous stabilization and a correct positioning of the pedicle screws in almost 98%. In our study, no screw was so much malpositioned that revision surgery would have been necessary. LEVEL OF EVIDENCE: Level III - Case-control study.

Single-nucleotide polymorphism-defined class I and class III major histocompatibility complex genetic subregions contribute to natural long-term nonprogression in HIV infection.

We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1-infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1-infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP-associated SNPs are ordered in ≥4 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype.

Healthcare-acquired infections in rehabilitation units of the Lombardy Region, Italy.

BACKGROUND: Little data are available on the frequency and risk factors for infection in patients in rehabilitation units. METHODS: This was a 2-year retrospective cohort study conducted in 131 rehabilitation units (RUs) of the Lombardy Region, including those for patients requiring musculoskeletal, cardiac, respiratory, neurological and general geriatric rehabilitation. RUs were stratified into three groups by infection rate calculated from administrative data, and a random sample of RUs in each group was selected for analysis. Discharges from these RUs were randomly selected for chart review, and healthcare-acquired infection was confirmed using CDC/NHSN definitions. A logistic regression analysis explored the association among demographic variables of age, sex, type of rehabilitation unit, Charlson comorbidity score, and location prior to RU admission for selected infections. RESULTS: For the 3,028 discharges from 28 RUs, hospital administrative data had a sensitivity of 0.45 and a positive predictive value of 0.89 to identify infections in the chart review. At least one infection occurred in 14.9% of patient discharges, with 71% of infections being urinary, 8.0% respiratory, and 5% skin and soft tissue. Urinary infection was associated with female sex [odds ratio (OR) 1.48, 95% confidence interval (CI) 1.13-1.93], age 75-85 years (OR 2.21, 95% CI 1.12-4.34), Charlson comorbidity score of ≥3 (OR 1.54, 95% CI 1.10-2.17), and the transfer from acute care (OR 1.45, 95% CI 1.04-2.02). For respiratory infection, male sex (OR 3.06, 95% CI 1.51-6.18), comorbidity score of 1 or 2 (OR 2.16, 95% CI 1.08-4.36), and transfer from a healthcare setting other than an acute care hospital were independent risks (OR 3.14, 95% CI 1.15-8.53). CONCLUSION: Infections are common in residents of these rehabilitation units, and risk factors may differ with type of infection. The proportion of infections which may be prevented and effective prevention strategies need to be determined.

Clinical, serologic and instrumental data of ten patients affected by sclerodermatous chronic graft versus host disease: similarities and differences in respect to systemic sclerosis.

Chronic graft versus host disease (cGVHD), the most common late complication of allogeneic haematopoietic stem cell transplantation (HSCT), may present with sclerodermatous lesions resembling in some cases the cutaneous involvement of systemic sclerosis (SSc). Certain pathogenetic findings connect the two diseases. In this report we describe ten subjects affected by cGVHD who underwent the examinations routinely carried out to stage SSc patients. Demographic, clinical, serologic and instrumental data were recorded. These patients showed differences in appearance, extent and progression of the sclerodermatous lesions with greater involvement of the trunk and proximal part of the limbs than the extremities. In seven subjects ANA test was positive; scleroderma-associated autoantibodies were not detected in any of the cases. Moreover, typical organ involvement of SSc was not found. Only one patient developed Raynauds phenomenon after HSCT and only one patient demonstrated a nailfold videocapillaroscopic scleroderma pattern. Except for cutaneous involvement of cGVHD, that may resemble SSc, the clinical features of the two diseases are quite different, suggesting that the fibrotic process characterizing cGVHD and SSc has different etiologies and different initial pathobiologic events.

A short course of pegylated interferon-alpha in acute HCV hepatitis.

Acute hepatitis C virus (HCV) infection evolves to chronicity in 50-84% cases. Treatment with interferon-alpha (IFN-alpha) was repeatedly found to provide sustained cure rates higher than that in chronic HCV infection, but the optimal treatment strategy has not yet been defined. In a multicentre open-label study, we investigated the therapeutic performance of a short course of pegylated (peg) IFN-alpha in patients with acute HCV hepatitis. Peg IFN-alpha2b, 1.0-1.5 micro g/kg weekly, was administered for 12 weeks. Forty-six patients were enrolled; 26 of them were intravenous drug users. Eleven patients had jaundice. Treatment was started within 1-90 days from the peak alanine aminotransferase. Treatment was well tolerated with a single dropout (2%). Thirty-three of 46 patients (72%) had a sustained virological response (SVR) after a 6 months post-treatment follow-up, 8 (17%) relapsed after treatment and 4 were nonresponders (9%). A lower peak viraemia, receiving at least 1.2 micro g/kg of peg IFN-alpha, and a negative HCV-RNA at week 4 and week 12 were predictors of SVR. Thus, in patients with early (week 4) viral response, a short course of peg IFN-alpha at a weekly dose >1.2 micro g/kg, may be a valuable option for the treatment of acute HCV hepatitis.

Enoximone maintains intestinal villus blood flow during endotoxemia.

BACKGROUND: The objective of this study was to determine the effects of a continuous infusion of the phosphodiesterase inhibitor enoximone on mucosal villus blood flow in a normotensive model of endotoxemia. METHODS: Twenty-four anesthetized and ventilated rats underwent laparotomy and a ileal portion was exteriorized and opened by an antimesenteric incision. The ileal segment was fixed on a plexiglass stage with the mucosal surface upward. Microcirculatory parameters were assessed by intravital videomicroscopy. The animals were randomly assigned to receive one of three treatments: infusion of Escherichia coli lipopolysaccharides (LPS, 2 mg/kg/h) without phosphodiesterase inhibitor pretreatment (LPS group); or infusion of LPS with enoximone pretreatment (10 microg x kg(-1) x min(-1), start 30 min before LPS infusion, enoximone group), or infusion of an eqivalent volume of NaCl 0.9% (control group). Macrohemodynamic parameters (MAP, HR) and microhemodynamic parameters of ileal mucosa (mean diameter of central arterioles = DA, and mean erythrocyte velocity within the arterioles = VE) were measured 30 min before and at 0, 60, and 120 min after induction of endotoxemia. Mucosal villus blood flow was calculated from DA and VE. RESULTS: In this normotensive endotoxemia model MAP remained stable in the control and the LPS group but significantly decreased in the enoximone group. The endotoxin-induced decrease of VE and DE of central arterioles of mucosal villi could be prevented. Thus, mucosal villus blood flow did not decrease compared to the LPS group. CONCLUSIONS: Our results indicate that enoximone during an early stage of sepsis contributes to systemic hypotension but prevents mucosal hypoperfusion.

Modifications of cardiac autonomic profile associated with a shift schedule of work.

BACKGROUND: Shift work is associated with an increased rate of cardiovascular diseases and accidents. Discordance between circadian rhythms of stress-related biological variables and the work-sleep schedule might explain the reduced efficiency of work. It is not clear whether a shift schedule of work may induce similar discordance in the 24-hour oscillatory pattern of the cardiac autonomic control in respect to the work-sleep periods. METHODS AND RESULTS: Twenty-two healthy male blue-collar shift workers underwent 24-hour ECG recordings during each of the 3 different shifts (first, 6 AM to 2 PM; second, 2 to 10 PM; third, 10 PM to 6 AM). Spectral analysis of heart rate variability over 24 hours provided the normalized markers of cardiac sympathetic (LF(nu)) and vagal (HF(nu)) modulation of the sinoatrial node activity and of the sympathovagal balance (LF/HF). LF(nu) and LF/HF exhibited 24-hour oscillations with different times of maximum and minimum in accordance with the working and sleeping periods, respectively. Lower values of LF(nu) and LF/HF suggestive of a reduced cardiac sympathetic modulation were present when the job task was performed at night compared with the values observed when the work was performed during morning and evening. CONCLUSIONS: Continuous weekly changes of time of maximum and minimum in the cardiac sympathetic and vagal autonomic control may play a role in the excessive rate of cardiovascular diseases in shift workers. The reduced values of the indexes of cardiac sympathetic modulation during night work might be related to the presence of sleepiness or diminished alertness, which in turn could facilitate errors and accidents.

Influence of amrinone on intestinal villus blood flow during endotoxemia.

PURPOSE: The objective of this study was to determine the effects of a continuous infusion of the phosphodiesterase (PDE) inhibitor amrinone on mucosal villus blood flow in a normotensive model of endotoxemia. MATERIALS AND METHODS: Twenty-four anesthetized and ventilated rats underwent laparotomy, and an ileal portion was exteriorized and opened by an antimesenteric incision. The ileal segment was fixed on a plexiglass stage with the mucosal surface upward. Microcirculatory parameters were assessed by intravital videomicroscopy. The animals were randomly assigned to receive one of three treatments: infusion of Escherichia coli lipopolysaccharides (LPS, 2 mg/kg/h) without phosphodiesterase inhibitor pretreatment (LPS group); or infusion of LPS with amrinone pretreatment (40 microg/kg/min, start 30 minutes before LPS infusion) (amrinone group), or infusion of equivalent volumes of NaCl 0.9% (control group). Macrohemodynamic parameters (MAP, HR) and microhemodynamic parameters of ileal mucosa (mean diameter of central arterioles = D(A) and mean erythrocyte velocity within the arterioles = VE) were measured 30 minutes before and at 0, 60, and 120 minutes after induction of endotoxemia. Mucosal villus blood flow was calculated from D(A) and VE. RESULTS: In this normotensive endotoxemia model, MAP remained stable in the control and the LPS group but significantly decreased in the amrinone group.The endotoxin-induced decrease of V(E) and D(A) of central arterioles of mucosal villi could be attenuated and prevented, respectively. Thus, the endotoxin-induced decrease of mucosal villus blood flow was diminished but not fully restored by amrinone infusion. CONCLUSION: Our results indicate that amrinone during an early stage of sepsis is of limited value. It attenuates mucosal hypoperfusion but contributes to systemic hypotension.

Influence of amrinone on tissue oxygenation of jejunal mucosa during endotoxemia.

BACKGROUND: The intestinal mucosa is the portion of the gut most susceptible to impaired perfusion and oxygen delivery. The phosphodiesterase (PDE) inhibitor amrinone has been proposed to improve oxygen delivery and tissue perfusion during sepsis. The objective of this study was to investigate the effects of amrinone on arterial oxygenation (Pao(2)) and tissue oxygenation (Ptio(2)) of jejunal mucosa during endotoxemia. MATERIALS AND METHODS: Forty anesthetized and ventilated rats were laparotomized and a jejunal portion was exteriorized and fixed on a plexiglass stage. The jejunum was punctured and a Clark-type microcatheter Po(2) probe and a microthermocouple were placed on the mucosa to measure Ptio(2). The animals were randomly assigned to receive one of the four treatments: infusion of Escherichia coli lipopolysaccharides (LPS, 2 mg/kg/h) without amrinone pretreatment (LPS group); infusion of LPS with amrinone pretreatment (40 microg/kg/min, start 30 min before LPS infusion, amrinone + LPS group); no treatment with either amrinone or LPS (control group); treatment with amrinone without LPS infusion (amrinone group). Mean arterial pressure (MAP), heart rate (HR), Pao(2), and Ptio(2) were measured 30 min before and 0, 60, and 120 min after induction of endotoxemia. RESULTS: MAP remained stable in the control and LPS groups. In the amrinone + LPS group MAP decreased within the first 30 min of amrinone infusion and decreased further during endotoxemia. Pao(2) remained stable in the control group and decreased in the LPS group. This endotoxin-induced decrease in Pao(2) was attenuated in the amrinone + LPS group. The mucosal Ptio(2) decreased in the LPS group but remained stable in both the control and amrinone + LPS groups. CONCLUSIONS: Pretreatment with amrinone was able to diminish a decrease in Pao(2) during endotoxemia, indicating that pulmonary dysfunction was attenuated. Endotoxin-induced tissue hypoxia of the intestinal mucosa, however, could be fully prevented, indicating that an additional improvement in compromised tissue perfusion had occurred.

Milrinone improves intestinal villus blood flow during endotoxemia.

PURPOSE: To determine whether the compromised intestinal villus blood flow in a rat model of endotoxemia could be improved by continuous infusion of the phosphodiesterase (PDE) inhibitor milrinone. METHODS: Twenty-four anesthetized and ventilated rats were laparotomized and an ileal portion was exteriorized and opened by an antimesenteric incision. The ileal segment was fixed with the mucosal surface upward. Microcirculatory parameters were assessed by intravital videomicroscopy. The animals were randomly assigned to receive one of three treatments: infusion of Escherichia coli lipopolysaccharides without phosphodiesterase inhibitor pretreatment (=LPS group); or infusion of LPS with milrinone pretreatment (= milrinone group), or without infusion of LPS or milrinone (=control group). Macrohemodynamic parameters (MAP, HR) and microhemodynamic parameters of ileal mucosa (mean diameter of central arterioles = D(A) and mean erythrocyte velocity within the arterioles= V(E)) were measured 30 min before and at 0, 60, and 120 min after induction of endotoxemia. Mucosal villus blood flow was calculated from D(A) and V(E). RESULTS: In the milrinone group MAP decreased 60 min after induction of endotoxemia whereas it remained stable in the control and the LPS group. In both groups given endotoxin V(E) decreased after start of LPS infusion. In contrast, D(A) decreased in the LPS group, but increased in the milrinone group after 120 min of endotoxemia. Thus, the endotoxin-induced decrease of intestinal villus blood flow was diminished but not fully restored by milrinone infusion. CONCLUSION: Our results indicate that milrinone has some beneficial microcirculatory effects during endotoxemia. Although it contributed to systemic hypotension, it attenuated intestinal mucosal hypoperfusion.