Biomarkers of cell damage, neutrophil and macrophage activation associated with in-hospital mortality in geriatric COVID-19 patients.

BACKGROUND: The risk for symptomatic COVID-19 requiring hospitalization is higher in the older population. The course of the disease in hospitalised older patients may show significant variation, from mild to severe illness, ultimately leading to death in the most critical cases. The analysis of circulating biomolecules involved in mechanisms of inflammation, cell damage and innate immunity could lead to identify new biomarkers of COVID-19 severity, aimed to improve the clinical management of subjects at higher risk of severe outcomes. In a cohort of COVID-19 geriatric patients (n= 156) who required hospitalization we analysed, on-admission, a series of circulating biomarkers related to neutrophil activation (neutrophil elastase, LL-37), macrophage activation (sCD163) and cell damage (nuclear cfDNA, mithocondrial cfDNA and nuclear cfDNA integrity). The above reported biomarkers were tested for their association with in-hospital mortality and with clinical, inflammatory and routine hematological parameters. Aim of the study was to unravel prognostic parameters for risk stratification of COVID-19 patients. RESULTS: Lower n-cfDNA integrity, higher neutrophil elastase and higher sCD163 levels were significantly associated with an increased risk of in-hospital decease. Median (IQR) values observed in discharged vs. deceased patients were: 0.50 (0.30-0.72) vs. 0.33 (0.22-0.62) for n-cfDNA integrity; 94.0 (47.7-154.0) ng/ml vs. 115.7 (84.2-212.7) ng/ml for neutrophil elastase; 614.0 (370.0-821.0) ng/ml vs. 787.0 (560.0-1304.0) ng/ml for sCD163. The analysis of survival curves in patients stratified for tertiles of each biomarker showed that patients with n-cfDNA integrity < 0.32 or sCD163 in the range 492-811 ng/ml had higher risk of in-hospital decease than, respectively, patients with higher n-cfDNA integrity or lower sCD163. These associations were further confirmed in multivariate models adjusted for age, sex and outcome-related clinical variables. In these models also high levels of neutrophil elastase (>150 ng/ml) appeared to be independent predictor of in-hospital death. An additional analysis of neutrophil elastase in patients stratified for n-cfDNA integrity levels was conducted to better describe the association of the studied parameters with the outcome. CONCLUSIONS: On the whole, biomarkers of cell-free DNA integrity, neutrophil and macrophage activation might provide a valuable contribution to identify geriatric patients with high risk of COVID-19 in-hospital mortality.

The association between low skeletal muscle mass and delirium: results from the nationwide multi-centre Italian Delirium Day 2017.

INTRODUCTION: Delirium and sarcopenia are common, although underdiagnosed, geriatric syndromes. Several pathological mechanisms can link delirium and low skeletal muscle mass, but few studies have investigated their association. We aimed to investigate (1) the association between delirium and low skeletal muscle mass and (2) the possible role of calf circumference mass in finding cases with delirium. METHODS: The analyses were conducted employing the cross-sectional "Delirium Day" initiative, on patient 65 years and older admitted to acute hospital medical wards, emergency departments, rehabilitation wards, nursing homes and hospices in Italy in 2017. Delirium was diagnosed as a 4 + score at the 4-AT scale. Low skeletal muscle mass was operationally defined as calf circumference ≤ 34 cm in males and ≤ 33 cm in females. Logistic regression models were used to investigate the association between low skeletal muscle mass and delirium. The discriminative ability of calf circumference was evaluated using non-parametric ROC analyses. RESULTS: A sample of 1675 patients was analyzed. In total, 73.6% of participants had low skeletal muscle mass and 24.1% exhibited delirium. Low skeletal muscle mass and delirium showed an independent association (OR: 1.50; 95% CI 1.09-2.08). In the subsample of patients without a diagnosis of dementia, the inclusion of calf circumference in a model based on age and sex significantly improved its discriminative accuracy [area under the curve (AUC) 0.69 vs 0.57, p < 0.001]. DISCUSSION AND CONCLUSION: Low muscle mass is independently associated with delirium. In patients without a previous diagnosis of dementia, calf circumference may help to better identify those who develop delirium.

Total urinary polyphenols and longitudinal changes of bone properties. The InCHIANTI study.

The aim of this study was to evaluate the association of levels of urinary total polyphenols considered as a proxy measure of polyphenol intake, with longitudinal changes of bone properties, in the InCHIANTI study. Dietary intake of polyphenols appears to be associated with future accelerated deterioration of bone health. INTRODUCTION: Polyphenols, micronutrients ingested through plant-based foods, have antioxidant and anti-inflammatory properties and may contribute to osteoporosis prevention. We evaluated associations of high levels of urinary total polyphenols (UTP), a proxy measure of polyphenol intake, with longitudinal changes of bone properties in a representative cohort of free-living participants of the InCHIANTI study. METHODS: The InCHIANTI study enrolled representative samples from the registry list of two towns in Tuscany, Italy. Baseline data were collected in 1998 and follow-up visits in 2001 and 2004. Of the 1453 participants enrolled, 956 consented to donate a 24-h urine sample used to assess UTP, had dietary assessment, a physical examination, and underwent a quantitative computerized tomography (pQCT) of the tibia. From pQCT images, we estimated markers of bone mass (BM), diaphyseal design (DD), and material quality (MQ). Mixed models were used to study the relationship between baseline tertiles of UTP with changes of the bone characteristics over the follow-up. RESULTS: At baseline, higher levels of UTP were positively correlated with markers of BM, DD, and MQ. Compared with lower tertile of UTP, participants in the intermediate and highest tertiles had higher cortical bone area, cortical mineral content, and cortical thickness. However, participants in the intermediate and highest UTP tertiles experienced accelerated deterioration of these same parameters over the follow-up compared with those in the lowest UTP tertile. CONCLUSIONS: Dietary intake of polyphenols estimated by UTP and dietary questionnaire was associated with long-term accelerated deterioration of bone health. Our study does not support the recommendation of increasing polyphenol intake for osteoporosis prevention.

Is the fast-track process efficient and safe for older adults admitted to the emergency department?

BACKGROUND: The efficiency of the fast-track (FT) process in the management of patients in Emergency Departments is well demonstrated, but there is a lack of research focused on older adults. The aim of our study was to verify whether the FT process is efficient and safe for older adults admitted to ED. METHODS: Observational case-control single-centre study. RESULTS: Five hundred four cases and 504 controls were analysed. The mean age was 75 years, and there was a predominance of women. In total 96% of subjects were classified with a "less-urgent" tag. The length of stay was significantly lower in the fast-track group than in the control group (median 178 min, interquartile range 184 min, and 115 min, interquartile range 69 min, respectively, p < 0.001), as well as the time spent between the ED physician's visit and patient discharge (median 78 min, interquartile range 120 min, and median 3 min, interquartile range 6 min, respectively, p < 0.001). There weren't any increases in the number of unplanned readmissions within 48 h, 7 days and 30 days. CONCLUSIONS: The fast-track appears to be an efficient and safe strategy to improve the management of older adults admitted to the ED with minor complaints.

3-T magnetic resonance imaging simultaneous automated multimodal approach improves detection of ambiguous visual hippocampal sclerosis.

BACKGROUND AND PURPOSE: To evaluate if an automatic magnetic resonance imaging (MRI) processing system may improve detection of hippocampal sclerosis (Hs) in patients with mesial temporal lobe epilepsy (MTLE). METHODS: Eighty consecutive patients with a diagnosis of MTLE and 20 age- and sex-matched controls were prospectively recruited and included in our study. The entire group had 3-T MRI visual assessment of Hs analysed by two blinded imaging epilepsy experts. Logistic regression was used to evaluate the performances of neuroradiologists and multimodal analysis. RESULTS: The multimodal automated tool gave no evidence of Hs in all 20 controls and classified the 80 MTLE patients as follows: normal MRI (54/80), left Hs (14/80), right Hs (11/80) and bilateral Hs (1/80). Of note, this multimodal automated tool was always concordant with the side of MTLE, as determined by a comprehensive electroclinical evaluation. In comparison with standard visual assessment, the multimodal automated tool resolved five ambiguous cases, being able to lateralize Hs in four patients and detecting one case of bilateral Hs. Moreover, comparing the performances of the three logistic regression models, the multimodal approach overcame performances obtained with a single image modality for both the hemispheres, reaching a global accuracy value of 0.97 for the right and 0.98 for the left hemisphere. CONCLUSIONS: Multimodal quantitative automated MRI is a reliable and useful tool to depict and lateralize Hs in patients with MTLE, and may help to lateralize the side of MTLE especially in subtle and uncertain cases.

Multimodal MRI analysis of the corpus callosum reveals white matter differences in presymptomatic and early Huntington's disease.

Recent magnetic resonance imaging (MRI) studies suggest that abnormalities in Huntington's disease (HD) extend to white matter (WM) tracts in early HD and even in presymptomatic stages. Thus, changes of the corpus callosum (CC) may reflect various aspects of HD pathogenesis. We recruited 17 HD patients, 17 pre-HD subjects, and 34 healthy age-matched controls. Three-dimensional anatomical MRI and diffusion tensor images of the brain were acquired on a 3T scanner. Combining region-of-interest analyses, voxel-based morphometry, and tract-based spatial statistics, we investigated callosal thickness, WM density, fractional anisotropy, and radial and axial diffusivities. Compared with controls, pre-HD subjects showed reductions of the isthmus, likely due to myelin damage. Compared with pre-HD subjects, HD patients showed reductions of isthmus and body, with axonal damage confined to the body. Compared with controls, HD patients had significantly decreased callosal measures in extended regions across almost the entire CC. At this disease stage, both myelin and axonal damage are detectable. Supplementary multiple regression analyses revealed that WM reduction density in the isthmus as well as Disease Burden scores allowed to predict the "HD development" index. While callosal changes seem to proceed in a posterior-to-anterior direction as the diseases progresses, this observation requires validation in future longitudinal investigations.

Underprescription of medications in older adults: causes, consequences and solutions-a narrative review.

PURPOSE: Under-prescription is defined as the omission of a medication that is indicated for the treatment of a condition or a disease, without any valid reason for not prescribing it. The aim of this review is to provide an updated overview of under-prescription, summarizing the available evidence concerning its prevalence, causes, consequences and potential interventions to reduce it. METHODS: A PubMed search was performed, using the following keywords: under-prescription; under-treatment; prescribing omission; older adults; polypharmacy; cardiovascular drugs; osteoporosis; anticoagulant. The list of articles was evaluated by two authors who selected the most relevant of them. The reference lists of retrieved articles were screened for additional pertinent studies. RESULTS: Although several pharmacological therapies are safe and effective in older patients, under-prescription remains widespread in the older population, with a prevalence ranging from 22 to 70%. Several drugs are underused, including cardiovascular, oral anticoagulant and anti-osteoporotic drugs. Many factors are associated with under-prescription, e.g. multi-morbidity, polypharmacy, dementia, frailty, risk of adverse drug events, absence of specific clinical trials in older patients and economic factors. Under-prescription is associated with negative consequences, such as higher risk of cardiovascular events, worsening disability, hospitalization and death. The implementation of explicit criteria for under-prescription, the use of the comprehensive geriatric assessment by geriatricians, and the involvement of a clinical pharmacist seem to be promising options to reduce under-prescription. CONCLUSION: Under-prescription remains widespread in the older population. Further studies should be performed, to provide a better comprehension of this phenomenon and to confirm the efficacy of corrective interventions.

Infratentorial lesion volume correlates with sensory functional system in multiple sclerosis patients: a 3.0-Tesla MRI study.

PURPOSE: This study sought to correlate lesion volume in infratentorial areas using 3.0-T proton-density (PD)-weighted images with disability scales and appropriate functional system scores in patients with multiple sclerosis (MS). MATERIALS AND METHODS: We examined 20 consecutive patients (13 women and 7 men) with a median age of 47 years (range 26-70). Neurological examination included the Expanded Disability Status Scale and its functional systems, the Barthel Index (BI) and the Rivermead Mobility Index (RMI). MRI scans were performed on a system operating at 3.0 T using a quadrature birdcage head coil. Acquired images imported as Digital Imaging and Communication in Medicine (DICOM) files, and the region of interest (ROI) files were converted to Neuroimaging Informatics Technology Initiative (NIfTI) format and normalised to the Montreal Neurological Institute (MNI) standard template. An automated segmentation algorithm was used to distinguish between supratentorial and infratentorial areas. Normalisation to the magnetisation-prepared rapid acquisition with gradient echo (MPRAGE) T1-weighted sequence allowed lesion volume estimation in the different anatomical areas. RESULTS: A significant correlation was found between infratentorial lesion volume and the sensory functional system score (rho=0.76, p=0.002). No significant correlation was found between supratentorial lesion volume and Expanded Disability Status Scale (EDSS), RMI and BI scores. CONCLUSIONS: The described method, by means of anatomical assignment of MS lesions, allows detection of significant correlation coefficients between clinical and MRI lesion burden in MS patients at the infratentorial level.

Texture-Modified Diet for Improving the Management of Oropharyngeal Dysphagia in Nursing Home Residents: An Expert Review.

OBJECTIVES: This paper provides evidence-based and, when appropriate, expert reviewed recommendations for long-stay residents who are prescribed texture-modified diets (TMDs), with the consideration that these residents are at high risk of worsening oropharyngeal dysphagia (OD), malnutrition, dehydration, aspiration pneumonia, and OD-associated mortality, poorer quality of life and high costs. DESIGN: Nestlé Health Science funded an initial virtual meeting attended by all authors, in which the unmet needs and subsequent recommendations for OD management were discussed. The opinions, results, and recommendations detailed in this paper are those of the authors, and are independent of funding sources. SETTING: OD is common in nursing home (NH) residents, and is defined as the inability to initiate and perform safe swallowing. The long-stay NH resident population has specific characteristics marked by a shorter life expectancy relative to community-dwelling older adults, high prevalence of multimorbidity with a high rate of complications, dementia, frailty, disability, and often polypharmacy. As a result, OD is associated with malnutrition, dehydration, aspiration pneumonia, functional decline, and death. Complications of OD can potentially be prevented with the use of TMDs. RESULTS: This report presents expert opinion and evidence-informed recommendations for best practice on the nutritional management of OD. It aims to highlight the practice gaps between the evidence-based management of OD and real-world patterns, including inadequate dietary provision and insufficient staff training. In addition, the unmet need for OD screening and improvements in therapeutic diets are explored and discussed. CONCLUSION: There is currently limited empirical evidence to guide practice in OD management. Given the complex and heterogeneous population of long-stay NH residents, some 'best practice' approaches and interventions require extensive efficacy testing before further changes in policy can be implemented.

EuGMS Task and Finish group on Fall-Risk-Increasing Drugs (FRIDs): Position on Knowledge Dissemination, Management, and Future Research.

Falls are a major public health concern in the older population, and certain medication classes are a significant risk factor for falls. However, knowledge is lacking among both physicians and older people, including caregivers, concerning the role of medication as a risk factor. In the present statement, the European Geriatric Medicine Society (EuGMS) Task and Finish group on fall-risk-increasing drugs (FRIDs), in collaboration with the EuGMS Special Interest group on Pharmacology and the European Union of Medical Specialists (UEMS) Geriatric Medicine Section, outlines its position regarding knowledge dissemination on medication-related falls in older people across Europe. The EuGMS Task and Finish group is developing educational materials to facilitate knowledge dissemination for healthcare professionals and older people. In addition, steps in primary prevention through judicious prescribing, deprescribing of FRIDs (withdrawal and dose reduction), and gaps in current research are outlined in this position paper.

EuGMS Task and Finish group on Fall-Risk-Increasing Drugs (FRIDs): Position on Knowledge Dissemination, Management, and Future Research.

Falls are a major public health concern in the older population, and certain medication classes are a significant risk factor for falls. However, knowledge is lacking among both physicians and older people, including caregivers, concerning the role of medication as a risk factor. In the present statement, the European Geriatric Medicine Society (EuGMS) Task and Finish group on fall-risk-increasing drugs (FRIDs), in collaboration with the EuGMS Special Interest group on Pharmacology and the European Union of Medical Specialists (UEMS) Geriatric Medicine Section, outlines its position regarding knowledge dissemination on medication-related falls in older people across Europe. The EuGMS Task and Finish group is developing educational materials to facilitate knowledge dissemination for healthcare professionals and older people. In addition, steps in primary prevention through judicious prescribing, deprescribing of FRIDs (withdrawal and dose reduction), and gaps in current research are outlined in this position paper.

Dietary antioxidants as potential pharmacological agents for ischemic stroke.

Acute ischemic stroke is a leading cause of death and severe disability in industrialised countries and also in many developing countries. An excessive amount of free radicals is generated during cerebral ischemia, which significantly contributes to brain damage. Therefore, an increasing interest has been devoted to the potential benefits of antioxidant compounds in ischemic stroke patients. In this review, we examined the most relevant observational studies concerning the relationship between dietary antioxidants and ischemic stroke as well as clinical trials investigating the effects of single or multiple antioxidant supplementation in the prevention or treatment of acute ischemic stroke. Furthermore, we reviewed the most promising antioxidant compounds, i.e. dehydroascorbic acid, alpha-tocotrienol, gamma-tocopherol, flavonoids, resveratrol and gingko biloba, tested in animal models of acute ischemic stroke. Finally, we carefully evaluated the reasons for the discrepancy between experimental and clinical studies, and provided recommendations to improve the translation of the results obtained in animal models to patients with acute ischemic stroke.

Bilateral damage to the mammillo-thalamic tract impairs recollection but not familiarity in the recognition process: a single case investigation.

Focal damage confined to the hippocampus may result in recognition deficits characterized by a dissociation between impaired recollection and preserved familiarity. Here, we report a single case of an amnesic patient with bilateral damage to the anterior part of the thalamus, who presented with a neuropsychological profile suggesting such a dissociation. We hypothesized that this focal damage involved the so-called Delay and Brion's circuit, which has been theorized to subserve episodic memory processes, but at a different anatomical level than in patients with hippocampal lesions. Using two independent experimental paradigms (remember/know and confidence receiver operating characteristics [ROC]) and recruiting a sex- and age-matched group of healthy controls, we demonstrated that this patient's recognition deficits were due to a selective impairment of recollection with a normal familiarity process. The patient underwent an ad hoc brain MRI study, and a quantitative analysis of his MR images was performed. Tissue damage extended bilaterally to the mammillo-thalamic tract, with complete preservation of the medio-dorsal thalamic nuclei. Our findings support the idea that the same functional specialization hypothesized for the different sub-regions of the mesial temporal lobe might also extend to the thalamus. This case will be discussed in light of its implications in support of recent theories, which regard recollection and familiarity as independent processes associated with different neural circuits.

Omega-6 and omega-3 fatty acids predict accelerated decline of peripheral nerve function in older persons.

Pre-clinical studies suggest that both omega-6 and omega-3 fatty acids have beneficial effects on peripheral nerve function. Rats feed a diet rich in polyunsaturated fatty acids (PUFAs) showed modification of phospholipid fatty acid composition in nerve membranes and improvement of sciatic nerve conduction velocity (NCV). We tested the hypothesis that baseline plasma omega-6 and omega-3 fatty acids levels predict accelerated decline of peripheral nerve function. Changes between baseline and the 3-year follow-up in peripheral nerve function was assessed by standard surface ENG of the right peroneal nerve in 384 male and 443 female participants of the InCHIANTI study (age range: 24-97 years). Plasma concentrations of selected fatty acids assessed at baseline by gas chromatography. Independent of confounders, plasma omega-6 fatty acids and linoleic acid were significantly correlated with peroneal NCV at enrollment. Lower plasma PUFA, omega-6 fatty acids, linoleic acid, ratio omega-6/omega-3, arachidonic acid and docosahexanoic acid levels were significantly predicted a steeper decline in nerve function parameters over the 3-year follow-up. Low plasma omega-6 and omega-3 fatty acids levels were associated with accelerated decline of peripheral nerve function with aging.

A Fully Automated, Atlas-Based Approach for Superior Cerebellar Peduncle Evaluation in Progressive Supranuclear Palsy Phenotypes.

BACKGROUND AND PURPOSE: The superior cerebellar peduncle is damaged in progressive supranuclear palsy. However, alterations differ between progressive supranuclear palsy with Richardson syndrome and progressive supranuclear palsy-parkinsonism. In this study, we propose an automated tool for superior cerebellar peduncle integrity assessment and test its performance in patients with progressive supranuclear palsy with Richardson syndrome, progressive supranuclear palsy-parkinsonism, Parkinson disease, and healthy controls. MATERIALS AND METHODS: Structural and diffusion MRI was performed in 21 patients with progressive supranuclear palsy with Richardson syndrome, 9 with progressive supranuclear palsy-parkinsonism, 20 with Parkinson disease, and 30 healthy subjects. In a fully automated pipeline, the left and right superior cerebellar peduncles were first identified on MR imaging by using a tractography-based atlas of white matter tracts; subsequently, volume, mean diffusivity, and fractional anisotropy were extracted from superior cerebellar peduncles. These measures were compared across groups, and their discriminative power in differentiating patients was evaluated in a linear discriminant analysis. RESULTS: Compared with those with Parkinson disease and controls, patients with progressive supranuclear palsy with Richardson syndrome showed alterations of all superior cerebellar peduncle metrics (decreased volume and fractional anisotropy, increased mean diffusivity). Patients with progressive supranuclear palsy-parkinsonism had smaller volumes than those with Parkinson disease and controls and lower fractional anisotropy than those with Parkinson disease. Patients with progressive supranuclear palsy with Richardson syndrome had significantly altered fractional anisotropy and mean diffusivity in the left superior cerebellar peduncle compared with those with progressive supranuclear palsy-parkinsonism. Discriminant analysis with the sole use of significant variables separated progressive supranuclear palsy-parkinsonism from progressive supranuclear palsy with Richardson syndrome with 70% accuracy and progressive supranuclear palsy-parkinsonism from Parkinson disease with 74% accuracy. CONCLUSIONS: We demonstrate the feasibility of an automated approach for extracting multimodal MR imaging metrics from the superior cerebellar peduncle in healthy subjects and patients with parkinsonian. We provide evidence that structural and diffusion measures of the superior cerebellar peduncle might be valuable for computer-aided diagnosis of progressive supranuclear palsy subtypes and for differentiating patients with progressive supranuclear palsy-parkinsonism from with those with Parkinson disease.

Frailty of older age: the role of the endocrine--immune interaction.

The so-called demographic transition has changed the age structure of the population worldwide, with profound effects on societal organization. The growing number and percentage of old and very old people has compelled the scientific community to focus on age related diseases and peculiar consequences of aging itself such as disability and frailty. Understanding the pathophysiology of frailty, a syndrome characterized by a reduced functional reserve and impaired adaptive capacity that results from cumulative declines of multiple subsystems, and causes increased vulnerability to adverse outcomes, is a major topic in aging research. Aging processes induce multiple changes in the hormones network (menopause, andropause, somatopause and adrenopause), in the immune system, and can modulate their efficiency and effectiveness in determining a response to stressors. These triggering events can unmask frailty in older people. Starting from these assumptions, we analyzed the relationship of the endocrine and immune networks in aging and in the different domains that are characteristically associated with the frailty syndrome, such as disability and sarcopenia, as well as in diseases related to aging such as Alzheimer's dementia and Congestive Heart Failure.

Correlates of bone quality in older persons.

PURPOSE OF THE STUDY: In a population-based sample of older persons, we studied the relationship between tibial bone density and geometry and factors potentially affecting osteoporosis. METHODS: Of the 1260 participants aged 65 years or older eligible for the InCHIANTI study, 1155 received an interview and 915 (79.2%) had complete data on tibial QCT scans and other variables used in the analysis presented here. The final study population included 807 persons (372 men and 435 women, age range 65-96 years) after exclusion of participants affected by bone diseases or treated with drugs that interfere with bone metabolism. RESULTS: In both sexes, calf cross-sectional muscle area (CSMA) was significantly and independently associated with total bone cross-sectional area (tCSA) and cortical bone cross-sectional area (cCSA) but not with trabecular or cortical volumetric bone mineral density (vBMD). Bioavailable testosterone (Bio-T) was independently associated with both trabecular and cortical vBMD in both sexes. In women, independently of confounders, 25(OH)-vitamin D was positively associated with tCSA and cortical vBMD, while PTH was negatively associated with cortical vBMD. IL-1 beta was negatively correlated with cortical vBMD in women, while TNF-alpha was associated with enhanced bone geometrical adaptation in men. CONCLUSIONS: Physiological parameters that are generically considered risk factors for osteoporosis were associated with specific bone parameters assessed by tibial QCT. Factors known to be associated with increased bone reabsorption, such as 25(OH)-vitamin D, PTH and Bio-T, affected mainly volumetric BMD, while factors associated with bone mechanical stimulation, such as CSMA, affected primarily bone geometry. Our results also suggested that pro-inflammatory cytokines might be considered as markers of bone resorption.