Ingestion of heated tobacco sticks containing a micro-blade by children: the importance of performing a radiograph.

INTRODUCTION: Some tobacco sticks, such as TEREA™ heat sticks for IQOS ILUMA™, contain a blade. Both the nicotine part of the device and the micro-blade can be ingested by children. CASE SUMMARIES: We report two children, an 18-month-old boy and a 10-month-old girl, who ingested a heat stick containing a micro-blade. IMAGES: Radiography revealed the micro-blade to be in the child's mouth in the first case and the stomach in the second. Endoscopy was performed on the second child, confirming the presence of the blade in the stomach. CONCLUSION: We recommend performing a radiograph on all children who ingest tobacco sticks containing a micro-blade. If a metallic object is present, we recommend endoscopic removal to avoid traumatic lesions from the sharp edges.

Clinical characteristics of acute lacosamide poisoning: Pavia Poison Control Centre experience.

AIMS: Lacosamide is a third-generation antiepileptic drug used as adjunctive therapy for partial seizures. Since its approval in 2008 very few cases of lacosamide overdose have been described in literature. The aim of our study was to evaluate clinical characteristics of acute lacosamide poisoning. METHODS: A retrospective observational study was performed including all cases of acute lacosamide poisoning referred to Pavia Poison Control Centre from January 2012 to December 2021. For each patient age, sex, ingested dose, coingestants, clinical manifestations, treatment and outcome were collected. RESULTS: A total of 31 subjects (median age 39 years, [interquartile range: 26.5-46.5]; females 22/31) were included. The median lacosamide ingested dose was 1500 mg [650-2800]. In 35.5% of cases lacosamide was the single ingested substance, while in 64.5% coingestants were also present. Coingestants varied from a minimum of 1 to a maximum of 3, with the more common being benzodiazepines and valproic acid. Clinical manifestations were present in 87% patients the most common were: vomiting (29%); seizures (29%), coma (25.8%), drowsiness (25.8%), confusion (12.9%), agitation (12.9%), tachycardia (12.9%), tremors (9.7%), bradycardia (9.7%), headache (6.5%) and hypertension (3.2%). The median lacosamide ingested dose was significantly higher in patients that experienced coma compared to patient who did not (2800 vs. 800 mg; P = .0082). Orotracheal intubation was necessary in 32.3% of patients. All patients fully recovered. CONCLUSION: Lacosamide acute overdose may lead to a severe clinical picture. Dentral nervous system symptoms predominated, particularly seizures and coma occurred in a high percentage of cases.

Methylglyoxal-induced neurotoxic effects in primary neuronal-like cells transdifferentiated from human mesenchymal stem cells: Impact of low concentrations.

In the last decades, advanced glycation end-products (AGEs) have aroused the interest of the scientific community due to the increasing evidence of their involvement in many pathophysiological processes including various neurological disorders and cognitive decline age related. Methylglyoxal (MG) is one of the reactive dicarbonyl precursors of AGEs, mainly generated as a by-product of glycolysis, whose accumulation induces neurotoxicity. In our study, MG cytotoxicity was evaluated employing a human stem cell-derived model, namely, neuron-like cells (hNLCs) transdifferentiated from mesenchymal stem/stromal cells, which served as a source of human based species-specific "healthy" cells. MG increased ROS production and induced the first characteristic apoptotic hallmarks already at low concentrations (≥10 µM), decreased the cell growth (≥5-10 µM) and viability (≥25 µM), altered Glo-1 and Glo-2 enzymes (≥25 µM), and markedly affected the neuronal markers MAP-2 and NSE causing their loss at low MG concentrations (≥10 µM). Morphological alterations started at 100 µM, followed by even more marked effects and cell death after few hours (5 h) from 200 µM MG addition. Substantially, most effects occurred as low as 10 µM, concentration much lower than that reported from previous observations using different in vitro cell-based models (e.g., human neuroblastoma cell lines, primary animal cells, and human iPSCs). Remarkably, this low effective concentration approaches the level range measured in biological samples of pathological subjects. The use of a suitable cellular model, that is, human primary neurons, can provide an additional valuable tool, mimicking better the physiological and biochemical properties of brain cells, in order to evaluate the mechanistic basis of molecular and cellular alterations in CNS.

Coronary thrombosis after European adder bite in a patient on dual antiplatelet therapy: A case report.

INTRODUCTION: Until now very few cases of an adverse cardiovascular event have been described following European viper envenomation (Aravanis et al., 1982) (Aravanis et al., 1982) (Aravanis et al., 1982) (Aravanis et al., 1982). In fact, cardiac toxicity following snake bite is rare and primary reported from tropical and subtropical areas with only twenty-one cases of myocardial infarction reported in literature. Herein, we report a case of European viper envenomation associated with coronary artery thrombosis complicated by acute myocardial infarction and cardiac arrest. CASE REPORT: A 62-year-old man, with a history of cardiovascular disease, on dual antiplatelet therapy with ticagrelor and acetylsalicylic acid, was admitted to the Emergency Department, after a bite, on the right hand, from a snake recognized by a herpetologist as a Vipera aspis francisciredi. At ED presentation, 2 hours after the bite, he manifested with vomiting, hypotension (90/60 mmHg) and mild oedema at the bite site. Standard electrocardiogram and troponin were normal at admission. One hour after the admission the patient developed cardiocirculatory arrest (ACC) with return of spontaneous circulation (ROSC) after cardiopolmunary resuscitation. Post ROSC-ECG showed an ST-elevation on anteroseptal and lateral leads and 1-vial of Viper Venom Antitoxin (Biomed®) was i.v. administered. During the next 3 hours three other episodes of ACC occurred, always with restoration of spontaneous circulation. Percutaneous transluminal coronary angiography showed a thrombus on the bifurcation of anterior descending coronary artery and diagonal 1 without an underlined atherosclerotic plaque. Neurologic clinical manifestations also occurred 12 hours after the bite: bilateral ptosis and facial paresthesia and a second vial of the same viper antivenom administered. The patient was discharged after 9 days of hospitalization without sequelae. CONCLUSIONS: Our case show that cardiotoxicity is a rare but possible event after snake envenomation in Europe, even if with mechanisms remains to be studied. Vipera aspis has been known to cause primarily neurotoxic manifestations, but a coagulation factor X activator have also been isolated from its venom. Moreover, a specific serine peptidase that can target both PAR1 and PAR3, that are responsible for alternate pathways of platelet aggregation, have been characterized in the venom of a viper. Coronary thrombosis in our case could thus be secondary to a combination of prothrombotic systemic state and platelets dysfunction, in a patient with predisposing factors. Antivenom specific antidotal therapy role in preventing cardiotoxicity still need to be elucidated, but it remains the mainstay of treatment together with coronary angiography if necessary.

Case series of Chlorophyllum molybdites intoxication in Sicily: an "alien" mushroom species in Europe.

INTRODUCTION: Mushroom poisoning is an important cause of intoxication worldwide. The toxic mechanism remains frequently unknown and the diffusion of non-endemic species may cause the emergence of new syndromes. An example is the widespread of Chlorophyllum molybdites in Sicily. CASE SERIES: Pavia Poison Centre was recently involved in the management of 10 intoxications caused by the ingestion of Chlorophyllum molybdites, which was not considered part of the Italian mycological species. The clinical syndrome was characterized by severe gastrointestinal symptoms. In paediatric or vulnerable patients, it may bring to hypovolemic shock that necessitate intensive support. The possibly confusion with amatoxins-containing mushrooms may complicate the management. CONCLUSIONS: Chlorophyllum molybdites is widespread on the oriental coast of Sicily and it could be confused with "parasol mushrooms". Cooperation between emergency physicians, clinical toxicologist and mycologist, supported by improving of laboratory tests, is essential for the appropriate clinical management. Climate changes and migration flows can interfere with the diffusion of new species and the development of novel syndromes.

Accidental ingestion of sodium molybdate at the workplace followed by short-term biomonitoring.

INTRODUCTION: Most of the molybdenum (Mo) is used in metallurgical applications, the tetrathiomolybdate form is an experimental chelating agent for Wilson's disease. Human data of acute Mo exposure are lacking and, no report of no-observed-adverse-effect level (NOAEL) has been described until now. Case-study: We report a case of acute occupational exposure to molybdenum, with the related plasma and urine molybdenum concentrations, caused by an accidental ingestion of a sip of an anti-corrosion liquid for metal containing sodium molybdate. Our purpose was to evaluate potential systemic toxicity of molybdenum and to evaluate the dose-response/dose-effect relationship. We estimated the amount of ingested molybdenum to make a mg/kg relationship and performed repeated urine and plasma molybdenum determinations. The patient was hospitalized for three days to monitor possible development of acute symptoms/biochemical alterations. DISCUSSION: We estimated the amount of the sip around 50 ml, with an estimation of a total of 5 gr of sodium molybdate that, for the patient bodyweight of 80 kg, would mean 62,5 mg/kg of ingested Mo. Blood and urine samples collected 2 hours after ingestion showed 50 mcg/L (reference range: 0.43 - 1.8 mcg/L) and 630 mcg/L (refence range: up to 116 mcg/L) of Mo respectively, confirming acute exposure. The patients remained asymptomatic confirming that an estimated oral dose of Mo of 62.5 mg/kg was not associated with adverse effects. CONCLUSIONS: Our value, being extrapolated by a single case, will require further confirmations from other studies to allow a full evaluation of a NOAEL. Nevertheless, it does not preclude its use in evaluating the probable absence of adverse effect in the context of acute Mo exposure.

Significant variations of dangerous exposures during COVID-19 pandemic in Italy: a possible association with the containment measures implemented to reduce the virus transmission.

BACKGROUND: In response to the COVID-19 health emergency, mass media widely spread guidelines to stop the virus transmission, leading to an excessive and unaware use of detergents and disinfectants. In Italy and in other countries this tendency caused a significant increase of exposures to these products in 2020. Evaluating data collected by the Italian Pavia Poison Centre (PPC), this study intends to examine the relationship between the COVID-19 lockdown and the variations of exposures to specific product categories possibly associated to the containment measures implemented. Simultaneously, this work shows the effectiveness of the European Product Categorisation System (EuPCS) in surveillance activities of dangerous chemicals. METHODS: Exposure cases managed by the PPC during March-May 2020 (lockdown) and during the same months of 2017-2018-2019 were compared. Differences in categorical variables were tested with the Chi-square test. The level of significance was set at Alpha = .05. The study included all EuPCS groups but specifically focused on cleaners, detergents, biocides and cosmetics. RESULTS: During the lockdown, calls from private citizens showed a highly significant increase (+ 11.5%, p < .001) and occupational exposures decreased (- 11.7%, p = .011). Among Cleaners, exposures to Bleaches slightly increased while Drain cleaning products went through a significant reduction (- 13.9%, p = .035). A highly significant increase of exposures to Disinfectants was observed (+ 7.7%, p = .007), particularly to those for surfaces (+ 6.8%, p = .039). Regarding Cosmetics, both handwashing soaps and gel products significantly increased (respectively: + 25.0, p = .016 and + 9.7%, p = .028). Among children 1-5 years, the statistical significance is reached with exposures to Dishwashing detergents (+ 13.1%, p = .032), handwashing soaps (+ 28.6%, p = .014) and handwashing gel products (+ 16.8%, p = .010). Contrarily, Liquid Laundry Detergent Capsules decreased in a highly significant manner (- 25%; p = .001). The general severity of exposures showed a highly significant decrease (Moderate: - 10.1%, p = .0002). CONCLUSIONS: This study investigated the relationship between the COVID-19 lockdown and the variations of exposures to some product categories related to the containment measures. The results obtained support any action to be taken by Competent Authorities to implement measures for a safer use of cleaners/disinfectants. This paper shows the benefit in applying the EuPCS to categorize products according to their intended use, though an extension of this system to products not covered by CLP Regulation may be a further advantage.

Guttate psoriasis: a case of unusual evolution of an occupation-related skin chemical burns.

INTRODUCTION: Chemical burns are a risk in domestic and occupational accidents due to the common use of caustic agents. Long-term sequelae are normally due to the amount of skin and underlying tissues damaged. We describe a case of work-related chemical burns with unusual evolution in guttate psoriasis. CASE REPORT: A 36 years-old man was admitted to the Emergency Department (ED) three-hours after a work accident. During the cleaning of an industrial hydraulic system, a jet of hydrochloric acid 20% injured his face and upper limbs. At ED admission, he presented first and second-degree skin burns on the frontal region, on the scalp, on the right forearm, and earlobe. Plastic surgery management consisted in wound topical dressing with silver sulfadiazine and paraffin gauze twice a week for one month. Forty-eight hours after the latter topical treatment (45-days after the work accident), in the same anatomical regions of the previous burn scars, he developed a skin reaction with itchy erythema. The application of topical products was suspended without improvement, excluding an allergic reaction. Within few days, a generalized guttate psoriasis was evident on the whole body. DISCUSSION: Despite many prevention actions, work-related burns are a relatively common cause of hospitalization and may involve up to 80% of patients admitted to a burn unit. Guttate psoriasis has not been described as a sequelae of chemical burns. In our case, the others most frequent factors causing guttate psoriasis have been ruled out. Considering the temporal link between the development of guttate psoriasis and the work accident, hydrochloric acid skin burns might have promoted the systemic inflammatory mediators' mechanism involved in the development of guttate psoriasis lesion's after the dermal injury.

Overall Efficacy and Safety of Safinamide in Parkinson's Disease: A Systematic Review and a Meta-analysis.

BACKGROUND AND OBJECTIVE: Safinamide is a novel anti-parkinsonian drug with possible anti-dyskinetic properties. Parkinson's disease (PD) is a complex disease. The objective of this systematic review and meta-analysis is to evaluate the efficacy and safety of safinamide administration compared to placebo in PD patients on multiple outcomes. METHODS: PubMed, EMBASE, Cochrane CENTRAL, LILACS, and trial databases were searched up to 23 December 2020 for randomized controlled studies (RCTs) comparing safinamide to placebo, alone or as add-on therapy in PD. Data were extracted from literature and regulatory agencies. Primary outcomes were ON-time without troublesome dyskinesia, OFF-time, and Unified Parkinson's Disease Rating Scale (UPDRS) section III (UPDRS-III). Secondary outcomes included any dyskinesia rating scale (DRS), ON-time with troublesome dyskinesia, UPDRS-II, and Parkinson's Disease Questionnaire 39 (PDQ-39). In order to estimate mean difference (MD) and odds ratios with 95% confidence intervals (CI), generic inverse variance and Mantel-Haenszel methods were used for continuous and dichotomous variables, respectively. Analyses were performed grouping by PD with (PDwMF) or without (PDwoMF) motor fluctuations, safinamide dose, and concomitant dopaminergic treatment. Summary of findings with GRADE were performed. RESULTS: Six studies with a total of 2792 participants were identified. In PDwMF patients, safinamide 100 mg as add-on to levodopa (L-dopa) significantly increased ON-time without troublesome dyskinesia (MD = 0.95 h; 95% CI from 0.41 to 1.49), reduced OFF-time (MD = - 1.06 h; 95% CI from - 1.60 to - 0.51), and improved UPDRS-III (MD = - 2.77; 95% CI from - 4.27 to - 1.28) with moderate quality of evidence. Similar results were observed for the 50 mg dose. However, the quality of evidence was moderate only for ON-time without troublesome dyskinesia, whereas for OFF-time and UPDRS-III was low. In PDwoMF patients taking a single dopamine agonist, safinamide 100 mg resulted in little to no clinically significant improvement in UPDRS-III (MD = - 1.84; 95% CI from - 3.19 to - 0.49), with moderate quality of evidence. Conversely, in PDwoMF patients, the 200 mg and 50 mg doses showed nonsignificant improvement in UPDRS-III, with very low and moderate quality of evidence, respectively. In PDwMF patients taking safinamide 100 mg or 50 mg, nonsignificant differences were observed for ON-time with troublesome dyskinesia and DRS, with high and low quality of evidence, respectively. In the same patients, UPDRS-II was significantly improved at the 100 mg and 50 mg dose, with high and moderate quality of evidence. In PDwoMF, UPDRS-II showed a little yet significant difference only at 100 mg, with low quality of evidence. PDQ-39 resulted significantly improved only with the 100 mg dose in PDwMF, with low quality of evidence. CONCLUSION: Overall, safinamide is effective in PDwMF patients taking L-dopa both at 100 and 50 mg daily. Evidence for efficacy in early PD is limited. Further trials are needed to better evaluate the anti-dyskinetic properties of safinamide.

Poisoning related to therapeutic error in prolonged low-dose methotrexate treatment.

AIMS: To study the predictive factors for the development of clinical manifestations in poisoning due to the erroneous taking of low-dose methotrexate (MTX). METHODS: A retrospective observational study was performed. Only cases of erroneous administration in non-oncologic outpatients were included (July 2008-March 2020). RESULTS: Forty-one cases were included. All patients were taking MTX for the first time. In 36 cases, patients took MTX daily instead of weekly. In the other five patients, MTX was sold instead of methylergometrine. Clinical manifestations were absent in 12/41 patients (29.3%). All 29 (70.7%) symptomatic patients recognized the medication error when they developed clinical manifestations: dermatological, haematological and gastrointestinal symptoms. Statistical results showed that symptomatic patients were older, received a higher amount of total dose and were treated for longer. Moreover, the probability of being symptomatic increases as a function of age and of total dose. Asymptomatic patients were treated with folinic acid (30 mg/m2 /day) for 5 days. Symptomatic patients were treated with folinic acid together with treatments for the specific clinical manifestations. No patients were treated with glucarpidase. All patients fully recovered. CONCLUSIONS: When MTX is prescribed for the first time, it is important to clearly communicate with patients to avoid therapeutic errors. In our experience, age, total dose taken and number of days of assumption are predictive for the presence/absence of clinical manifestations. These parameters must be evaluated together to identify patients needing maximum starting treatment with folinic acid and closer monitoring.

Foodborne Botulism: Clinical Diagnosis and Medical Treatment.

Botulinum neurotoxins (BoNTs) produced by Clostridia species are the most potent identified natural toxins. Classically, the toxic neurological syndrome is characterized by an (afebrile) acute symmetric descending flaccid paralysis. The most know typical clinical syndrome of botulism refers to the foodborne form. All different forms are characterized by the same symptoms, caused by toxin-induced neuromuscular paralysis. The diagnosis of botulism is essentially clinical, as well as the decision to apply the specific antidotal treatment. The role of the laboratory is mandatory to confirm the clinical suspicion in relation to regulatory agencies, to identify the BoNTs involved and the source of intoxication. The laboratory diagnosis of foodborne botulism is based on the detection of BoNTs in clinical specimens/food samples and the isolation of BoNT from stools. Foodborne botulism intoxication is often underdiagnosed; the initial symptoms can be confused with more common clinical conditions (i.e., stroke, myasthenia gravis, Guillain-Barré syndrome-Miller-Fisher variant, Eaton-Lambert syndrome, tick paralysis and shellfish or tetrodotoxin poisoning). The treatment includes procedures for decontamination, antidote administration and, when required, support of respiratory function; few differences are related to the different way of exposure.

Analysis of fomepizole safety based on a 16-year post-marketing experience in France.

Introduction: Fomepizole has been recommended as first-line antidote to treat ethylene glycol and methanol poisoning. Despite more than 30 years of utilization, the safety of fomepizole when used clinically has not been well documented. Based on the long-standing clinical experience with fomepizole in France, we investigated its safety profile in patients treated for suspected toxic alcohol poisoning.Methods: We designed a 16-year post-marketing study to evaluate the indications for fomepizole prescriptions and to investigate its safety. Data were retrospectively collected using a standardized questionnaire sent each month by post to each French hospital that ordered fomepizole during the month before. The response rate to our survey was 59%.Results: Five hundred and thirty-six patients [188 females/348 males; age, 46 years [34-55] (median [25th-75th percentiles])] were treated with fomepizole [cumulative dose, 18.6 mg/kg [15.5-26.3] (1,268 mg [900-2,100])]. Ethylene glycol/methanol poisoning was confirmed in 275 patients (51%) while a nontoxic exposure was diagnosed in 147 patients (27%). Toxic alcohol poisoning was misdiagnosed in the remaining 114 patients (21%), before the assessment of an alternative poisoning or non-poisoning diagnosis. Fifty adverse reactions were attributed to fomepizole in 36 patients (7%) including general reactions (N = 22), local reactions (N = 22) and laboratory test impairments (N = 6). All were considered mild and transient. None required stopping fomepizole. The most frequent adverse effects were injection site pain/burning (N = 13), nausea/vomiting (N = 8), vessel puncture site inflammation (N = 7), drowsiness/confusion (N = 5) and serum aminotransferase elevation (N = 3). None of the fatalities (N = 37, 7%) or persistent symptoms on discharge (N = 9; 2%) was related to fomepizole.Conclusion: Our longitudinal cohort study supports the safety of fomepizole administered to treat presumed EG and methanol poisoning.

Fomepizole to treat disulfiram-ethanol reaction: a case series.

Introduction: Disulfiram-ethanol reaction (DER) due to acetaldehyde accumulation occurs after drinking ethanol during disulfiram therapy. DER may result in life-threatening toxicity requiring urgent critical care. Fomepizole, an alcohol dehydrogenase inhibitor used to treat toxic alcohol poisoning, has been suggested for treating DER by preventing the metabolism of ethanol to acetaldehyde. However, its effectiveness and safety have been poorly assessed in this setting.Cases: Ten DER patients (median age, 40 years; 7 males/3 females) were included in the study. DER features consisted of consciousness impairment (median Glasgow coma score, 13; need for mechanical ventilation, 30%) with flushing (50%), vomiting (40%), electrocardiogram abnormalities (30%) and circulatory failure requiring norepinephrine (30%). Patients were successfully treated with a single intravenous infusion of fomepizole (median dose, 7.5 mg/kg). The three patients receiving norepinephrine did not improve until fomepizole was administered. The other seven patients improved promptly following fomepizole infusion without requirement for vasopressor support. All patients fully recovered. Local pain at the injection site was the only reported adverse reaction in one patient.Conclusion: Our case series supports the effectiveness and safety of fomepizole in rapidly reversing DER-induced vasodilatation and toxicity.

Tectus niloticus (Tegulidae, Gastropod) as a Novel Vector of Ciguatera Poisoning: Clinical Characterization and Follow-Up of a Mass Poisoning Event in Nuku Hiva Island (French Polynesia).

Ciguatera fish poisoning (CFP) is the most prevalent non-bacterial food-borne form of poisoning in French Polynesia, which results from the consumption of coral reef fish naturally contaminated with ciguatoxins produced by dinoflagellates in the genus Gambierdiscus. Since the early 2000s, this French territory has also witnessed the emergence of atypical forms of ciguatera, known as ciguatera shellfish poisoning (CSP), associated with the consumption of marine invertebrates. In June 2014, nine tourists simultaneously developed a major and persistent poisoning syndrome following the consumption of the gastropod Tectus niloticus collected in Anaho, a secluded bay of Nuku Hiva Island (Marquesas Archipelago, French Polynesia). The unusual nature and severity of this event prompted a multidisciplinary investigation in order to characterize the etiology and document the short/long-term health consequences of this mass-poisoning event. This paper presents the results of clinical investigations based on hospital medical records, medical follow-up conducted six and 20 months post-poisoning, including a case description. This study is the first to describe the medical signature of T. niloticus poisoning in French Polynesia and contributed to alerting local authorities about the potential health hazards associated with the consumption of this gastropod, which is highly prized by local communities in Pacific island countries and territories.

Intentional ingestion of elemental mercury requiring multi-step decontamination and prophylactic appendectomy: a case report and treatment proposal.

BACKGROUND: Ingestion of elemental mercury (Hg0) is considered non-toxic. After massive ingestion, local intestinal complications may develop: retention within appendix is quite frequent but treatment is debated. We describe a case of intentional ingestion of Hg0 requiring multi-step decontamination and prophylactic appendectomy. Case detail: A 19-year-old woman was admitted to ED for abdominal pain. History revealed ingestion of large amount of Hg0 as suicide attempt. To prevent absorption, facilitate elimination, and avoid complications a conservative approach was started. Due to inefficacy of initial maneuvers colonoscopy with irrigation/aspiration was performed, repeated whole bowel irrigation was continued and second colonoscopy was performed to clean residual metal. Abdominal plain films confirmed the presence of retained mercury within the appendix in asymptomatic patient. To reduce risk of appendicitis, potential perforation, and possibly systemic toxicity, a prophylactic laparoscopic appendectomy was performed at day 5 with removal of all retained mercury without peritoneal spillage. Highest mercury concentration was 22.7 mcg/L in serum (1-4.5 mcg/L) and 5.1 mcg/L in urine (0.1-5 mcg/L). CONCLUSIONS: After ingestion, metal retention in appendix is quite frequent. Evidence about optimal treatment are different and based on case reports. A multi-step approach with multidisciplinary evaluation tailored to the patient is suggested.