Dupilumab-associated ocular adverse events are predicted by low tear break-up time and correlate with high IL-33 tear concentrations in patients with atopic dermatitis.

Dupilumab, blocking IL-4 and IL-13 signals, improves atopic dermatitis and Quality of Life but might be also associated with the occurrence of ocular adverse events (OAEs). The main objective of our prospective study was to characterize the cytokine and chemokine profile in the tear fluid of dupilumab-treated patients with moderate-to- severe atopic dermatitis and to identify biomarkers predicting the occurrence of ocular adverse events. Patients with moderate-to-severe AD underwent dermatological and ophthalmological evaluation at the baseline (T0) and week 16 or at the time of an eventual ocular adverse events (T1). A multiplex immunoassay measuring multiple cytokines and chemokines in the tear fluid extracted during ocular examination at both T0 and T1 was performed. Thirty-nine patients with moderate-to-severe AD and treated with dupilumab were included in the study. Baseline tear fluid levels revealed a significantly higher concentration of type 2 cytokines and chemokines in AD patients than healthy controls. The occurrence of ocular adverse events during dupilumab therapy was associated with a significant increase of IL-33 tear fluid levels and a significantly lower tear break-up time, this latter also identified as predictive factor. Our findings suggest that the ophthalmological examination should be considered a valid support to identify patients at risk of developing OAEs and to provide their appropriate management.

Does ABS ensure good performance in emergency braking for less skilled motorcyclists?

This study aims to investigate whether motorcyclists are able to use the full potential of anti-lock braking systems (ABS) in demanding braking situations that maintain the natural coupling of action and perception of emergency events, or whether instead the lack of braking skills in riders makes ABS almost ineffective and comparable to non-ABS brakes on dry pavement. Six experienced riders performed two experimental tests. First test included 12 emergency braking trials in a realistic scenario using a mock-up of an intersection conflict with a car initiating a left turn manoeuvre across the path (LTAP) of a motorcycle approaching from the opposite direction as an unpredicted moving hazard. Second test included three trials in a planned self-timed hard braking. The speed at the onset of braking was 35-45 km/h. The braking performance was measured from the initiation of brake pressure until the full stop of the vehicle. Front wheel ABS usage was determined by the pressure in the master cylinder and wheel callipers. The testing resulted in 85 data runs with full stop braking manoeuvres. Results revealed four categories of riders classified by their front wheel ABS usage during the emergency braking tests, which included two riders who underused front wheel ABS (9.6% and 27.4% of braking time on average). The worst case resulted in a significantly longer braking distance (braking deceleration of 5.2 m/s2). The highest skilled rider, who reached initial jerks close to 30 m/s3, used the ABS of the front wheel 93.7% of the braking time on average, resulting in a braking deceleration of 7.71 m/s2. Overall, the best braking performance was achieved in trials where the front ABS was activated for more than 80% of the braking. In planned self-timed hard braking test, where riders have more time to plan the braking manoeuvre, the experience rider with lowest performance during the emergency braking test improved braking efficiency and was able to increase ABS activation from 9.6% to 26.8% of the time, achieving a deceleration of 6.24 m/s2. ABS is demonstrated to reduce stopping distances and to improve stability under all braking conditions, but such features are not enough to guarantee a good braking performance in emergency events if the riders have not the skills to utilize the full braking power of the motorcycle. Less skilled riders, even with ABS, may not have the confidence to increase braking power further when reaching high decelerations that push them to the limit of their stabilisation control in emergency braking, thus increasing braking distance with potentially life-threatening consequences. Our results suggest that many experience riders still need knowledge and skill to make the ABS work to its optimum in emergency events to avoid crashes. Further research with larger sample sizes including the full diversity of the motorcyclist population is recommended to determine the actual proportion of motorcyclists underusing ABS.

Peer Education strategies for promoting prevention of doping in different populations.

BACKGROUND: In the field of doping prevention, alongside the traditional functions of repression and control of the phenomenon, educational aspects are becoming increasingly important. Article 18 of the World Anti doping Code obliges the signatories to invest in anti-doping education with the aim of preserving the spirit of sport. The educational commitment should involve young people in health promotion interventions for the prevention of risk behaviors. Therefore, our attention has focused on finding the mechanisms that lead people to make certain behavioral choices. MATERIAL AND METHODS: In the context of preventive programs, to counter the doping phenomenon through health promotion programs, the most recognized method is peer education, particularly with adolescents. It is an educational method according to which some members of a group are empowered and trained to carry out specific activities with their peers. It is constituted as an example of equal relationship and finds its basis in cooperation and solidarity with the aim of increasing empowerment and a healthy development of the identity and collective dimension in young people. RESULTS: Numerous experts - biologists / nutritionists, hygienists, sports coaches, psychologists, teachers of physical education in secondary schools and other stakeholders have actively participated in the co-construction of a training package aimed at activating cascade training processes on the knowledge and skills of peer education in contexts of youth aggregation, such as schools, gyms, sports associations, social gatherings of all kinds. The path allowed to define a peer education model capable of enabling the participants to activate health promotion interventions for the prevention of doping risk behaviors, each in their own setting. CONCLUSIONS: In conclusion, we can say that prevention programs are the more effective the more they are addressed to young people and adolescents and provide interactive and action-oriented interventions. Successful initiatives aim to emphasize the development of life skills and to influence numerous determinants of behavior, including individual attitudes, knowledge, motivations, interpersonal relationships and social norms. If the aim is to act on the change of behavior, the efforts will be more successful if the content of the intervention will give due consideration to the context in which it applies and the target population, involving it and addressing its specific needs and values.

The prevention of doping and the improper use of drugs and food supplements in sports and physical activities: a survey on the activity of the prevention departments of Italian local health authorities.

INTRODUCTION: Doping is an important public health problem widespread not only among elite athletes, but also among amateur and recreational athletes and the general population. In Italy the introduction of doping prevention within the Essential Levels of Care (LEA) with the DPCM 12/1/2017 represents a crucial step towards the implementation of education and health promotion interventions. In this context, the Departments of Prevention (DP) of the Local Health Authorities (LHA) have to play a fundamental role, becoming the cultural and operational reference on this issue. As part of the "Doping prevention: development of a permanent educational tool coordinated by the National Health Service Prevention Departments" project, funded by the Italian Ministry of Health, a survey was conducted on the activities carried out by the DP regarding doping prevention and improper use and abuse of drugs and food supplements in sports and physical activities, as a basis for the harmonization of organizational structures and prevention programs and the creation of a collaboration network at a regional and national level. METHODS: A semi-structured questionnaire consisting of 11 questions, prepared on an electronic platform, was sent to the DP of all the Italian LHA. RESULTS: A total of 38 DP out of 131 (29%) completed the questionnaire, with representation from all regions. 42.1% of DP carried out or are still running programs for the prevention of doping, a percentage that decreases to 27% considering the programs for the prevention of misuse and abuse of drugs and food supplements in sports and in physical activities; in less than half of the DP, 37.5% and 41.7%, respectively, dedicated funds have been allocated. The professionals most involved in prevention of doping are the Specialists in Sport Medicine (81.3%) followed by Specialists in Hygiene (43.8%) and Psychologists (37.5%), while Health Care Assistants (50%) are the professionals most involved in the prevention of the improper use of drugs and food supplements, followed by Specialists in Hygiene and Specialists in Sport Medicine (40%). Most of the DP (71.9%) believe that the introduction of programs to prevent and counteract doping in the LEA will have repercussions on their approach against doping. CONCLUSIONS: The survey, although conducted on a limited sample, has provided an important framework relating to programs for the prevention of doping and the misuse and abuse of drugs and food supplements in sports and in the physical activities carried out by DP. A remarkable heterogeneity has been highlighted, both at national and regional level. It is urgent to provide DP with homogeneous and effective organizational models and adequate operational tools, paying particular attention to the training of all the professionals involved. It is also essential to implement permanent monitoring tools.

Dietary supplements, drugs and doping in the sport society.

Consumption of supplements and the use/abuse of drugs to support athletic performance is increasingly growing. The aim of this paper is to approach the phenomenon by providing a tool to develop critical awareness of these problems. By reviewing scientific articles, we collected information on the use of licit and illicit substances among professional and non-professional athletes, showing a widespread scenario also based on false myths. The use of supplements, drugs and doping substances represents a complex and still debated issue, that deserves greater consideration among both sportsmen and health operators. A more critical and informed approach to these topics can support empowerment and a conscious use of drugs by respecting eating habits, own health and healthy lifestyles.

Erice 2018 Charter on the role of the National Health Service in the prevention of doping

The Erice 2018 Charter was unanimously approved at the conclusion of the 53rd Residential Course of the International School of Epidemiology and Preventive Medicine "Adapted Physical Activity in Sport, Wellness and Fitness; the role of the Departments of Prevention and of the National Health Service in doping prevention and health promotion", held on 15-19 May 2018 in Erice, Italy, at the "Ettore Majorana" Foundation and Centre for Scientific Culture, and promoted by the Study Group on "Movement Sciences for Health" of the Italian Society of Hygiene, Preventive Medicine and Public Health. The event was part of a larger project supported by the Ministry of Health aimed at preventing doping in the general population involved in sport and physical activities. After an intense discussion the participants focused on ten statements involving the following critical issues: responsibility, priority, message, alphabetization, networks and alliances, school promoting health, player and opportunities, competences, know-how, programming and acting. These statements provide hints to approach doping within a public health frame and summarize the role of the Departments of Prevention and NHS in promoting and coordinating preventive actions with other institutions and stakeholders. Doping represents a complex phenomenon related to cultural, social, economic and legal issues. In addition to regulatory or repressive actions, education to health and legality is proposed as the fundamental strategy to contrast doping by promoting healthy lifestyles, based on scientific knowledge and respect for legality.

External vs. endonasal dacryocystorhinostomy: has the current view changed?

In past years, external dacryocystorhinostomy has been considered the gold standard in terms of functional outcome for treatment for nasolacrimal duct obstruction. In comparison, interest in the use of the recently developed endonasal dacyocystorhinostomy procedure has been rekindled because of advances in instrumentation. For the past 10 years, differences in the outcomes between the two techniques have been reduced; thus, currently, the choice of the type of surgery is associated with the experience of the surgeon, resources available in the healthcare system and patient preferences.

Atherosclerotic coronary plaque in subjects with diabetic neuropathy: the prognostic cardiovascular role of Charcot neuroarthropathy--a case-control study.

The aim of this study was to investigate the severity of coronary artery disease (CAD) and the plaque composition in neuropathic type 2 diabetic subjects with and without Charcot neuroarthropathy (CN) undergoing multidetector computed tomography coronary angiography (MDCT-CA). The study was a single-center, observational, with unmatched case-control design. We selected 17 CN patients and 18 patients with diabetic neuropathy (DN) without CN. In all the patients, multidetector computed tomography was performed to assess the coronary artery calcium score (CACS) and degree of coronary artery stenosis. Patients were classified as positive in the presence of significant CAD if there was at least one stenosis >50 % on MDCT-CA. The invasive coronary angiography was performed in case of significant stenosis detected with MDCT-CA, both as reference to standard and eventually as treatment. Groups were matched for age, sex, and traditional CAD risk factors. As compared to DN individuals, CN exhibited higher rates of significant coronary stenoses (p = 0.027; OR 7.7 [1.3-43.5]). However, no significant differences were observed in the CACS, which reflects plaque burden, in the two groups (p = 0.759). No significant differences were observed comparing CACS distribution in all subjects for stenosis higher/equal or lower than 50 % (p = 0.320). Finally, no significant differences were observed comparing CACS distribution in CN and DN subjects for coronary stenoses higher/equal or lower than 50 %. Our results suggest that CN patients have a higher prevalence of severe coronary plaques compared to DN patients. Nevertheless, coronary plaques in CN patients did not exhibit an increased degree of calcification.

Intraorbital injection of rituximab: a new approach for active thyroid-associated orbitopathy, a prospective case series.

AIM: The aim of this paper was to examine the efficacy and the safety of intraorbital administration of the monoclonal anti-CD20 antibody rituximab (RTX) to treat patients affected by thyroid-associated orbitopathy (TAO) unresponsive to conventional therapy. METHODS: Five patients with active moderately-severe TAO unresponsive to systemic glucocorticoids were studied. After a complete ophthalmological examination, disease activity and severity were assessed by the clinical activity score (CAS) and the NO SPECS scoring system. Computed tomography scans were performed in all patients. Patients were treated with intraorbital injection of RTX 10 mg once a week for one month repeated once one month apart. The patients were followed every three months until 18 months. RESULTS: In all patients treated with RTX, CAS was significantly reduced (p< 0,005), inactive phase of TAO was reached in four out of five patients. No patients experienced major side effects, minor side effects were reported in two patients. CONCLUSION: Intraorbital injection of RTX is a safe and useful promising therapeutic option for active TAO.

[Micromedullary thyroid carcinoma: school experience]. / Il microcarcinoma midollare della tiroide: esperienza di Scuola.

Medullary microcarcinomas occurrence are rare and fortuitous, it's usually related to the calcitonin measurement, that's the gold standard for the diagnosis. In other cases performing a thyroidectomy for a benign thyroid disease it's found a sub-centimeter tumor. Actually it's not clear the most appropriate surgical treatment for those kind of tumors because the number of cases in literature is limited and because there are different surgical approaches. In this study 17 patients were operated for medullary thyroid microcarcinoma and the Authors found central lymph node metastases in 33.3% of cases. The Authors, analyzing those results, think that total thyroidectomy with lymphadenectomy of the central compartement is the best choice in a sporadic microcarcinoma, while a total thyroidectomy without lymphadenectomy should be performed when the microcarcinomas are incidentals.

[Case-mix index and length of hospitalization]. / L'indice di case-mix e la durata della degenza.

The ACG (Adjusted Clinical Groups) case-mix system is a classification method of diseases of patients, focused on the person. Depending on the pattern of these morbid conditions, the ACG system assigns each patient to a single group (an ACG group), which allows to capture the effects of a group of diseases in estimates of resource use. Diseases are classified into a diagnostic group (ADG) according to 5 clinical dimensions: duration (acute, recurrent or chronic), severity (minor/major vs stable/unstable), diagnostic assessment (symptoms vs diseases), etiology (infectious, traumatic or other), specialty (medical, surgical, obstetric, ...). All diseases can be classified into these dimensions and into one of 32 groups. The ACG case-mix system uses an algorithm to classify each patient into one of 93 ACG categories. Each person is assigned to an ACG according to his ADG combination, his age and his gender. With the repayment system "case-mix", surgery has become central for all great hospitals in virtue of its great productive potential. The case-mix index is one of the factors which influence the duration of hospitalization. The case-mix system has emphasized the importance of the duration of hospitalization, encouraging the planning of programs in order to discharge patients early after surgical operations. It has also stimulated the surgical activity in operating units with "budget" forecasts in which resources are provided according to an expected level of specialist surgery.

[Medullary thyroid carcinoma: a study about 28 operated patients]. / Carcinoma midollare della tiroide: studio su 28 casi operati.

In this study on 28 operated patients, the Authors show that total thyroidectomy with elective central neck dissection and ipsilateral neck dissection is the most appropriate surgical treatment for medullary thyroid carcinoma. Pathologic study on lymph nodes removed in central and in latero-cervical compartments showed malignancy respectively in 75% and in 70% of the cases. However the role of elective ipsilateral lateral neck dissection remains controversial.

[Retroperitoneal giant mixed sarcoma. Case report]. / Un caso di sarcoma misto retroperitoneale gigante.

The Authors present a rare case of voluminous retroperitoneal tumor in a 41 years old woman. CT scan showed a solid abdominal expansive mass, with compression and displacement of the left lobe of the liver, spleen, stomach, pancreas, and left kidney. The patient underwent surgery for excision of a giant retroperitoneal mass. Surgery was uneventful. The patients recovered well. Histology showed a mixed liposarcoma and angiosarcoma with high grade of malignancy and positivity for vimentin, factor VIII, CD34, CD31 and negativity for S-100, CD68, AMS, AML. The prognosis of these tumours is closely related to local recurrence, histological type, size and radical surgery. A low-grade malignancy tumor, small sized and completely resected leads to a good prognosis. Radiation therapy and chemotherapy do not seem to have a strong influence on the prognosis. An aggressive surgical approach is the first choice for the treatment of such tumors. The resection of adjacent organs may be required for radical surgery.

[Two cases of synchronous papillary and medullary thyroid carcinoma]. / Due casi di carcinomi tiroidei sincroni di tipo midollare e papillifero.

The Authors describe two cases of simultaneous association of papillary and medullary thyroid carcinoma. They emphasize the treatment of these cases stressing the correlation between the therapeutic criteria and the malignancy of medullary carcinoma.

64 slice cardiovascular CT in the emergency department: concepts and first experiences.

PURPOSE: The purpose of this study was to evaluate contrast-enhanced electrocardiogram (ECG)-gated 64-slice computed tomography (CT) angiography of the thorax as a triage tool in patients with acute equivocal chest pain. MATERIAL AND METHODS: Technical principles and diagnostic algorithms for using a single ECG-gated 64-slice CT scan for triple rule-out of acute pulmonary embolism, aortic dissection, acute coronary syndromes and other diseases of the chest are introduced. Our experience using this test in 23 patients are reviewed and exemplary cases are illustrated. The total length of hospitalisation and charges for Emergency Department care at the time of discharge were compared with a matched control population that underwent catheter angiography for emergent cardiac workup. Statistical analyses were performed with an independent Student's t test. Mann-Whitney rank sum test was also used on variables that did not have equal variance. RESULTS: Of the 23 patients, 11 presented without pathological findings, two with extensive pulmonary embolism, two with definite coronary artery disease (CAD) but stenosis <50% and eight with significant CAD (>50% stenosis). Catheter angiography was performed in the latter group, confirming the CT findings in all cases. Nine patients without CT findings were discharged on the same day. In comparison with the control group, length of hospitalisation (p=0.009) and total hospital charges (p<0.001) were significantly reduced. CONCLUSIONS: Our initial experience shows that ECG-gated 64- slice CT angiography of the entire thorax is technically feasible and enables rapid triage of patients to determine underlying cardiac and noncardiac reasons for chest pain. This test may thus help to significantly reduce costs and length of hospitalisation. Prospective studies involving larger groups of patients are required to confirm these findings.

Pharmacokinetics of a new extended-release nifedipine formulation following a single oral dose, in human volunteers.

This study aimed to define the pharmacokinetics of nifedipine following oral administration of a new extended-release formulation. Twelve healthy volunteers of both sexes, aged 39 +/- 4 years, were treated with a single oral tablet of a new extended-release formulation containing 40 mg of nifedipine. Samples of venous blood were taken before dosing, after 30 min and at 1, 2, 4, 8, 12, 16, 20 and 24 h after administration. Nifedipine concentration was measured by means of a high-performance liquid chromatography method. Noncompartmental pharmacokinetics parameters were then calculated. The plasma concentration of nifedipine increased slowly and in seven subjects biphasic peaks occurred. The mean values were as follows: t(max): 8.5 +/- 1.2 h; C(max): 36.55 +/- 6.76 ng/ml; AUC: 347.06 +/- 51.61 ng/h/ml; AUC 409.99 +/- 61.08 ng/h/ml; A(half-life): 2.26 +/- 0.36 h; D(half-life): 2.43 +/- 0.44 h; E(half-life): 4.62 +/- 0.79 h. Twenty-four hours after administration nifedipine was still detectable (3.17 +/- 0.67 ng/ml). Arterial blood pressure decreased and heart rate increased concurrently and proportionally to the increase in nifedipine concentration. Extended-release nifedipine formulations have better tolerability profiles than immediate-release formulations, which are at present not recommended in the treatment of hypertension, hypertensive crises or myocardial infarction. This new extended-release formulation has interesting pharmacokinetic parameters and may be effective in conditions in which dihydropyridine calcium channel blockers are indicated.

Endovascular repair of an aorto-left renal vein fistula due to a ruptured abdominal aortic aneurysm after EVAR.

PURPOSE: To report an unusual late complication of endovascular aneurysm repair: an arteriovenous fistula between the aneurysm sac and a retro-aortic left renal vein following sac expansion due to a type III endoleak. CASE REPORT: A 79-year-old man developed an arteriovenous fistula between the aneurysm sac and a retro-aortic left renal vein 67 months after endovascular aneurysm exclusion (EVAR). Aneurysm rupture was due to disconnection between the right iliac limb and an extender cuff. The problem was repaired percutaneously with another endograft bridging the two prostheses. At 16 months, the aneurysm sac diameter was decreased; there was no evidence of the AV fistula, and the patient was free from any complication related to the EVAR. CONCLUSIONS: This case emphasizes the need of close surveillance even in the late postoperative course of these patients. Moreover, this rare event confirmed that endovascular techniques can play an important role in treating emergent complications.

Type II lumbar endoleaks: hemodynamic differentiation by contrast-enhanced ultrasound scanning and influence on aneurysm enlargement after endovascular aneurysm repair.

OBJECTIVE: The objective of this study was to differentiate type II lumbar endoleaks on the basis of dynamic features identified by contrast-enhanced ultrasound scanning (CUS) and to evaluate the role of this differentiation in detecting abdominal aortic aneurysm (AAA) enlargement > or =1 mL/mo. METHODS: Eighteen male patients (mean age, 71.8 years) with type II lumbar endoleak suspected at CUS underwent computed tomography angiography (CTA) and digital subtraction angiography (DSA). On CTA, AAA volumes and endoleak visualization and volume were assessed. At CUS, performed after a bolus of 1.5 to 2.4 mL of a second generation blood pool contrast agent, the following parameters were evaluated: presence of contrast material within the aneurysmal sac (endoleak), delay of endoleak detection (wash-in) and disappearance (washout) from the beginning of contrast injection, visualization of inflow and outflow vessels, and presence of cavity filling. Statistical analysis was performed regarding endoleak features at CUS, endoleak detection at CTA, and rate of AAA enlargement. RESULTS: DSA confirmed all the endoleaks. Mean +/- standard deviation wash-in and washout times were 121.9 +/- 132.6 and 337.2 +/- 193.7 seconds, respectively; a significant relation was observed between these two parameters (P < .01, analysis of variance). By Youden plots, endoleaks were classified as hyperdynamic when wash-in was <100 seconds (n = 10, 55.5%) and/or washout was <520 seconds (n = 13, 72.2%). A slower washout was associated with nonvisualized outflow (66.7%) and/or inflow arteries (66.7%) ( P < .05). Eight endoleaks (44.4%) were missed at CTA; it occurred in hypodynamic endoleaks, absence of detectable inflow or outflow vessels, and absence of cavity filling at CUS (P < .05). Overall mean AAA volume increase rate was 1.1 +/- 1.7 mL/mo. By multiple logistic regression model, the washout time > or = 520 seconds was the only independent predictor of AAA volume increase > or = 1 mL/mo (8 patients, 44.4%). CONCLUSION: Type II lumbar endoleaks show different hemodynamic features at CUS, which might influence the rate of aneurysm enlargement, addressing the need for treatment.

Abdominal aortic aneurysm: contrast-enhanced US for missed endoleaks after endoluminal repair.

PURPOSE: To evaluate contrast material-enhanced ultrasonography (US) for depiction of endoleaks after endovascular abdominal aortic aneurysm repair (or endovascular aneurysm repair [EVAR]) in patients with aneurysm enlargement and no evidence of endoleak. MATERIALS AND METHODS: From November 1998 to February 2003, 112 patients underwent EVAR. At follow-up, duplex US and biphasic multi-detector row computed tomographic (CT) angiography were performed. In 10 patients (group A), evident aneurysm enlargement was observed, with no evidence of complications, at both CT angiography and duplex US. Group A patients, 10 men (mean age, 69.6 years +/- 10 [standard deviation]), underwent US after intravenous bolus injection of a second-generation contrast agent, with continuous low-mechanical index (0.01-0.04) real-time tissue harmonic imaging. Group B patients, 10 men (mean age, 71.3 years +/- 8.2) with aneurysm shrinkage and no evidence of complications, and group C patients, 10 men (mean age, 73.2 years +/- 6) with CT angiographic evidence of endoleak, underwent contrast-enhanced US. Digital subtraction angiography (DSA) was performed in groups A and C. Endoleak detection and characterization were assessed with imaging modalities used in groups A-C; at contrast-enhanced US, time of detection of endoleak, persistence of sac enhancement, and morphology of enhancement were evaluated. RESULTS: In group A, contrast-enhanced US depicted one type I, six type II, one type III, and two undefined endoleaks that were not detected at CT angiography. All leakages were characterized by slow and delayed echo enhancement detected at longer than 150 seconds after contrast agent administration. DSA results confirmed findings in all patients; percutaneous treatment was performed. In group B, contrast-enhanced US did not show echo enhancement; in group C, results with this modality confirmed findings at CT angiography and DSA. CONCLUSION: Contrast-enhanced US depicts endoleaks after EVAR, particularly when depiction fails with other imaging modalities.