Direct Oral Anticoagulants and Concomitant Anti-seizure Medications: A Retrospective, Case-Control Study in a Real-World Setting.

PURPOSE: Although prescription of direct oral anticoagulants (DOACs) for epileptic patients on anti-seizure medications (ASMs) is on the increase, international guidelines pose strict restrictions because this may lead to pharmacologic interactions. However, current evidence on their clinical relevance remains scanty. This retrospective, case-control study assessed the frequency of ischemic/hemorrhagic events and epileptic seizures involving DOAC-ASM cotherapy in the real world, compared with DOAC and ASM monotherapy, in age- and gender-matched controls. METHODS: Data on patients who had been prescribed a concomitant DOAC and ASM therapy for at least 6 months were extracted from the database of the Pharmaceutical Service of the Alessandria Province (Italy). After exclusions, the case group included 124 patients, 44 on valproic acid (VPA) and 80 on levetiracetam (LEV) concomitant with a DOAC, and it was compared with the DOAC-control and ASM-control groups. The clinical and laboratory data were extracted from the electronic archives of the hospitals in the same province. FINDINGS: Two (1.6%) ischemic and 2 (1.6%) major hemorrhagic events were observed in the case group. Four (3.2%) ischemic and no hemorrhagic events occurred in the DOAC-control group. There were no statistically significant differences in the ischemic and hemorrhagic events between the case group (patients on concomitant LEV or VPA who were prescribed a DOAC) and the DOAC-control group, and there was no difference in the recurrence rate of epileptic seizures between the case group and the ASM-control group. IMPLICATIONS: Although this study has some limits, mainly the small sample size, our findings indicate that neither LEV nor VPA concomitant treatment significantly affects the effects of DOACs in a real-world setting.

Alexithymia Increases Pericranial and Cervical Muscle Tenderness in Women with Migraine.

Background/Objectives: Alexithymia is characterized by a deficit in identifying and communicating feelings. Emerging evidence suggests that alexithymia is highly prevalent in migraine, in a complex interplay with psychiatric comorbidity. Pericranial/cervical muscle tenderness is a remarkable clinical feature in a large proportion of migraine patients. This pilot study aimed at investigating the relationship between alexithymia and pericranial/cervical muscle tenderness in female migraineurs. Methods: A total of 42 female patients fulfilling the diagnostic criteria for migraine were enrolled into this pilot, observational, cross-sectional study after informed consent was obtained. Each patient underwent a psychological assessment to identify any alexithymia by means of TAS-20, anxiety/mood comorbidity (by means of STAI-Y1 STAI-Y2, BDI-II), and migraine-related disability (by means of HIT-6), and a physical cranial/cervical musculoskeletal examination. Palpation of pericranial and cervical muscles was carried out in the standardized manner. A Cumulative Muscle Tenderness (CUM) score (0-6) was calculated for each patient. A multivariate analysis was performed to investigate any association amongst the TAS-20 score, the CUM score, and the following covariates: BDI-II, STAI-Y1, STAI-Y2, and HIT-6 scores, age, disease duration, monthly migraine days, and average head pain intensity in the previous three months. Results: Overall, 35.6% of the sample had alexithymia. The multivariate analysis detected a linear and independent relationship between the TAS-20 and CUM scores, with a statistically significant (p = 0.017) association. Conclusions: This pilot study suggests that alexithymia plays a role in increasing pericranial/cervical muscle tenderness in migraine, independently from psychiatric comorbidity. A novel therapeutical approach, targeting alexithymia, may well reduce muscular tenderness in female migraineurs.

Predicting amyloid-PET status in a memory clinic: The role of the novel antero-posterior index and visual rating scales.

INTRODUCTION: Visual rating scales are increasingly utilized in clinical practice to assess atrophy in crucial brain regions among patients with cognitive disorders. However, their capacity to predict Alzheimer's disease (AD)-related pathology remains unexplored, particularly within a heterogeneous memory clinic population. This study aims to assess the accuracy of a novel visual rating assessment, the antero-posterior index (API) scale, in predicting amyloid-PET status. Furthermore, the study seeks to determine the optimal cohort-based cutoffs for the medial temporal atrophy (MTA) and parietal atrophy (PA) scales and to integrate the main visual rating scores into a predictive model. METHODS: We conducted a retrospective analysis of brain MRI and high-resolution TC scans from 153 patients with cognitive disorders who had undergone amyloid-PET assessments due to suspected AD pathology in a real-world memory clinic setting. RESULTS: The API scale (cutoff ≥1) exhibited the highest accuracy (AUC = 0.721) among the visual rating scales. The combination of the cohort-based MTA and PA threshold with the API yielded favorable accuracy (AUC = 0.787). Analyzing a cohort of MCI/Mild dementia patients below 75 years of age, the API scale and the predictive model improved their accuracy (AUC = 0.741 and 0.813, respectively), achieving excellent results in the early-onset population (AUC = 0.857 and 0.949, respectively). CONCLUSION: Our study emphasizes the significance of visual rating scales in predicting amyloid-PET positivity within a real-world memory clinic. Implementing the novel API scale, alongside our cohort-based MTA and PA thresholds, has the potential to substantially enhance diagnostic accuracy.

Association between Mortality and Lung Low Attenuation Areas in NSCLC Treated by Surgery.

BACKGROUND: to test the association with overall survival (OS) of low attenuation areas (LAAs) quantified by staging computed tomography (CT) of patients who underwent radical surgery for nonsmall-cell lung cancer (NSCLC). METHODS: patients who underwent radical surgery for NSCLC at our institution between 1 January 2017 and 30 November 2021 were retrospectively evaluated. Patients who performed staging or follow-up CTs in other institutions, who received lung radiotherapy or chemotherapy, and who underwent previous lung surgery were excluded. At staging and 12-months follow-up CT, LAAs defined as voxels <-950 Hounsfield units, were extracted by software. The percent of LAAs relative to whole-lung volume (%LAAs) and the ratio between LAAs in the lobe to resect and whole-lung LAAs (%LAAs lobe ratio) were calculated. Cox proportional hazards regression analysis was used to test the association between OS and LAAs. RESULTS: the final sample included 75 patients (median age 70 years, IQR 63-75 years; females 29/75, 39%). It identified a significant association with OS for pathological stage III (HR, 6.50; 95%CI, 1.11-37.92; p = 0.038), staging CT %LAAs ≥ 5% (HR, 7.27; 95%CI, 1.60-32.96; p = 0.010), and staging CT %LAA lobe ratio > 10% (HR, 0.24; 95%CI 0.05-0.94; p = 0.046). CONCLUSIONS: in patients with NSCLC who underwent radical surgery, a %LAAs ≥ 5% and a %LAA lobe ratio > 10% at staging CT are predictors, respectively, of shorter and longer OS. The LAA ratio to the whole lung at staging CT could be a critical factor to predict the overall survival of the NSCLC patients treated by surgery.

Acute Budd-Chiari Syndrome with Complete Portal Vein Thrombosis Complicated by Hepato-Renal Syndrome Treated Successfully by Emergent TIPS with Rheolytic Thrombectomy.

We described a case of a 73-year-old female admitted to the emergency department with acute hepatic and renal failure (hepato-renal syndrome, HRS) due to acute Budd-Chiari syndrome associated with complete portal vein thrombosis (BCS-PVT) for an unknown cause. Despite the initial therapy with anticoagulants, a sudden impairment of the renal function requiring hemodialysis was observed. The hepatic transplant was excluded for patient age and clinical conditions. Thus, the patient was successfully treated by emergent transjugular intrahepatic portosystemic shunt (TIPS) previous rheolytic thrombectomy of the PVT with AngioJet Ultra PE Thrombectomy System (Boston Scientific, Marlborough, MA, USA). After the procedure, the sudden resolution of the HRS was observed, and the patient is alive 13 months after hospital dismission with no TIPS dysfunction. In conclusion, emergent extended TIPS with the usage of rheolytic thrombectomy device in patient with acute BCS-PVT complicated by HRS is feasible by experienced operators and provide resolution of the HRS.

Are Interstitial Lung Abnormalities a Prognostic Factor of Worse Outcome in COVID-19 Pneumonia?

PURPOSE: To assess the association between interstitial lung abnormalities (ILAs) and worse outcome in patients affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19)-related pneumonia. MATERIALS AND METHODS: The study included patients older than 18 years, who were admitted at the emergency department between February 29 and April 30, 2020 with findings of COVID-19 pneumonia at chest computed tomography (CT), with positive reverse-transcription polymerase chain reaction nasal-pharyngeal swab for SARS-CoV-2, and with the availability of prepandemic chest CT. Prepandemic CTs were reviewed for the presence of ILAs, categorized as fibrotic in cases with associated architectural distortion, bronchiectasis, or honeycombing. Worse outcome was defined as intensive care unit (ICU) admission or death. Cox proportional hazards regression analysis was used to test the association between ICU admission/death and preexisting ILAs. RESULTS: The study included 147 patients (median age 73 y old; 95% CIs: 71-76-y old; 29% females). On prepandemic CTs, ILA were identified in 33/147 (22%) of the patients, 63% of which were fibrotic ILAs. Fibrotic ILAs were associated with higher risk of ICU admission or death in patients with COVID-19 pneumonia (hazard ratios: 2.73, 95% CIs: 1.50-4.97, P =0.001). CONCLUSIONS: In patients affected by COVID-19 pneumonia, preexisting fibrotic ILAs were an independent predictor of worse prognosis, with a 2.7 times increased risk of ICU admission or death. Chest CT scans obtained before the diagnosis of COVID-19 pneumonia should be carefully reviewed for the presence and characterization of ILAs.

CT perfusion extended window ischemic core estimation: Bayesian algorithm versus oscillation index singular value decomposition.

BACKGROUND AND PURPOSE: Ischemic core estimation by CT perfusion (CTp) is a diagnostic challenge, mainly because of the intrinsic noise associated with perfusion data. However, an accurate and reliable quantification of the ischemic core is critical in the selection of patients for reperfusion therapies. Our study aimed at assessing the diagnostic accuracy of two different CTp postprocessing algorithms, that is, the Bayesian Method and the oscillation index singular value decomposition (oSVD). METHODS: All the consecutive stroke patients studied in the extended time window (>4.5 hours from stroke onset) by CTp and diffusion-weighted imaging (DWI), between October 2019 and December 2021, were enrolled. The agreement between both algorithms and DWI was assessed by the Bland-Altman plot, Wilcoxon signed-rank test, Spearman's rank correlation coefficient, and the intraclass correlation coefficient (ICC). RESULTS: Twenty-four patients were enrolled (average age: 72 ± 15 years). The average National Institutes of Health Stroke Scale was 14.42 ± 6.75, the median Alberta Stroke Program Early CT score was 8.50 (interquartile range [IQR] = 7.75-9), and median time from stroke onset to neuroimaging was 7.5 hours (IQR = 6.5-8). There was an excellent correlation between DWI and oSVD (ρ = .87, p-value < .001) and DWI and Bayesian algorithm (ρ = .94, p-value < .001). There was a stronger ICC between DWI and Bayesian algorithm (.97, 95% confidence interval [CI]: .92-.99, p-value < .001) than between DWI and oSVD (.59, 95% CI: .26-.8, p-value < .001). DISCUSSION: The agreement between Bayesian algorithm and DWI was greater than between oSVD and DWI in the extended window. The more accurate estimation of the ischemic core offered by the Bayesian algorithm may well play a critical role in the accurate selection of patients for reperfusion therapies.

Software-Based Assessment of Well-Aerated Lung at CT for Quantification of Predicted Pulmonary Function in Resected NSCLC.

Background: To test the agreement between postoperative pulmonary function tests 12 months after surgery (mpo-PFTs) for non-small cell lung cancer (NSCLC) and predicted lung function based on the quantification of well-aerated lung (WAL) at staging CT (sCT). Methods: We included patients with NSCLC who underwent lobectomy or segmentectomy without a history of thoracic radiotherapy or chemotherapy treatment with the availability of PFTs at 12 months follow-up. Postoperative predictive (ppo) lung function was calculated using the resected lobe WAL (the lung volume between −950 and −750 HU) at sCT. The Spearman correlation coefficient (rho) and intraclass correlation coefficient (ICC) were used to the test the agreement between WAL ppo-PFTs and mpo-PFTs. Results: the study included 40 patients (68 years-old, IQR 62−74 years-old; 26/40, 65% males). The WAL ppo-forced expiratory volume in 1 s (FEV1) and the ppo-diffusing capacity of the lung for carbon monoxide (%DLCO) were significantly correlated with corresponding mpo-PFTs (rho = 0.842 and 0.717 respectively; p < 0.001). The agreement with the corresponding mpo-PFTs of WAL ppo-FEV1 was excellent (ICC 0.904), while it was good (ICC 0.770) for WAL ppo-%DLCO. Conclusions: WAL ppo-FEV1 and WAL ppo-%DLCO at sCT showed, respectively, excellent and good agreement with corresponding mpo-PFTs measured 12 months after surgery for NSCLC. WAL is an easy parameter obtained by staging CT that can be used to estimate post-resection lung function for patients with borderline pulmonary function undergoing lung surgery.

Thoracic duct leakage in a patient with Type B-Non-Hodgkin lymphoma treated with transvenous retrograde access embolization: a case report.

Thoracic duct (TD) is the largest lymphatic vessel in the body and drains the lymph at the junction between the left subclavian and jugular veins. Chylothorax (CTX) represents an accumulation of lymphatic fluid in the pleural space. We present a case of a 65 years-old man with an histologically diagnosed mediastinal type B non-Hodgkin Lymphoma, treated with chemo-immunotherapy. CT scan during follow up showed significant left side pleural effusion, amounting to 2.8 litres after drainage. Conservative treatment with low fat parenteral nutrition was started without reduction of drainage output, then lymphangiography (LP) with Lipiodol was performed demonstrating a leak in the distal TD. CTX increased in the following days, and a further LP was performed. Using transvenous retrograde access we catheterized TD at the left subclavian jugular veins using a microcatheter. The leak was treated with multiple conventional and controlled delivery microcroils and cyanoacrylate, obtaining complete embolization without residual leak.

The Impact of Highly Effective Treatment in Pediatric-Onset Multiple Sclerosis: A Case Series.

INTRODUCTION: Pediatric-onset multiple sclerosis (POMS) is characterized by high inflammatory disease activity. Our aim was to describe the treatment sequencing and report the impact highly effective disease-modifying treatment (HET) had on disease activity. MATERIALS AND METHODS: Five consecutive patients with POMS were administered HET following lower efficacy drug or as initial therapy. Data on treatment sequencing, relapses and MRIs were collected during the follow-up. RESULTS: Our patients had an average age of 13.8 years (range 9-17) at diagnosis and 13.4 years (range 9-16) at disease onset, and 2/5 (40%) POMS were female. The pre-treatment average annualized relapse rate was 1.6 (range 0.8-2.8), and the average follow-up length was 5 years (range 3-7). A total of 2/5 (40%) patients were stable on HET at initial therapy, and 3/5 (60%) required an escalation to more aggressive treatment, even if two of them had been put on HET as initial treatment. Four out of five patients (80%) had No Evidence of Disease Activity-3 status (NEDA-3) at an average follow-up of 3 years (range 2-5). CONCLUSION: It has been observed that in a recent time period all the cases had prompt diagnosis, early HET or escalation to HET with a good outcome in 80% of the cases.

A "Post-mortem" of COVID-19-associated stroke: a case-control study.

OBJECTIVES: To assess whether COVID-19 could be a concurrent factor in the genesis and/or worsening of stroke and to provide data on COVID-19 -associated stroke patients during the first pandemic wave and comparative data on COVID-19 negative stroke patients in the same period. MATERIALS AND METHODS: This is a retrospective, observational, case-control, single centre study, carried out in a General Hospital in northern Italy. Sixty-three consecutive stroke patients were included, COVID-19-associated stroke was classified as cases and non COVID-19-associated stroke as controls. RESULTS: A total of 19/63 (28.8%) had a COVID-19-associated stroke, 11 /63 (17.5%) were haemorrhagic and 52/63 (82.5%) ischaemic. COVID-19-associated strokes were more severe (p-value 0.019) and had a higher risk of severe disability and/or death (OR 3.79, CI 95%: 1.21-11.93, p-value 0.19). The COVID-19-associated stroke patients with onset during hospitalization for COVID-19 had a more severe stroke than patients with COVID-19 onset during hospitalization for stroke (p-value 0.019). CONCLUSION: Although no relationship was observed between the stroke aetiology and COVID-19, intriguingly, COVID-associated stroke turned out to be more severe and disabling. Hopefully, further studies will provide more data and help in the management of this emerging population.

Multiple Sclerosis Treatment in the COVID-19 Era: A Risk-Benefit Approach.

The COVID-19 pandemic poses an ongoing global challenge, and several risk factors make people with multiple sclerosis (pwMS) particularly susceptible to running a severe disease course. Although the literature does report numerous articles on the risk factors for severe COVID-19 and vaccination response in pwMS, there is a scarcity of reviews integrating both these aspects into strategies aimed at minimizing risks. The aim of this review is to describe the risk of vulnerable pwMS exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the issues related to the SARS-CoV-2 vaccine and to evidence possible future strategies in the clinical management of pwMS. The authors searched for papers on severe COVID-19 risk factors, SARS-CoV-2 vaccination and people with multiple sclerosis in support of this narrative literature review. We propose a multilevel strategy aimed at: the evaluation of risk factors for severe COVID-19 in people with multiple sclerosis, identifying the most appropriate vaccination schedule that is safe for people on disease-modifying drugs (DMDs) and a strict follow-up of high-risk people with multiple sclerosis to allow for the prompt administration of monoclonal antibodies to manage COVID-19 risks in this patient population.

Spyglass percutaneous transhepatic lithotripsy of symptomatic recurrent lithiasis of the intrahepatic bile duct with distal stenosis.

In patients with symptomatic intrahepatic biliary lithiasis, the treatment is usually discussed by a multidisciplinary team. Although hepatectomy is considered as definitive treatment, when lobar atrophy is absent, endoscopic procedures are frequently proposed as first-line treatment due the low invasiveness and for sparing liver parenchyma. Percutaneous route is used in case of peroral approach failure. We present a case of recurrent symptomatic intrahepatic biliary lithiasis of the right posterior hepatic duct, sustained by downstream biliary stenosis. Peroral cholangioscopy failed to visualize the stone for the accompanying stenosis. Thus, the patient was successfully treated with percutaneous transhepatic lithotripsy performed with Spyglass direct visualization system II (Boston Scientific Inc., Natick, Massachusetts, USA). During the procedure, the biopsy of the biliary stenosis revealed fibrosis, which was treated by cholangioplasty with cutting balloon. After 15 months, the patient is asymptomatic, with moderate residual stenosis in absence of calculi at follow-up magnetic resonance cholangiography.

Change in the second exteroceptive suppression period of the temporalis muscle during erenumab treatment.

Comparative studies on the second exteroceptive suppression period (ES2) of the masseter or temporalis muscle in migraineurs and controls have provided conflicting results. As the interneurons responsible for ES2 are probably close to the trigeminal nucleus caudalis and receive afferents also from the anti-nociceptive system, the study of ES2 could provide information on neural circuits involved in migraine pathophysiology. The aim of this observational, pilot study was to assess whether erenumab treatment may affect the exteroceptive suppression reflex of the temporalis muscle activity in migraineurs. The exteroceptive suppression reflex of the temporalis muscle activity was previously studied in a small case series of three chronic female migraineurs and after 4 months of beneficial erenumab treatment, administered according to current clinical indications. There was a statistically significant decrease in ES2 latency (p-value 0.039) and duration (p-value 0.030) after treatment. The change observed in the temporalis ES2 during erenumab treatment indicates that ES2 may play some kind of role as a neurophysiological marker and that this monoclonal antibody can modulate the brainstem circuits involved in migraine pathophysiology, at least indirectly. Further studies are required to confirm this intriguing hypothesis.

Predictors of the multiwire technique use in carotid artery stenting.

OBJECTIVES: The multiwire technique (MWT) in carotid artery stenting (CAS), characterized by the use of more than one guidewire to support guiding catheter in patients with hostile neck anatomy, increases procedural time, enhancing the risk of periprocedural stroke. The aim of the present study was to identify which factors are predictors of the MWT use in CAS, in order to stratify patients with longer procedure at potential higher risk of periprocedural stroke. METHODS: The study retrospectively included patients who underwent CAS for stenotic plaque between January 2015 and December 2019. Exclusion criteria was incomplete clinical data. For each patients were registered clinical data, main aortic arch and supra-aortic vessel anatomical features, carotid plaque characteristics, and procedural details. The sample was divided in two group on the basis of the number of guides used during the stenting procedure: one guide (standard technique, ST) or more than one guidewire (MWT) to support the guiding catheter. Differences between groups were tested by Chi-square text or Fisher's exact test and Mann-Whitney U test. Logistic regression analysis was used to identify predictors for the use of the MWT. The area under the ROC (AUC) curve was used to assess performance of the model to predict the use of the multiwire technique. RESULTS: The final sample included 146 of the 204 (71%) patients who underwent CAS during the study period. The median age of the patients was 79 years (IQR 71-83 years) with 47/146 (32%) females. CAS was performed with MWT in 17/146 (12%) of the cases. MWT was used more likely in patients with aortic arch type II or III as compared to ST (71% vs 37%, P = 0.02) while plaques with heavy concentric calcifications were more frequent in ST as compared to MWT (38% vs 12%, P = 0.03). At multivariable analysis aortic arch type II or III (OR 5.08, 95% CI 1.48-17.93, P < 0.01), plaque stenosis > 79% (OR 4.13, 95% CI 1.03-16.61, P = 0.04), and plaque heavy concentric calcifications (OR 0.19, 95% CI 0.04-0.94, P = 0.04) were independent predictors of MWT use. The model showed an AUC of 0.827 (95% CI 0.756-0.884) for the prediction of the MWT use during CAS. CONCLUSIONS: Aortic arch type II or III, carotid plaque with stenosis higher than 79% of the lumen or without heavy concentric calcifications were predictors for the use of the MWT during CAS. These features should be considered during planning of CAS as hallmark of vascular stiffness and therefore of higher procedure complexity.

Computed Tomography Texture Analysis of Carotid Plaque as Predictor of Unfavorable Outcome after Carotid Artery Stenting: A Preliminary Study.

Novel biomarkers are advocated to manage carotid plaques. Therefore, we aimed to test the association between textural features of carotid plaque at computed tomography angiography (CTA) and unfavorable outcome after carotid artery stenting (CAS). Between January 2010 and January 2021, were selected 172 patients (median age, 77 years; 112/172, 65% men) who underwent CAS with CTA of the supra-aortic vessels performed within prior 6 months. Standard descriptors of the density histogram were derived by open-source software automated analysis obtained by CTA plaque segmentation. Multiple logistic regression analysis, receiver operating characteristic (ROC) curve analysis and the area under the ROC (AUC) were used to identify potential prognostic variables and to assess the model performance for predicting unfavorable outcome (periprocedural death or myocardial infarction and any ipsilateral acute neurological event). Unfavorable outcome occurred in 17/172 (10%) patients (median age, 79 years; 12/17, 70% men). Kurtosis was an independent predictor of unfavorable outcome (odds ratio, 0.79; confidence interval, 0.65-0.97; p = 0.029). The predictive model for unfavorable outcome including CTA textural features outperformed the model without textural features (AUC 0.789 vs. 0.695, p = 0.004). In patients with stenotic carotid plaque, kurtosis derived by CTA density histogram analysis is an independent predictor of unfavorable outcome after CAS.

Not all is COVID19: a case of eclampsia and posterior reversible encephalopathy syndrome in the emergency room.

In the so called COVID19 era, headache, fever and gastrointestinal symptoms are highly suggestive for SARS-CoV-2 infection, but in all the cases presenting to the emergency room, clinicians should always keep in mind alternative diagnoses, particularly if the patient is pregnant.  Life-threatening diseases, such as eclampsia and posterior reversible encephalopathy syndrome (PRES), should be promptly recognized and treated. Eclampsia is defined as a seizure occurring in association with pre-eclampsia, and it represents one of the major and serious obstetric disorders associated with significant maternal and perinatal morbidity and mortality. PRES is a distinctive clinical and imaging syndrome characterized by acute headaches, visual impairment, seizures, and altered sensorium, that can be associated with severe eclampsia. Emergency clinicians should always consider eclampsia in the differential diagnosis of headache in pregnant women. The prompt and accurate diagnosis of eclampsia/PRES is crucial to prevent adverse maternal and perinatal outcomes. Here we describe the case of a young pregnant woman admitted to our emergency department for fever, dyspnea, headache, nausea and vomiting, who developed generalized tonic clonic seizures and a subsequent status epilepticus due to eclampsia and PRES.