Learning ability correlates with brain atrophy and disability progression in RRMS

Objective To assess the prognostic value of practice effect on Paced Auditory Serial Addition Test (PASAT) in multiple sclerosis. Methods We compared screening (day a '14) and baseline (day 0) PASAT scores of 1009 patients from the FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial. We grouped patients into high and low learners if their PASAT score change was above or below the median change in their screening PASAT quartile group. We used Wilcoxon test to compare baseline disease characteristics between high and low learners, and multiple regression models to assess the respective impact of learning ability, baseline normalised brain volume and treatment on brain volume loss and 6-month confirmed disability progression over 2 years. Results The mean PASAT score at screening was 45.38, increasing on average by 3.18 from day a '14 to day 0. High learners were younger (p=0.003), had lower Expanded Disability Status Scale score (p=0.031), higher brain volume (p<0.001) and lower T2 lesion volume (p=0.009) at baseline. Learning status was not significantly associated with disability progression (HR=0.953, p=0.779), when adjusting for baseline normalised brain volume, screening PASAT score and treatment arm. However, the effect of fingolimod on disability progression was more pronounced in high learners (HR=0.396, p<0.001) than in low learners (HR=0.798, p=0.351; p for interaction=0.05). Brain volume loss at month 24 tended to be higher in low learners (0.17%, p=0.058), after adjusting for the same covariates. Conclusions Short-term practice effects on PASAT are related to brain volume, disease severity and age and have clinically meaningful prognostic implications. High learners benefited more from fingolimod treatment

Protective Effects of Home T2DM Treatment with Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Co-transporter-2 Inhibitors Against Intensive Care Unit Admission and Mortality in the Acute Phase of the COVID-19 Pandemic: A Retrospective Observational Study in Italy

Introduction: Type 2 diabetes mellitus (T2DM) is a relevant risk factor for severe forms of COVID-19 (SARS coronavrus 2 [SARS-CoV-2] disease 2019), and calls for caution because of the high prevalence of T2DM worldwide and the high mortality rates observed in patients with T2DM who are infected with SARS-CoV-2. People with T2DM often take dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1ras), or sodium-glucose co-transporter-2 inhibitors (SGLT-2is), all of which have clear anti-inflammatory effects. The study aimed to compare (i) the severity and duration of hospital stay between patients with T2DM categorized by pre-hospitalization drug class utilization and (ii) the COVID-19-related death rates of those three groups.Methods: We designed an observational, retrospective, multi-center, population-based study and extracted the hospital admission data from the health care records of 1916 T2DM patients over 18 years old who were previously on GLP-1ra, SGLT-2i, or DPP-4i monotherapy and were hospitalized for COVID-19 (diagnosis based on ICD.9/10 codes) between January 2020 and December 2021 in 14 hospitals throughout Italy. We analyzed general data, pre-admission treatment schedules, date of admission or transfer to the intensive care unit (ICU) (i.e., the index date; taken as a marker of increased COVID-19 disease severity), and death (if it had occurred). Statistics analyzed the impact of drug classes on in-hospital mortality using propensity score logistic regressions for (i) those admitted to intensive care and (ii) those not admitted to intensive care, with a random match procedure used to generate a 1:1 comparison without diabetes cohort replacement for each drug therapy group by applying the nearest neighbor method. After propensity score matching, we checked the balance achieved across selected variables if a balance was ever achieved. We then used propensity score matching between the three drug classes to assemble a sample in which each patient receiving an SGLT-2i was matched to one on a GLP-1ra, and each patient on a DPP-4i was matched to one on a GLP-1ra, adjusting for covariates. We finally used GLP-1ras as references in the logistic regression.Results: The overall mortality rate (MR) of the patients was 14.29%. The MR in patients with COVID was 53.62%, and it was as high as 42.42% in the case of associated T2DM, regardless of any glucose-lowering therapy. In those on DPP-4is, there was excess mortality; in those treated with GLP-1ras and SGLT-2is, the death rate was significantly lower, i.e., almost a quarter of the overall mortality observed in COVID-19 patients with T2DM. Indeed, the odds ratio (OR) in the logistic regression resulted in an extremely high risk of in-hospital death in individuals previously treated with DPP-4is [incidence rate (IR) 4.02, 95% confidence interval (CI) 2.2-5.7) and only a slight, nonsignificantly higher risk in those previously treated with SGLT-2is (IR 1.42, 95% CI 0.6-2.1) compared to those on GLP-1ras. Moreover, the longer the stay, the higher the death rate, which ranged from 22.3% for &lt;= 3-day stays to 40.3% for 4- to 14-day stays (p &lt; 0.01 vs. the former) and 77.4% for over-14-day stays (p &lt; 0.001 vs. both the others).Discussion: Our data do not support a protective role of DPP-4is; indeed, this role has already been questioned due to previous observations. However, the data do show a strong protective effect of SGLT-2is and GLP-1ras.Beyond lowering circulating glucose levels, those two drug classes were found to exert marked anti-phlogistic effects: SGLT-2is increased adiponectin and reduced urate, leptin, and insulin concentrations, thus positively affecting overall low-grade inflammation, and GLP-1ras may also greatly help at the lung tissue level, meaning that their extra-glycemic effects extend well beyond those acknowledged in the cardiovascular and renal fields.Conclusions: The aforedescribed observational clinical data relating to a population of Italian inpatients with T2DM suggest that GLP-1ras and SGLT-2is can be considered antidiabetic drugs of choice against COVID-19, and might even prove beneficial in the event of any upcoming pandemic that has life-threatening effects on the pulmonary and cardiovascular systems

Rapidly fatal West Nile virus meningoencephalitis in an immunocompetent patient: a case report

Abstract Background West Nile virus (WNV) is a Flaviviridae most often transmitted by mosquitos. Clinical manifestations vary from no symptoms to neuroinvasive disease. Mortality is rare, but patients with neuroinvasive disease have a fatality rate of 4-14%. Diagnosis is made on epidemiological, clinical and serological criteria. Treatment is based on symptomatic and support therapy. WNV neuroinvasive disease seems associated to advancing age and diabetes, but poor prognosis risk factors are still not clearly recognized. During 2017-2018 10 patients affected by WNV infection were admitted to our Hospital (Policlinico of Modena): 3 patients had a rapid fatal outcome and 3 needed intensive care transfer. We report the most representative case. Case Report A 81-yr-old man from Emilia-Romagna was admitted to our unit with a 6 days history of fever (&gt;38℃), fatigue, nausea, vomiting, hiccough and mild cognitive impairment treated with amoxicillin. Past medical history: type 2 diabetes mellitus, arterial hypertension, permanent pacemaker for type 3 atrioventricular block. Referred exposure to farm animals. No recent travels abroad. Chest x-ray showed a retrocardiac opacity, so empiric levofloxacin was started for suspected community acquired pneumonia. After two days the patient began lethargic with a Glasgow Come Score &lt; 8. Neuroinvasive WNV disease was confirmed by electroencephalogram and rachicentesis. Before serologic results acyclovir and dexamethasone were initiated without benefit and patient diedon the fifth day after admission. Conclusions Risk factors for poor prognosis related to WNV Infection are still not clearly identified. Our patient underwent unexpected rapid clinical deterioration before invasive treatment could positively affect prognosis. This underlines the importance of clinical alert to WNV infections during transmission season in endemic areas and the necessity of more data on fatal WNV cases to define criteria to promptly recognize high-risk patients. Keywords encephalitis; meningoencephalitis; neuroinvasive disease; West Nile virus; fatal meningoencephalitis

Baseline risk factors of in-hospital mortality after surgery for acute type A aortic dissection: an ERTAAD study

Background Surgery for type A aortic dissection (TAAD) is associated with high risk of mortality. Current risk scoring methods have a limited predictive accuracy.Methods Subjects were patients who underwent surgery for acute TAAD at 18 European centers of cardiac surgery from the European Registry of Type A Aortic Dissection (ERTAAD).Results Out of 3,902 patients included in the ERTAAD, 2,477 fulfilled the inclusion criteria. In the validation dataset (2,229 patients), the rate of in-hospital mortality was 18.4%. The rate of composite outcome (in-hospital death, stroke/global ischemia, dialysis, and/or acute heart failure) was 41.2%, and 10-year mortality rate was 47.0%. Logistic regression identified the following patient-related variables associated with an increased risk of in-hospital mortality [area under the curve (AUC), 0.755, 95% confidence interval (CI), 0.729-0.780; Brier score 0.128]: age; estimated glomerular filtration rate; arterial lactate; iatrogenic dissection; left ventricular ejection fraction &lt;= 50%; invasive mechanical ventilation; cardiopulmonary resuscitation immediately before surgery; and cerebral, mesenteric, and peripheral malperfusion. The estimated risk score was associated with an increased risk of composite outcome (AUC, 0.689, 95% CI, 0.667-0.711) and of late mortality [hazard ratio (HR), 1.035, 95% CI, 1.031-1.038; Harrell's C 0.702; Somer's D 0.403]. In the validation dataset (248 patients), the in-hospital mortality rate was 16.1%, the composite outcome rate was 41.5%, and the 10-year mortality rate was 49.1%. The estimated risk score was predictive of in-hospital mortality (AUC, 0.703, 95% CI, 0.613-0.793; Brier score 0.121; slope 0.905) and of composite outcome (AUC, 0.682, 95% CI, 0.614-0.749). The estimated risk score was predictive of late mortality (HR, 1.035, 95% CI, 1.031-1.038; Harrell's C 0.702; Somer's D 0.403), also when hospital deaths were excluded from the analysis (HR, 1.024, 95% CI, 1.018-1.031; Harrell's C 0.630; Somer's D 0.261).Conclusions The present analysis identified several baseline clinical risk factors, along with preoperative estimated glomerular filtration rate and arterial lactate, which are predictive of in-hospital mortality and major postoperative adverse events after surgical repair of acute TAAD. These risk factors may be valuable components for risk adjustment in the evaluation of surgical and anesthesiological strategies aiming to improve the results of surgery for TAAD.Clinical Trial Registration https://clinicaltrials.gov, identifier NCT04831073

Outcome after Surgery for Iatrogenic Acute Type A Aortic Dissection

(1) Background: Acute Stanford type A aortic dissection (TAAD) may complicate the outcome of cardiovascular procedures. Data on the outcome after surgery for iatrogenic acute TAAD is scarce. (2) Methods: The European Registry of Type A Aortic Dissection (ERTAAD) is a multicenter, retrospective study including patients who underwent surgery for acute TAAD at 18 hospitals from eight European countries. The primary outcomes were in-hospital mortality and 5-year mortality. Twenty-seven secondary outcomes were evaluated. (3) Results: Out of 3902 consecutive patients who underwent surgery for acute TAAD, 103 (2.6%) had iatrogenic TAAD. Cardiac surgery (37.8%) and percutaneous coronary intervention (36.9%) were the most frequent causes leading to iatrogenic TAAD, followed by diagnostic coronary angiography (13.6%), transcatheter aortic valve replacement (10.7%) and peripheral endovascular procedure (1.0%). In hospital mortality was 20.5% after cardiac surgery, 31.6% after percutaneous coronary intervention, 42.9% after diagnostic coronary angiography, 45.5% after transcatheter aortic valve replacement and nihil after peripheral endovascular procedure (p = 0.092), with similar 5-year mortality between different subgroups of iatrogenic TAAD (p = 0.710). Among 102 propensity score matched pairs, in-hospital mortality was significantly higher among patients with iatrogenic TAAD (30.4% vs. 15.7%, p = 0.013) compared to those with spontaneous TAAD. This finding was likely related to higher risk of postoperative heart failure (35.3% vs. 10.8%, p < 0.0001) among iatrogenic TAAD patients. Five-year mortality was comparable between patients with iatrogenic and spontaneous TAAD (46.2% vs. 39.4%, p = 0.163). (4) Conclusions: Iatrogenic origin of acute TAAD is quite uncommon but carries a significantly increased risk of in-hospital mortality compared to spontaneous TAAD

Outcome after Surgery for Iatrogenic Acute Type A Aortic Dissection

(1) Background: Acute Stanford type A aortic dissection (TAAD) may complicate the outcome of cardiovascular procedures. Data on the outcome after surgery for iatrogenic acute TAAD is scarce. (2) Methods: The European Registry of Type A Aortic Dissection (ERTAAD) is a multicenter, retrospective study including patients who underwent surgery for acute TAAD at 18 hospitals from eight European countries. The primary outcomes were in-hospital mortality and 5-year mortality. Twenty-seven secondary outcomes were evaluated. (3) Results: Out of 3902 consecutive patients who underwent surgery for acute TAAD, 103 (2.6%) had iatrogenic TAAD. Cardiac surgery (37.8%) and percutaneous coronary intervention (36.9%) were the most frequent causes leading to iatrogenic TAAD, followed by diagnostic coronary angiography (13.6%), transcatheter aortic valve replacement (10.7%) and peripheral endovascular procedure (1.0%). In hospital mortality was 20.5% after cardiac surgery, 31.6% after percutaneous coronary intervention, 42.9% after diagnostic coronary angiography, 45.5% after transcatheter aortic valve replacement and nihil after peripheral endovascular procedure (p = 0.092), with similar 5-year mortality between different subgroups of iatrogenic TAAD (p = 0.710). Among 102 propensity score matched pairs, in-hospital mortality was significantly higher among patients with iatrogenic TAAD (30.4% vs. 15.7%, p = 0.013) compared to those with spontaneous TAAD. This finding was likely related to higher risk of postoperative heart failure (35.3% vs. 10.8%, p &lt; 0.0001) among iatrogenic TAAD patients. Five-year mortality was comparable between patients with iatrogenic and spontaneous TAAD (46.2% vs. 39.4%, p = 0.163). (4) Conclusions: Iatrogenic origin of acute TAAD is quite uncommon but carries a significantly increased risk of in-hospital mortality compared to spontaneous TAAD

Efficacy and safety outcomes in vitamin D supplement users in the fingolimod phase 3 trials

BACKGROUND:Low serum levels of 25-hydroxyvitamin D have been associated with worse outcomes in multiple sclerosis (MS) patients treated with interferon-beta. Association of vitamin D nutrition on the outcomes of other MS therapies has been studied less.OBJECTIVE:Whether patients in the phase 3 fingolimod trials using vitamin D supplements have better clinical, MRI and safety outcomes than non-users.MATERIALS AND METHODS:Pooled data from phase 3 FREEDOMS trials was analyzed post hoc. Vitamin D use was defined as 'non-users' (n = 562), 'casual users' (n = 157) and 'daily users' (usage 100% time in the study, n = 110).RESULTS:Expanded Disability Status Scale change from baseline to month 24, and annual relapse rate and proportion of patients with relapses were similar across the vitamin D user groups. Proportion of patients free of new/enlarging T2 lesions significantly favored vitamin D 'daily users' versus 'non-users'. Mean number of lesions were lower and proportion of patients free of gadolinium-enhanced T1-lesions were higher in the 'daily users'. At month 12, percent brain volume change was significantly lower in the 'daily users' versus 'non-users' and remained low at month 24 (non-significant). Incidence of depression was lower for vitamin D 'daily users' (non-significant).CONCLUSIONS:We observed improved MRI outcomes on percent brain volume change and proportion of patients free of new/enlarging T2 lesions, and a trend of less depression in the 'daily users' of vitamin D supplement in patients in the FREEDOMS trials.</p