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Background: Information on performance of multiple sclerosis (MS) diagnostic criteria is scarce for populations from Latin America, Asia, or the Caribbean. Objective: To assess performance of revised 2017 McDonald criteria as well as evaluate genetic ancestry in a group of MS patients from Argentina experiencing a debut demyelinating event. Methods: Demographic and clinical characteristics, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) findings and new T2 lesions were recorded at baseline and during relapses. Diagnostic accuracy in predicting conversion to clinically defined MS (CDMS) based on initial imaging applying revised 2017 criteria was evaluated and genetic ancestry-informative markers analyzed. Results: Of 201 patients experiencing their first demyelinating event (median follow-up 60 months), CDMS was confirmed in 67. We found 2017 diagnostic criteria were more sensitive (84% vs 67%) and less specific (14% vs 33%) than 2010 criteria, especially in a group of patients revised separately, presenting positive oligoclonal bands (88% vs 8%). Genetic testing performed in 128 cases showed 72% of patients were of European ancestry and 27% presented genetic admixture. Conclusion: 2017 McDonald criteria showed higher sensitivity and lower specificity compared with 2010 criteria, shortening both time-to-diagnosis and time-to-treatment implementation.

Iron deficiency (ID) represents one of the most prevalent nutritional deficits, affecting almost two billion people worldwide. Gestational iron deprivation induces hypomyelination due to oligodendroglial maturation deficiencies and is thus a useful experimental model to analyze oligodendrocyte (OLG) requirements to progress to a mature myelinating state. A previous proteomic study in the adult ID brain by our group demonstrated a pattern of dysregulated proteins involved in the tricarboxylic acid cycle and mitochondrial dysfunction. The aim of the present report was to assess bioenergetics metabolism in primary cultures of OLGs and astrocytes (ASTs) from control and ID newborns, on the hypothesis that the regulation of cell metabolism correlates with cell maturation. Oxygen consumption and extracellular acidification rates were measured using a Seahorse extracellular flux analyzer. ID OLGs and ASTs both exhibited decreased spare respiratory capacity, which indicates that ID effectively induces mitochondrial dysfunction. A decrease in glycogen granules was observed in ID ASTs, and an increase in ROS production was detected in ID OLGs. Immunolabeling of structural proteins showed that mitochondrial number and size were increased in ID OLGs, while an increased number of smaller mitochondria was observed in ID ASTs. These results reflect an unfavorable bioenergetic scenario in which ID OLGs fail to progress to a myelinating state, and indicate that the regulation of cell metabolism may impact cell fate decisions and maturation.

Early and significant results for a real-time, column-free miniaturized gas mass spectrometer in detecting target species with partial overlapping spectra are reported. The achievements have been made using both nanoscale holes as a nanofluidic sampling inlet system and a robust statistical technique. Even if the presented physical implementation could be used with gas chromatography columns, the aim of high miniaturization requires investigating its detection performance with no aid. As a study case, in the first experiment, dichloromethane (CH2Cl2) and cyclohexane (C6H12) with concentrations in the 6–93 ppm range in single and compound mixtures were used. The nano-orifice column-free approach acquired raw spectra in 60 s with correlation coefficients of 0.525 and 0.578 to the NIST reference database, respectively. Then, we built a calibration dataset on 320 raw spectra of 10 known different blends of these two compounds using partial least square regression (PLSR) for statistical data inference. The model showed a normalized full-scale root-mean-square deviation (NRMSD) accuracy of $$10.9\mathrm{\%}$$ 10.9 % and $$18.4\mathrm{\%}$$ 18.4 % for each species, respectively, even in combined mixtures. A second experiment was conducted on mixes containing two other gasses, Xylene and Limonene, acting as interferents. Further 256 spectra were acquired on 8 new mixes, from which two models were developed to predict CH2Cl2 and C6H12, obtaining NRMSD values of 6.4% and 13.9%, respectively.

Background and Aims: Dye-based chromoendoscopy (DBC) could be effective in increasing the adenoma detection rate (ADR) in patients undergoing colonoscopy, but the technique is time-consuming and its uptake is limited. We aimed to assess the effect of DBC on ADR based on available randomized controlled trials (RCTs). Methods: Four databases were searched up to April 2022 for RCTs comparing DBC with conventional colonoscopy (CC) in terms of ADR, advanced ADR, and sessile serrated adenoma detection rate as well as the mean adenomas per patient and non-neoplastic lesions. Relative risk (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes were calculated using random-effect models. The I2 test was used for quantifying heterogeneity. Risk of bias was evaluated with the Cochrane tool. Results: Overall, 10 RCTs (5334 patients) were included. Indication for colonoscopy was screening or surveillance (3 studies) and mixed (7 studies). Pooled ADR was higher in the DBC group versus the CC group (95% CI, 48.1% [41.4%-54.8%] vs 39.3% [33.5%-46.4%]; RR, 1.20 [1.11-1.29]), with low heterogeneity (I2 = 29%). This effect was consistent for advanced ADR (RR, 1.21 [1.03-1.42]; I2 = .0%), sessile serrated adenomas (6.1% vs 3.5%; RR, 1.68 [1.15-2.47]; I2 = 9.8%), and mean adenomas per patient (MD, .24 [.17-.31]) overall and in the right-sided colon (MD, .28 [.14-.43]). A subgroup analysis considering only trials using high-definition white-light endoscopy reduced the heterogeneity while still showing a significant increase in adenoma detection with DBC: 51.6% (95% confidence interval [CI], 47.1%-56.1%) and 59.1% (95% CI, 54.7-63.3%), RR = 1.14 (95% CI, 1.06-1.23), P = .0004, I2 = .0%, P = .50. Conclusions: Meta-analysis of RCTs showed that DBC increases key quality parameters in colonoscopy, supporting its use in everyday clinical practice.

Background and purpose: Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation. Method: Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number. Results: From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p=0.005) and more in smoker patients (OR 1.39; p=0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p=0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p=0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p=0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p=0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p=0.024), joint or muscle pain (G2, p=0.013) and ageusia and anosmia (G5, p < 0.001). All cases should be referred to variants up to Delta. Conclusion: Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID-19 symptoms.

RationaleDemographic characteristics of pulmonary arterial hypertension (PAH) patients have changed over time, but the effects of cardiovascular risk factors on risk status and pulmonary vascular resistance (PVR) reduction with initial oral combination therapy are not known. Therefore, we tested the relevance of cardiovascular comorbidities in this setting.MethodsThe study enrolled 181 treatment-naive PAH patients with a 6-month (IQR 144–363 days) right heart catheterisation and risk assessment after initial oral combination therapy.ResultsGroup A included 96 (53.0%) patients without cardiac comorbidities; Group B included 54 (29.8%) patients with one cardiac comorbidity; Group C included 31 (17.1%) patients with two cardiac comorbidities or more. Group C patients were older with a balanced sex distribution. There was a significant difference in PVR reduction moving from the absence to one or at least two cardiac comorbidities, respectively: median −45.0%, −30.3%, −24.3%. A European Respiratory Society/European Society of Cardiology low-risk status was present at first follow-up in 50 (52.0%) patients in Group A, 19 (35.1%) in Group B and 9 (29.0%) in Group C; a REVEAL 2.0 low-risk status was present at first follow-up in 41 (42.0%) patients in Group A, 15 (27.7%) in Group B and 7 (22.6%) in Group C. Group A patients were 2.3 times more likely to achieve/maintain a low-risk status compared with Group B and C (OR 2.27, 95% CI 1.15–4.54, p=0.02). No significant difference was observed between patients with non-cardiac comorbidities and those without comorbidities.ConclusionInitial oral combination therapy seems associated with a less effective response for patients with cardiovascular comorbidities compared with the others, related to the magnitude of treatment-induced decrease in PVR.

A prodrome is an early set of signs or symptoms that indicate the onset of a disease before more typical symptoms develop. Prodromal stages are well recognized in some neurological and immune-mediated diseases such as Parkinson disease, schizophrenia, type 1 diabetes mellitus and rheumatoid arthritis. Emerging evidence indicates that a prodromal stage exists in multiple sclerosis (MS), raising the possibility of intervention at this stage to delay or prevent the development of classical MS. However, much remains unclear about the prodromal stage of MS and considerable research is needed to fully characterize the prodrome and develop standardized criteria to reliably identify individuals with prodromal MS who are at high risk of progressing to a diagnosis of MS. In this Roadmap, we draw on work in other diseases to propose a disease framework for MS that incorporates the prodromal stage, and set out key steps and considerations needed in future research to fully characterize the MS prodrome, identify early disease markers and develop standardized criteria that will enable reliable identification of individuals with prodromal MS, thereby facilitating trials of interventions to slow or stop progression beyond the prodrome.

Background and purpose Some studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID‐19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID‐19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID‐19 severity amongst PwMS. Methods Data were retrieved from an Italian web‐based platform (MuSC‐19) which includes PwMS with COVID‐19. PM2.5 2016–2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID‐19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID‐19 severity. Results In all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID‐19 course (odds ratio 1.90; p = 0.009). Conclusions Even if several other factors explain the unfavourable course of COVID‐19 in PwMS, the role of air pollutants must be considered and further investigated., Air pollution, often assessed by particulate matter with diameter below 2.5 µg/m3, may contribute to severe COVID‐19 courses. 1087 patients were included, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died. Even if several other factors explain the unfavourable course of COVID‐19 in patients with multiple sclerosis, the role of air pollutants must be considered and further investigated.

Peripheral immune-checkpoint blockade with mAbs to programmed cell death receptor-1 (PD-1) (either nivolumab or pembrolizumab) or PD-Ligand-1 (PD-L1) (atezolizumab, durvalumab, or avelumab) alone or in combination with doublet chemotherapy represents an expanding treatment strategy for metastatic non-small cell lung cancer (mNSCLC) patients. This strategy lays on the capability of these mAbs to rescue tumor-specific cytotoxic T lymphocytes (CTLs) inactivated throughout PD-1 binding to PD-L1/2 in the tumor sites. This inhibitory interactive pathway is a physiological mechanism of prevention against dangerous overreactions and autoimmunity in case of prolonged and/or repeated CTL response to the same antigen peptides. Therefore, we have carried out a retrospective bioinformatics analysis by single-cell flow cytometry to evaluate if PD-1/PD-L1-blocking mAbs modulate the expression of specific peripheral immune cell subsets, potentially correlated with autoimmunity triggering in 28 mNSCLC patients. We recorded a treatment-related decline in CD4+ T-cell and B-cell subsets and in the neutrophil-to-lymphocyte ratio coupled with an increase in natural killer T (NKT), CD8+PD1+ T cells, and eosinophils. Treatment-related increase in autoantibodies [mainly antinuclear antibodies (ANAs) and extractable nuclear antigen (ENA) antibodies] as well as the frequency of immune-related adverse events were associated with the deregulation of specific immune subpopulations (e.g., NKT cells). Correlative biological/clinical studies with deep immune monitoring are badly needed for a better characterization of the effects produced by PD-1/PD-L1 immune-checkpoint blockade.

Mobility difficulties for people with Parkinson’s disease (PwPD) are more pronounced when they perform a simultaneous cognitive task while walking. Although it is known that neurodegeneration results in widespread motor and brain impairments, few studies have comprehensively examined possible physical and mental determinants of dual task walking in PwPD. In this cross-sectional study, we aimed to investigate if and how muscle strength (sit-to-stand 30s test), cognition (mini-mental state examination) and functionality (timed up and go test) affect walking performance (10-meter walking test) with and without arithmetic dual task from older adults with and without Parkinson’s disease. Walking speed was reduced by 16% and 11% with arithmetic dual task for PwPD (from 1.07 ± 0.28 to 0.91 ± 0.29 m.s-1, p < 0.001) and older adults (from 1.32 ± 0.28 to 1.16 ± 0.26 m.s-1, p = 0.002) compared to essential walking. The cognitive state was similar among the groups, but it was only associated with the dual-task walking speed in PwPD. In PwPD, lower limb strength was the better predictor of speed, whereas mobility was more related to it in older adults. Therefore, future exercise interventions aiming to improve walking in PwPD should consider these findings to maximize their effectiveness.

Background. Two-dimensional speckle tracking evaluation (2D-STE) is a useful tool to evaluate the complexity of atrial function by the analysis of the different phases of atrial deformation and by the combination with Doppler measurements of diastolic function. Aim of the study. To evaluate the role of the left atrial (LA) strain parameters to predict worsening chronic heart failure (CHF). Methods. We enrolled outpatients affected by CHF referred to our heart failure unit. Each patient underwent a medical visit, an electrocardiogram (ECG), and an echocardiographic examination. LA function was assessed by 2D-STE. The three phases of LA strain – i.e. the reservoir (LAr), the conduit (LAcd), and the contraction (LAct) – were evaluated. Moreover, the ratio between LAr and that of septal (LAr/Ees), lateral (LAr/Eel), and septal-lateral (LAr/Eem) E/e’ were evaluated. During follow-up, the worsening of heart failure was evaluated. Results. Two hundred twenty-eight patients were enrolled. During a mean follow-up of 14±7 months, 47 patients showed at least one event related to heart failure worsening (40 hospitalisations, 5 heart transplantations, and 19 cardiovascular deaths). During univariate Cox regression analysis, LAr, LAcd, LAct, LAr/Ees, LAr/Eel, and LAr/Eem were all associated with events related to heart failure worsening, but during multivariate regression analysis, only LAr (HR: 0.94; 95% CI: 0.91–0.98; p: 0.007), LAr/Ees (HR: 0.49; 95% CI: 0.30–0.78; p: 0.002), and LAr/Eem (HR: 0.65; 95% CI: 0.47–0.89; p: 0.008) remained significantly associated with the events. Finally, LASr/Ee’s showed accuracy in predicting outcomes greater than LASr (C-index 0.78 vs. 0.72, respectively). Conclusions. In CHF patients, the measure of the LA reservoir by 2D-STE is independently associated with heart failure worsening, but the accuracy in predicting the events is even greater when the reservoir is combined with the Doppler measures of diastolic function.

S1: Analysis of p50 NF-κB ablation in myeloid cells (p50Fl/Fl; Lyz2Cre mice) and enterocytes (p50Fl/Fl; VillinCre mice). S2: Analysis of inflammatory gene expression at different phases of colitisassociated CRC (CAC) development. S3: Lack of p50 NF-κB exacerbates DSS-induced colitis. S4: Genetic ablation of p50 unleashes anti-tumor M1-polarized activation of TAMs. S5: Lack of p50 shapes gut associated immune populations in AOM/DSS treated. S6: Lack of p50 selectively impairs lamina propria monocytes/macrophages accumulation in steady state conditions. mice. S7: Wt and p50-/- mice show similar levels of proliferative colonic cancer cells. S8: Nuclear accumulation of p50 in TAM at the inner tumor tissue does not correlate with CRC patients' outcome.

CRC patients table

Although tumor-associated macrophages (TAM) display a M2-skewed tumor-promoting phenotype in most cancers, in colorectal cancer, both TAM polarization and its impact remain controversial. We investigated the role of the M2-polarizing p50 NF-κB subunit in orchestrating TAM phenotype, tumor microenvironment composition, and colorectal cancer progression. We first demonstrated, by parallel studies in colitis-associated cancer (CAC) and in genetically driven ApcMin mouse models, that the p50-dependent inhibition of M1-polarized gut inflammation supported colorectal cancer development. In accordance with these studies, p50–/– mice displayed exacerbated CAC with fewer and smaller tumors, along with enhanced levels of M1/Th1 cytokines/chemokines, including IL12 and CXCL10, whose administration restrained CAC development in vivo. The inflammatory profile supporting tumor resistance in colons from p50–/– tumor bearers correlated inversely with TAM load and positively with both recruitment of NK, NKT, CD8+ T cells and number of apoptotic tumor cells. In agreement, myeloid-specific ablation of p50 promoted tumor resistance in mice, whereas in colorectal cancer patients, a high number of p50+ TAMs at the invasive margin was associated with decreased IL12A and TBX21 expression and worse postsurgical outcome. Our findings point to p50 involvement in colorectal cancer development, through its engagement in the protumor activation of macrophages, and identify a candidate for prognostic and target therapeutic intervention. Cancer Immunol Res; 6(5); 578–93. ©2018 AACR.

VEGFC induced tumor growth is not associated with intestinal inflammation. Related to Figure 2

S5 T cell gating strategy. Related to Figure 3. S6 FACS gating strategy for TAM and tumoral LEC and RNA sequencing validation. Related to Figure 4

Ovalbumin immunization is enhanced by VEGFR3 blockage. Related to Figure 3

VEGFR3 is expressed on LVs and macrophages in non-metastatic colorectal cancer. Related to Figure 1

Colorectal cancer is a major cause of cancer-related death in Western countries and is associated with increased numbers of lymphatic vessels (LV) and tumor-associated macrophages (TAM). The VEGFC/VEGFR3 pathway is regarded as the principal inducer of lymphangiogenesis and it contributes to metastases; however, no data are available regarding its role during primary colorectal cancer development. We found that both VEGFC and VEGFR3 were upregulated in human nonmetastatic colorectal cancer, with VEGFR3 expressed on both LVs and TAMs. With the use of three different preclinical models of colorectal cancer, we also discovered that the VEGFC/VEGFR3 axis can shape both lymphatic endothelial cells and TAMs to synergistically inhibit antitumor immunity and promote primary colorectal cancer growth. Therefore, VEGFR3-directed therapy could be envisioned for the treatment of nonmetastatic colorectal cancer.Significance:The prolymphangiogenic factor VEGFC is abundant in colorectal cancer and activates VEGFR3 present on cancer-associated macrophages and lymphatic vessels; activation of VEGFR3 signaling fosters cancer immune escape, resulting in enhanced tumor growth.

S7 LEC immunosuppressive function. Related to Figure 5. S8Macrophage depletion strategy. Related to Figure 6

Purpose: To better understand patients’ perspectives on virtual care (VC) delivered by advanced practice physiotherapists (APPs) for hip/knee, foot/ankle, shoulder/elbow, and low back related symptoms. Method: A patient satisfaction questionnaire was developed and distributed electronically to all patients seen by APPs from August 1, 2020 to January 31, 2021. The questionnaire contained quantitative items using a 5-point Likert scale and open-ended questions that yielded qualitative findings. Descriptive statistics were applied to the quantitative data. Qualitative findings were analyzed using a qualitative description approach to identify recurrent themes. Results: Response rate was 74% (374/505) across all clinics. Videoconference was the most common delivery method (91.7%). Overall satisfaction with VC was very high (4.7–4.8/5). Emergent qualitative themes were related to Personal Connection; Preparatory Materials; Virtual Physical Examination; Practical Advantages of VC; Virtual Waiting Room; and Technical Issues. Conclusion: Overall, across several facets including personal connection, patient experience with VC for a variety of musculoskeletal conditions was rated high. Clinically, a systematic approach to the physical examination with preparatory patient education materials was key to positive patient experience.

For decades, cardiologists have largely underestimated the role of the right heart in heart failure due to left heart disease. Nowadays, the importance of evaluating right ventricular (RV) structure and function in left heart failure is well documented and this concept has been emphasized in the most recent heart failure guidelines. However, several relevant questions remain unanswered such as the following: (a) which imaging technique (standard or 3D echocardiography or strain imaging or cardiac magnetic resonance) and, more, which parameters should be used to grade the severity of RV dysfunction? (b) do less widespread and less applied diagnostic tools such as cardiopulmonary stress testing and bioelectrical impedance analysis play a role in this field? (c) are there specific biochemical aspects of RV failure? (d) why notion of pathophysiology of heart and lung interaction are so well appreciated at an academic level but are not applied in the clinical setting? The present review has been prepared by the Heart Failure (HF) working group of the Italian Society of Cardiology and its main objective is to improve our understanding on RV dysfunction in heart failure.

Right heart failure (RHF) is a clinical syndrome in which symptoms and signs are caused by dysfunction and/or overload of the right heart structures, predominantly the right ventricle (RV), resulting in systemic venous hypertension, peripheral oedema and finally, the impaired ability of the right heart to provide tissue perfusion. Pathogenesis of RHF includes the incompetence of the right heart to maintain systemic venous pressure sufficiently low to guarantee an optimal venous return and to preserve renal function. Virtually, all myocardial diseases involving the left heart may be responsible for RHF. This may result from coronary artery disease, hypertension, valvular heart disease, cardiomyopathies and myocarditis. The most prominent clinical signs of RHF comprise swelling of the neck veins with an elevation of jugular venous pressure and ankle oedema. As the situation worsens, fluid accumulation becomes generalised with extensive oedema of the legs, congestive hepatomegaly and eventually ascites. Diagnosis of RHF requires the presence of signs of elevated right atrial and venous pressures, including dilation of neck veins, with at least one of the following criteria: (1) compromised RV function; (2) pulmonary hypertension; (3) peripheral oedema and congestive hepatomegaly. Early recognition of RHF and identifying the underlying aetiology as well as triggering factors are crucial to treating patients and possibly reversing the clinical manifestations effectively and improving prognosis.

Background Optical diagnosis of colonic polyps is poorly reproducible outside of high volume referral centers. The present study aimed to assess whether real-time artificial intelligence (AI)-assisted optical diagnosis is accurate enough to implement the leave-in-situ strategy for diminutive (≤ 5 mm) rectosigmoid polyps (DRSPs). Methods Consecutive colonoscopy outpatients with ≥ 1 DRSP were included. DRSPs were categorized as adenomas or nonadenomas by the endoscopists, who had differing expertise in optical diagnosis, with the assistance of a real-time AI system (CAD-EYE). The primary end point was ≥ 90 % negative predictive value (NPV) for adenomatous histology in high confidence AI-assisted optical diagnosis of DRSPs (Preservation and Incorporation of Valuable endoscopic Innovations [PIVI-1] threshold), with histopathology as the reference standard. The agreement between optical- and histology-based post-polypectomy surveillance intervals (≥ 90 %; PIVI-2 threshold) was also calculated according to European Society of Gastrointestinal Endoscopy (ESGE) and United States Multi-Society Task Force (USMSTF) guidelines. Results Overall 596 DRSPs were retrieved for histology in 389 patients; an AI-assisted high confidence optical diagnosis was made in 92.3 %. The NPV of AI-assisted optical diagnosis for DRSPs (PIVI-1) was 91.0 % (95 %CI 87.1 %–93.9 %). The PIVI-2 threshold was met with 97.4 % (95 %CI 95.7 %–98.9 %) and 92.6 % (95 %CI 90.0 %–95.2 %) of patients according to ESGE and USMSTF, respectively. AI-assisted optical diagnosis accuracy was significantly lower for nonexperts (82.3 %, 95 %CI 76.4 %–87.3 %) than for experts (91.9 %, 95 %CI 88.5 %–94.5 %); however, nonexperts quickly approached the performance levels of experts over time. Conclusion AI-assisted optical diagnosis matches the required PIVI thresholds. This does not however offset the need for endoscopistsʼ high level confidence and expertise. The AI system seems to be useful, especially for nonexperts.

Two-dimensional strain echocardiography (2D-SE) is a reliable method for measuring deformation of the left ventricle.Aim of the study was to determine changes in 2D-SE parameters over time collected during dipyridamole stress echo-cardiography (dipy-stress) and prognosis of patients with non-diagnostic dipy-stress results.In the first phase of the study, assessment of a prospective enrolled population with a non-diagnostic dipy-stress test result was conducted, checking through coronary CT angiography (CCTA) the presence of coronary artery disease (CAD). In the follow-up phase, an echocardiographic re-evaluation and outcome analysis during a mean follow-up of 78 months was carried out.In the first phase, Global Circumferential Strain (GCS) values were similar in the CCTA positive and CCTA negative groups at rest and after stress. For Global Longitudinal Strain (GLS), there was a significant reduction (p.0001) in the CCTA positive group compared to the CCTA negative group. After 78 ± 9 months none of the enrolled patients experimented cardiac events. Values of GCS, both at rest and after stress, did not differ statistically comparing follow-up values with baseline ones. No statistically significant changes were seen in the same analysis for GLS rest and stress values, between baseline and follow-up in the two groups.Performing 2D-SE during dipy-stress can detect mild CAD that conventional stress-tests miss. Patients with mild coronary stenosis may have a favorable mid-term prognosis, but efforts should be made to investigate the decrease trend in GLS, at rest and after stress, reported in this patient group.

The outstanding clinical expansion of monoclonal antibodies (mAbs) to programmed cell death receptor-1 (PD-1) (nivolumab and pembrolizumab) and PD-1 ligand-1 (PDL-1) (atezolizumab, avelumab and durvalumab) has received an increasing level of interest regarding immunotherapy and multidrug combinations, for the treatment of a number of common human malignancies. Some patients treated with these agents receive remarkable benefits in term of quality of life, progression-free (PFS) and overall survival (OS). However, a significant percentage of these patients experience immune-related adverse events (irAEs), while others present with an ultra-rapid disease progression, defined as hyperprogression. Research in to the mechanisms related to these events is an active field of investigation worldwide, whose results are expected to provide new insights to design new combinations, to identify potentially responsive patients and to prevent irAEs’ occurrence

Multiple sclerosis (MS), especially in its progressive phase, involves early axonal and neuronal damage resulting from a combination of inflammatory mediators, demyelination, and loss of trophic support. During progressive disease stages, a microenvironment is created within the central nervous system (CNS) favoring the arrival and retention of inflammatory cells. Active demyelination and neurodegeneration have also been linked to microglia (MG) and astrocyte (AST)-activation in early lesions. While reactive MG can damage tissue, exacerbate deleterious effects, and contribute to neurodegeneration, it should be noted that activated MG possess neuroprotective functions as well, including debris phagocytosis and growth factor secretion. The progressive form of MS can be modeled by the prolonged administration to cuprizone (CPZ) in adult mice, as CPZ induces highly reproducible demyelination of different brain regions through oligodendrocyte (OLG) apoptosis, accompanied by MG and AST activation and axonal damage. Therefore, our goal was to evaluate the effects of a reduction in microglial activation through orally administered brain-penetrant colony-stimulating factor-1 receptor (CSF-1R) inhibitor BLZ945 (BLZ) on neurodegeneration and its correlation with demyelination, astroglial activation, and behavior in a chronic CPZ-induced demyelination model. Our results show that BLZ treatment successfully reduced the microglial population and myelin loss. However, no correlation was found between myelin preservation and neurodegeneration, as axonal degeneration was more prominent upon BLZ treatment. Concomitantly, BLZ failed to significantly offset CPZ-induced astroglial activation and behavioral alterations. These results should be taken into account when proposing the modulation of microglial activation in the design of therapies relevant for demyelinating diseases. Cover Image for this issue: https://doi.org/10.1111/jnc.15394.

Supplemental material, sj-docx-3-msj-10.1177_13524585231161494 for Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study by Gavin Giovannoni, Alexey Boyko, Jorge Correale, Gilles Edan, Mark S Freedman, Xavier Montalban, Kottil Rammohan, Dusan Stefoski, Bassem Yamout, Thomas Leist, Aida Aydemir, Laszlo Borsi and Elisabetta Verdun di Cantogno in Multiple Sclerosis Journal

We study semiclassically the dynamics of a quantum $p$-spin glass model starting from initial states defined in microcanonical shells. We compute different chaos estimators, such as the Lyapunov exponent and the Kolmogorov-Sinai entropy, and find a marked maximum as a function of the energy of the initial state. By studying the relaxation dynamics and the properties of the energy landscape we show that the maximal chaos emerges in correspondence with the fastest spin relaxation and the maximum complexity, thus suggesting a qualitative picture where chaos emerges as the trajectories are scattered over the exponentially many saddles of the underlying landscape. We also observe hints of ergodicity breaking at low energies, indicated by the correlation function and a maximum of the fidelity susceptibility., Comment: 14+17 pages, 8 figures

Supplemental material, sj-docx-3-msj-10.1177_13524585231161494 for Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study by Gavin Giovannoni, Alexey Boyko, Jorge Correale, Gilles Edan, Mark S Freedman, Xavier Montalban, Kottil Rammohan, Dusan Stefoski, Bassem Yamout, Thomas Leist, Aida Aydemir, Laszlo Borsi and Elisabetta Verdun di Cantogno in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-msj-10.1177_13524585231161494 for Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study by Gavin Giovannoni, Alexey Boyko, Jorge Correale, Gilles Edan, Mark S Freedman, Xavier Montalban, Kottil Rammohan, Dusan Stefoski, Bassem Yamout, Thomas Leist, Aida Aydemir, Laszlo Borsi and Elisabetta Verdun di Cantogno in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-msj-10.1177_13524585231161494 for Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study by Gavin Giovannoni, Alexey Boyko, Jorge Correale, Gilles Edan, Mark S Freedman, Xavier Montalban, Kottil Rammohan, Dusan Stefoski, Bassem Yamout, Thomas Leist, Aida Aydemir, Laszlo Borsi and Elisabetta Verdun di Cantogno in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-msj-10.1177_13524585231161494 for Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study by Gavin Giovannoni, Alexey Boyko, Jorge Correale, Gilles Edan, Mark S Freedman, Xavier Montalban, Kottil Rammohan, Dusan Stefoski, Bassem Yamout, Thomas Leist, Aida Aydemir, Laszlo Borsi and Elisabetta Verdun di Cantogno in Multiple Sclerosis Journal

Supplemental material, sj-docx-2-msj-10.1177_13524585231161494 for Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study by Gavin Giovannoni, Alexey Boyko, Jorge Correale, Gilles Edan, Mark S Freedman, Xavier Montalban, Kottil Rammohan, Dusan Stefoski, Bassem Yamout, Thomas Leist, Aida Aydemir, Laszlo Borsi and Elisabetta Verdun di Cantogno in Multiple Sclerosis Journal

Supplemental material, sj-docx-2-msj-10.1177_13524585231161494 for Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study by Gavin Giovannoni, Alexey Boyko, Jorge Correale, Gilles Edan, Mark S Freedman, Xavier Montalban, Kottil Rammohan, Dusan Stefoski, Bassem Yamout, Thomas Leist, Aida Aydemir, Laszlo Borsi and Elisabetta Verdun di Cantogno in Multiple Sclerosis Journal

Objective: Most contemporary data concerning the frequency and causes of multiple sclerosis (MS) misdiagnosis are from North America and Europe with different healthcare system structure and resources than countries in Latin America. We sought to determine the frequency, and potential contributors to MS misdiagnosis in patients evaluated at an MS referral center in Argentina. Methods: The study was a retrospective medical record review. We included patients evaluated at the MS Clinic at Fleni between April 2013 and March 2021. Diagnoses prior to consultation, final diagnoses after consultation, demographic, clinical and paraclinical data, and treatment were extracted and classified. Results: Seven hundred thirty-six patients were identified. Five hundred seventy-two presented with an established diagnosis of MS and after evaluation, misdiagnosis was identified in 89 (16%). Women were at 83% greater risk of misdiagnosis ( p = 0.034). The most frequent alternative diagnoses were cerebrovascular disease, radiological isolated syndrome (RIS), and headache. Seventy-four (83%) of misdiagnosed patients presented with a syndrome atypical for demyelination, 62 (70%) had an atypical brain magnetic resonance imaging (MRI), and 54 (61%) were prescribed disease-modifying therapy. Conclusion: Sixteen percent of patients with established MS were subsequently found to have been misdiagnosed. Women were at higher risk for misdiagnosis. Expert application of the McDonald criteria may prevent misdiagnosis and its associated morbidity and healthcare system cost.

Background and Purpose: No current consensus exists on the best anesthetic management of ischemic stroke patients undergoing mechanical thrombectomy. Both conscious sedation (CS) and general anesthesia (GA) are currently considered valid anesthetic strategies, yet patients managed under CS may require emergent conversion to GA, which has been associated with worse outcomes. The aim of this study was to analyze the conversion rate and potential risk factors for GA conversion during mechanical thrombectomy. Methods: Two-hundred and twenty-seven patients with consecutive acute anterior circulation ischemic stroke treated with mechanical thrombectomy and initiated under CS or local anesthesia were included in this retrospective analysis. Conversion rate to GA was calculated, while univariate and multivariate analysis were used to identify risk factors. Results: Twenty patients (8.8%) were switched to GA. Multivariate analysis identified procedure duration (odds ratio [OR] 1.01, 95% confidence interval [CI] 1.00–1.02, p value 0.028), tandem stroke (OR 8.57, 95% CI 2.06–35.7, p value 0.003), Sequential Organ Failure Assessment (SOFA) (OR 1.76, 95% CI 1.19–2.61, p value 0.005), and number of pharmacological agents used (OR 5.76, 95% CI 2.49–13.3, p value Conclusion: In our study, tandem occlusion, longer endovascular procedures, SOFA, and number of pharmacological agents used predicted the risk of emergent conversion to GA in stroke patients undergoing endovascular treatment. Prospective studies investigating optimal CS strategies are deemed necessary.

Background and aims Takotsubo syndrome (TTS) is an acute heart failure syndrome featured by a reversible left ventricular systolic dysfunction. However, few data have been reported about prevalence of non-cardiovascular comorbidities as chronic neurological disorders in TTS patients. Aim of this study was to compare clinical features, short- and long-term outcome among TTS patients with history of neurological disorder. Methods 2301 patients with TTS were enrolled in a multicenter prospective European registry from July 2002 to November 2021. Clinical features, in- and out-of-hospital MACE, laboratory and imaging data were collected and a long-term follow-up was performed. Results Prevalence of history of neurological disorder was 17% (n= 400 pts). Most represented neurological conditions were previous cerebrovascular disorders (ischemic stroke and transient ischemic attack, 36.2%), followed by neurodegenerative disorders (30.7%, including cognitive disorders and motion disorders), tensive migraine (10%) and epilepsy (9.5%). Neurological Patients developed TTS more frequently after a physical trigger (46.2% vs 33.8%, p During hospitalization neurological patients had longer in-hospital stay (10±11 days vs 8±8 days, p Long-term mortality was higher in patients with history of neurological disorders (23.5% vs 10%, p Conclusions Patients with history of neurological disorders and TTS have different clinical features and worse prognosis with higher short-term and long-term mortality.

Background Systemic sclerosis (SSc) is a connective tissue disease characterized by the fibrosis of skin and internal organs, frequent immunity abnormalities and alterations in microvasculature. Among SSc complications, Pulmonary Hypertension (PH) is a frequent and severe one. Many echocardiographic parameters are used to assess pulmonary pressure and Right Ventricle (RV) dimension and function in these patients, from classical echocardiographic indexes to the most recent Speckle-Tracking Echocardiography (STE), while flow-mediated vasodilation (FMD) is the most common method to assess vascular reactivity. Aim of the study To evaluate any possible relations between endothelial function and RV dimension and function in patients with SSc. Method 48 sclerodermic patients underwent to echocardiographic examination and FMD, searching for relations between RV dimension and function and endothelial function indexes. For the RV we considered: 1) the eccentricity index (EI), 2) the fractional area change (FAC), 3) the ratio TAPSE/PAPs, 4) the RV basal diameter, 5) the RV free-wall strain and 6) the tricuspid regurgitation velocity; for the endothelium we evaluated the absolute difference between the radial artery diameters before and after 5 minutes of ischemia. We used a t-Student test (t-test) for unpaired samples with similar variances to verify the hypothesis that patients with altered RV parameters show a lower value in the absolute difference between radial diameters. Results Only EI and endothelial function showed a significant relation. In fact, with a level of confidence of the 95% we can say that patients with an EI>=1,1 report a minor increase in radial artery diameter than patients with EI Conclusions In patients affected by SSc, the endothelial function is related to eccentricity index. Multicenter studies are needed in order to confirm the results of our study

Background Takotsubo syndrome (TTS) is an acute heart failure syndrome featured by a reversible left ventricular systolic dysfunction with significant rate of in- and out-of-hospital mayor cardiac adverse events (MACE). Aim of the study To evaluate the possible role of hypochloremia as prognostic marker at short- and long-term follow-up in subjects with TTS. Methods 305 consecutive patients were enrolled in a multicenter international registry. Clinical, laboratory and echocardiographic evaluations were performed at admission and during hospitalization. Incident hypochloremia (serum chloride level below 97 mEq/l) during hospitalization was recorded. In-hospital MACE, short- and long-term mortality was recorded. Results Mean admission serum chloride levels were 102±5 mEq/l. 97 out of 305 (37%) patients experienced incident hypochloremia. Patients with incident hypochloremia were older (78±10 vs 73±12 years, p=0.01), had lower admission LVEF (34±8% vs 37±8%, p=0.009), and longer hospital stay (9±4 vs 7±4 days, p=0.0003). During hospitalization patients with incident hypochloremia had higher rates of complication (45% vs 32%, p=0.01), lower levels of natremia and azotemia at admission and discharge. At long term follow-up incident hypochloremia was associated with increased risk of MACE (49% vs 32%, p=0.005) and death (42% vs 24%, p=0.002, log rank p Conclusion Incident hypochloremia is a common finding among hospitalized patients with TTS, associated with higher risk of in-hospital events and long-term MACE and death.

Background Sodium glucose cotransporter type 2 inhibitors (SGLT2i), also called gliflozins, are playing an emerging role for the treatment of heart failure with reduced left ventricle ejection fraction (HFrEF). However, the direct effects of SGLT2i on left and right ventricular remodeling and function have not been completely clarified. We therefore aimed to assess clinical response to gliflozins focusing on echocardiographic evaluation and identify any predictive factors with a machine learning approach. Methods Based on Random Forest, a robust and consolidated machine learning approach, we carried out a single subject analysis to evaluate to which extent patients treated with gliflozins can effectively be distinguished from patients undergoing non-gliflozins treatments. Besides, we carried out an eXplainability analysis using Shapley values to outline the clinical parameters which mostly took advantage by gliflozins. Finally, machine learning experiments were designed to highlight the presence of specific clinical patterns undermining the gliflozins effectiveness. Results 5-fold cross-validation analyses showed that gliflozin treatment was identified with a 0.70 ± 0.03% accuracy; the most important parameters supporting such accuracy were Right Ventricle S’ Velocity (RV S’), Left Ventricle End Systolic Diameter (LVESD) and E/e’ ratio. Low Tricuspid Annular Plane Systolic Excursion (TAPSE) values along with high LVESD and End Diastolic Volume (EDV) values are likely to impair the gliflozin effectiveness. Conclusions Treatment with gliflozins resulted in an improvement of several echocardiographic parameters related to biventricular function and left ventricle remodeling. Several clinical parameters, as simple echocardiographic parameters, may accurately predict the cardiovascular response to gliflozins treatment.

Rationale Demographic characteristics of pulmonary arterial hypertension (PAH) patients have changed over time, but the effects of cardiovascular risk factors on risk status and pulmonary vascular resistance (PVR) reduction with initial oral combination therapy are not known. Therefore, we tested the relevance of cardiovascular comorbidities in this setting. Methods The study enrolled 181 treatment-naive PAH patients with a 6- months (IQR 144-363 days) right heart catheterization and risk assessment after initial oral combination therapy. Results Group-A, 96 (53.0%) patients without cardiac comorbidities; Group-B, 54 (29.8%) patients with one cardiac comorbidity; Group-C, 31 (17.1%) patients with ≥2 cardiac comorbidities. Group-C patients were older with a balanced gender distribution. There was a significant difference in PVR reduction moving from the absence to one or ≥2 cardiac comorbidities, respectively, median -45.0%, -30.3%, -24.3%. A ERS/ESC low-risk status was present at first follow-up in 50 (52.0%) patients in Group-A, 19 (35.1%) in Group-B, and 9 (29.0%) in Group-C; a REVEAL 2.0 low-risk status was present at first follow-up in 41 (42.0%) patients in Group-A, 15 (27.7%) in Group-B, and 7 (22.6%) in Group-C. Group-A patients were 2.3 times more likely to achieve/maintain a low risk status compared with Group-B and -C (OR 2.27, 95% C.I. 1.15-4.54, p=0.02). No significant difference was observed between patients with non-cardiac comorbidities and those without comorbidities. Conclusion Initial oral combination therapy seems associated with a less effective response for patients with cardiovascular comorbidities compared with the others, related to the magnitude of treatment- induced decrease in PVR.