Search

637 Background: The combination of neutrophil to lymphocyte (NLR), bone metastases and IMDC score in the novel prognostic Meet-URO score has shown a higher prognostic performance than the IMDC score alone in mRCC pts receiving ≥2nd line nivolumab or cabozantinib in two retrospective analyses and 1st line nivolumab-ipilimumab in a real-world prospective study [http://bit.ly/Meet-URO15_score]. Further validation is needed since this score represents an easy prognostic tool for clinical practice with no additional costs. Methods: A real-world analysis of elderly (≥70 yo) mRCC pts treated with any line cabozantinib was conducted in the multicenter observational prospective Zebra study. Baseline Meet-URO score was assessed. The primary endpoint was overall survival (OS) and the Harrell’s c-index was calculated to compare accuracy of survival prediction of the Meet-URO and IMDC scores. Results: 104 mRCC pts received cabozantinib as 1st (38%), 2nd (20%), 3rd (33%) and 4th (8%) line, with a median follow-up of 11.2 months (mo) and a median overall survival (mOS) of 18.4 mo. According to the IMDC score, favorable- (15%), intermediate- (65%) and poor-risk (19%) pts had a mOS not reached (NR), 15.6 and of 5.7 mo, respectively (p = 0.011). Reclassifying the population according to the Meet-URO score, we observed that group 1 (10%) and group 2 (25%) had both mOS NR, whereas group 3 (33%), group 4 (25%) and group 5 (8%) had a mOS of 13.6, 12.5 and 3.7 mo, respectively (p = 0.001). Moreover, the Meet-URO score maintained its discrimination ability also merging group 1-2 vs 3-4 vs 5 (p < 0.001). NLR < 3.2 was the heaviest component of the score (p < 0.001, mOS 24.8 vs 11.5 mo). The Meet-URO score (using both original with 5 groups and modified with 3 groups) has shown a higher prognostic power than the IMDC score alone (c-index of 0.686 and 0.676 vs 0.622). Conclusions: This analysis confirmed the higher accuracy in survival stratification of the Meet-URO score compared with the IMDC score alone also in a specific population like elderly mRCC pts treated with cabozantinib. NLR was confirmed as a strong prognostic factor with cabozantinib. Further applications of the Meet-URO score in mRCC pts treated with first-line immune-combinations are planned and highly awaited. Clinical trial information: 2018/116/PU .

Background In multiple sclerosis, the correlation between white matter lesion volumes (LV) and expanded disability status scale (EDSS) is at best moderate, leading to the “clinico-radiological paradox”, influenced by many factors, including the lack of information on the spatial localisation of each lesion on synthetic metrics such as LV. We used a probabilistic approach to provide the volume of WM tracts that may be disconnected by lesions and to evaluate its correlation with EDSS. Methods Forty-five patients (aged 37.4 ± 6.8 years, mean ± standard deviation; 30 females; 29 relapsing-remitting, 16 progressive) underwent 3-T magnetic resonance imaging. Both LV and the volume of the tracts crossing the lesioned regions (disconnectome volume, DV) were calculated using BCBtoolkit and correlated with EDSS. Results T1-weighted LV and DV significantly correlated with EDSS (p ≤ 0.006 r ≥ 0.413) as it was for T2-weighted LV and T2-weighted DV (p ≤ 0.004 r ≥ 0.430), but only T1-weighetd and T2-weighted DVs were EDSS significant predictors (p ≤ 0.001). The correlations of T1-weighted and T2-weighted LV with EDSS were significantly mediated by DV, while no effect of LV on the EDSS-DV correlation was observed. Conclusion The volume of disconnected WM bundles mediates the LV-EDSS correlation, representing the lonely EDSS predictor.

BACKGROUND: A posterior crossbite occurs when the top back teeth bite inside the bottom back teeth. The prevalence of posterior crossbite is around 4% and 17% of children and adolescents in Europe and America, respectively. Several treatments have been recommended to correct this problem, which is related to such dental issues as tooth attrition, abnormal development of the jaws, joint problems, and imbalanced facial appearance. Treatments involve expanding the upper jaw with an orthodontic appliance, which can be fixed (e.g. quad‐helix) or removable (e.g. expansion plate). This is the third update of a Cochrane review first published in 2001. OBJECTIVES: To assess the effects of different orthodontic treatments for posterior crossbites. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched four bibliographic databases up to 8 April 2021 and used additional search methods to identify published, unpublished and ongoing studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of orthodontic treatment for posterior crossbites in children and adults. DATA COLLECTION AND ANALYSIS: Two review authors, independently and in duplicate, screened the results of the electronic searches, extracted data, and assessed the risk of bias of the included studies. A third review author participated to resolve disagreements. We used risk ratios (RR) and 95% confidence intervals (CIs) to summarise dichotomous data (event), unless there were zero values in trial arms, in which case we used odds ratios (ORs). We used mean differences (MD) with 95% CIs to summarise continuous data. We performed meta‐analyses using fixed‐effect models. We used the GRADE approach to assess the certainty of the evidence for the main outcomes. MAIN RESULTS: We included 31 studies that randomised approximately 1410 participants. Eight studies were at low risk of bias, 15 were at high risk of bias, and eight were unclear. Intervention versus observation For children (age 7 to 11 years), quad‐helix was beneficial for posterior crossbite correction compared to observation (OR 50.59, 95% CI 26.77 to 95.60; 3 studies, 149 participants; high‐certainty evidence) and resulted in higher final inter‐molar distances (MD 4.71 mm, 95% CI 4.31 to 5.10; 3 studies, 146 participants; moderate‐certainty evidence). For children, expansion plates were also beneficial for posterior crossbite correction compared to observation (OR 25.26, 95% CI 13.08 to 48.77; 3 studies, 148 participants; high‐certainty evidence) and resulted in higher final inter‐molar distances (MD 3.30 mm, 95% CI 2.88 to 3.73; 3 studies, 145 participants, 3 studies; moderate‐certainty evidence). In addition, expansion plates resulted in higher inter‐canine distances (MD 2.59 mm, 95% CI 2.18 to 3.01; 3 studies, 145 participants; moderate‐certainty evidence). The use of Hyrax is probably effective for correcting posterior crossbite compared to observation (OR 48.02, 95% CI 21.58 to 106.87; 93 participants, 3 studies; moderate‐certainty evidence). Two of the studies focused on adolescents (age 12 to 16 years) and found that Hyrax increased the inter‐molar distance compared with observation (MD 5.80, 95% CI 5.15 to 6.45; 2 studies, 72 participants; moderate‐certainty evidence). Intervention A versus intervention B When comparing quad‐helix with expansion plates in children, quad‐helix was more effective for posterior crossbite correction (RR 1.29, 95% CI 1.13 to 1.46; 3 studies, 151 participants; moderate‐certainty evidence), final inter‐molar distance (MD 1.48 mm, 95% CI 0.91 mm to 2.04 mm; 3 studies, 151 participants; high‐certainty evidence), inter‐canine distance (0.59 mm higher (95% CI 0.09 mm to 1.08 mm; 3 studies, 151 participants; low‐certainty evidence) and length of treatment (MD −3.15 months, 95% CI −4.04 to −2.25; 3 studies, 148 participants; moderate‐certainty evidence). There was no evidence of a difference between Hyrax and Haas for posterior crossbite correction (RR 1.05, 95% CI 0.94 to 1.18; 3 studies, 83 participants; moderate‐certainty evidence) or inter‐molar distance (MD −0.15 mm, 95% CI −0.86 mm to 0.56 mm; 2 studies of adolescents, 46 participants; moderate‐certainty evidence). There was no evidence of a difference between Hyrax and tooth‐bone‐borne expansion for crossbite correction (RR 1.02, 95% CI 0.92 to 1.12; I² = 0%; 3 studies, 120 participants; low‐certainty evidence) or inter‐molar distance (MD −0.66 mm, 95% CI −1.36 mm to 0.04 mm; I² = 0%; 2 studies, 65 participants; low‐certainty evidence). There was no evidence of a difference between Hyrax with bone‐borne expansion for posterior crossbite correction (RR 1.00, 95% CI 0.94 to 1.07; I² = 0%; 2 studies of adolescents, 81 participants; low‐certainty evidence) or inter‐molar distance (MD −0.14 mm, 95% CI −0.85 mm to 0.57 mm; I² = 0%; 2 studies, 81 participants; low‐certainty evidence). AUTHORS' CONCLUSIONS: For children in the early mixed dentition stage (age 7 to 11 years old), quad‐helix and expansion plates are more beneficial than no treatment for correcting posterior crossbites. Expansion plates also increase the inter‐canine distance. Quad‐helix is more effective than expansion plates for correcting posterior crossbite and increasing inter‐molar distance. Treatment duration is shorter with quad‐helix than expansion plates. For adolescents in permanent dentition (age 12 to 16 years old), Hyrax and Haas are similar for posterior crossbite correction and increasing the inter‐molar distance. The remaining evidence was insufficient to draw any robust conclusions for the efficacy of posterior crossbite correction.

Healthcare-related SARS-CoV-2 infection is an issue of particular concern during the pandemic. It has important repercussions on the National Health System, which represents a source of medical-legal health disputes. In the healthcare context, there are reports of negative screening at hospital admission (via nasopharyngeal swabs) and subsequent diagnosis of SARS-CoV-2 infection during hospitalization. Such cases cannot be considered a priori of healthcare-related infections but require extensive in-depth evaluation. In this study, we propose an empirical classification to frame cases of SARS-CoV-2 infection diagnosed in the hospital (first negative admission swab, with subsequent positive test during hospitalization). The classification is based on five categories: nosocomial, probably nosocomial, indeterminate, probably community, and community cases. We analyzed patients who died after testing positive for SARS-CoV-2 during hospitalization (with initial negative screening) in the largest hospital in Northwest Italy from February 2020 to 31 December 2021. A total of 383 cases were tracked and are listed as follows: 41 cases (11%) were classified as nosocomial (i.e., 3.2% of COVID-19 deaths). In contrast, 71 cases (19%) were classified as probably nosocomial, 69 (18%) were indeterminate (i.e., the clinical, radiological, and laboratory characteristics did not provide information on the genesis of the infection), 166 (43%) were classified as probably community cases, and 36 (9%) were defined as community cases. Deceased patients with nosocomial SARS-CoV-2 infection constituted the following: 3.23% (41/1266) with respect to the total number of COVID-19 deaths, 1.1% (41/3789) with respect to those who entered the hospital with a negative swab and 0.82% (41/4672) with respect to the total of deaths from any cause of death. In this paper we discuss the topic and issues of nosocomial COVID-19 in hospitalized patients and address the medicolegal implications.

To determine the effect of geriatric comanagement on clinical outcomes of older patients undergoing surgery for gastrointestinal cancer.This was a single-center, nonrandomized, before-and-after study, which compared patient outcomes before and after the implementation of geriatric comanagement in an oncological surgery division.The study included patients aged 70 or older, who were treated for a gastrointestinal cancer at the Oncological Surgery Division of the Policlinico San Martino Hospital (Genoa, Italy). Patients from the control group were treated between January 2015 and October 2018, and the patients who received geriatric comanagement during their stay in the surgical ward were treated between November 2018 and December 2019.Patients from both groups received a preoperative comprehensive geriatric assessment in the preoperative phase and were followed according to the Enhanced Recovery After Surgery model in the perioperative period. In the geriatric comanagement group, targeted interventions during daily geriatrician-led ward rounds were performed. Inverse probability weighting was used to adjust estimates for potential baseline confounders.A total of 207 patients were included: 107 in the control group and 90 who received geriatric comanagement. Overall, patients from both groups had similar demographic and clinical characteristics with a median [interquartile range (IQR)] age of 80.0 (77.0, 84.0) years and a pre-frail phenotype [median (IQR) 40-item Frailty Index 0.15 (0.10, 0.26)]. In the geriatric comanagement group, a significant reduction in grade I-V complications (adjusted odds ratio 0.29; 95% CI 0.21-0.40); Plt; .001) and in 1-year readmissions (adjusted hazard ratio 0.53; 95% CI 0.28-0.98; Plt; .044) was observed. No difference between the 2 groups in terms of 1-year mortality was detected.Our study supports the implementation of geriatric comanagement in the care of older patients undergoing surgery for gastrointestinal cancer.

Background Isavuconazole is the newest triazole antifungal approved for the treatment of invasive aspergillosis (IA) and invasive mucormycosis in adult patients. Objectives To characterize the assessment of the blood levels of isavuconazole and their association with efficacy and toxicity. Methods From January 2017 to May 2018, blood samples obtained from patients receiving isavuconazole were analysed for therapeutic drug monitoring. Factors influencing the blood concentrations of isavuconazole, such as weight, length of treatment, route of administration and results of selected liver function tests, were analysed in univariate and multivariate models. The receiver operating characteristic (ROC) curve was analysed to detect the best cut-off for isavuconazole toxicity. Results A total of 264 isavuconazole blood concentrations in 19 patients were analysed. The median value of isavuconazole concentration in all patients during the first 30 days of therapy was 3.69 mg/L (range 0.64–8.13 mg/L). A linear increase of 0.032 mg/L (range 0.023–0.041 mg/L) for each day of treatment (P = 0.002) was observed. In multivariate analysis the association between the length of treatment and higher levels of isavuconazole (P Conclusions Isavuconazole was efficacious and well tolerated. Side effects, mainly gastrointestinal, were associated with prolonged administration and high serum levels.

Objective To evaluate inter- and intra-rater reliability of background parenchymal enhancement (BPE) assessment across breast MRI sequences. Materials and methods Institutional review board approval was obtained and the requirement for consent was waived. Three radiologists qualitatively categorized BPE on 150 breast MRI using a four-point scale (minimal, mild, moderate or marked) according to BI-RADS category system. According to MR-sequence used for the assessment of BPE, inter-rater and intra-rater reliability across a simulated reading strategy with four options was performed: (1) initial contrast-enhanced (CE) fat-suppressed T1-weighted images (2) initial CE subtracted images (3) maximum-intensity-projection (MIP) of the first CE subtracted images (4) combination of initial CE fat-suppressed T1-weighted, initial CE subtracted and MIP images. Raters repeated BPE assessment of 45 breast MRI four weeks after the initial assessment. Gwet’s AC1 index with ordinal weights was used to assess reliabilities. Results Gwet’s index for the reliability among the three raters was 0.68 (0.63-0.74) using initial contrast-enhanced fat-suppressed T1 weighted images, 0.74 (0.69-0.80) using subtracted images, 0.80 (0.76-0.83) using MIP, 0.80 (0.77-0.84) using a combination of the initial contrast-enhanced fat-suppressed T1 weighted, initial contrast-enhanced subtracted and MIP images. Test-retest reliability was 0.81 (0.60–1.00) for rater 1, 0.77 (0.55-0.98) for rater 2, 0.79 (0.59-0.99) for rater 3 using the combination of initial contrast-enhanced fat-suppressed T1 weighted, initial contrast-enhanced subtracted and MIP images. Conclusions Overall, the combination of all CE MRI images showed the highest reliability of BPE assessment. However, MIP showed a high reliability with lower reading time compared to the combination of all CE MRI images.

Invasive candidiasis is associated with high morbidity and mortality in critically ill patients, i.e. patients admitted to Intensive Care Units (ICUs) or in surgical wards. There are no clinical signs or specific symptoms and even though early diagnosis risk scores and rapid tests are available, none of such strategies has an equally-optimal level of sensitivity and specificity. In the era of Electronic Health Records (EHRs), several clinical studies exploited Machine Learning (ML) models and large database of features to improve the diagnosis accuracy. The main aim of this work is to build a wide dataset which can be exploited to apply ML models to further improve the early recognition of candidemia at the bedside of patients with compatible signs and symptoms.

Invasive candidiasis is associated with high morbidity and mortality in critically ill patients, i.e. patients admitted to Intensive Care Units (ICUs) or in surgical wards. There are no clinical signs or specific symptoms and even though early diagnosis risk scores and rapid tests are available, none of such strategies has an equally-optimal level of sensitivity and specificity. In the era of Electronic Health Records (EHRs), several clinical studies exploited Machine Learning (ML) models and large database of features to improve the diagnosis accuracy. The main aim of this work is to build a wide dataset which can be exploited to apply ML models to further improve the early recognition of candidemia at the bedside of patients with compatible signs and symptoms.

Background Interleukin-1 plays a pivotal role in the inflammatory response during cytokine storm syndromes. Objective To analyse the efficacy and safety of early anti-inflammatory treatment (AIT) with i.v anakinra with or without glucocorticoids (GC) in COVID19 pneumonia. Methods We performed a retrospective single-centre cohort study on patients admitted for COVID19 pneumonia from February 26th to April 29th, 2020 to assess the efficacy of early AIT with i.v. Anakinra (100mg every 8 hours for 3 days, with tapering) alone or in combination with GC (i.v. methylprednisolone, 1-2 mg/kg daily, with tapering). Standard of care (SOC) treatment was: hydroxychloroquine and/or azithromycin with or without antivirals and anticoagulants. Late rescue AIT with anakinra or tocilizumab was also evaluated. Treatment effect on Overall Survival (OS) was assessed by a Propensity Score adjusted Cox model. Results 128 patients were analyzed; 63 received early AIT (30 anakinra, 33 anakinra and CG) at admission; 65 patients (44 with SOC, 21 SOC plus late rescue AIT) did not and were used as controls. After adjusting for all the unbalanced baseline covariates, early AIT reduced the hazard of mortality by 74% (adjusted HR=0.26, p, Graphical abstract, Capsule summary: This study provide evidence that the early use of Anakinra alone or with glucocorticoids allows a prompt amelioration of the inflammatory and respiratory parameters, reducing the mortality rate in patients with severe COVID-19 pneumonia.

Background: The MuSC-19 project is an Italian cohort study open to international partners that collects data on multiple sclerosis (MS) patients with COVID-19. During the second wave of the pandemic, serological tests became routinely available. Objective: To evaluate the seroprevalence of anti-SARS-CoV-2 antibodies according to the use of disease-modifying therapy (DMT) in a subset of patients included in the MuSC-19 data set who had undergone a serological test. Methods: We evaluated the association between positive serological test results and time elapsed since infection onset, age, sex, Expanded Disability Status Scale score, comorbidities and DMT exposure using a multivariable logistic model. Results: Data were collected from 423 patients (345 from Italy, 61 from Turkey and 17 from Brazil) with a serological test performed during follow-up. Overall, 325 out of 423 tested patients (76.8%) had a positive serological test. At multivariate analysis, therapy with anti-CD20 was significantly associated with a reduced probability of developing antibodies after COVID-19 (odds ratio (OR) = 0.20, p = 0.002). Conclusion: Patients with MS maintain the capacity to develop humoral immune response against SARS-COV-2, although to a lesser extent when treated with anti-CD20 drugs. Overall, our results are reassuring with respect to the possibility to achieve sufficient immunization with vaccination.

Introduction The Italian Society of Anti-Infective Therapy (SITA) and the Italian Society of Pulmonology (SIP) constituted an expert panel for developing evidence-based guidance for the clinical management of adult patients with coronavirus disease 2019 (COVID-19) outside intensive care units. Methods Ten systematic literature searches were performed to answer ten different key questions. The retrieved evidence was graded according to the Grading of Recommendations Assessment, Development, and Evaluation methodology (GRADE). Results and Conclusion The literature searches mostly assessed the available evidence on the management of COVID-19 patients in terms of antiviral, anticoagulant, anti-inflammatory, immunomodulatory, and continuous positive airway pressure (CPAP)/non-invasive ventilation (NIV) treatment. Most evidence was deemed as of low certainty, and in some cases, recommendations could not be developed according to the GRADE system (best practice recommendations were provided in similar situations). The use of neutralizing monoclonal antibodies may be considered for outpatients at risk of disease progression. For inpatients, favorable recommendations were provided for anticoagulant prophylaxis and systemic steroids administration, although with low certainty of evidence. Favorable recommendations, with very low/low certainty of evidence, were also provided for, in specific situations, remdesivir, alone or in combination with baricitinib, and tocilizumab. The presence of many best practice recommendations testified to the need for further investigations by means of randomized controlled trials, whenever possible, with some possible future research directions stemming from the results of the ten systematic reviews. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00487-7.

Background: It is unclear how multiple sclerosis (MS) affects the severity of Covid-19. Methods: Hospitalization, Intensive Care Unit (ICU) admission and death after Covid-19 diagnosis of 1362 MS patients were compared to the age and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher-risk: EDSS>3 or at least one comorbidity, lower-risk: EDSS

Background The primary aim of the study was determining the validation of the modified 19-item Frailty Index (mFI-19), based on the standard procedure for creating a frailty index scoring in the accumulation deficit theory of Rockwood and comparing it with the gold standard comprehensive geriatric assessment (CGA) in old age patients with hip fracture. As a secondary aim, we compared prognostic accuracies of mFI-19 and CGA in predicting long-term mortality after surgery. Materials and methods A total of 364 older patients with hip fractures, each a candidate for surgery, were consecutively enrolled. All were subjected to CGA and mFI-19 at baseline and time to death (years from hip surgery) were collected prospectively. Results Mean patient age was 86.5 (SD: 5.65) years. The most common clinical phenotype (77%) was frail. Both CGA and mFI-19 performed similarly in predicting long-term mortality (Harrell's C-index: 0.66 and 0.68, respectively). Conclusions The mFI-19 was validated, compared to the gold standard CGA, based on a systematic process for creating a frailty index in relation to the accumulation deficit. This is one of few prospective studies addressing long-term mortality in older adults with hip fractures, invoking a methodologically robust frailty screening assessment.

The aim of this retrospective study was to assess the rate of full donor chimerism (F-DC) in patients with myelofibrosis, prepared for an allogeneic stem cell transplant, with one or two alkylating agents. We analyzed 120 patients with myelofibrosis, for whom chimerism data were available on day +30. There were two groups: 42 patients were conditioned with one alkylating agent (ONE-ALK), either thiotepa or busulfan or melphalan, in combination with fludarabine, whereas 78 patients were prepared with two alkylating agents, thiotepa busulfan and fludarabine (TBF). Patients receiving TBF were older (57 vs 52 years), were less frequently splenectomized pre-HSCT (31% vs 59%), had more frequently intermediate-2/high DIPSS scores (90% vs 74%), were grafted more frequently from alternative donors (83% vs 33%) and received more frequently ruxolitinib pre-HSCT (26% vs 7%). The proportion of patients with F-DC on day +30, in the TBF vs the ONE-ALK group, was respectively 87% vs 45% (P < .001). The 5-year cumulative incidence of relapse was 9% in the TBF group, vs 43% for the ONE-ALK group (P < .001). The 5-year actuarial disease-free survival was 63% for TBF and 38% for the ONE-ALK group (P = .004). In conclusion, early full donor chimerism is a prerequisite for long term control of disease in patients with myelofibrosis, undergoing an allogeneic HSCT. The combination of two alkylating agents in the conditioning regimen, provides a higher chance of achieving full donor chimerism on day+30, and thus a higher chance of long term disease free survival.

Background/objectives Several studies supported the beneficial effects of the Mediterranean diet (MeDi) on chronic diseases. In Multiple Sclerosis (MS), the MeDi might interfere with systemic inflammatory state, gut microbiota, and comorbidities. The Med Diet Score (MDS) estimates the adherence to the MeDi and the cardiovascular (CV) risk. Aims of our study were i) to photograph lifestyle and diet habits of a southern Italy cohort of people with MS (pwMS), and ii) to investigate the impact of the MeDi on MS clinical outcomes. Subjects/methods We conducted a multi-center, cross-sectional study, enrolling 435 consecutive consenting pwMS, attending the outpatient clinics for routine follow-up visits. Participants underwent a clinical examination and a 29-item self-administered questionnaire on life and dietary habits. Disease phenotype, Expanded Disability Status Scale (EDSS), MS Severity Score (MSSS), waist circumference (WC), Body Mass Index (BMI), therapies, and comorbidities, were updated. MDS was assessed and correlated with current and retrospective clinical data. Results 75.8% of respondents were interested in nutrition, 72.8% were non-smokers, 52.9% performed physical activity, and 45.6% used food supplements. MDS was higher in pwMS with normal WC (p = 0.031), and inversely correlated with MSSS (p = 0.013) and EDSS (p = 0.012) at survey time. MDS did not correlate with the total number of relapses (before and after diagnosis) (p = 0.372). Metabolic comorbidities were associated with an increased 10-year CV risk (r = 0.85, p = 0.002). Conclusion Our findings suggest a putative beneficial effect of the MeDi on WC, MS course and disability. Given the role of chronic systemic inflammation in maintenance of autoimmunity and secondary neurodegeneration, both involved in long-term disability, we may suppose a beneficial effect of the MeDi on MS long-term disability outcomes, probably mediated by a modulation of the gut microbiota and the low-grade chronic systemic inflammation.

Background: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need. Methods: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites. Results: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS – mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups. Conclusion: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations.

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18–4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (

Background: Tracheostomy can be performed safely in patients with coronavirus disease 2019 (COVID-19). However, little is known about the optimal timing, effects on outcome, and complications. Methods: A multicenter, retrospective, observational study. This study included 153 tracheostomized COVID-19 patients from 11 intensive care units (ICUs). The primary endpoint was the median time to tracheostomy in critically ill COVID-19 patients. Secondary endpoints were survival rate, length of ICU stay, and post-tracheostomy complications, stratified by tracheostomy timing (early versus late) and technique (surgical versus percutaneous). Results: The median time to tracheostomy was 15 (1–64) days. There was no significant difference in survival between critically ill COVID-19 patients who received tracheostomy before versus after day 15, nor between surgical and percutaneous techniques. ICU length of stay was shorter with early compared to late tracheostomy (p &lt, 0.001) and percutaneous compared to surgical tracheostomy (p = 0.050). The rate of lower respiratory tract infections was higher with surgical versus percutaneous technique (p = 0.007). Conclusions: Among critically ill patients with COVID-19, neither early nor percutaneous tracheostomy improved outcomes, but did shorten ICU stay. Infectious complications were less frequent with percutaneous than surgical tracheostomy.

Objectives: Switching between treatments is an opportunity for patients with multiple sclerosis (MS) to ameliorate disease control or safety. The aim of this study was to investigate the impact of switching from fingolimod (FTY) or natalizumab (NTZ) to ocrelizumab (OCR) on disease activity. Methods: We retrospectively enrolled 165 patients treated with OCR from 11 MS centres. We assessed the association of demographic and clinical characteristics on relapse rate (RR) and activity on magnetic resonance imaging (MRI) during wash-out and after 6 months of treatment with OCR through univariable and multivariable negative binomial regression models. Results: We registered a total of 35 relapses during the wash-out period. Previous treatment with FTY, relapses in the previous year, and relapsing-remitting course were associated with higher RR. In the first 6 months of OCR, 12 patients had clinical or MRI disease activity. Higher Expanded Disability Status Scale (EDSS) and higher lymphocyte count at OCR start were associated with a reduced probability of relapse. Discussion and Conclusion: This study confirms that withdrawal from sequestering agents as FTY increases the risk of relapses in the wash-out period. Nevertheless, starting OCR before achieving complete immune reconstitution could limit its effectiveness in the first 6 months probably because trapped lymphocytes escape the CD20-mediated depletion.

Background: This study aimed to investigate SARS-CoV-2 transmission among co-workers at the University of Genoa, Italy, during the second COVID-19 pandemic wave. Methods: A cross-sectional study was carried out in October 2020 – March 2021: RT-PCR confirmed cases of COVID-19 notified to the Occupational Health Service were included in the analysis. Results: Among the n = 201 notified cases, contact tracing of n = 53 individuals identified n = 346 close contacts. The household setting (IRR = 36.8; 95% CI: 4.9-276.8; p < 0.001) and sharing eating areas (IRR = 19.5; 95% CI: 2.5-153.9; p = 0.005) showed the highest Secondary Attack Rates (SARs) compared to the office setting. Fatigue (IRR= 17.1; 95% CI: 5.2-55.8; p < 0.001), gastrointestinal symptoms (IRR= 6.6; 95% CI: 2.9-15.2; p< 0.001) and cough (IRR= 8.2; 95% CI: 3.7-18.2; p= p< 0.001) were associated with transmission of infection. Polysymptomatic cases (IRR= 23.1; 95% CI: 3.1-169.2; p = 0.02) were more likely to transmit the infection. Among COVID-19 index cases aged >60 years (OR = 7.7; 95% CI: 1.9-31.9; p = 0.0046) SARs were higher than in other age groups. Wearing respiratory protections by both the case and the close contact resulted an effective measure compared with no use (IRR = 0.08; 95% CI: 0.03-0.2; p = < 0.0001). Conclusions: Accurate infection monitoring and contact tracing was useful to identify the main situations Conclusions: Accurate infection monitoring and contact tracing was useful to identify the main situations of SARS-CoV-2 transmission in the workplace, and hence for risk assessment and prevention programs.

Simple Summary CD8+ T lymphocytes are among the immune cells reputed to kill tumor cells. Head and neck squamous cell carcinoma (HNSCC) has a poor clinical outcome despite the presence of a rich CD8+ T cell tumor infiltrate. This may be due to alterations of tumor infiltrating CD8+ T cells. Here, we performed a characterization of infiltrating CD8+ T cells in a cohort of 30 HNSCC patients. The results showed that differential intratumoral frequency of CD8+CD28+ T cells, CD8+CD28− T cells, and CD8+CD28−CD127−CD39+ Treg distinguished between HNSCC patients who did or did not respond to treatment. Moreover, we identified an intratumoral CD8+CD28- T cell subpopulation, which expressed markers of both exhausted (i.e., with impaired effector functions) and regulatory (i.e., exerting suppressive activities) cells. This suggests that in HNSCC effector T cells progressively undergo exhaustion and acquisition of regulatory properties, hampering their anti-tumor functions. Abstract Head and neck squamous cell carcinoma (HNSCC) has a poor clinical outcome despite the presence of a rich CD8+ T cell tumor infiltrate in the majority of patients. This may be due to alterations of tumor infiltrating CD8+ T cells. Here, we performed a characterization of HNSCC infiltrating CD8+ T cells in a cohort of 30 patients. The results showed that differential intratumoral frequency of CD8+CD28+ T cells, CD8+CD28− T cells, and CD8+CD28−CD127−CD39+ Treg distinguished between HNSCC patients who did or did not respond to treatment. Moreover, high PD1 expression identified a CD8+CD28− T cell subpopulation, phenotypically/functionally corresponding to CD8+CD28−CD127−CD39+ Treg, which showed a high expression of markers of exhaustion. This observation suggests that development of exhaustion and acquisition of regulatory properties may configure the late differentiation stage for intratumoral effector T cells, a phenomenon we define as effector-to-regulatory T cell transition.

BACKGROUND Sun exposure is the main external risk factor for keratinocytic non-melanoma skin cancer (NMSC). Outdoor workers are at increased risk but the relationship of NMSC with occupational solar exposure is often confounded by concurrent recreational sun exposure. We compared the percentage of outdoor workers in NMSC patients versus controls without history of NMSC and assessed occupational and recreational sun exposure in both groups, evaluating also other risk factors and use of protective measures. METHODS Adult NMSC patients and controls without history of NMSC or actinic keratoses, matched for sex and age range, were recruited in Dermatology Departments of seven Italian University Hospitals, with a 1:2 patient/control ratio whenever possible. Data were collected using specifically designed questionnaires. RESULTS 834 patients and 1563 controls were enrolled. History of outdoor work was significantly (p=0.033) more frequent in patients. Patients were more sun exposed from outdoor leisure activities (p=0.012) and sunbathed for longer periods (p=0.13) and between 12 pm and 3.30 pm (p=0.011). Cumulative sun exposure during hobbies was similar between patients and controls in outdoor workers, higher (p

Purpose To compare ultrasound (US)-guided injections and surgery for the treatment of meralgia paresthetica (lateral femoral cutaneous neuropathy). Methods Two reviewers, independently, up to 10 October 2020 retrieved Studies that assessed the outcome of US-guided injections and surgery for the treatment of meralgia paresthetica from major medical libraries. Predefined inclusion and exclusion criteria were adopted. Results 399 studies were initially found, and the meta-analysis was conducted on 10 studies for a total of 149 patients. US-guided injections were done in three studies, surgery in seven studies. N = 38 % (57/149) of patients were treated with US-guided injection and 62 % (92/149) were treated with surgery. After US-guided injections, 85 % (49/57) of patients were treated successfully, whereas 80 % (74/92) were treated with surgery successfully from the clinical point of view. Differences were not statistically significant even with a slight heterogeneity of studies and outcome pooled on random-effect model. No comparative cohort study or RCT was conducted. Conclusion This meta-analysis showed that there was no statistically significant difference in treatment of meralgia paresthetica with ultrasound-guided injection or surgery. A RCT to compare a standardized US-guided approach versus surgery is essential to compare these techniques properly.

PURPOSE Unmet needs for advanced-disease cancer patients are fatigue, pain, and emotional support. Little information is available about the feasibility of interventions focused on patient-reported outcome measurement developed according to the Medical Research Council (MRC) Framework in advanced-disease cancer patients. We aimed to pilot a nurse-led complex intervention focused on QoL assessment in advanced-disease cancer patients. METHODS The INFO-QoL study was based on an exploratory, nonequivalent comparison group, pre-test-post-test design. Study sites received either the INFO-QoL intervention or usual care. Adult advanced-disease cancer patients admitted to hospice inpatient units that gave their informed consent were included in the study. Subjects were 187 patients and their families and 19 healthcare professionals. We evaluated feasibility, acceptability, and patients' outcomes using the Integrated Palliative Care Outcome Scale. RESULTS Nineteen healthcare professionals were included. The mean competence score increased significantly over time (p

We aimed to assess the prevalence of and factors associated with anti- severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positivity in a large population of adult volunteers from five administrative departments of the Liguria and Lombardia regions. A total of 3609 individuals were included in this analysis. Participants were tested for anti-SARS-CoV-2 antibodies [Immunoglobulin G (IgG) and M (IgM) class antibodies] at three private laboratories (Istituto Diganostico Varelli, Medical Center, and Casa della Salute di Genova). Demographic data, occupational or private exposure to SARS-CoV-2-infected patients, and prior medical history consistent with SARS-CoV-2 infection were collected according to a preplanned analysis. The overall seroprevalence of anti-SARS-CoV-2 antibodies (IgG and/or IgM) was 11.0% [398/3609; confidence interval (CI) 10.0%–12.1%]. Seroprevalence was higher in female inmates than in male inmates (12.5% vs. 9.2%, respectively, p = 0.002), with the highest rate observed among adults aged >55 years (13.2%). A generalized estimating equations model showed that the main risk factors associated with SARS-CoV-2 seroprevalence were the following: an occupational exposure to the virus [Odd ratio (OR) = 2.36; 95% CI 1.59–3.50, p = 0.001], being a long-term care facility resident (OR = 4.53; 95% CI 3.19–6.45, p = 0.001), and reporting previous symptoms of influenza-like illness (OR = 4.86; 95% CI 3.75–6.30, p = 0.001) or loss of sense of smell or taste (OR = 41.00; 95% CI 18.94–88.71, p = 0.001). In conclusion, we found a high prevalence (11.0%) of SARS-CoV-2 infection that is significantly associated with residing in long-term care facilities or occupational exposure to the virus. These findings warrant further investigation into SARS-CoV-2 antibody prevalence among the Italian population.

BACKGROUND: The Sit-to-Stand (STS) test is widely used in clinical practice as an indicator of lower-limb functionality decline, especially for older adults. Hitherto, due to its high variability, there is no standard approach for categorising the STS motion pattern, and the vision-based evaluation remains the most reliable method to evaluate people’ performance. This paper presents a comparative analysis between visual assessments and an automated-software approach for the categorisation of STS, relying on registrations from a force plate. METHODS: A group of 5 participants (30 ± 6 years) took part in 2 different sessions of visual inspections on 200 STS movements randomly extracted from a dataset of 742 acquisitions under self-paced and controlled speed conditions. Assessors were asked to identify three specific STS events from the Ground Reaction Force, simultaneously with the software analysis: the start of the trunk movement (Initiation), the beginning of the stable upright stance (Standing) and the sitting movement (Sitting). The Test-Retest Reliability between first and second visual evaluations was compared with the Inter-Rater Agreement between visual and software assessments, as indexes of human and software performance, respectively.RESULTS: No statistical differences between methods were found for the identification of the Initiation and the Sitting events at self-paced speed and for only the Sitting event at controlled speed. The estimated significant values of maximum discrepancy between visual and automated assessments were 0.200 s [0,039; 0.361] in unconstrained conditions and 0,340 s [0,014; 0,666] for standardised movements.CONCLUSIONS: The software assessments displayed an overall good agreement against visual evaluations of the Ground Reaction Force, relying, at the same time, on objective measures. In this sense, the proposed approach can provide robust and consistent data in the field of Big Data analytics, augmenting the performance of artificial intelligence methods for Human Activity Recognition tasks.

Background. We recently reported that enhanced [18F]-fluorodeoxyglucose (FDG) uptake in skeletal muscles predicts disease aggressiveness in patients with amyotrophic lateral sclerosis (ALS). The present experimental study aimed to assess whether this predictive potential reflects the link between FDG uptake and redox stress that has been previously reported in different tissues and disease models. Methods. The study included 15 SOD1G93A mice (as experimental ALS model) and 15 wildtype mice (around 120-days-old). Mice were submitted to micro-PET imaging. Enzymatic pathways and response to oxidative stress were evaluated in harvested quadriceps and hearts by biochemical, immunohistochemical and immunofluorescence analysis. Colocalization between the endoplasmic reticulum (ER) and the fluorescent FDG analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) was performed in fresh skeletal muscle sections. Finally, mitochondrial ultrastructure and bioenergetics were evaluated in harvested quadriceps and hearts.Results. FDG retention was significantly higher in hindlimb skeletal muscles of symptomatic SOD1G93A mice with respect to control ones. This difference was not explained by any acceleration in glucose degradation through glycolysis or cytosolic pentose phosphate pathway (PPP). Similarly, it was independent of inflammatory infiltration. Rather, the high FDG retention in SOD1G93A skeletal muscle was associated with an accelerated generation of reactive oxygen species. This redox stress selectively involved the ER and the local PPP triggered by hexose-6P-dehydrogenase. ER involvement was confirmed by the colocalization of the 2-NBDG with a vital ER tracker. The oxidative damage in transgenic skeletal muscle was associated with a severe impairment in the crosstalk between ER and mitochondria combined with alterations in mitochondrial ultrastructure and fusion/fission balance. The expected respiratory damage was confirmed by a deceleration in ATP synthesis and oxygen consumption rate. These same abnormalities were represented to a markedly lower degree in the myocardium, as a sample of non-voluntary striated muscle.Conclusion. Skeletal muscle of SOD1G93A mice reproduces the increased FDG uptake observed in ALS patients. This finding reflects the selective activation of the ER-PPP in response to significant redox stress associated with alterations of mitochondrial ultrastructure, networking, and connection with the ER itself. This scenario is less severe in cardiomyocytes suggesting a relevant role for either communication with synaptic plaque or contraction dynamics.

IntroductionCoronavirus disease 2019 (COVID-19) can lead to respiratory failure due to severe immune response. Treatment targeting this immune response might be beneficial but there is limited evidence on its efficacy.The aim of this study was to determine if early treatment of patients with COVID-19 pneumonia with tocilizumab and/or steroids was associated with better outcome.MethodsThis observational single-center study included patients with COVID-19 pneumonia who were not intubated and received either standard of care (SOC, controls) or SOC plus early (within 3 days from hospital admission) anti-inflammatory treatment. SOC consisted of hydroxychloroquine 400mg bid plus, in those admitted before March 24th, also darunavir/ritonavir. Anti-inflammatory treatment consisted of either tocilizumab (8mg/kg intravenously or 162mg subcutaneously) or methylprednisolone 1 mg/kg for 5 days or both. Failure was defined as intubation or death, and the endpoints were failure-free survival (primary endpoint) and overall survival (secondary) at day 30. Difference between the groups was estimated as Hazard Ratio by a propensity score weighted Cox regression analysis (HROW).ResultsOverall, 196 adults were included in the analyses. They were mainly male (67.4%), with comorbidities (78.1%) and severe COVID-19 pneumonia (83.7%). Median age was 67.9 years (range, 30-100) and median PaO2/FiO2200 mmHg (IQR 133-289). Among them, 130 received early anti-inflammatory treatment with: tocilizumab (n=29, 22.3%), methylprednisolone (n=45, 34.6%), or both (n=56, 43.1%). The adjusted failure-free survival among tocilizumab/methylprednisolone/SOC treated patients vs. SOC was 80.8% (95%CI, 72.8-86.7) vs. 64.1% (95%CI, 51.3-74.0), HROW0.48, 95%CI, 0.23-0.99; p=0.049. The overall survival among tocilizumab/methylprednisolone/SOC patients vs. SOC was 85.9% (95%CI, 80.7-92.6) vs. 71.9% (95%CI, 46-73), HROW0.41, 95%CI: 0.19-0.89, p=0.025.ConclusionEarly adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients with COVID-19 pneumonia.

This comparative effectiveness research study examines propensity scores adjustment in multiple sclerosis studies comparing disease-modifying treatments.

Background In clinical practice, there is the need to optimize imaging usage in MM patients. Accordingly, the aim of this paper was to develop a simple computed tomography (CT) scoring method for MM, able to shorten and simplify the interpretation time with good intra- and inter-reader reliability. This method, named MSBDS (Myeloma Spine and Bone Damage Score) was developed with the final aim to use standard total-body CT in the routine practice of MM centres as a complement of standard evaluations in patients undergoing stem cells transplantation. Methods We used a widely accepted consensus formation method and literature research during three structured face-to-face meetings specifically designed to combine opinions from a group of experts with proven experience in multiple myeloma care and/or musculoskeletal CT to facilitate the consensus on the field of study topics and the contents of the MSBDS score. Seven practical requisites for the MSBDS score were agreed. A total of 70 MM patients (mean age, 60 years ±9.2 [standard deviation]; range, 35–70 years) undergoing total-body CT was included to develop MSBDS scores. Patients data were already stored in the Radiological database for other Research studies IRB approved (054/2019). Readers to test the MSDMS were radiologists and clinicians involved in MM care or expert in bone damage scores with different level of experience in musculoskeletal and total body CT. Readers were blinded to the clinical data of the patients. Results The MSBDS scores based on the consensus work described above and literature analysis was finalized. MSBDS is based on an additive scale with assessment of a total body CT with the bone window one time and includes indicators of structural bone damage and instability or fracture risk. The total score is given by the sum of item scores for abnormalities detected. Its values range from 0 (minimum) to values > 10 where 10 is represented by high-risk patients. In high-risk patients immediate surgical or radiation oncologist consultation is suggested. Conclusions The MSBDS descriptive criteria are easy, highly reproducible and can be considered as a strong base for harmonizing total body CT interpretation in multiple myeloma patients undergoing stem cell transplantation.

The aim of this study was to determine the feasibility of diffusion basis spectrum imaging in multiple sclerosis at 7 T and to investigate the pathological substrates of tissue damage in lesions and normal-appearing white matter. To this end, 43 patients with multiple sclerosis (24 relapsing-remitting, 19 progressive), and 21 healthy control subjects were enrolled. White matter lesions were classified in T1-isointense, T1-hypointense and black holes. Mean values of diffusion basis spectrum imaging metrics (fibres, restricted and non-restricted fractions, axial and radial diffusivities and fractional anisotropy) were measured from whole brain white matter lesions and from both lesions and normal appearing white matter of the corpus callosum. Significant differences were found between T1-isointense and black holes (P ranging from 0.005 to

Background and purpose The importance of upper limb function in multiple sclerosis (MS) is increasingly recognized, especially for the evaluation of patients with progressive MS with reduced mobility. Two sensor-engineered gloves, able to measure quantitatively the timing of finger opposition movements, were previously used to assess upper limb disability in MS. The aims of the present study were: (1) to confirm the association between glove-derived variables and standard measures of MS disability in a larger cohort; (2) to assess the correlation with quantitative magnetic resonance imaging (MRI) and quality of life (QoL) measures; and (3) to determine if the glove-derived variables offer advantages over the standard measure for assessing upper limb function in MS, namely, the Nine-Hole Peg Test (9HPT). Methods Sixty-five patients with MS, stable on disease-modifying treatment, were evaluated at baseline using the glove, and through clinical examination (Expanded Disability Status Scale, Symbol Digit Modalities Test, Timed 25-Foot Walk Test and 9HPT), MRI evaluation and QoL questionnaires. Correlations between the glove-derived variables and clinical, MRI and QoL variables were assessed using Spearman's rank correlation coefficient analysis. Results Glove-derived variables significantly differed between patients with relapsing-remitting and those with progressive MS, with similar or slightly higher correlations of the 9HPT with clinical variables. We found greater correlations of the QoL physical component with glove-derived variables than with the 9HPT, and a significant correlation of its mental component with the glove-derived variables but not with the 9HPT. Conclusion The study results, confirming previous findings and showing advantages over the 9HPT, encourage the investigation of sensitivity to change in glove-derived variables in a longitudinal setting.

Studies comparing the effects of natalizumab and fingolimod in relapsing–remitting multiple sclerosis (RRMS) are limited. We aimed to compare natalizumab and fingolimod effects on clinical, neuropsychological, and MRI measures in RRMS patients after 2 years of treatment. RRMS patients starting natalizumab (n = 30) or fingolimod (n = 25) underwent neurologic, neuropsychological, and brain MRI assessments at baseline, month (M) 6, M12, and M24. Volumes of lesions, brain, gray matter (GM), white matter (WM), and deep GM were measured. Fifteen healthy controls (HC) were also scanned at baseline and M24. Treatment groups were matched for baseline variables. At M24 versus baseline, both drugs reduced the relapse rate (p value

The aim of this study was to evaluate the capability of sequences acquired on a 7-T MRI scanner, within times and anatomical coverage appropriate for clinical studies, to identify cortical lesions (CLs) in patients with Multiple Sclerosis (MS). Furthermore, we aimed to confirm the clinical significance of CL, testing the correlations between gray matter (GM) lesions and clinical scores. A 7-T MRI protocol included 3D-T1-weighted and T2*-weighted sequences. Images were evaluated independently by three readers of different experience, and the number of CLs was recorded. Between-rater concordance was assessed calculating the intraclass correlation coefficient (ICC). Lin’s concordance correlation coefficient was used to compare CL detection between sequences, while partial correlations and multivariable regression models were used to study the relationship between CL and clinical data. Forty MS patients (M/F, 17/23; 44.7 ± 12.6 years) were enrolled in this study, and CLs were identified in 35/40 subjects (87.5%). CL detection rate on 3D-T1-weighted images was significantly correlated with the detection rate on T2*-weighted images (r = 0.99; p

ObjectiveCladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data.MethodsData from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity.ResultsAll weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis.ConclusionIn patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity.Classification of evidenceThis study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab.

Background: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS). Objective: To investigate the effectiveness and safety of rituximab in relapsing–remitting (RR) and progressive MS. Methods: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed. Results: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p Conclusion: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

Objectives Along with deficit of attention, level of arousal is a primary criterion for the diagnosis of delirium. The Observational Scale of Level of Arousal (OSLA) is a quick, simple, and observational instrument used to evaluate the variation of arousal for rapid screening of delirium in clinical practice. The current study aims to perform a cross-cultural adaption of and to validate the Italian version of the OSLA scale to detect delirium in older aged, hospitalized patients. Design Longitudinal study. Setting and Participants In hospital and transitional care setting. Old age patients. Methods A cross-cultural adaptation of the OSLA from English into Italian was conducted, including back-translation. The validation of the OSLA was assessed in 116 older patients (age >65 years) admitted to geriatric, internal medicine, and transitional care wards. The 4 “A”s Test serves as the gold standard for the measurement of delirium. Results Incident delirium was assessed longitudinally at different time points during hospitalization. The Italian version of OSLA demonstrated adequate internal consistency, specificity, sensitivity, agreement, test-retest reliability, and sensitivity to change, indicating adequate its clinometric properties in the detection of delirium in a real world hospitalized cohort of older adults. Conclusions and Implications The current study is among the few studies to assess arousal as a core feature of delirium by virtue of a longitudinal assessment of delirium, moving a step forward in the implementation of a brief and easy to use delirium-screening tool for the measurement of important clinical outcomes in a frail, old aged hospitalized population.

Extending the natalizumab interval after the 24th administration could reduce the risk of progressive multifocal leukoencephalopathy (PML). The objective is to evaluate the noninferiority of the efficacy of an extended interval dosing (EID) compared with the standard interval dosing (SID) of natalizumab. It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses

Background: The approval of an increasing number of disease modifying drugs for the treatment of Multiple Sclerosis (MS) creates new challenges for patients and clinicians on the first treatment choice. The main aim of this study was to assess factors impacting first therapy choice in a large Italian MS cohort. Methods: Newly diagnosed relapsing-remitting (RR) MS patients (2010-2018) followed in 24 Italian MS centres were included in the study. We evaluated the association of baseline demographics, clinical and MRI characteristics to the first treatment choice by logistic regression models applied to pre-defined binary alternatives: dimethyl fumarate vs injectables (interferon and glatiramer acetate), teriflunomide vs injectables, fingolimod vs dimethyl fumarate and fingolimod vs natalizumab. Results: We enrolled 3025 patients in the period between January 2010 and June 2018. Relapses in the previous year (OR = 2.75; p = 0.001), presence of spinal cord lesions (OR = 1.80; p = 0.002) and higher number (>9) of T2 lesions on the baseline brain MRI scan (OR = 1.65; p = 0.022) were the factors associated to dimethyl fumarate choice as first therapy vs an injectable drug. Older age (OR = 1.06; p < 0.001), male sex (OR = 2.29; p = 0.001) and higher EDSS (OR = 1.36; p < 0.001) were the factors associated with the choice of teriflunomide vs injectables. In more recent years, dimethyl fumarate (OR = 3.23; p < 0.001) and teriflunomide (OR = 2.53; p < 0.001) were chosen more frequently than injectables therapies. The main determinant for the choice of fingolimod as compared with dimethyl fumarate was a higher EDSS (OR = 1.56; p = 0.001), while there was a weak association with a longer disease duration (p = 0.068) and a longer time from onset to diagnosis (p = 0.085). Compared to fingolimod, natalizumab was preferred in patients with a younger age (OR = 0.95; p = 0.003) and higher EDSS (OR = 1.45; p = 0.007) and a shorter disease duration (OR = 0.52; p = 0.076). Conclusion: Many factors guided therapeutic decision for our Italian cohort of MS patients; they are mainly related to MS disease activity, baseline EDSS, disease duration and age.

Background Little is known about the incidence and risk of intensive care unit (ICU)-acquired bloodstream infections (BSI) in critically ill patients with coronavirus disease 2019 (COVID-19). Materials and methods This retrospective, single-centre study was conducted in Northern Italy. The primary study objectives were as follows: (a) to assess the incidence rate of ICU-acquired BSI and (b) to assess the cumulative risk of developing ICU-acquired BSI. Results Overall, 78 critically ill patients with COVID-19 were included in the study. Forty-five episodes of ICU-acquired BSI were registered in 31 patients, with an incidence rate of 47 episodes (95% confidence interval [CI] 35-63) per 1000 patient-days at risk. The estimated cumulative risk of developing at least one BSI episode was of almost 25% after 15 days at risk and possibly surpassing 50% after 30 days at risk. In multivariable analysis, anti-inflammatory treatment was independently associated with the development of BSI (cause-specific hazard ratio [csHR] 1.07 with 95% CI 0.38-3.04 for tocilizumab, csHR 3.95 with 95% CI 1.20-13.03 for methylprednisolone and csHR 10.69 with 95% CI 2.71-42.17 for methylprednisolone plus tocilizumab, with no anti-inflammatory treatment as the reference group; overall P for the dummy variable = 0.003). Conclusions The incidence rate of BSI was high, and the cumulative risk of developing BSI increased with ICU stay. Further study will clarify if the increased risk of BSI we detected in COVID-19 patients treated with anti-inflammatory drugs is outweighed by the benefits of reducing any possible pro-inflammatory dysregulation induced by SARS-CoV-2.

Multiple sclerosis (MS) is usually diagnosed in women during their childbearing years. Currently, no consensus exists on whether pregnancy can delay the first episode of demyelination or clinically isolated syndrome (CIS).To investigate the association of pregnancy with time to CIS onset.This multicenter cohort study collected reproductive history (duration of each pregnancy, date of delivery, length of breastfeeding) on all participants between September 1, 2016, and June 25, 2019. Adult women being treated at the MS outpatient clinics of 4 tertiary hospitals in 2 countries (Charles University and General University Hospital in Prague, Czech Republic; Royal Melbourne Hospital in Melbourne, Australia; Alfred Hospital in Melbourne, Australia; and John Hunter Hospital in Newcastle, Australia) were recruited to participate in the study. Preexisting data (date of CIS onset, date of birth, sex, date of clinical onset, and Expanded Disability Status Scale result) were collected from MSBase, an international registry of long-term prospectively collected data on patients with MS. Data analyses were performed from June 1, 2019, to February 3, 2020.Gravida (defined as any pregnancy, including pregnancy that ended in miscarriage and induced abortion) and parity (defined as childbirth after gestational age of more than 20 weeks, including livebirth and stillbirth) before CIS onset.Time to CIS onset. The following were assessed: (1) whether women with previous pregnancies and childbirths had a delayed onset of CIS compared with those who had never been pregnant and those who had never given birth, and (2) whether a dose response existed, whereby a higher number of gravidity and parity was associated with a later onset of CIS.Of the 2557 women included in the study, the mean (SD) age at CIS onset was 31.5 (9.7) years. Of these women, before CIS onset, 1188 (46%) had at least 1 pregnancy and 1100 (43%) had at least 1 childbirth. The mean (SD) age at first pregnancy was 23.3 (4.5) years and at first childbirth was 23.8 (4.5) years. Women with previous pregnancies and childbirths had a later onset of CIS compared with those who had never been pregnant (HR, 0.68; 95% CI, 0.62-0.75; P .001), with a median delay of 3.3 (95% CI, 2.5-4.1) years. Women who had given birth also had a later CIS onset compared with women who had never given birth (HR 0.68; 95% CI, 0.61-0.75; P .001), with a similar median delay of 3.4 (95% CI, 1.6-5.2) years. A higher gravidity and parity number was not associated with delay in CIS onset.This study suggests an association between previous pregnancies and childbirths and timing of CIS onset, but having more pregnancies or childbirths did not appear to be associated with a later CIS onset. Further studies are needed to help explain the mechanisms behind the associations between pregnancy and onset of multiple sclerosis.

In the last 10 years, many new therapeutic options have been approved in advanced prostate cancer (PCa) patients, granting a more prolonged survival in patients with metastatic disease, which, nevertheless, remains incurable. The emphasis on immune checkpoint inhibitors (ICIs) has led to many trials in this setting, with disappointing results until now. Therefore, we discuss the immunobiology of PCa, presenting ongoing trials and the available clinical data, to understand if immunotherapy could represent a valid option in this disease, and which subset of patients may be more likely to benefit. Current evidence suggests that the tumor microenvironment needs a qualitative rather than quantitative evaluation, along with the genomic determinants of prostate tumor cells. The prognostic or predictive value of immunotherapy biomarkers, such as PD-L1, TMB, or dMMR/MSI-high, needs further evaluation in PCa. Monotherapy with immune checkpoint inhibitors (ICIs) has been modestly effective. In contrast, combined strategies with other standard treatments (hormonal agents, chemotherapy, PARP inhibitors, radium-223, and TKIs) have shown some results. Immunotherapy should be better investigated in biomarker-selected patients, particularly with specific pathway aberrations (e.g., AR-V7 variant, HRD, CDK12 inactivated tumors, MSI-high tumors). Lastly, we present new possible targets in PCa that could potentially modulate the tumor microenvironment and improve antitumor activity with ICIs.

Using placebo data from 3 randomized multiple sclerosis (MS) trials with uniform inclusion criteria, we investigated heterogeneity of Expanded Disability Status Scale (EDSS) progression by geographical areas. Our analysis revealed a significantly lower EDSS progression in Eastern European countries (10.8%) compared with Western Europe (13.1%) or the USA/Canada (21.4%, p < 0.001); EDSS improvement behaved the same way. This heterogeneity is not explained by differences of baseline variables. No differences were detected on more easily quantifiable measures, the Timed 25-Foot Walk or the Multiple Sclerosis Functional Composite. At a time when disease progression represents the target for future interventions in MS, establishment of more quantitative and objective outcomes remains a key priority of MS research. Ann Neurol 2018;84:621-625.

There is increasing evidence that autism spectrum disorder (ASD) subjects have also motor impairments. Toe walking (TW) is a phenomenon that can be found in ASD subjects during gait, even if this condition was found not to be necessarily related only to walking, since these children often also stand and run on their tiptoes. Since persistent TW in ASD subjects may contribute to secondary shortening of the Achilles's tendon, it becomes important to have an assessment tool and/or outcome measure for both the clinical and rehabilitative settings. The aim of this systematic review is to critically evaluate and describe the methods employed to assess toe walking in ASD subjects. The systematic review protocol was previously registered on PROSPERO. We conducted an extensive literature search in PubMed, CINAHL, PsycINFO, The Cochrane Library, and Scopus databases. There were no restrictions on the types of study design eligible for inclusion. Ten studies were included in the systematic review. Risk of bias of the included studies was conducted using the following instruments depending on the study types: STROBE Statement, Cochrane risk of bias tool, and CARE checklist. Almost all the included studies (8/10) proposed a tip-toe behavior (TTB) assessment only during walking. Nine out of ten of the included studies assessed TTB using a qualitative methodology. The results evidenced the heterogeneity of qualitative methods and a lack of a structured quantitative test to assess toe walking in ASD subjects. Autism Res 2018, 11: 1404-1415. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY ABSTRACT: Toe walking (TW) is a phenomenon that can be found during ASD subject's gait. The persistence of this behavior may contribute to secondary Achilles's tendon shortening. In this perspective it becomes important to have an assessment tool and/or outcome measure for both the clinical and rehabilitative settings. The current systematic review aimed to describe the methods employed to assess TW. The results evidenced the lack and the need of a structured quantitative test to assess TW in ASD subjects.

Background: Patient-reported outcomes (PROs) may help patients and clinicians in selecting disease-modifying therapies (DMTs) for multiple sclerosis (MS). Objective: To evaluate PRO differences among first-line DMTs for relapsing-remitting (RR) people with MS (pwMS). Methods: Multicenter study. RR pwMS on first-line DMTs completed Fatigue Severity Scale (FSS), PROs Indices for MS (PRIMUS), 36-item Short-Form Health Survey (SF-36), treatment satisfaction questionnaire for medication (TSQM), Beck Depression Inventory-II (BDI-II), and Symbol Digit Modalities Test (SDMT). Differences among PROs across DMTs were tested by ANOVA. Multivariable linear regressions were used to investigate associations between PROs and the treatment group. Results: Two-hundred eighty pwMS were enrolled: 56% were on interferons (INF), 22% on dimethylfumarate (DMF), 13% on glatiramer acetate, and 9% on teriflunomide (Teri). Compared with INF, pwMS on Teri were the oldest, with higher disability, worst depression at BDI, worst cognitive performances at SDMT (p = 0.001), fatigue at FSS (p = 0.001), and activity limitation and quality of life respectively at PRIMUS (p = 0.005) and SF-36 Mental Composite Score (p < 0.001); pwMS on DMF reported highest side effects and, together with pwMS on Teri, better treatment satisfaction at TSQM. Conclusions: Compared with INF-treated patients, pwMS on DMF and Teri reported the best treatment satisfaction, although DMF-treated pwMS reported higher side effects and those on Teri the worst QoL and fatigue; however, the older age, higher disability and depression, and worse cognitive performance of pwMS on Teri suggest to be careful in evaluating these results.