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Immune checkpoint inhibitors have significantly improved the therapeutic scenario of many different advanced malignancies and could be an effective treatment strategy in synchronous or metachronous tumors. The authors describe the clinical case of a patient who experienced a long-lasting response of his metastatic renal cell carcinoma and an optimal response of his locally advanced cutaneous squamous cell carcinoma to immunotherapy. The systemic treatment was chosen based on a literature review of several clinical reports, since there was no prospective study on anti-PD-1 blockade activity in cutaneous squamous cell carcinoma when the patient started the treatment. This clinical case supports the growing evidence for immunotherapy as a valid treatment option across different types of advanced tumors.Immunotherapy is an effective treatment strategy across different cancer types and could be a valid treatment strategy in patients with multiple malignant tumors. In this scenario, in fact, the main challenge is to choose a systemic treatment which could be active on both tumors with an acceptable toxicity profile. The authors report the clinical case of a patient with metastatic renal cell carcinoma and a disfiguring cutaneous cancer of the zygomatic region who experienced a durable response of the renal tumor and almost a complete clinical response of the cutaneous cancer.

T1 Magnetization Prepared Two Rapid Acquisition Gradient Echo (MP2RAGE) with compress sensing (CS) has been proposed as an improvement of the standard MPRAGE sequence with multiple advantages including reduced acquisition time needed to provide a quantitative 3D anatomical image coupled with T1-map. Here we investigated the agreement between FreeSurfer-derived volume measurements obtained from MPRAGE and CS MP2RAGE acquisitions.MPRAGE and CS MP2RAGE images of 37 subjects (14 patients with neurodegenerative disorders and 23 healthy controls) were acquired on a 3 T MR scanner and grey matter volumes were extracted using standard FreeSurfer parcellation. Lin's concordance correlation coefficient (Lin's CCC), Bland-Altman analysis, Passing-Bablok regression and DICE similarity coefficient were calculated to assess the agreement between the two.We found a good correspondence for most of the regions examined, with 93.5 % of them showing a mean DICE index0.70. Poorer results were found with Lin's CCC especially for subcortical labels across patients. The Bland-Altman analysis showed CS MP2RAGE tended to measure lower cortical volumes compared to MPRAGE but in most cases the difference wasn't statistically relevant. The Passing-Bablock regression indicated overall an absence of systematic constant and proportional bias when CS MP2RAGE was used instead of MPRAGE.We found a good concordance for volumes obtained from MPRAGE and CS MP2RAGE images using FreeSurfer, suggesting a possible role of CS MP2RAGE for structural analysis with significant advantages like shorter acquisition time and the possibility to simultaneously obtain quantitative T1-maps of the brain enriching the diagnostic power of this technique.

Mild behavioral impairment (MBI) has been increasingly regarded as the neurobehavioral axis of predementia risk states, but a specific investigation of its detection as a potential marker of prodromal dementia in motor neuron diseases (MNDs) is still lacking. The aims of our study were therefore to explore MBI in MNDs both at onset and over the disease course, and to evaluate its relationship with baseline and longitudinal cognitive features.Sixty MND patients with cognitive/behavioral, mood, and motor examinations were recruited and followed longitudinally for up to 15 months. Associations between baseline MBI symptoms and clinical features were tested using the Spearman correlation coefficient. Based on longitudinal data, relative deltas of variation for each cognitive measure were generated, and linear regression models were then used to evaluate the role of baseline MBI symptoms in predicting longitudinal rates of cognitive decline.At disease onset, the most impaired MBI domain was affective/emotional dysregulation, followed by impulse dyscontrol, apathy, and social inappropriateness. Greater MBI symptoms correlated with more severe baseline motor, cognitive/behavioral, and mood disturbances (p values from0.001 to 0.05). Longitudinally, the greatest decline was observed in the affective/emotional dysregulation domain, followed by impulse dyscontrol, apathy, and social inappropriateness. Greater MBI symptoms at onset were significant predictors of more severe longitudinal cognitive decline in both amyotrophic lateral sclerosis (ALS)-specific and ALS-nonspecific functions (p values from0.001 to 0.03).MBI represents a valuable clinical marker of incident cognitive decline in MNDs, and its evaluation has good potential for detecting dementia in its preclinical/prodromal phase.

BackgroundThe Spinnaker study evaluated survival outcomes and prognostic factors in patients with advanced non-small-cell lung cancer receiving first-line chemoimmunotherapy in the real world. This sub-analysis assessed the immunotherapy-related adverse effects (irAEs) seen in this cohort, their impact on overall survival (OS) and progression-free survival (PFS), and related clinical factors.MethodsThe Spinnaker study was a retrospective multicentre observational cohort study of patients treated with first-line pembrolizumab plus platinum-based chemotherapy in six United Kingdom and one Swiss oncology centres. Data were collected on patient characteristics, survival outcomes, frequency and severity of irAEs, and peripheral immune-inflammatory blood markers, including the neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII).ResultsA total of 308 patients were included; 132 (43%) experienced any grade irAE, 100 (32%) Grade 1–2, and 49 (16%) Grade 3–4 irAEs. The median OS in patients with any grade irAES was significantly longer (17.5 months [95% CI, 13.4–21.6 months]) than those without (10.1 months [95% CI, 8.3–12.0 months]) (pConclusionsThese results confirm survival outcome benefits in patients with irAEs and suggest a higher likelihood of Grade 1–2 irAEs in patients with lower NLR or SII values or according to the NHS-Lung score.

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.

Randomised controlled trials (RCTs) with systemic therapies for patients with pre-treated mesothelioma have reported equivocal efficacy results and generated a degree of clinical uncertainty about the choice of active treatment in this poor prognosis malignancy.To compare the effectiveness and safety and weigh the benefit of different systemic treatments in patients with pre-treated mesothelioma by systematic review, meta-analysis and network meta-analysis of RCTs. Full-text articles and abstracts were searched on PubMed, EMBASE, Cochrane Library and oncology conferences proceedings from 2005 through November 2021 for phase 2 and 3 RCTs. The protocol was submitted to the PROSPERO registry. Reporting followed the PRISMA guideline. Outcomes of interest were overall survival (OS) and progression-free (PFS), grade ≥3 treatment-related (Tr) adverse events (AEs), Tr-deaths and Tr-AEs leading to treatment discontinuation.Nine trials at low risk of bias by Cochrane Collaboration's methodology were included, encompassing 2789 patients. Five studies showed PFS benefit in the experimental treatment. In two studies, OS was prolonged by immunotherapy (versus placebo) or by adding an antiangiogenic agent to chemotherapy. Reported Tr-AE were lower with single-agent anti-PD1 compared with chemotherapy or placebo. The meta-analysis revealed a beneficial global effect on OS and PFS from experimental treatments (HR 0.86, 95% CI 0.77-0.96, p = 0.0083 and HR 0.79, 95% CI 0.72-0.86, p 0.001), that for the PFS significantly favoured the comparison with non-active treatments (HR 0.73, 95% CI 0.66-0.81, p 0.001). Younger patients (i.e. 65-70 years) appeared to benefit the most in OS (HR 0.71, 95% CI 0.55-0.92, p = 0.04). The risk of serious Tr-AEs and Tr-deaths was not significantly increased by experimental treatments (RR 1.38, 95% CI 0.81-2.35, p = 0.24 and RR 2.07, 95% CI 0.69-6.24, p = 0.19, respectively) that instead increased TrAEs leading to treatment discontinuation (RR 2.9, 95% CI 1.44-6.08, p = 0.003). The network meta-analysis did not identify any superior treatment in PFS.For patients with pre-treated MPM, single-agent anti-PD1 or chemotherapy ± the antiangiogenic agent can be considered active and safe systemic therapeutic options, particularly for younger patients.

Background Positron Emission Tomography (PET) imaging with Prostate-Specific Membrane Antigen (PSMA) and Fluorodeoxyglucose (FDG) represent promising biomarkers for risk-stratification of Prostate Cancer (PCa). We verified whether the expression of genes encoding for PSMA and enzymes regulating FDG cellular uptake are independent and additive prognosticators in PCa. Methods mRNA expression of genes involved in glucose metabolism and PSMA regulation obtained from primary PCa specimens were retrieved from open-source databases and analyzed using an integrative bioinformatics approach. Machine Learning (ML) techniques were used to create predictive Progression-Free Survival (PFS) models. Cellular models of primary PCa with different aggressiveness were used to compare [18F]F-PSMA-1007 and [18F]F-FDG uptake kinetics in vitro. Confocal microscopy, immunofluorescence staining, and quantification analyses were performed to assess the intracellular and cellular membrane PSMA expression. Results ML analyses identified a predictive functional network involving four glucose metabolism-related genes: ALDOB, CTH, PARP2, and SLC2A4. By contrast, FOLH1 expression (encoding for PSMA) did not provide any additive predictive value to the model. At a cellular level, the increase in proliferation rate and migratory potential by primary PCa cells was associated with enhanced FDG uptake and decreased PSMA retention (paralleled by the preferential intracellular localization). Conclusions The overexpression of a functional network involving four glucose metabolism-related genes identifies a higher risk of disease progression since the earliest phases of PCa, in agreement with the acknowledged prognostic value of FDG PET imaging. By contrast, the prognostic value of PSMA PET imaging is independent of the expression of its encoding gene FOLH1. Instead, it is influenced by the protein docking to the cell membrane, regulating its accessibility to tracer binding.

Hospitalized patients with coronavirus disease 2019 (COVID-19) can be classified into different clinical phenotypes based on their demographic, clinical, radiology, and laboratory features. We aimed to validate in an external cohort of hospitalized COVID-19 patients the prognostic value of a previously described phenotyping system (FEN-COVID-19) and to assess the reproducibility of phenotypes development as a secondary analysis. Patients were classified in phenotypes A, B or C according to the severity of oxygenation impairment, inflammatory response, hemodynamic and laboratory tests according to the FEN-COVID-19 method. Overall, 992 patients were included in the study, and 181 (18%), 757 (76%) and 54 (6%) of them were assigned to the FEN-COVID-19 phenotypes A, B, and C, respectively. An association with mortality was observed for phenotype C vs. A (hazard ratio [HR] 3.10, 95% confidence interval [CI] 1.81–5.30, p < 0.001) and for phenotype C vs. B (HR 2.20, 95% CI 1.50–3.23, p < 0.001). A non-statistically significant trend towards higher mortality was also observed for phenotype B vs. A (HR 1.41; 95% CI 0.92–2.15, p = 0.115). By means of cluster analysis, three different phenotypes were also identified in our cohort, with an overall similar gradient in terms of prognostic impact to that observed when patients were assigned to FEN-COVID-19 phenotypes. The prognostic impact of FEN-COVID-19 phenotypes was confirmed in our external cohort, although with less difference in mortality between phenotypes A and B than in the original study. Hospitalized patients with COVID-19 can be classified into different clinical phenotypes based on their demographic, clinical, radiology, and laboratory featuresIn this study, we externally confirmed the prognostic impact of clinical phenotypes previously identified by Gutierrez-Gutierrez and colleagues in a Spanish cohort of hospitalized patients with COVID-19, and the usefulness of their simplified probabilistic model for phenotypes assignmentThis could indirectly support the validity of both phenotype’s development and their extrapolation to other hospitals and countries for management decisions during other possible future viral pandemics Hospitalized patients with COVID-19 can be classified into different clinical phenotypes based on their demographic, clinical, radiology, and laboratory features In this study, we externally confirmed the prognostic impact of clinical phenotypes previously identified by Gutierrez-Gutierrez and colleagues in a Spanish cohort of hospitalized patients with COVID-19, and the usefulness of their simplified probabilistic model for phenotypes assignment This could indirectly support the validity of both phenotype’s development and their extrapolation to other hospitals and countries for management decisions during other possible future viral pandemics

The aim was to show the application of the prevalence estimator of Expanded Disability Status Scale (EDSS) improvement over time in patients treated with cladribine tablets in the phase III CLARITY/CLARITY extension trials.Relapsing-remitting multiple sclerosis patients who entered the CLARITY extension study were evaluated. Patients originally randomized in CLARITY to cladribine tablets 3.5 mg/kg and placebo in CLARITY extension (early cladribine [EC]) were compared to patients originally randomized to placebo and then assigned to cladribine tablets 3.5 mg/kg (delayed cladribine [DC]). The EC group was compared to the DC group on the prevalence of EDSS improvement over time and on the cumulative incidence of EDSS improvement. Prevalence of improvement was assessed by a new approach based on the difference of Kaplan-Meier estimators, whilst the incidence of improvement was assessed by standard Kaplan-Meier curves.A total of 98 patients in the EC group and 244 patients in the DC group were compared. Patients in the EC group showed a significantly higher (p = 0.011) prevalence of improvement at year 2 (EC 21.3%, 95% confidence interval [CI] 13.6-29.3; DC 8.9%, 95% CI 5.5-12.8) and at year 5 (EC 15.7%, 95% CI 8.2-23.7; DC 8.3%, 95% CI 4.5-12.4). The cumulative incidence of improvement was also significantly different (hazard ratio 1.82, 95% CI 1.13-2.94, p = 0.013).Assessment of the prevalence of EDSS improvement is an alternative outcome to assess if a treatment induces and maintains an improvement over the long term. This estimator was found to be more powerful than the cumulative incidence of improvement to detect a treatment effect of cladribine versus placebo over 5 years.

Defining immune mechanisms leading to multiple sclerosis (MS) is difficult, due to the great inter-individual difference in immune system responses. The anti-CD52 antibody alemtuzumab transiently abolishes differences in immune parameters among individuals, allowing analysis of subsequent immune cell repopulation patterns, and their possible role in MS.To evaluate the correlation between innate and adaptive immune cell subsets and disease activity in MS in the context of treatment with alemtuzumab.A two-center observational cohort of patients treated with alemtuzumab underwent immune profiling of T, B, and natural killer (NK) cells, biomarker, clinical and radiological follow-up.After treatment, the percentage of NK and B cells increased; NK, T- and B-cell populations underwent a profound rearrangement. Within the effector T-cell compartment, treatment led to a transient decrease, followed by an increase, of T-helper 1 cells, and to a transient decrease of T-helper 17 cells. Within the T-regulatory compartment, naïve T-regulatory cells increased. Within the B-cell compartment, memory B cells and mature B cells decreased, whereas transitional B cells increased. Within the NK cell compartment, CD56The results of this study provide novel evidence that NK cells influence reconstitution of adaptive immune cells upon alemtuzumab and that patients with a successful response to alemtuzumab have an early immune reconstitution dominated by NK cells.

The use of low-cost immersive virtual reality systems is rapidly expanding. Several studies started to analyse the accuracy of virtual reality tracking systems, but they did not consider in depth the effects of external interferences in the working area. In line with that, this study aimed at exploring the static-positional accuracy and the robustness to occlusions inside the capture volume of the SteamVR (1.0) tracking system. To do so, we ran 3 different tests in which we acquired the position of HTC Vive PRO Trackers (2018 version) on specific points of a grid drawn on the floor, in regular tracking conditions and with partial and total occlusions. The tracking system showed a high inter- and intra-rater reliability and detected a tilted surface with respect to the floor plane. Every acquisition was characterised by an initial random offset. We estimated an average accuracy of 0.5 ± 0.2 cm across the entire grid (XY-plane), noticing that the central points were more accurate (0.4 ± 0.1 cm) than the outer ones (0.6 ± 0.1 cm). For the Z-axis, the measurements showed greater variability and the accuracy was equal to 1.7 ± 1.2 cm. Occlusion response was tested using nonparametric Bland–Altman statistics, which highlighted the robustness of the tracking system. In conclusion, our results promote the SteamVR system for static measures in the clinical field. The computed error can be considered clinically irrelevant for exercises aimed at the rehabilitation of functional movements, whose several motor outcomes are generally measured on the scale of metres.

Background and purpose: Real-world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease-modifying therapies (DMTs). Our aim was to provide real-world data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab. Methods: Sixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation. Results: We studied 322 patients (mean age 36.8years, median EDSS score 3, median follow-up 1.94years). Previous treatments were: fingolimod (106), natalizumab (80), first-line oral agents (56), first-line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty-five patients were treatment-naïve. The pre-alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p&nbsp

The current prognostic models for patients with advanced urinary tract cancers were developed and validated in the chemotherapy setting. As immunotherapy has become the backbone of novel treatments, updated prognostic scores are needed.A comprehensive analysis of inflammatory indexes from peripheral blood and clinical factors was planned on the entire real-world cohort of pretreated patients with advanced urinary tract carcinoma receiving atezolizumab in the prospective, single-arm, phase IIIb SAUL study. Univariable and multivariable analyses with overall survival as the primary endpoint, bootstrap internal validation, Schneeweiss scoring system and calibration test were performed to develop a novel immunotherapy prognostic score.Thirteen clinical variables from 1001 patients were analyzed. The following eight prognostic factors were included in a model: ECOG PS, liver and bone metastases, histology, pre-treatment steroids, systemic immune-inflammatory index (i.e., neutrophils-to-lymphocytes ratio times platelets count), hemoglobin and lactate dehydrogenase. The prognostic model was able to stratify patients into five risk groups with significantly different (P0.001) median overall survival of NR, 18.0, 8.7, 4.6 and 2.4 months, respectively. The c-index for OS was higher than the Bellmunt Score one (0.702 vs. 0.672).A novel 5-class prognostic model contemporary to immunotherapy provides robust prognostic discrimination of patients with advanced urinary tract carcinoma homogeneously treated with immunotherapy through baseline affordable and reproducible clinical and laboratory factors. It could be quickly adopted in clinical practice to inform patients about prognosis with immunotherapy and assess the benefit of novel immunotherapy combinations in clinical trials.

Background Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era. Methods We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups. Results Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32–0.60, p p = 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 (p = 0.038) and associated with a longer OS for the first three prognostic groups (p p = 0.54). Conclusions Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score.

Background The current prognostic models for patients with advanced urinary tract cancers were developed and validated in the chemotherapy setting. As immunotherapy has become the backbone of novel treatments, updated prognostic scores are needed. Methods A comprehensive analysis of inflammatory indexes from peripheral blood and clinical factors was planned on the entire real-world cohort of pretreated patients with advanced urinary tract carcinoma receiving atezolizumab in the prospective, single-arm, phase IIIb SAUL study. Univariable and multivariable analyses with overall survival as the primary endpoint, bootstrap internal validation, Schneeweiss scoring system and calibration test were performed to develop a novel immunotherapy prognostic score. Results Thirteen clinical variables from 1001 patients were analysed. The following eight prognostic factors were included in a model: ECOG PS, liver and bone metastases, histology, pre-treatment steroids, systemic immune-inflammatory index (i.e., neutrophils-to-lymphocytes ratio times platelets count), haemoglobin and lactate dehydrogenase. The prognostic model was able to stratify patients into five risk groups with significantly different (p < 0.001) median overall survival of NR, 18.0, 8.7, 4.6 and 2.4 months, respectively. The c-index for OS was higher than the Bellmunt score one (0.702 vs 0.672). Conclusions A novel 5-class prognostic model contemporary to immunotherapy provides robust prognostic discrimination of patients with advanced urinary tract carcinoma homogeneously treated with immunotherapy through baseline affordable and reproducible clinical and laboratory factors. It couls be quickly adopted in clinical practice to inform patients about prognosis with immunotherapy and assess the benefit of novel immunotherapy combinations in clinical trials.

Serum beta-D-glucan (BDG) determination plays an important role in the diagnosis of candidemia among critically ill patients admitted to the intensive care unit (ICU). However, BDG levels measured may be lower in the case of infections caused by some non

BackgroundOver the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time.MethodsAll patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3–4.ResultsA total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria.ConclusionsContrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression.

To analyse the course of multiple sclerosis (MS) after fingolimod withdrawal in a multicentre cohort. Patients who discontinued fingolimod were included. Relapses, Expanded Disability Status Scale (EDSS), and new/gadolinium-enhancing lesions on magnetic resonance imaging (MRI) were assessed during the last year on fingolimod, and in the year after discontinuation. Wilcoxon test was used to analyse the difference in EDSS and relapses between the two periods, and to compare lymphocyte counts at discontinuation and 3 months later. Demographic and clinical variables were evaluated using univariable and multivariable logistic regression analyses. Patients were 230 (females 66.1%; mean age 38 years; median EDSS 3). Fingolimod was discontinued due to inefficacy in 57%, and 87.4% started another treatment. Relapse was observed in 33% of the patients in the year after discontinuation. Severe reactivation was observed in 15%. During the first 6 months after discontinuation, new/enhancing lesions were seen in 62/116 patients. Higher age at the fingolimod discontinuation was found to be associated with a lower probability of inflammatory activity (p = 0.001) and severe reactivation (p = 0.007) during the year after discontinuation. Lower lymphocyte count was a risk factor for clinical, radiological, and severe activity (p = 0.02, p = 0.002, p = 0.01, respectively). The main reason for the discontinuation of fingolimod was inefficacy. One-third of the patients had a relapse during the year after discontinuation, 15% experienced a severe reactivation, and approximately 50% of patients with available MRI scan had new/enhancing lesions. The risk factors for disease activity after discontinuation were low lymphocyte count and younger age.

Background: Researchers may be tempted to favorably distort the interpretation of their findings when reporting the abstract (i.e., spin). Spin bias overemphasizes the beneficial effects of the intervention compared with the results shown in the full text. Objective: To assess the occurrence of spin bias and incompleteness in reporting abstracts in post-stroke upper limb (UL) rehabilitation randomized clinical trials (RCTs). Methods: A sample of 120 post-stroke UL rehabilitation RCTs (indexed in PEDro database), published in English between 2012 and 2020, was included. The completeness of reporting and spin were assessed using the Consolidated Standards of Reporting Trials for Abstracts (CONSORT-A) and the spin checklist. The relationship between CONSORT-A and spin checklist scores with RCT and journal characteristics was assessed. Results: CONSORT-A and spin checklist scored 5.3±2.4 (max 15-points, higher scores indicating better reporting) and 5.5±2.0 (max 7-points, higher scores indicating presence of spin), respectively; Significant differences were detected between abstract and full-text scores in the CONSORT-A checklist (p

BackgroundSecond and third-generation ALK inhibitors (ALKIs) have been recently approved for ALK-translocated lung cancer treatment, improving - and expanding - the first-line scenario.MethodsIn this systematic review and metanalysis, we investigated the efficacy and safety of next-generation ALKIs in untreated advanced ALK-translocated lung cancer patients, searching for randomized phase III controlled trials through databases (PubMed, EMBASE, and the Cochrane Library). Inclusion and exclusion of studies, quality assessment, data extraction, and synthesis were independently accomplished by two reviewers, with discrepancies adjudicated by a third reviewer. Stata (StataCorp., v.16) software was used for the metanalysis.ResultsIn total, seven randomized controlled trials met our inclusion criteria. Comparing the results of next-generation ALKIs and control therapy (crizotinib or chemotherapy), next-generation ALKIs significantly improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), any lesion (aCNSRR) and measurable lesions of central nervous system response rate (mCNSRR). Safety results were similar between the experimental and control groups.ConclusionOur analysis confirmed that next-generation ALKIs are the preferred first-line treatment option for ALK-translocated lung cancer. They are superior to crizotinib or chemotherapy in several clinical endpoints, including OS, PFS, ORR and CNS disease control, without increased toxicity. In the absence of head-to-head data, the choice between these molecules should be guided by physician experience and preference, drug-specific safety profile and schedule.

We prospectively studied immunological response against SARS-CoV-2 after vaccination among healthcare workers without (group A) and with previous infection (group B). The analyses were collected at T0 (before the BNT162b2), T1 (before the second dose), T2 and T6 (1 and 6 months after the second dose). For cellular immune response, the activation-induced cell marker assay was performed with CD4 and CD8 Spike peptide megapools expressed as Stimulation Index. For humoral immune response, we determined antibodies to Spike-1 and nucleocapsid protein. The linear mixed model compared specific times to T0. The CD4+ Spike response overall rate of change was significant at T1 (p = 0.038) and at T2 (p < 0.001), while decreasing at T6. For CD8+ Spike reactivity, the interaction between the time and group was significant (p = 0.0265), and the p value for group comparison was significant at the baseline (p = 0.0030) with higher SI in previously infected subjects. Overall, the anti-S Abs significantly increased from T1 to T6 compared to T0. The group B at T6 retained high anti-S titer (p < 0.001). At T6, in both groups we found a persistent humoral response and a high CD4+ T cell response able to cross recognize SARS-COV-2 variants including epsilon, even if not a circulating virus at that time.

BACKGROUND AND AIMS Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a worldwide spread since early 2020 and a lot of studies concerning the diagnostic and prognostic role of chest computed tomography (CT) on coronavirus disease (COVID-19) has been published. Renal involvement might be present in up to 75% of cases, significantly impacting on the prognosis. The aim of this study is to clarify the role of opportunistic kidney assessment on non-enhanced chest CT and to evaluate if radiological findings could be associated with relevant clinical information regarding kidney function and patient's prognosis in hospitalized patients with COVID-19. METHOD We collected data on patient demographics, comorbidities, chronic medications, vital signs, baseline laboratory test results and in-hospital treatment in patients with COVID-19 consecutively admitted to our Institution who underwent chest CT. The standard chest CT-scan acquired in full inspiration include large part of both kidneys as per protocol. Three regions of interest (ROI) of 0.5–0.7 cm2 were positioned in every kidney, right and left to include both the cortex and the medulla. The mean values of attenuation of kidney regions were analysed. The primary and secondary outcomes were the occurrence of acute kidney injury (AKI), in-hospital and 9 months of death for all causes. RESULTS A total of 86 patients with COVID-19 and unenhanced chest CT were analyzed splitting the cohort into CT renal parenchyma attenuation (RPA) quartiles. Patients with a CT RPA below 24 Hounsfield unit (HU) were more likely to develop AKI when compared with other patients (×2 = 2.77, P = .014). An AKI-specific cut-off point of RPA was identified by performing a survival receiver operating characteristic (ROC) curve. At multivariate logistic regression analysis, being in the first quartile of CT RPA was associated with a four-times higher risk of AKI (Table 1) after adjustment for age, gender, hypertension, kidney function at admission and other comorbidities. During a mean 22 ± 15 days of admission, 32 patients died (37.2%). Patients with lower values of RPA at CT (first quartile, CONCLUSION The association between AKI and RPA

Critically ill patients with coronavirus disease 2019 (COVID-19) may develop COVID-19-associated pulmonary aspergillosis (CAPA), which impacts their chances of survival. Whether positive bronchoalveolar lavage fluid (BALF) mycological tests can be used as a survival proxy remains unknown.

Introduction Available evidence from observational studies and meta-analyses has highlighted an increased mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections (BSI) compared with their carbapenem-susceptible (CSKP) counterparts, but the exact reasons for this outcome difference are still to be determined. Methods We updated the search of a previous meta-analysis through four databases up to April 2018. A two-stage individual-patient data (IPD) meta-analysis was conducted, building an adjusting model to account for age, comorbidities and activity of empirical and targeted antimicrobial therapy. The protocol was registered on PROSPERO (identifier: CRD42018104256). Results IPD data were obtained from 14 out of 28 eligible observational studies. A total of 1952 patients were investigated: 1093 in the CRKP group and 859 in the CSKP group. Patients with CRKP-BSI had a twofold risk of death compared with CSKP-infected patients [adjusted odds ratio (aOR) 2.17; 95% confidence interval (CI) 1.56–3.04; I2 = 44.1%]. Mortality was higher in patients with CRKP BSI, in both the subgroup of absent/inactive (aOR 1.75; 95% CI 1.24–2.47; I2 = 0) and of active initial therapy (aOR 2.66; 95% CI 1.70–4.16; I2 = 16%) as well as in case of active targeted therapy (aOR 2.21; 95% CI 1.36–3.59; I2 = 58%). Conclusion Resistance to carbapenem is associated with worse outcome in patients with BSI by Klebsiella pneumoniae even adjusting for comorbidities and treatment appropriateness according to in vitro activity of empirical and targeted therapy. This applies to a scenario dominated by colistin-based therapies for CRKP. Further studies are needed to compare the mortality difference between CRKP and CSKP cases in the light of new anti-CRKP antimicrobials. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00408-8.

ObjectiveTo determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplantation in a large cohort of patients with MS.MethodsTo be included, a minimum dataset (consisting of age, MS phenotype, Expanded Disability Status Scale [EDSS] score at baseline, information on transplantation technology, and at least 1 follow-up visit after transplantation) was required.ResultsTwo hundred ten patients were included (relapsing-remitting [RR] MS 122 [58%]). Median baseline EDSS score was 6 (1–9); mean follow-up was 6.2 (±5.0) years. Among patients with RRMS, disability worsening–free survival (95% confidence interval [CI]) was 85.5% (76.9%–94.1%) at 5 years and 71.3% (57.8%–84.8%) at 10 years. In patients with progressive MS, disability worsening–free survival was 71.0% (59.4%–82.6%) and 57.2% (41.8%–72.7%) at 5 and 10 years, respectively. In patients with RRMS, EDSS significantly reduced after aHSCT (p = 0.001; mean EDSS change per year −0.09 [95% CI −0.15% to −0.04%]). In patients with RRMS, the use of the BCNU+Etoposide+Ara-C+Melphalan (BEAM) + anti-thymocyte globulin (ATG) conditioning protocol was independently associated with a reduced risk of no evidence of disease activity 3 failure (hazard ratio 0.27 [95% CI 0.14–0.50], p < 0.001). Three patients died within 100 days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007.ConclusionsaHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM + ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity.Classification of EvidenceThis study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.

Contains fulltext : 237989.pdf (Publisher’s version ) (Closed access) BACKGROUND: Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19. METHODS: For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491). FINDINGS: 209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO(2)/FiO(2)), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20-0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO(2)/FiO(2). In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17-0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12-0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37-1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59-3·10]). INTERPRETATION: Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L. FUNDING: Sobi.

The Sit-to-Stand (STS) test is used in clinical practice as an indicator of lower-limb functionality decline, especially for older adults. Due to its high variability, there is no standard approach for categorising the STS movement and recognising its motion pattern. This paper presents a comparative analysis between visual assessments and an automated-software for the categorisation of STS, relying on registrations from a force plate. 5 participants (30 ± 6 years) took part in 2 different sessions of visual inspections on 200 STS movements 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 absolute agreement between the repeated raters' assessments as well as between the raters' and software's assessment in the first trial, were considered as indexes of human and software performance, respectively. 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 [0.039; 0.361] s in unconstrained conditions and 0.340 [0.014; 0.666] s for standardised movements. The software assessments displayed an overall good agreement against visual evaluations of the Ground Reaction Force, relying, at the same time, on objective measures.

There is increasing interest in assessing whether machine learning (ML) techniques could further improve the early diagnosis of candidemia among patients with a consistent clinical picture. The objective of the present study is to validate the accuracy of a system for the automated extraction from a hospital laboratory software of a large number of features from candidemia and/or bacteremia episodes as the first phase of the AUTO-CAND project. The manual validation was performed on a representative and randomly extracted subset of episodes of candidemia and/or bacteremia. The manual validation of the random extraction of 381 episodes of candidemia and/or bacteremia, with automated organization in structured features of laboratory and microbiological data resulted in ≥99% correct extractions (with confidence interval < ±1%) for all variables. The final automatically extracted dataset consisted of 1338 episodes of candidemia (8%), 14,112 episodes of bacteremia (90%), and 302 episodes of mixed candidemia/bacteremia (2%). The final dataset will serve to assess the performance of different ML models for the early diagnosis of candidemia in the second phase of the AUTO-CAND project.

TPS753 Background: Several studies suggested that response to immunotherapy may be influenced by many factors, including peripheral blood biomarkers, the composition of I-TME and different molecular expression pathways. In mRCC patients, immunotherapy has become part of clinical practice, but the identification of patients most likely to respond to checkpoint inhibitors is still an unmet clinical need. Moreover, there are no validated and clinically applicable gene expression panels as prognostic and/or predictive response biomarkers. To date, three major groups of immune-related gene expression were identified in mRCC: the angiogenesis pathway, the T-effector pathway and the mixed pathway (doi: 10.1038/s41598-020-58804-y). Each group of gene expression seems to be responsible for a different type of immune response in the I-TME. However, a significant association with treatment response to immunotherapy has not yet been demonstrated. Methods: The Meet-URO 18 is a multicentric retrospective translational study aimed at identifying distinctive molecular patterns of the I-TME with a prognostic and predictive role in mRCC (primary objective). Pretreated mRCC patients receiving ≥2nd line nivolumab have been divided according to clinical benefit in responders (PFS ≥ 12 months) versus non-responders (PFS ≤ 3 months). Secondary objectives include the correlation between primary tumor and metastases to identify a potential inter-tumor heterogeneity and the correlation with survival and response outcomes. Histological samples of primary tumors and/or metastases have been collected for the transcriptomic analyses together with clinical data of patients from medical records. The transcriptomic characterization of the I-TME of the primary tumor and/or metastases will be performed using the analytical platform "nCounter" of NanoString®, which analyzes the expression of 71 genes involved in angiogenesis, immunomodulation mediated by T-effector response, mechanisms of tumor invasion and mechanisms of calcium channel flows. The gene-panel include a group of 66 genes previously demonstrated to be related in the immune-response in mRCC (doi: 10.1038/s41598-020-58804-y) and 5 housekeeping genes (RPS13, PPIA, RPL27, RP2, B-ACT).

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 .

Critically ill patients with coronavirus disease 2019 (COVID-19) may develop COVID-19-associated pulmonary aspergillosis (CAPA), which impacts their chances of survival. Whether positive bronchoalveolar lavage fluid (BALF) mycological tests can be used as a survival proxy remains unknown. We conducted a

The aim of this study was the evaluation of the long-term effect on shear bond strength (SBS) of orthodontic brackets treated with or without a fluoride-releasing system.A total of 80 bovine teeth were randomly divided into 2 groups (G1, G2): in G1 teeth were treated with a fluoride-releasing system (Fluor Protector, Ivoclar Vivadent, Schaan, Liechtenstein) and with spectrum (Micerium, Genoa, Italy); in G2 only spectrum was used. Shear bond strength (SBS) was measured in MPa 24 hours after bonding (T0) and after 30 (T1), 60 (T2), 90 (T3) and 180 days (T4).A repeated measures ANOVA on rank-transformed data was used and differences in time between G1 and G2 were revealed (P0.001). From 3 months mean measurement of G1 was higher than G2 (P=0.015). No difference was revealed between T3 and T4 in either group (P=0.48 for G1 and P=0.46 for G2).After 3 months, G1 showed a significantly higher value than G2. Both groups did not show changes in shear bond strength between month 3 and month 6.

Objectives To verify the incidence of calcified brain metastases (CBM), illustrating the different presentation patterns and histology of primary tumor. Methods A series of 1002 consecutive brain computed tomography (CT) scans of patients with known primary tumors was retrospectively assessed. CBM were defined by the presence of calcification within intra-axial-enhancing lesions; identification of CBM was based on visual examination and ROI analysis (> 85 Hounsfield units). Also, calcifications in the primary tumor of all patients with brain metastases were evaluated. In CBM patients, we investigated the type of calcifications (punctate, nodular, cluster, ring, coarse), the histology of primary tumor, and if a previous RT was performed. Results Among 190 (18.9%) patients with brain metastatic disease, 34 presented with CBM (17.9%). Sixteen patients were previously treated with RT, while 18 presented calcifications ab initio (9.5% of all brain metastases). The majority of patients with CBM had a primitive lung adenocarcinoma (56%), followed by breast ductal invasive carcinoma (20%) and small cell lung carcinoma (11.8%). CBM were single in 44.1% of patients and multiple in 55.9%. With regard to the type of calcifications, the majority of CBM were punctate, without specific correlations between calcification type and histology of primary tumor. No patients with ab initio CBM had calcifications in primary tumor. Conclusion In conclusion, our data show that CBM are more common than usually thought, showing an incidence of 9.5% ab initio in patients with brain metastases. This study underlines that neuroradiologists should not overlook intraparenchymal brain calcifications, especially in oncologic patients. Key Points • Among the differential diagnosis of brain intraparenchymal calcifications, metastases are considered uncommon and found predominantly in patients treated with radiotherapy (RT). • Our data show that CBM are more common than usually thought, showing an incidence of 9.5% ab initio in patients with brain metastases. • A proportion of intraparenchymal brain calcifications, especially in oncologic patients, might represent evolving lesions and neuroradiologists should not overlook them to avoid a delay in diagnosis and treatment.

Background: The concept of improvement of disability recently emerged as a new target in multiple sclerosis (MS) studies since the approval of new potent drugs and for testing drugs for neuroprotection and repair. Objective: To propose a simple estimator for assessing and comparing the prevalence of improvement over time between groups. Methods: The prevalence of a transient condition takes into account the incidence and the duration of such condition. We propose here the application of a modified Kaplan–Meier estimator to evaluate and compare between groups the prevalence of improvement over time in a cohort of 121 patients treated with autologous hematopoietic stem cell transplantation. Results: The prevalence of improvement after 5 years from transplant was 50.3% (95%CI: [38.0–63.0]) in relapsing–remitting patients and 6.5% (95%CI: [0–17.8]) in secondary-progressive patients ( p Conclusion: This study shows the relevance of a new estimator of prevalence of improvement in MS. This estimator gives simple information on whether a drug can induce a durable improvement in disability and can be considered a potential outcome for trials assessing drugs for neuroprotection or repair.

Background The aim of this systematic review and meta-analysis was to assess the effect of anesthesia maintenance with volatile agents compared with propofol on both short- and long-term mortality (primary outcomes) and major clinical events in adults undergoing cardiac surgery with cardiopulmonary bypass. Methods Randomized clinical trials on the effects of current volatile anesthetics versus propofol in adults undergoing cardiac surgery with cardiopulmonary bypass were searched (1965 to September 30, 2019) in PubMed, the Cochrane Library, and article reference lists. A random effect model on standardized mean difference for continuous outcomes and odds ratio for dichotomous outcomes were used to meta-analyze data. Results In total, 37 full-text articles (42 studies, 8,197 participants) were included. The class of volatile anesthetics compared with propofol was associated with lower 1-yr mortality (5.5 vs. 6.8%; odds ratio, 0.76 [95% CI, 0.60 to 0.96]; P = 0.023), myocardial infarction (odds ratio, 0.60 [95% CI, 0.39 to 0.92]; P = 0.023), cardiac troponin release (standardized mean difference, −0.39 [95% CI, −0.59 to −0.18], P = 0.0002), need for inotropic medications (odds ratio, 0.40 [95% CI, 0.24 to 0.67]; P = 0.0004), extubation time (standardized mean difference, −0.35 [95% CI, −0.68 to −0.02]; P = 0.038), and with higher cardiac index/output (standardized mean difference, 0.70 [95% CI, 0.37 to 1.04]; P < 0.0001). The class of volatile anesthetics was not associated with changes in short-term mortality (1.63 vs. 1.65%; odds ratio, 1.04 [95% CI, 0.73 to 1.49]; P = 0.820) and acute kidney injury (odds ratio, 1.25 [95% CI, 0.77 to 2.03]; P = 0.358). Conclusions In adults undergoing cardiac surgery with cardiopulmonary bypass, the class of volatile anesthetics was superior to propofol with regard to long-term mortality, as well as to many secondary outcomes indicating myocardial protection. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

To retrospectively evaluate the different performances of T1-SE and T1-GE sequences in detecting hypointense lesions in multiple sclerosis (MS), to quantify the degree of microstructural damage within lesions and to correlate them with patient clinical status. Sixty clinically isolated syndrome (CIS) and MS patients underwent brain magnetic resonance imaging (MRI) on 1.5-T and 3-T scanners. We identified T2 fluid-attenuated inversion recovery hyperintense lesions with no hypointense signal on T1-SE/T1-GE (a), hypointense lesions only on T1-GE (b), and hypointense lesions on both T1-SE and T1-GE sequences (c). We compared mean lesion number (LN) and volume (LV) identified on T1-SE and T1-GE sequences, correlating them with Expanded Disability Status Scale (EDSS); fractional anisotropy (FA) and mean diffusivity (MD) values inside each lesion type were extracted and normal-appearing white matter (NAWM). Thirty-five patients were female. Mean age was 39.2 (± 7.8); median EDSS was 3 (± 2). There were 23 CIS, 21 relapsing–remitting (RR), and 16 progressive MS. T1-GE and T1-SE LN and LV were significantly different (p

Background Biologic therapy for psoriasis is effective but not always long-lasting and sometimes needs to be switched. Objective We aimed to evaluate the drug survival (ie, the time from initiation to discontinuation) of each biologic and the factors affecting survival to identify better switching strategies and improve drug survival. Methods In total, 195 psoriasis patients treated in our unit during 2006-2018 were retrospectively observed. Descriptive statistical analyses and logistic regression models were performed. Kaplan–Meier survival curves and multivariate Cox models adjusted for confounding variables were used to estimate and compare drug survival. Results Overall, 90.6% of patients achieved an ≥75% reduction in their baseline Psoriasis Area and Severity Index score. In 2018, the most frequently used biologic was ustekinumab (47/169, 27.8%). Patients with higher baseline Psoriasis Area and Severity Index scores were more likely to be switched (P = .0399, odds ratio 1.08). In naive patients, ustekinumab showed longer drug survival (>7.0 years), but in biologic-experienced patients, we found no significant differences in drug survival. Previous biologic therapies increased the need for switching (P = .014, hazard ratio 1.20). Switching between biologic classes yielded longer drug survival than switching within biologic classes (P = .003, hazard ratio 0.48). Limitations As a single-center, retrospective real-life study, the data were not perfectly homogeneous. Conclusion Switching between biologic classes might increase drug survival but retrospective studies designed ad hoc are needed to confirm this better switching strategy.

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.

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.

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.

Introduction: Older adults are more susceptible to severe COVID-19, with increased all-cause mortality. This has been attributed to their multimorbidity and disability. However, it remains to be established which clinical features of older adults are associated with severe COVID-19 and mortality. This information would aid in an accurate prognosis and appropriate care planning. Here, we aimed to identify the chronic clinical conditions and the comorbidity clusters associated with in-hospital mortality in a cohort of older COVID-19 patients who were admitted to the IRCCS Policlinico San Martino Hospital, Genoa, Italy, between January and April 2020.Methods: This was a retrospective cohort study including 219 consecutive patients aged 70 years or older and is part of the GECOVID-19 study group. During the study period, upon hospital admission, demographic information (age, sex) and underlying chronic medical conditions (multimorbidity) were recorded from the medical records at the time of COVID-19 diagnosis before any antiviral or antibiotic treatment was administered. The primary outcome measure was in-hospital mortality.Results: The vast majority of the patients (90%) were >80 years; the mean patient age was 83 ± 6.2 years, and 57.5% were men. Hypertension and cardiovascular disease, along with dementia, cerebrovascular diseases, and vascular diseases were the most prevalent clinical conditions. Multimorbidity was assessed with the Cumulative Illness Rating Scale. The risk of in-hospital mortality due to COVID-19 was higher for males, for older patients, and for patients with dementia or cerebral-vascular disease. We clustered patients into three groups based on their comorbidity pattern: the Metabolic-renal-cancer cluster, the Neurocognitive cluster and the Unspecified cluster. The Neurocognitive and Metabolic-renal-cancer clusters had a higher mortality compared with the Unspecified cluster, independent of age and sex.Conclusion: We defined patterns of comorbidity that accurately identified older adults who are at higher risk of death from COVID-19. These associations were independent of chronological age, and we suggest that the identification of comorbidity clusters that have a common pathophysiology may aid in the early assessment of COVID-19 patients with frailty to promote timely interventions that, in turn, may result in a significantly improved prognosis.

Serum beta-D-glucan (BDG) determination plays an important role in the diagnosis of candidemia among critically ill patients admitted to the intensive care unit (ICU). However, BDG levels measured may be lower in the case of infections caused by some non-albicans species, such as C. parapsilosis and C. auris. The aim of this single-center study was to investigate the sensitivity of serum BDG for the diagnosis of candidemia stratified according to causative Candida species in ICU patients. This was a single-center, retrospective study, including all adult patients admitted to ICU during the period 2018–2021. All episodes of candidemia with a determination of BDG available within 3 days before or after positive blood culture were recorded. The preplanned primary objective was to investigate the sensitivity of serum BDG to detect candidemia early and the effect of different Candida species. The secondary objective was to measure serum BDG in patients with candidemia from different Candida species. In total, 146 candidemia episodes in 118 patients were analyzed. Median BDG value for C. albicans candidemia (182 pg/mL) was higher than that observed for C. parapsilosis (78 pg/mL, p = 0.015) and C. auris (48 pg/mL, p = 0.022). The overall sensitivity of BDG for the diagnosis of candidemia was low (47%, 95% CI 39–55%). In conclusion, in critically ill patients admitted to ICU, serum BDG levels for candidemia were different among species, with lower levels confirmed for C. parapsilosis and C. auris. Serum BDG sensitivity for early detection of candidemia was lower than previously reported in other ICU populations.

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 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.