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There is growing interest in exploiting the advances in artificial intelligence and machine learning (ML) for improving and monitoring antimicrobial prescriptions in line with antimicrobial stewardship principles. Against this background, the concepts of interpretability and explainability are becoming increasingly essential to understanding how ML algorithms could predict antimicrobial resistance or recommend specific therapeutic agents, to avoid unintended biases related to the “black box” nature of complex models. In this commentary, we review and discuss some relevant topics on the use of ML algorithms for antimicrobial stewardship interventions, highlighting opportunities and challenges, with particular attention paid to interpretability and explainability of employed models. As in other fields of medicine, the exponential growth of artificial intelligence and ML indicates the potential for improving the efficacy of antimicrobial stewardship interventions, at least in part by reducing time-consuming tasks for overwhelmed health care personnel. Improving our knowledge about how complex ML models work could help to achieve crucial advances in promoting the appropriate use of antimicrobials, as well as in preventing antimicrobial resistance selection and dissemination.

Cognitive reserve (CR) is a multidimensional construct based on lifelong engagement in cognitively stimulating domains, including education, occupation and leisure activities, that plays a crucial role in mitigating the presentation of dementia. To date, the contribution of each CR subdomain in the development of dementia is under-investigated. This study is aimed at assessing the association of CR subdomains with cognitive status, accounting for sex and age in an old-age population. 317 older adults were recruited with a diagnosis of subjective cognitive impairment, mild cognitive impairment, and dementia due to Alzheimer's disease or mixed-type dementia. Cognitive Reserve Index questionnaire (CRIq) was used to assess CR. Patients were stratified based on sex and dementia staging (CDR). Significant variables from univariate analysis entered a multivariate ordinal regression model, using CDR as the dependent variable. The results showed that the leisure activities subdomain was the main determinant of cognitive status (OR 0.90, 95%CI 0.82-1.00,  = 0.003); CR and sex did not show any interaction. Unlike education and occupation, leisure activities may be considered a lifelong, dynamic contributor to CR. These findings highlight the importance of refining CR assessment, with particular attention to leisure activities as a potentially modifiable target for dementia prevention.

BackgroundAutologous haematopoietic stem cell transplantation (AHSCT) is increasingly used as a one-off disease-modifying therapy for aggressive forms of multiple sclerosis (MS). We report real-world effectiveness of AHSCT for MS in the UK.MethodsThis retrospective open-label study included patients with (pw)MS treated with AHSCT between 2002 and 2023 in 14 UK centres. Outcomes included relapse-free survival (RFS), MRI activity-free survival (MFS), progression-free survival (PFS) and no evidence of disease activity (NEDA-3). We assessed 6-month confirmed Expanded Disability Status Scale (EDSS) score progression or improvement compared with pre-treatment. Treatment-related mortality (TRM) was defined as death from any cause within 100 days post-autologous graft reinfusion.Results364 pwMS were included (median age 40 years; 58% female). Of these, 271 pwMS had adequate neurological follow-up data: 168 (62%) had relapsing-remitting MS (pwRRMS) and 103 (38%) had progressive MS (pwPMS). Median disease duration from symptom onset was 10 years (IQR 6–14), EDSS 6 (IQR 4.0–6.5) and follow-up from AHSCT 46 months. At 2 and 5 years from AHSCT, RFS was 94.6% and 88.6%; MFS 93.1% and 80.1%; PFS 83.5% and 62.4%; NEDA-3 72.3% and 46.2%. pwRRMS had significantly higher rates of PFS (p=0.007) and NEDA-3 (p=0.001) than pwPMS. RRMS was a predictor of EDSS improvement, whose prevalence was 24.2% at 2 years and 20.4% at 5 years. TRM was 1.4% (n=5/364).ConclusionsIn this cohort with high EDSS at baseline and including pwPMS, AHSCT led to durable remission of inflammatory activity and stabilisation or improvement of neurological disability, particularly in pwRRMS.

The diffuse large B-cell lymphoma (DLBCL) variant of Richter transformation (DLBCL-RT) is typically chemoresistant with poor prognosis. Aiming to explore a chemotherapy-free treatment combination that triggers anti-tumour immune responses, we conducted a phase 2 study of atezolizumab (a PD-L1 inhibitor) in combination with venetoclax and obinutuzumab in patients with DLBCL-RT. This was a prospective, open-label, multicentre, single-arm, investigator-initiated, phase 2 study in 15 hospitals in Italy and Switzerland. Eligible patients had a confirmed diagnosis of chronic lymphocytic leukaemia or small lymphocytic lymphoma as per the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with biopsy-proven transformation to DLBCL; had not previously received treatment for DLBCL-RT, although they could have received chronic lymphocytic leukaemia therapies; were aged 18 years or older; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. No previous treatment with any of the drugs in the triplet combination was allowed. Patients received 35 cycles of 21 days of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on day 8 and day 15 of cycle 1; 1000 mg on day 1 of cycles 2–8) and intravenous atezolizumab (1200 mg on day 2 of cycle 1 and 1200 mg on day 1 of cycles 2–18), and continuous oral venetoclax (ramp-up from 20 mg/day on day 15 of cycle 1 according to chronic lymphocytic leukaemia schedule, then 400 mg/day from day 1 of cycle 3 to day 21 of cycle 35). The primary endpoint was overall response rate at day 21 of cycle 6 in the intention-to-treat population. We considered an overall response rate of 67% or more to be clinically active, rejecting the null hypothesis of a response of 40% or less. The study is registered with ClinicalTrials.gov, NCT04082897, and has been completed. Between Oct 9, 2019, and Oct 19, 2022, 28 patients were enrolled (12 [43%] male patients and 16 [57%] female patients). Median follow-up was 16·8 months (IQR 7·8–32·0). At cycle 6, 19 of 28 patients showed a response, yielding an overall response rate of 67·9% (95% CI 47·6–84·1). Treatment-emergent adverse events that were grade 3 or worse were reported in 17 (61%; 95% CI 40·6–78·5) of 28 patients, with neutropenia being the most frequent (11 [39%; 21·5–59·4] of 28 patients). Serious treatment-emergent adverse events were reported in eight (29%; 14·2–48·7) patients, which were most commonly infections (five [18%; 6·1–36·9] of 28 patients). There were two (7%) deaths attributable to adverse events during the study: one from sepsis and one from fungal pneumonia, which were not considered as directly treatment-related by the investigators. Six (21·4%) patients had immune-related adverse events, none of which led to discontinuation. No tumour lysis syndrome was observed. The atezolizumab, venetoclax, and obinutuzumab triplet combination was shown to be active and safe, suggesting that this chemotherapy-free regimen could become a new first-line treatment approach in patients with DLBCL-RT. Roche.

Introduction Stratifying the risk of recurrence for surgically treated papillary renal cell carcinoma (pRCC) could be challenging. Prognostic models are crucial for patient counselling and individualized surveillance. The GRANT score is one of the models suggested by guidelines to predict prognosis of surgically treated pRCC. This study aims to externally validate the GRANT score using a three-risk group stratification in a large cohort of pRCC patients. Materials and Methods The present analysis utilized retrospective data from pRCC patients who underwent radical or partial nephrectomy. The GRANT score parameters included tumor grade, age, pathological T-stage, and N-stage. Patients were stratified into three risk groups (0-1 vs 2 vs 3-4 risk factors). Cancer-specific survival (CSS) was assessed using the Kaplan-Meier method, and differences between groups were evaluated using the log-rank test. Harrell's c-index was used to measure model accuracy, and restricted mean survival time (RMST) was calculated for up to 120 months. Results A total of 1942 patients were included. The median follow-up was 64.6 months. At 60 months, CSS was 93.2% (95%CI 91.7%-94.6%) for group 1, 60.8% (95%CI 54.0%-78.6%) for group 2, and 26% (95%CI 15.7%-42.9%) for group 3, with significant differences between each group (p < 0.001). The median CSS was not reached for group 1 (95%CI NR-NR), 86.0 months in group 2 (95%CI 65-NR), and 22.8 months in group 3 (95%CI 16.4-48.0). The c-index for CSS was 0.732. The RMST at 120 months was 113.3 months for group 1, 75.9 months for group 2, and 56.6 months for group 3, with a statistically significant difference (p < 0.001). Conclusion The GRANT score effectively stratified surgically treated pRCC patients into three risk groups, demonstrating good prognostic accuracy. This validation supports the GRANT score's utility as a reliable and easy-to-use prognostic tool.

Purpose To combine peripheral blood indices and clinical factors in a prognostic score for metastatic castration-resistant prostate cancer (mCRPC) patients treated with radium-223 dichloride ([ 223 Ra]RaCl 2 ). Patients and methods Baseline neutrophil-to-lymphocyte ratio (NLR), derived NLR (donor), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), Eastern Cooperative Oncology Group performance status (ECOG PS), Gleason score (GS) group, number of bone metastases, prostate-specific antigen (PSA), alkaline phosphatase (ALP), line of therapy, previous chemotherapy, and the presence of lymphadenopathies were collected from seven Italian centers between 2013 and 2020. Lab and clinical data were assessed in correlation with the overall survival (OS). Inflammatory indices were then included separately in the multivariable analyses with the prognostic clinical factors. The model with the highest discriminative ability (c-index) was chosen to develop the BIO-Ra score. Results Five hundred and nineteen mCRPC patients (median OS: 19.9 months) were enrolled. Higher NLR, dNLR, PLR, and SII and lower LMR predicted worse OS (all with a p  < 0.001). The multivariable model including NLR, ECOG PS, number of bone metastases, ALP, and PSA (c-index: 0.724) was chosen to develop the BIO-Ra score. Using the Schneeweiss scoring system, the BIO-Ra score identified three prognostic groups (36%, 27.3%, and 36.6% patients, respectively) with distinct median OS (31, 26.6, and 9.6 months, respectively; hazard ratio: 1.62, p  = 0.008 for group 2 vs. 1 and 5.77, p  < 0.001 for group 3 vs. 1). Conclusions The BIO-Ra score represents an easy and widely applicable tool for the prognostic stratification of mCRPC patients treated with [ 223 Ra]RaCl 2 with no additional costs.

Background Nowadays, different therapeutic options are available for the first-line treatment of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy in all mRCC patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk category, even though TKI monotherapy is still a therapeutic option in selected patients. However, comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. For this reason, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear. Methods The REGAL study is a multicentric prospective observational study enrolling mRCC patients treated with first-line systemic therapy according to clinical practice in a real-world setting. A retrospective cohort of mRCC patients who received first-line systemic therapy from the 1st of January 2021 will also be included. The primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice; secondary objectives included the assessment of the prognostic performance of the novel prognostic Meet-URO score (IMDC score + neutrophil-to-lymphocyte ratio + bone metastases) compared with the IMDC score and the comparison between treatment strategies according to response and survival outcomes and toxicity profile. Discussion Considering the high number of therapeutic first-line strategies available for mRCC, the identification of clinical prognostic and predictive factors to candidate patients to a preferable systemic therapy is still an unmet clinical need. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients, to identify the clinical predictive and prognostic factors and the different performances between the ICI-based combinations according to response, survival and toxicity. Trial Registration CESC IOV 2023-78.

ObjectivesThe 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.MethodsA 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.ResultsForty 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 < 0.001), with high concordance between readers (ICC ≥ 0.995). CLs were significantly correlated with both motor and cognitive scores (all with p ≤ 0.04).ConclusionsCL can be identified over the whole brain at 7-T in MS using a 3D-T1-weighted volume, acquired in a clinically feasible time and with comparable performance to that achievable using the T2*-weighted sequence. Based on the central role of CL in the development of clinical disability, we suggest that 3D-T1-weighted volume may play a role in the evaluation of CL in MS undergoing MRI on ultra-high-field scanners.Key Points• Cortical lesions can be identified in a clinically feasible time with a 7-T protocol, which includes a 3D-T1-weighted volume.• Cortical lesions correlated significantly with both motor and cognitive disability in MS patients.• Given their correlation with clinical disability, evaluation of a cortical lesion on a 7-T clinical protocol could help in the management of MS patients.

Background/Objectives: The Rapid Geriatric Assessment (RGA) is a tool designed to screen for frailty, sarcopenia, anorexia related to aging, and cognitive impairment. This study aimed to translate and validate the RGA for use among Italian community-dwelling older adults. Methods: This cross-cultural study involved 100 community-dwelling older adults randomly recruited through convenience sampling from general practitioner offices in Genoa (Italy), between January and June 2019. The RGA includes the Simple FRAIL Questionnaire Screening Tool, SARC-F Screening for Sarcopenia, Simplified Nutritional Assessment Questionnaire (SNAQ), and Rapid Cognitive Screening (RCS). These were validated against gold-standard tools: the Abbreviated Comprehensive Geriatric Assessment (aCGA) and Multidimensional Prognostic Index (MPI). Additional assessments included the Timed Up and Go (TUG) and Handgrip test. The validation process included forward–backward translation, synthesis, and consensus by independent reviewers. Psychometric properties, internal consistency (Cronbach alpha), and validity correlations were analyzed. Results: The RGA demonstrated satisfactory psychometric properties, with internal consistency (Cronbach alpha = 0.59) and significant validity correlations (RGA and aCGA, rho = 0.34, p = 0.001; RGA and MPI, rho = 0.49, p < 0.001). Discriminant validity was confirmed by significant correlations between specific subitems and reference measures: FRAIL with TUG (p < 0.05), SARC-F with Handgrip strength (p = 0.013), SNAQ with BMI, and RCS with MMSE (p < 0.001). Conclusions: The Italian version of the RGA is a reliable screening tool for geriatric syndromes in community-dwelling older adults. While it does not replace a CGA, the RGA may identify individuals who may benefit from further evaluation using a complete CGA.

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.