Therapeutic lag: Is treatment effect delayed in progressive MS?

BACKGROUND: Randomized clinical trials (RCTs) in progressive multiple sclerosis (MS) often revealed non-significant treatment effects on disability progression. OBJECTIVES: To investigate whether the failure to detect a significant benefit from treatment may be motivated by a delay in treatment effect, possibly related to baseline characteristics. METHODS: We re-analyzed data from two RCTs testing interferon-beta and glatiramer-acetate versus placebo in progressive MS with no significant effect on EDSS progression. We first designed a time-dependent Cox model with no treatment effect up to time = t0, and constant hazard ratio (HR) after time = t0. We selected the best-fitting t0 from 0 (standard Cox model) to 2.5 years. Furthermore, we modeled the delay as a function of baseline EDSS and fitted the resulting Cox model to the merged dataset. RESULTS: The time-dependent Cox model revealed a significant benefit of treatment delayed by t0 = 2.5 years for the SPECTRIMS study (HR = 0.65 (0.43-0.98), p = 0.041), and delayed by t0 = 2 years for the PROMISE study (HR = 0.65, (0.42-0.99), p = 0.044). In the merged dataset, the HR for the EDSS-dependent delayed effect was 0.68 (0.56, 0.82), p < 0.001. CONCLUSION: The assumption of a delayed treatment effect improved the fit to the data of the two examined RCTs, uncovering a significant, although shifted, benefit of treatment.

Extra-prostatic extension grading system: correlation with MRI features and integration of capsular enhancement sign for "enhanced" detection of T3a lesions.

PURPOSE: This study aims to confirm the diagnostic accuracy of extra-prostatic extension (EPE) grading system and to explore the predictive capabilities of the prostate MRI while considering various MRI features such as lesion location, apparent diffusion coefficient (ADC) values and capsular enhancement sign (CES). METHODS: Our monocentric study is based on a retrospective analysis of 99 patients who underwent radical prostatectomy from January 2021 to January 2023. The observers reviewed for each lesion, including location (transitional or peripheral zone, anterior or posterior location), capsular contact length, irregular bulging of the capsule, asymmetry of the neurovascular bundle, obliteration of the recto-prostatic angle, macroscopic EPE, ADC value, and CES. RESULTS: Among 99 patients, 31 patients had EPE. Lesions with EPE have broadercapsule contact (24 mm vs 12 mm) with contact ≥14 mm being the optimal cut-off for EPE discrimination. Among the morphological MRI criteria used to determine the EPE, the one with major sensitivity was shown to be bulging (sen 81%), while macroscopic extension had highest specificity (100%). Univariate analysis showed as significative risk factors for EPE: capsular contact ≥14 mm (P < .001), International Society of Urological Pathology score ≥3 (P = .005), CES (P < .001), bulging (P = .001), neurovascular bundle asymmetry (P < .001) and EPE score ≥2 (P < .001), and in multivariate analysis CES (P = .001) and EPE score ≥2 (P = .004) were significant. The AUC of the EPE score was 0.76, raised to 0.83 when combining it with CES (P = .11). CONCLUSION: CES in the setting of multiparametric MRI can increase diagnostic accuracy for the prediction of extracapsular disease. ADVANCES IN KNOWLEDGE: This study highlights the potential of contrast media in prostate cancer local staging.

Ideal cardiovascular health and risk of death in a large Swedish cohort.

BACKGROUND: Ideal cardiovascular health (CVH) can be assessed by 7 metrics: smoking, body mass index, physical activity, diet, hypertension, dyslipidemia and diabetes, proposed by the American Heart Association. We examined the association of ideal CVH metrics with risk of all-cause, CVD and non-CVD death in a large cohort. METHODS: A total of 29,557 participants in the Swedish National March Cohort were included in this study. We ascertained 3,799 deaths during a median follow-up of 19 years. Cox regression models were used to estimate hazard ratios with 95% confidence intervals (95% CIs) of the association between CVH metrics with risk of death. Laplace regression was used to estimate 25th, 50th and 75th percentiles of age at death. RESULTS: Compared with those having 6-7 ideal CVH metrics, participants with 0-2 ideal metrics had 107% (95% CI = 46-192%) excess risk of all-cause, 224% (95% CI = 72-509%) excess risk of CVD and 108% (31-231%) excess risk of non-CVD death. The median age at death among those with 6-7 vs. 0-2 ideal metrics was extended by 4.2 years for all-causes, 5.8 years for CVD and 2.9 years for non-CVD, respectively. The observed associations were stronger among females than males. CONCLUSIONS: The strong inverse association between number of ideal CVH metrics and risk of death supports the application of the proposed seven metrics for individual risk assessment and general health promotion.

Adenovirus infection in adult patients undergoing allogeneic hematopoietic stem cell transplant: Incidence, clinical management, and outcome.

BACKGROUND: Adenovirus infection (ADVi) is an emergent complication in adult patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with poor outcome. Available data on risk factors and optimal management of ADVi in adult allo-HSCT recipients are limited, and recommendations on monitoring and pre-emptive therapy are mainly based on pediatric data. METHODS: In this single-center, retrospective study, we reported all cases of positive ADV-DNA from adult patients undergoing allo-HSCT in the period 2014-2019. The study aimed to describe the incidence of ADVi at day +180 post-transplant. Secondly to describe timing, clinical presentation, risk factors, and outcome of ADVi and to analyze the application of a screening strategy in our cohort. RESULTS: In 445 allo-HSCT recipients, the day +180 incidence was: 9% (39/445) for ADVi, 5% (24/445) for ADV viremia (ADVv), and 3% (15/445) for localized ADVi. The median time to ADVi was 65 (IQR 19; 94) days after HSCT. ADVv-related mortality was 13% (3/24), all cases occurring with blood max-ADV-DNA > 10^3 cp/mL. Independent risk factors for ADVi were diagnosis of lymphoproliferative disease (p = .011) and acute graft-versus-host-disease (p = .021). CONCLUSIONS: In our cohort, ADVi and ADVv were more frequent than previously reported. ADVv with max-ADV-DNA > 10^3 cp/mL was associated with ADV-related mortality, thus careful monitoring and early initiation of treatment are advisable.

Emulating randomised clinical trials in relapsing-remitting multiple sclerosis with non-randomised real-world evidence: an application using data from the MSBase Registry.

BACKGROUND: To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon ß-1a (IFN) using observational data. METHODS: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression. RESULTS: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51). CONCLUSIONS: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research.

Profiling migraine patients according to clinical and psychophysical characteristics: clinical validity of distinct migraine clusters.

AIMS: Investigate if different clinical and psychophysical bedside tools can differentiate between district migraine phenotypes in ictal/perictal (cohort 1) and interictal (cohort 2) phases. METHOD: This observational study included two independent samples in which patients were subgrouped into distinct clusters using standardized bedside assessment tools (headache frequency, disability, cervical active range of motion, pressure pain threshold in different areas): (A) cohort 1-ictal/perictal migraine patients were subgrouped, based on previous studies, into two clusters, i.e., Cluster-1.1 No Psychophysical Impairments (NPI) and Cluster-1.2 Increased Pain Sensitivity and Cervical Musculoskeletal Dysfunction (IPS-CMD); (B) cohort 2-interictal migraine patients were subgrouped into three clusters, i.e., Cluster-2.1 NPI, Cluster-2.2 IPS, and Cluster-2.3 IPS-CMD. Clinical characteristics (multiple questionnaires), somatosensory function (comprehensive quantitative sensory testing (QST)), and cervical musculoskeletal impairments (cervical musculoskeletal assessment) were assessed and compared across headache clusters and a group of 56 healthy controls matched for sex and age. RESULTS: Cohort 1: A total of 156 subjects were included. Cluster-1.2 (IPS-CMD) had higher headache intensity (p = 0.048), worse headache-related (p = 0.003) and neck-related disability (p = 0.005), worse quality of life (p = 0.003), and higher symptoms related to sensitization (p = 0.001) and psychological burden (p = 0.005) vs. Cluster-1.1(NPI). Furthermore, Cluster-1.2 (IPS-CMD) had (1) reduced cervical active and passive range of motion (p < 0.023), reduced functionality of deep cervical flexors (p < 0.001), and reduced values in all QST(p < 0.001) vs. controls, and (2) reduced active mobility in flexion, left/right lateral flexion (p < 0.045), and reduced values in QST (p < 0.001) vs. Cluster-1.1 (NPI). Cohort 2: A total of 154 subjects were included. Cluster-2.3 (IPS-CMD) had (1) longer disease duration (p = 0.006), higher headache frequency (p = 0.006), disability (p < 0.001), and psychological burden (p = 0.027) vs. Cluster-2.2 (IPS) and (2) higher headache-related disability (p = 0.010), neck-related disability (p = 0.009), and higher symptoms of sensitization (p = 0.018) vs. Cluster-2.1 (NPI). Cluster-2.3(IPS-CMD) had reduced cervical active and passive range of motion (p < 0.034), and reduced functionality of deep cervical flexors (p < 0.001), vs. controls, Custer-2.1 (NPI), and Cluster-2.2 (IPS). Cluster-2.2 (IPS) and 2.3 (IPS-CMD) had reduced QST values vs. controls (p < 0.001) and Cluster-2.1 (p < 0.039). CONCLUSION: A battery of patient-related outcome measures (PROMs) and quantitative bedside tools can separate migraine clusters with different clinical characteristics, somatosensory functions, and cervical musculoskeletal impairments. This confirms the existence of distinct migraine phenotypes and emphasizes the importance of migraine phases of which the characteristics are assessed. This may have implications for responders and non-responders to anti-migraine medications.

Neutralizing monoclonal antibodies for the prevention of severe COVID-19: a retrospective study during Omicron BA.1 variant surge.

Among treatment options for Coronavirus disease 2019 (COVID-19), monoclonal antibodies (mAbs) showed to be effective in preventing disease progression, but real-world data during the Omicron variant surge are still lacking. Multicentre retrospective study evaluating the effectiveness of sotrovimab and casirivimab-imdevimab in fragile patients with mild SARS-CoV-2 infection between November 2021 and March 2022. Unfavourable outcome was defined as increased need for oxygen supplementation and/or death. Of 268 study-participants, 12 (4.48%) previously needed supplemental oxygen, while 6 (2.24%) had active solid neoplasia (2.24%); 186 (69%) have previously received SARS-CoV-2 vaccination. Overall, 22 (8%) had unfavourable outcomes (42% versus 6% of patients with and without previous oxygen need and 50% versus 7% of patients with and without active solid neoplasia). Both supplemental oxygen therapy before SARS-CoV-2 infection and solid malignant tumour have shown to be risk factors for treatment failure. Log-rank test did not identify differences between sotrovimab and casirivimab-imdevimab treatment. Despite diffusion of Omicron variant, the rate of unfavourable outcome was higher than expected. The presence of underlying risk factors, including solid cancer and previous oxygen therapy are independently associated with risk of COVID-19 progression, suggesting the need for antiviral treatments not limited to mAbs and implementation of vaccine campaign.

Effect of SARS-CoV-2 vaccination in a vulnerable COVID-19 cohort: a real-life experience in an Italian Hospital.

Clinical trials demonstrated that SARS-CoV-2 vaccines reduce COVID-19-related mortality and morbidity. We describe the effect of vaccination on COVID-19-patients admitted at our hospital. Retrospective, single-center study conducted in Genoa, Italy, including patients ≥18years hospitalized for COVID-19 from May to December 2021. Demographical and clinical data were collected, vaccinated (group-A) and not-vaccinated (group-B) patients were compared. Impact of vaccination on mortality, ICU admission, and oxygen need was studied using Cox proportional hazards and logistic regression models after adjusting for propensity scores. Overall, 395 patients SARS-CoV-2 infected were included, of which 150 (38%) were vaccinated and 245 (62%) were not vaccinated. Patients in group-A were older, more disable, and with higher morbidity. Overall, 64 patients (16%) died within 30 days from admission, 34 in Group A (23%), and 30 in group B (12%). However, no statistically significant differences were observed (group-A versus group-B: HR 0.83, 95% CI 0.49-1.40, p = 0.483). On the other hand, vaccination was protective in terms of ICU admission (OR = 0.23, p = 0.046) and oxygen need (OR = 0.33, p = 0.008). Our study confirms that SARS-CoV-2 vaccination reduces morbidity among patients hospitalized for COVID-19. The still high mortality in our cohort of vaccinated individuals could be partially due to vulnerable conditions of our patients.

Useful outcome measures in INPH patients evaluation.

Introduction: Idiopathic normal pressure hydrocephalus (INPH) is a neurological disorder that is potentially reversible and clinically characterized by a specific triad of symptoms, including gait disturbance, cognitive disorders, and urinary incontinence. In INPH assessment, the most commonly used test is the Timed Up and Go test (TUG), but a more comprehensive assessment would be necessary. The first aim of the present study is to verify the sensitivity of a protocol with both clinical and instrumental outcome measures for gait and balance in recognizing INPH patients. The second aim is to verify the most important spatio-temporal parameters in INPH assessment and their possible correlations with clinical outcome measures. Methods: Between January 2019 and June 2022, we evaluated 70 INPH subjects. We assessed balance performances with the Berg Balance Scale (BBS), Short Physical Performance Battery (SPPB), and TUG, both single (ST) and dual task (DT). We also performed an instrumental gait assessment with the GAITRite electronic walkway system, asking the patients to walk on the carpet for one minute at normal speed, fast speed, and while performing a dual task. We compared the results with those of 20 age-matched healthy subjects (HS). Results: INPH patients obtained statistically significant lower scores at the BBS, SPPB, and TUG DT but not at the TUG ST, likely because the DT involves cognitive factors altered in these subjects. Concerning instrumental gait evaluation, we found significant differences between HS and INPH patients in almost all spatio-temporal parameters except cadence, which is considered a relevant factor in INPH guidelines. We also found significant correlations between balance outcome measures and gait parameters. Discussion: Our results confirm the usefulness of BBS and suggest improving the assessment with SPPB. Although the TUG ST is the most commonly used test in the literature to evaluate INPH performances, it does not identify INPH; the TUG DT, instead, might be more useful. The GAITRite system is recognized as a quick and reliable tool to assess walking abilities and spatio-temporal parameters in INPH patients, and the most useful parameters are stride length, stride width, speed, and the percentage of double support. Both clinical and instrumental evaluation may be useful in recognizing subjects at risk for falls.

Assessing the duration of EDSS improvement after a therapy start: A novel approach applied to the long-term extension of the PRISMS study.

BACKGROUND: In a chronic and progressive disease such as multiple sclerosis (MS), the improvement on Expanded Disability Status Scale (EDSS) can be a transient event. Therefore, estimating the prevalence of disability improvement over time, accounting both for improvement incidence and duration, is of interest. The aim of this study was to show the application of a simple estimator for the proportion of patients with sustained improvement over time using data from the long-term extension of the PRISMS trial. METHODS: A total of 534 relapsing-remitting MS (RRMS) patients from the PRISMS trial were included. Patients with a baseline EDSS of 0 were excluded. Patients were randomized to placebo (n = 178), subcutaneous interferon beta-1a (sc IFN ß-1a) 22 µg (n = 181) or sc IFN ß-1a 44 µg (n = 175). At Year 2, patients receiving placebo were re-randomized to sc IFN ß-1a 22 µg or 44 µg (delayed sc IFN ß-1a) while patients receiving sc IFN ß-1a 22 µg or 44 µg continued their initial regimen. Patients were followed up for over 7 years post-randomization. Disability improvement was defined as a 1-point decrease in EDSS from baseline confirmed at 6 months. Prevalence of improvement was estimated as difference of Kaplan-Meier (KM) estimators while the cumulative incidence of improvement was calculated using the standard KM curves. RESULTS: No significant differences in cumulative incidence of EDSS improvement at 3 years between delayed sc IFN ß-1a (20.3%) and sc IFN ß-1a 22 µg (20.8%; p = 0.49) or 44 µg (21.3%; p = 0.33). When taking duration of improvement into account, the proportion of patients showing an improved condition after 3 years was 10.1% with delayed sc IFN ß-1a, 11.3% with sc IFN ß-1a 22 µg (p = 0.17) and 15.4% with sc IFN ß-1a 44 µg (p = 0.037) that was substantially maintained over the long term. CONCLUSIONS: With the use of this new statistical methodology, it is possible to estimate the time to improvement as well as the duration of improvement, information that is better suited to describing a non-final outcome like disability improvement. In this case, early sc IFN ß-1a 44 µg initiation had a greater proportion of patients with a sustained disability improvement over a long period of follow-up as compared to patients who had initially been randomized to placebo. In contrast, no significant differences on the cumulative incidence of improvement were observed.

Treatment Effect on Brain Atrophy Correlates with Treatment Effect on Cognition in Multiple Sclerosis.

OBJECTIVE: The purpose of this study was to evaluate the extent to which treatment effect on magnetic resonance imaging (MRI)-derived measures of brain atrophy and focal lesions can mediate, at the trial level, the treatment effect on cognitive outcomes in multiple sclerosis (MS). METHODS: We collected all published randomized clinical trials in MS lasting at least 2 years and including as end points: active MRI lesions (defined as new/enlarging T2 lesions), brain atrophy (defined as a change in brain volume between month 12 and month 24), and change in cognitive performance (assessed by the Paced Auditory Serial Addition Test [PASAT]). Relative reductions were used to quantify the treatment effect on MRI markers (lesions and atrophy), whereas the standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used to quantify the treatment effects on cognition. A linear regression, weighted for trial size, was used to assess the relationship between the treatment effects on MRI markers and cognition. RESULTS: Fourteen trials including more than 8,813 patients with MS were included in the meta-regression. Treatment effect on cognition was strongly associated with the treatment effect on brain atrophy (R2 = 0.79, p < 0.001), but was not correlated with the treatment effect on active MRI lesions (R2 = 0.16, p = 0.14). INTERPRETATION: Results reported here suggest that brain atrophy, a well-established MRI marker in MS clinical trials, can be used as a main outcome for clinical trials with drugs targeting cognitive impairment and neurodegeneration. ANN NEUROL 2023;94:925-932.

Trigeminocervical pain sensitivity during the migraine cycle depends on headache frequency.

OBJECTIVE: This experimental study aimed to assess pain sensitivity in low-frequency episodic migraine (LFEM), high-frequency episodic migraine (HFEM), and chronic migraine (CM) patients across the different phases of the migraine cycle. METHOD: In this observational, experimental study, clinical characteristics (diary and time from the last/next headache attack), and quantitative sensory testing (QST) (wind-up pain ratio (WUR) and pressure pain threshold (PPT) from the trigeminal area and PPT from the cervical spine) was performed. LFEM, HFEM, and CM were assessed in each of the 4 migraine phases (HFEM and LFEM: interictal, preictal, ictal, and postictal; CM: interictal and ictal) and compared vs. each other's (matched for the phase) and controls. RESULTS: A total of 56 controls, 105 LFEM, 74 HFEM, and 32 CM were included. No differences in QST parameters were observed between LFEM, HFEM, and CM in any of the phases. During the interictal phase and when comparing with controls the following were found: 1) LFEM had lower trigeminal PPT (p = 0.001) and 2) lower cervical PPT (p = 0.001). No differences were observed between HFEM or CM and healthy controls. During the ictal phase and when comparing with controls the following were found: HFEM and CM had 1) lower trigeminal PPTs (HFEM p = 0.001; CM = p < 0.001), 2) lower cervical PPT s (HFEM p = 0.007; CM p < 0.001), and 3) higher trigeminal WUR (HFEM p = 0.001, CM p = 0.006). No differences were observed between LFEM and healthy controls. During the preictal phase and when comparing with controls the following were found: 1) LFEM had lower cervical PPT (p = 0.007), 2) HFEM had lower trigeminal (p = 0.013) and 3) HFEM had lower cervical (p = .006) PPTs. During the postictal phase and when comparing with controls the following were found: 1) LFEM had lower cervical PPT (p = 0.003), 2) HFEM had lower trigeminal PPT (p = 0.005), and 3) and HFEM had lower cervical (p = 0.007) PPTs. CONCLUSION: This study suggested that HFEM patients have a sensory profile matching CM better than LFEM. When assessing pain sensitivity in migraine populations, the phase with respects to headache attacks is of utmost importance and can explain the inconsistency in pain sensitivity data reported in the literature.

Migraine patients with and without neck pain: Differences in clinical characteristics, sensitization, musculoskeletal impairments, and psychological burden.

AIMS: This study aims to assess differences in clinical characteristics across healthy controls and migraine patients with (MNP) and without (MwoNP) neck pain. METHOD: This study assessed: headache frequency; headache disability index (HDI); central sensitization inventory (CSI); Hospital Anxiety (HADS-A) and Depression (HADS-D) scale; active range of motion (AROM); flexion rotation test (FRT); activation pressure score (APS); number of active/latent myofascial trigger points (MTrPs) in head/neck muscles; number of positive cervical vertebral segments (C1/C2) who reproduce migraine pain; wind-up ratio (WUR); mechanical pain threshold (MPT) and static pressure pain threshold (sPPT) over the trigeminal area; sPPT and dynamic PPT (dPPT) over the cervical area; sPPTs and MPT over the hand. RESULTS: Compared to controls, MNP had: worse CSI, HADS-A, and HADS-D (all, p < 0.002); reduced AROM (flexion, extension, left lateral-flexion, and right-rotation), FRT, APS, and a higher number of MTrPs and positive cervical vertebral segments (all, p < 0.020); reduced trigeminal MPT and sPPT, cervical sPPT and dPPT, hand MPT and sPPT (all, p < 0.006). Compared to controls, MwoNP had: worse CSI, and HADS-A (all, p < 0.002); reduced AROM (flexion, and left lateral-flexion), FRT, APS, and a higher number of MTrPs and positive cervical vertebral segments (all, p < 0.017); reduced trigeminal MPT and cervical dPPT (all, p < 0.007). Compared to MwoNP, MNP had higher headache frequency, worse HDI and CSI (all, p < 0.006); reduced AROM (flexion, and right rotation) (all, p < 0.037); reduced cervical dPPT (all, p < 0.002). CONCLUSION: MNP had worse headache characteristics, more pronounced cervical musculoskeletal impairments, enhanced signs and symptoms related to sensitization, and worse psychological burden compared to MwoNP.

Health related quality of life in the domain of physical activity predicts confirmed disability progression in people with relapsing remitting multiple sclerosis.

INTRODUCTION: The diagnosis of the progression phase of Multiple Sclerosis (MS) is still retrospective and based on the objectivation of clinical disability accumulation. OBJECTIVES: To assess whether the Patient Reported Outcomes Measures (PROMs) scores predict the occurrence of disease progression within three years of follow-up. METHODS: Observational prospective multicenter study. Stable Relapsing-Remitting MS (RRMS) patients were enrolled. At enrollment, patients completed the following PROMs: Beck Depression Inventory- II, The Treatment Satisfaction Questionnaire for Medications, Medical Outcomes Study Short Form 36- Item (SF36), Fatigue Severity Scale. EDSS was assessed at enrollment and three years later. The outcome measure was defined as the occurrence of confirmed disability progression (CDP) within three years of follow-up. Univariable and multivariable logistic regression models were performed to study the association between the final score of each test and the outcome. RESULTS: SF36-Physical Functioning (SF36-PF) was the only independent variable associated with the outcome. The ROC curve analysis determined a score of 77.5 at SF36-PF as the cut-off point identifying patients experiencing CDP within three years of follow-up [AUC: 0.66 (95% CI: 0.56-0.75)]. CONCLUSIONS: RRMS patients scoring higher (>77.5) at SF36-PF subscale have a higher likelihood to experience CDP within the next three years.

Profiling migraine patients according to clinical and psychophysical characteristics: a cluster analysis approach.

AIM: This study aims to profile migraine patients according clinical and psychophysical characteristics. METHOD: In this observational study, two cohorts of migraine patients(episodic/chronic) were included. Cohort-1: ictal/perictal phase; Cohort-2: interictal phase.The following variables were assessed: headache frequency; disability; cervical active range of motion(AROM) in flexion, extension, right/left lateral flexion, right/left rotation; pressure-pain threshold(PPT) over: temporalis, two cervical areas(C1/C4 vertebral segments), and two distal pain-free areas(hand/leg). Cluster analysis was performed using the K-means algorithm. Differences across clusters were investigated. RESULTS: Cohort-1: 100 patients were included, and two clusters were identified. Cluster-1.1 (19%), Cluster-1.2 (81%). Cluster 1.1 had a higher percentage of men (P = .037) and higher disability (P = .003) compared to Clusters 1.2. Cluster 1.2 had reduced AROM in flexion, extension, and left/right lateral flexion (P < .037), and lower PPT value in all areas (P < .001) compared to Cluster 1.1. Cohort-2: 98 patients were included and three clusters were identified. Cluster-2.1(18%), Cluster-2.2(45%), and Cluster-2.3(37%). Cluster-2.1 had a higher percentage of men compared to clusters-2.2 and 2.3 (P = .009). Cluster-2.3 had higher headache frequency, and disability compared to Cluster-2.2 (P < .006), and higher disability compared to Cluster-2.1 (P = .010). Cluster-2.3 had reduced AROM in all directions compared to Clusters-2.1 and 2.2 (P < .029). Clusters-2.2 and 2.3 have lower PPT values in all areas compared to Cluster-1.1 (P < .001). CONCLUSION: In the Ictal/perictal phase, two clusters were identified according to clinical and psychophysical characteristics, with one group showing no psychophysical impairment and one with increased pain-sensitivity and cervical musculoskeletal-dysfunctions.In the interictal phase, three clusters could be identified, with one group showing no psychophysical impairment, one increased pain-sensitivity, and one increased pain sensitivity and cervical musculoskeletal-dysfunctions.

One-year follow-up comparison of two hybrid closed-loop systems in Italian children and adults with type 1 diabetes.

Background and aims: Tandem Control-IQ and MiniMed 780G are the main Advanced Hybrid Closed Loop (AHCL) systems currently available in pediatric and adult patients with Type 1 Diabetes (T1D). The aim of our study was to evaluate glycemic control after 1-year of follow-up extending our previous study of 1-month comparison between the two systems. Methods: We retrospectively compared clinical and continuous glucose monitoring (CGM) data from the patients included in the previous study which have completed 1-year observation period. The study population consisted of 74 patients, 42 Minimed 780G users and 32 Tandem Control-IQ users. Linear mixed models with random intercept were performed to study the variations over time and the interaction between time and system; Mann-Whitney or T-test were used to compare systems at 1-year. Results: Both systems have been shown to be effective in maintaining the glycemic improvement achieved one month after starting AHCL. Significant changes over time were observed for TIR, TAR, TAR>250mg/dl, average glucose levels and SD (p<0.001). At 1-year follow-up Minimed 780G obtained better improvement in TIR (p<0.001), TAR (p=0.002), TAR>250mg/dl (p=0.001), average glucose levels (p<0.001). The comparison of the glycemic parameters at 1-year showed a significant superiority of Minimed 780G in terms of TIR (71% vs 68%; p=0.001), TAR (p=0.001), TAR>250 (p=0.009), average glucose levels(p=0.001) and SD (p=0.031). Conclusions: The use of AHCL systems led to a significant improvement of glycemic control at 1-month, which is maintained at 1-year follow-up. MiniMed is more effective than Tandem in reaching the International recommended glycemic targets. Continuous training and education in the use of technology is essential to get the best out of the most advanced technological tools.

Reliability of patient-reported toxicities during adjuvant chemotherapy.

BACKGROUND: Patient-reported outcomes (PROs) are validated tools to assess the impact of efficacy and toxicities of cancer treatments on patients' health status. Because of the demonstrated little reliability of humans in reporting memories of painful experiences, this work explores the reliability of cancer patients in reporting chemotherapy-related toxicities. AIM: This study aims to evaluate the concordance between toxicities experienced by the patients during chemotherapy and toxicities reported to the doctor at the end of the cycles. METHODS: Questionnaires concerning chemotherapy-related toxicities were administered on days 2, 5, 8, 11, 14, and 17 of each chemo cycle and at the end of the same cycle to patients undergoing adjuvant chemotherapy. The co-primary end-points were Lins's concordance correlation coefficient (CCC) and mean difference between real-time and retrospective toxicity assessments. RESULTS: In total, 7182 toxicity assessments were collected from 1096 questionnaires. Concordance was observed between the retrospective evaluations and the toxicity assessments at early (day 2), peak (maximum toxicity), late (day 14 or 17), and mean real-time evaluations for each chemotherapy cycle (CCC for mean ranging from 0.52 to 0.77). No systematic discrepancy was found between real-time and retrospective evaluations, except for peak, which was systematically underestimated retrospectively. CONCLUSIONS: Toxicities reported by the patients to the doctor at the end of each chemotherapy cycle reflect what they actually experienced without any substantial distortion. This result is very relevant both for the clinical implications in daily patients' management and in the light of the current growing impact on digital monitoring of PROs.

Short Course of Antifungal Therapy in Patients With Uncomplicated Candida Bloodstream Infection: Another Case of Less Is More in the Clinical Setting?

Background: The objective of this study was to compare the clinical outcomes of patients receiving a short course (SC) vs a prolonged course (PC) of antifungal therapy for uncomplicated Candida bloodstream infections (BSIs). Methods: All episodes of uncomplicated Candida BSI from September 1, 2018, to August 31, 2020, were reviewed. We compared the primary (all-cause 90-day mortality) and secondary study end points (1-year recurrent Candida BSI and all-cause 1-year mortality) among patients who underwent SC (5-11 days) or PC (12-24 days) therapy using propensity score analysis with the inverse probability of treatment weighting (IPTW) method. Results: A total of 114 patients with uncomplicated Candida BSI were included: 35 (30.7%) were classified into the SC group (median [interquartile range {IQR}], 9 [7-11] days) and 79 (69.3%) into the PC group (median [IQR], 14 [14-16] days). Patients in the SC group compared with the PC group had a higher rate of hospitalization in the surgical ward (40.0% vs 19.0%; P = .02) or septic shock at the time of Candida BSI onset (11.4% vs 1.3%; P = .03). The risk of 90-day mortality was not different between the SC and PC groups (n = 8 [22.9%] vs 17 [21.5%], respectively; IPTW-adjusted subdistribution hazard ratio [sHR], 0.67; 95% CI, 0.31-1.47; P = .20). The risk for recurrent Candida BSI within 1 year of completing therapy (IPTW-adjusted sHR, 1.07; 95% CI, 0.20-5.80; P = .94) or for all-cause 1-year mortality (IPTW-adjusted HR, 0.72; 95% CI, 0.35-1.50; P = .38) did not differ between groups. Conclusions: Receiving a short vs prolonged course of antifungal therapy did not affect mortality or BSI recurrence in patients with uncomplicated candidemia.

A novel immunotherapy prognostic score for patients with pretreated advanced urInary TrAct CArcinoma from the subgroup analysis of the SAUL study: the ITACA 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 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 (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 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.