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Computed tomography (CT) is commonly used for paediatric thoracic diseases but involves radiation exposure and often requires intravenous contrast. We evaluated the performance of a magnetic resonance imaging (MRI) protocol including a 3D zero echo time (3D-ZTE) sequence for radiation-free and contrast-free imaging of the paediatric chest. In this prospective, single-centre study, children aged 6-16 years underwent chest CT and MRI within 48 h. CT and MRI exams were independently assessed by two paediatric radiologists. The primary outcome was the image quality of the 3D-ZTE sequence using a scoring system based on the acceptability of the images obtained and visibility of bronchial structures, vessels and fissures. Secondary outcomes included radiologists' ability to detect lung lesions on 3D-ZTE MRI images compared with CT images. Seventy-two children were included. Overall, the image quality achieved with the 3D-ZTE MRI sequence was inferior to that of CT for visualising pulmonary structures, with satisfactory lung image quality observed for 81.9% (59/72) and 100% (72/72) of patients, respectively. However, MRI sensitivity was excellent (above 90%) for the detection of certain lesions such as lung consolidation, proximal mucoid impactions, pulmonary cysts, ground glass opacities and honeycombing. Intermodality agreement (MRI versus CT) was consistently higher for the senior reader compared to the junior reader., Conclusion: Despite its overall lower image quality compared to CT, and the additional years of experience required for accurate interpretation, the 3D-ZTE MRI sequence demonstrated excellent sensitivity for several lesions, making it an appropriate imaging method in certain indications., What Is Known: • Chest radiography and CT are the main imaging modalities for paediatric thoracic diseases but involve radiation exposure and CT often requires IV contrast. • MRI is promising for radiation-free lung imaging in children but faces challenges of low signal-to-noise ratio and motion artefacts., What Is New: • An MRI protocol including a 3D zero echo time (ZTE) sequence allows satisfactory visualisation of lung parenchyma in 82% of children. • Despite overall inferior image quality compared to CT, MRI demonstrated excellent sensitivity for several lesions, making it an appropriate imaging method in certain indications., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mucopolysaccharidoses (MPS) disorders are a group of ultra-rare, inherited, lysosomal storage diseases caused by enzyme deficiencies that result in accumulation of glycosaminoglycans (GAGs) in cells throughout the body including the brain, typically leading to early death. Current treatments do not address the progressive cognitive impairment observed in patients with neuronopathic MPS disease. The rarity and clinical heterogeneity of these disorders as well as pre-existing brain disease in clinically diagnosed patients make the development of new therapeutics utilizing a traditional regulatory framework extremely challenging. Children with neuronopathic MPS disorders will likely sustain irreversible brain damage if randomized to a placebo or standard-of-care treatment arm that does not address brain disease. The United States Food and Drug Administration (FDA) recognized these challenges, and, in 2020, issued final guidance for industry on slowly progressive, low-prevalence, rare diseases with substrate deposition that result from single enzyme defects, outlining a path for generating evidence of effectiveness to support accelerated approval based on reduction of substrate accumulation [1]. Neuronopathic MPS disorders, which are characterized by the accumulation of the GAG heparan sulfate (HS) in the brain, fit the intended disease characteristics for which this guidance was written, but to date, this guidance has not yet been applied to any therapeutic candidate for MPS. In February 2024, the Reagan-Udall Foundation for the FDA convened a public workshop for representatives from the FDA, patient advocacy groups, clinical and basic science research, and industry to explore a case study of using cerebrospinal fluid (CSF) HS as a relevant biomarker to support accelerated approval of new therapeutics for neuronopathic MPS disorders. This review provides a summary of the MPS presentations at the workshop and perspective on the path forward for neuronopathic MPS disorders., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joseph Muenzer: Consultant and/or served on advisory boards for Takeda, Sanofi, REGENXBIO, Denali Therapeutics, Inc., and JCR Pharmaceuticals. Carole Ho: Employment and stock ownership with Denali Therapeutics, Inc. Heather Lau: Employment and stock ownership with Ultragenyx Pharmaceutical, Inc. Mark Dant: None. Maria Fuller: Research and travel support from Abeona, BioMarin, Denali Therapeutics, Inc., Paradigm, Sanofi-Genzyme, Takeda (formerly Shire), REGENXBIO, Taysha Gene Therapies, and Ultragenyx. Nidal Boulos: Employment with REGENXBIO. Patricia Dickson: Research support from BioMarin Pharmaceutical Inc., Alnylam, and M6P Therapeutics; consultant for Mandos Health. Matthew Ellinwood: Honoraria, travel, conference registration, and/or consultancy paid to or received by the Society from: ACMG, APHL, Denali Therapeutics, EdiGene Biotechnology USA, Eli Lilly and Company, EveryLife Foundation for Rare Diseases, Global Genes (Rare Drug Dev. Symp.), Guidepoint Global, LLC, PRECISIONadvisors, REGENXBIO, Inc., Terrapin (World Orphan Drug Cong-USA), WORLDSymposium™. Simon Jones: Investigator and consultant for Sanofi, Takeda, Ultragenyx, Orchard Therapeutics, Intrabio, Mina, Prevail, and Denali Therapeutics, Inc.; consultant for Ultragenyx. Eric Zanelli: Shareholder of Allievex. Cara O'Neill: Consultant and/or serve on advisory councils for BioMarin Pharmaceutical, Denali Therapeutics, Inc., JCR Pharmaceuticals, Novel Pharma, and Ultragenyx., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The International Classification of Functioning, Disability, and Health (ICF) is growing in importance in cardiac rehabilitation (CR) as the number of elderly comorbid patients increases., Aim: To classify through the ICF framework a group of post-cardiac surgery (CS) and chronic heart failure (CHF) patients undergoing rehabilitation. Then, to compare the two groups and identify possible factors at admission that could affect ICF evaluations at discharge., Design: Observational retrospective real-life study., Setting: Two inpatient CR units., Population: Consecutive CS and CHF patients admitted for CR (January-December 2019)., Methods: Clinical, anthropometric data and functional status at admission and discharge were extracted from patient health records. A set of 26 ICF codes regarding body functions (b) and activities (d) was analyzed to identify: 1) the qualifiers attributed (from 0=no impairment to 4=severe impairment) for each code, 2) the percent distribution of qualifiers (0/1/2/3/4) attributed per patient. We then evaluated changes in both (1) and (2 - defined as ICF Delta%) from admission to discharge., Results: All patients (55% males; mean age 73±12 years) showed an improvement post-rehabilitation in the ICF qualifiers attributed (P<0.0001 for all codes). CS patients (N.=150) were less functionally impaired at admission than CHF (N.=194) (P<0.05 for all codes), and at discharge showed greater Delta% in the qualifiers 0/1/2 attributed than CHF (P<0.0001 for b codes; P<0.05 for d codes). Delta% for qualifiers 3 and 4 was similar in the two groups. No impairment at admission (qualifier 0), CS group, and presence/complexity of comorbidities were identified as possible covariates influencing ICF qualifiers at discharge, impacting the rate of both no/mild impairment (ICF% aggregate 0+1 - adjusted R 2 =0.627; P<0.0001) and moderate impairment (ICF% qualifier 2 - adjusted R 2 =0.507; P<0.0001)., Conclusions: CHF patients showed a worse ICF picture at admission and less improvement at discharge than CS. The presence and complexity of comorbidities negatively influenced the ICF classification at discharge, especially in CHF patients., Clinical Rehabilitation Impact: This study shows the utility of ICF classification in CR as a means for describing, measuring, and comparing patient functioning across the care continuum.

In Chronic Heart Failure (CHF) patients, psychological and cognitive variables and their association with treatment adherence have been extensively reported in the literature, but few are the investigations in older people. The present study aimed to evaluate the psychological, cognitive, and adherence to treatment profile of older (>65 years) CHF patients, the interrelation between these variables, and identify possible independent predictors of self-reported treatment adherence. CHF inpatients undergoing cardiac rehabilitation were assessed for: anxiety, depression, cognitive impairment, positive and negative affect, and self-reported adherence (adherence antecedents, pharmacological adherence, and non-pharmacological adherence). 100 CHF inpatients (mean age: 74.9 ± 7.1 years) were recruited. 16% of patients showed anxiety and 24.5% depressive symptoms; 4% presented cognitive decline. Cognitive functioning negatively correlated to depression, anxiety, and negative affect (p < 0.01). The adherence antecedents (disease acceptance, adaptation, knowledge, and socio-familiar support) negatively correlated to anxiety (p < 0.05), depression (p < 0.001), and negative affect (p < 0.05), while they positively correlated to positive affect (p < 0.01). Pharmacological adherence negatively correlated to anxiety and negative affect (p < 0.05). Conversely, non-pharmacological adherence and positive affect positively correlated (p < 0.05). Furthermore, depression and anxiety negatively predicted adherence antecedents (β = -0.162, p = 0.037) and pharmacological adherence (β = -0.171, p = 0.036), respectively. Finally, positive affect was found as an independent predictor of non-pharmacological adherence (β = 0.133, p = 0.004). In cardiac rehabilitation, a specific psychological assessment focused on anxiety, depression, and affect can provide useful information to manage CHF older patients' care related to treatment adherence. In particular, positive affect should be targeted in future interventions to foster patients' non-pharmacological adherence.

Mucopolysaccharidosis Type IIIB (MPS IIIB) is an ultrarare, fatal pediatric disease with no approved therapy. It is caused by mutations in the gene encoding for lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). Tralesinidase alfa (TA) is a fusion protein comprised of recombinant NAGLU and a modified human insulin-like growth factor 2 that is being developed as an enzyme replacement therapy for MPS IIIB. Since MPS IIIB is a pediatric disease the safety/toxicity, pharmacokinetics and biodistribution of TA were evaluated in juvenile non-human primates that were administered up to 5 weekly intracerebroventricular (ICV) or single intravenous (IV) infusions of TA. TA administered by ICV slow-, ICV isovolumetric bolus- or IV-infusion was well-tolerated, and no effects were observed on clinical observations, electrocardiographic or ophthalmologic parameters, or respiratory rates. The drug-related changes observed were limited to increased cell infiltrates in the CSF and along the ICV catheter track after ICV administration. These findings were not associated with functional changes and are associated with the use of ICV catheters. The CSF PK profiles were consistent across all conditions tested and TA distributed widely in the CNS after ICV administration. Anti-drug antibodies were observed but did not appear to significantly affect the exposure to TA. Correlations between TA concentrations in plasma and brain regions in direct contact with the cisterna magna suggest glymphatic drainage may be responsible for clearance of TA from the CNS. The data support the administration of TA by isovolumetric bolus ICV infusion to pediatric patients with MPS IIIB., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Emma McCullagh reports a relationship with Allievex Corporation that includes: consulting or advisory. Jami L. Trombley reports a relationship with BioMarin Pharmaceutical Inc that includes: consulting or advisory. Randall P. Reed reports a relationship with BioMarin Pharmaceutical Inc that includes: consulting or advisory. Eric L. Adams reports a relationship with BioMarin Pharmaceutical Inc that includes: consulting or advisory. Robert B. Boyd reports a relationship with BioMarin Pharmaceutical Inc that includes: consulting or advisory. Mark T. Butt reports a relationship with BioMarin Pharmaceutical Inc that includes: consulting or advisory. Jason Pinkstaff reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Emma McCullagh reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Anita Grover reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Andrew C. Melton reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Anu Cherukuri reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Jill CM Wait reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Annalisa Nguyen reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Sundeep Chandra reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Joshua Henshaw reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Charles A. O’Neill reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Eric Zanelli reports a relationship with Allievex Corporation that includes: employment and equity or stocks. Joseph Kovalchin reports a relationship with Allievex Corporation that includes: employment and equity or stocks., (© 2023 The Authors.)

BackgroundSanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS levels, prevent brain atrophy, and potentially delay cognitive decline.MethodsIn this phase I/II open-label study, patients with MPS type IIIB (n = 22) were treated with tralesinidase alfa administered i.c.v. The patients were monitored for drug exposure; total HS and HS nonreducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma; anti-drug antibody response; brain, spleen, and liver volumes as measured by MRI; and cognitive development as measured by age-equivalent (AEq) scores.ResultsIn the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV.ConclusionAdministration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy.Trial registrationClinicaltrials.gov NCT02754076.FUNDINGBioMarin Pharmaceutical Inc. and Allievex Corporation.

Introduction: No studies have reported data on 2-year prevalence and recovery rates of self-reported COVID-19-related quantitative and qualitative olfactory and gustatory dysfunction. The aim of the present study was to estimate the 2-year prevalence and recovery rate of self-reported COVID-19-related olfactory and gustatory dysfunction in a cohort of patients with antecedent mild-to-moderate disease., Methods: This is a prospective observational study, measuring the prevalence of altered sense of smell or taste at follow-up and their variation from baseline, on adult patients consecutively assessed at Trieste University Hospital, who tested positive for SARS-CoV-2 RNA by polymerase chain reaction during March 2020., Results: Overall, 174 (68.8%), 53 (20.9%), and 36 (14.2%) of 253 responders reported an altered sense of smell or taste (SNOT-22 >0) at baseline, 12 months, and 24 months, respectively. Among the 174 patients who have complained a COVID-19-associated olfactory or gustatory dysfunction at baseline, 138 (79.3%) reported complete resolution of smell or taste impairment with 17 subjects (9.8%) recovering after more than 1 year after the initial infection, 33 (19.0%) reported a decrease in the severity, and only 3 (1.7%) reported that the symptom was unchanged at the 24-month interview. Twenty subjects (7.9%) complained of at least one qualitative long-term symptom., Conclusion: Two years after the infection, most patients experience a favourable evolution of COVID-19-related olfactory or gustatory dysfunction. A late recovery was observed in 10% of subjects., (© 2022 S. Karger AG, Basel.)

Objective: To characterize the longitudinal natural history of disease progression in pediatric subjects affected with mucopolysaccharidosis (MPS) IIIB., Study Design: Sixty-five children with a confirmed diagnosis of MPS IIIB were enrolled into 1 of 2 natural history studies and followed for up to 4 years. Cognitive and adaptive behavior functions were analyzed in all subjects, and volumetric magnetic resonance imaging analysis of liver, spleen, and brain, as well as levels of heparan sulfate (HS) and heparan sulfate nonreducing ends (HS-NRE), were measured in a subset of subjects., Results: The majority of subjects with MPS IIIB achieved an apex on both cognition and adaptive behavior age equivalent scales between age 3 and 6 years. Development quotients for both cognition and adaptive behavior follow a linear trajectory by which subjects reach a nadir with a score <25 for an age equivalent of 24 months by age 8 years on average and by 13.5 years at the latest. All tested subjects (n = 22) had HS and HS-NRE levels above the normal range in cerebrospinal fluid and plasma, along with signs of hepatomegaly. Subjects lost an average of 26 mL of brain volume (-2.7%) over 48 weeks, owing entirely to a loss of cortical gray matter (32 mL; -6.5%)., Conclusions: MPS IIIB exists along a continuum based on cognitive decline and cortical gray matter atrophy. Although a few individuals with MPS IIIB have an attenuated phenotype, the majority follow predicted trajectories for both cognition and adaptive behavior., Trial Registration: ClinicalTrials.gov identifiers NCT02493998, NCT03227042, and NCT02754076., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This systematic review and meta-analysis aims to estimate the prevalence and prognostic impact of retropharyngeal lymph node metastases (RLNMs) in oropharyngeal squamous cell carcinoma (OPSCC)., Methods: This meta-analysis was conducted according to PRISMA guidelines., Inclusion Criteria: studies with more than 20 patients reporting the prevalence or prognostic impact of RLNMs in OPSCC. Whenever available, data on HPV status and subsites were extracted., Results: Twenty-two articles were included. The overall prevalence of RLNMs in OPSCC was 13%, with no significant differences depending on HPV status. The highest prevalence was observed for posterior pharyngeal wall SCC (24%), followed by soft palate (17%), palatine tonsil (15%), and base of tongue (8%). RLNMs were associated with a significantly higher risk of death (HR:2.54;IC95%1.89-3.41) and progression (HR:2.44;IC95%1.80-3.30)., Conclusions: The prevalence of RLNMs in OPSCC was 13%, being higher in tumors of the posterior pharyngeal wall. RLNMs were associated with unfavorable outcomes., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and nonhuman primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well tolerated as compared with administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and nonreducing ends of HS in cerebrospinal fluid and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests and had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathologic, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects. SIGNIFICANCE STATEMENT: This work illustrates the efficacy and tolerability of tralesinidase alfa as a potential therapeutic for patients with mucopolysaccharidosis type IIIB (MPS IIIB) by documenting that administration to the central nervous system of MPS IIIB dogs prevents the accumulation of disease-associated glycosaminoglycans in lysosomes, hepatomegaly, cerebellar atrophy, and cognitive decline., (Copyright © 2022 by The Author(s).)

Purpose: The aim of the present study was to estimate the 1 year prevalence and recovery rate of self-reported chemosensory dysfunction in a series of subjects with previous mild-to-moderate symptomatic COVID-19., Methods: Prospective study based on the SNOT-22, item "sense of smell or taste" and additional outcomes., Results: 268/315 patients (85.1%) completing the survey at baseline also completed the follow-up interview. The 12 months prevalence of self-reported COVID-19 associated chemosensory dysfunction was 21.3% (95% CI 16.5-26.7%). Of the 187 patients who complained of COVID-19 associated chemosensory dysfunction at baseline, 130 (69.5%; 95% CI 62.4-76.0%) reported complete resolution of smell or taste impairment, 41 (21.9%) reported a decrease in the severity, and 16 (8.6%) reported the symptom was unchanged or worse 1 year after onset. The risk of persistence was higher for patients reporting a baseline SNOT-22 score ≥ 4 (OR = 3.32; 95% CI 1.32-8.36) as well as for those requiring ≥ 22 days for a negative swab (OR = 2.18; 95% CI 1.12-4.27)., Conclusion: A substantial proportion of patients with previous mild-to-moderate symptomatic COVID-19 characterized by new onset of chemosensory dysfunction still complained on altered sense of smell or taste 1 year after the onset., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Using an age and gender matched-pair case-control study, we aimed to estimate the long-term prevalence of psychophysical olfactory, gustatory , and chemesthesis impairment at least one year after SARS-CoV-2 infection considering the background of chemosensory dysfunction in non-COVID-19 population., Methodology: This case-controlled study included 100 patients who were home-isolated for mildly symptomatic COVID-19 between March and April 2020. One control regularly tested for SARS-CoV-2 infection and always tested negative was matched to each case according to gender and age. Chemosensory function was investigated by a comprehensive psychophysical evaluation including ortho- and retronasal olfaction and an extensive assessment of gustatory function. Differences in chemosensory parameters were evaluated through either Fisher’s exact test or Kruskal-Wallis test., Results: The psychophysical assessment of chemosensory function took place after a median of 401 days from the first SARS-CoV-2 positive swab. The evaluation of orthonasal smell identified 46% and 10% of cases and controls, respectively, having olfactory dysfunction, with 7% of COVID-19 cases being functionally anosmic. Testing of gustatory function revealed a 27% of cases versus 10% of controls showing a gustatory impairment. Nasal trigeminal sensitivity was significantly lower in cases compared to controls. Persistent chemosensory impairment was associated with emotional distress and depression., Conclusion: More than one year after the onset of COVID-19, cases exhibited an excess of olfactory, gustatory , and chemesthesis disturbances compared to matched-pair controls with these symptoms being associated to emotional distress and depression.

Objective: Recently, a novel host-related index, the Host-index (H-index), including both inflammatory and nutritional markers, has been described and observed to stratify prognosis in patients with squamous cell carcinoma (SCC) of the oral cavity more accurately than other host-related indexes This study aimed to investigate the prognostic performance of the H-index using pretreatment blood tests in patients receiving up-front surgery for SCC of the larynx., Methods: This retrospective observational study included a multicenter series of consecutive patients with SCC of the larynx diagnosed between 1 January 2009 and 31 July 2018, whose pretreatment blood tests were available and included the parameters necessary for the calculation of neutrophil to lymphocyte ratio (NLR) and the H-index. Their association with disease-free survival (DFS) and overall survival (OS) was measured., Results: A total of 231 patients were eligible for the present analysis (median [range] age, 68 [37-96] years; 191 [82.7%] men). The median follow-up was 73 months. In multivariable Cox proportional hazards regression models, increasing age (adjusted hazard ratio [aHR], 1.07 per year; 95% CI, 1.04-1.09), advanced pT stage (aHR = 1.71 95% CI: 1.07-2.71), and having close or positive surgical margins (aHR = 2.01; 95% CI: 1.21-3.33) were significantly associated with poor OS. Among blood parameters, a higher neutrophil count was a strong predictor of both worse DFS (aHR for recurrence/death = 2.34; 95% CI: 1.24-4.40) and OS (aHR for death = 2.67; 95% CI: 1.51-4.71). Among inflammatory blood indexes, while NLR was not significantly associated with DFS or OS, patients with H-index ≥8.37 showed a higher aHR for both recurrence/death (2.82; 95% CI: 1.65-4.79) and death (2.22; 95% CI: 1.26-3.89)., Conclusion: In conclusion, the present study confirms the prognostic value of pretreatment H-index, an easily measurable inflammatory and nutritional index, in patients with SCC of the larynx., Level of Evidence: III., Competing Interests: The authors declare that there is no potential conflict of interest., (© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC. on behalf of The Triological Society.)

Graft artery stenosis can have a significant short- and long-term negative impact on renal graft function. From the beginning of the COVID-19 pandemic, we noticed an unusual number of graft arterial anomalies following kidney transplant (KTx) in children. Nine children received a KTx at our center between February and July 2020, eight boys and one girl, of median age of 10 years. Seven presented Doppler features suggesting arterial stenosis, with an unusual extensive pattern. For comparison, over the previous 5-year period, persistent spectral Doppler arterial anomalies (focal anastomotic stenoses) following KTx were seen in 5% of children at our center. We retrospectively evidenced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in five of seven children with arterial stenosis. The remaining two patients had received a graft from a deceased adolescent donor with a positive serology at D0. These data led us to suspect immune postviral graft vasculitis, triggered by SARS-CoV-2. Because the diagnosis of COVID-19 is challenging in children, we recommend pretransplant monitoring of graft recipients and their parents by monthly RT-PCR and serology. We suggest balancing the risk of postviral graft vasculitis against the risk of prolonged dialysis when considering transplantation in a child during the pandemic., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The association among psychological, neuropsychological dysfunctions and functional/clinical variables in Chronic Heart Failure (CHF) has been extensively addressed in literature. However, only a few studies investigated those associations in the older population., Purpose: To evaluate the psychological/neuropsychological profile of older CHF patients, to explore the interrelation with clinical/functional variables and to identify potential independent predictors of patients' functional status., Methods: This study was conducted with a multi-center observational design. The following assessments were performed: anxiety (Hospital Anxiety and Depression Scale, HADS), depression (Geriatric Depression Scale, GDS), cognitive impairment (Addenbrooke's Cognitive Examination Revised, ACE-R), executive functions (Frontal Assessment Battery, FAB), constructive abilities (Clock Drawing Test, CDT), psychomotor speed and alternated attention (Trail Making Test, TMT-A/B), functional status (6-minute walking test, 6MWT) and clinical variables (New York Heart Association, NYHA; Brain Natriuretic Peptide, BNP; left ventricular ejection fraction, LVEF; left ventricular end diastolic diameter, LVEDD; left ventricular end diastolic volume, LVEDV; tricuspid annular plane systolic excursion, TAPSE)., Results: 100 CHF patients (mean age: 74.9±7.1 years; mean LVEF: 36.1±13.4) were included in the study. Anxious and depressive symptoms were observed in 16% and 24,5% of patients, respectively. Age was related to TMT-A and CDT (r = 0.49, p<0.001 and r = -0.32, p = 0.001, respectively), Log-BNP was related to ACE-R-Fluency subtest, (r = -0.22, p = 0.034), and 6MWT was related to ACE-R-Memory subtest and TMT-A (r = 0.24, p = 0.031 and r = -0.32, p = 0.005, respectively). Both anxiety and depression symptoms were related to ACE-R-Total score (r = -0.25, p = 0.013 and r = -0.32, p = 0.002, respectively) and depressive symptoms were related to CDT (r = -0.23, p = 0.024). At multiple regression analysis, Log-BNP and TMT-A were significant and independent predictors of functional status: worse findings on Log-BNP and TMT-A were associated with shorter distance walked at the 6MWT., Conclusions: Psychological and neuropsychological screening, along with the assessment of psychomotor speed (TMT-A), may provide useful information for older CHF patients undergoing cardiac rehabilitation., Competing Interests: The authors have declared that no competing interests exist.

Background: Despite therapeutic advances, chronic heart failure (CHF)-related mortality and hospitalization is still unacceptably high. Evidence shows that muscular wasting, sarcopenia, cachexia are independent predictors of mortality and morbidity in CHF and are signs of protein metabolism disarrangement (PMD), which involve all body proteins including circulating one. We postulate that circulating human serum albumin (HSA) could be a marker of PMD and catabolic low-grade inflammation (LGI) in CHF patients., Methods: One hundred sixty-six stable CHF patients (73% males), with optimized therapy referred to cardiac rehabilitation, were retrospectively divided into three groups based on their HSA concentration: ≥3.5 g/dL (normal value), 3.2-3.49 g/dL (low value); ≤3.19 g/dL (severe value). Hematochemical analyses (including circulating proteins and inflammatory markers) and body mass composition (by Bioelectrical Impedance Vector Analysis) were collected and compared. Correlations and multivariate regression were performed., Results: Despite being overweight (BMI=27 kg/m2), 75% of patients had reduced HSA (<3.5 g/dL) with suspectable sarcopenia, and 35% of all patients had remarkably lower albumin concentrations (<3.19 g/dL). Hypoalbuminemic patients were disable, older, with reduced muscular proteins, bilirubin and hemoglobin, increased extracellular water and LGI (P<0.01). HSA correlated with all of these parameters (all: P<0.01). Age, LGI, BMI, free-fat Mass, and bilirubin were independent predictors of HSA concentration. All these findings were male-dependent., Conclusions: HSA could be considered a simple marker of PMD and LGI in CHF patients. Evaluation of PMD and gender differences should be considered in new CHF clinical trials.

Background and Purpose: Triptans are 5-HT 1B/1D receptor agonists (that also display 5-HT 1F receptor affinity) with antimigraine action, contraindicated in patients with coronary artery disease due to their vasoconstrictor properties. Conversely, lasmiditan was developed as an antimigraine 5-HT 1F receptor agonist. To assess the selectivity and cardiovascular effects of lasmiditan, we investigated the binding, functional activity, and in vitro/in vivo vascular effects of lasmiditan and compared it to sumatriptan., Experimental Approach: Binding and second messenger activity assays of lasmiditan and other serotoninergic agonists were performed for human 5-HT 1A , 5-HT 1B , 5-HT 1D , 5-ht 1E , 5-HT 1F , 5-HT 2A , 5-HT 2B , and 5-HT 7 receptors, and the results were correlated with their potency to constrict isolated human coronary arteries (HCAs). Furthermore, concentration-response curves to lasmiditan and sumatriptan were performed in proximal and distal HCA, internal mammary, and middle meningeal arteries. Finally, anaesthetized female beagle dogs received i.v. infusions of lasmiditan or sumatriptan in escalating cumulative doses, and carotid and coronary artery diameters were measured., Key Results: Lasmiditan showed high selectivity for 5-HT 1F receptors. Moreover, the functional potency of the analysed compounds to inhibit cAMP increase through 5-HT 1B receptor activation positively correlated with their potency to contract HCA. In isolated human arteries, sumatriptan, but not lasmiditan, induced contractions. Likewise, in vivo, sumatriptan decreased coronary and carotid artery diameters at clinically relevant doses, while lasmiditan was devoid of vasoconstrictor activity at all doses tested., Conclusions and Implications: Lasmiditan is a selective 5-HT 1F receptor agonist devoid of vasoconstrictor activity. This may represent a cardiovascular safety advantage when compared to the triptans., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: It is unclear whether clinical models including the Partin tables (PT), the Memorial Sloan Kettering Cancer Center nomogram (MSKCCn), and the cancer of the prostate risk assessment (CAPRA) can benefit from incorporating multiparametric magnetic resonance imaging (mpMRI) when staging prostate cancer (PCa)., Purpose: To compare the accuracy of clinical models, mpMRI, and mpMRI plus clinical models in predicting stage ≥pT3 of PCa., Study Type: Prospective monocentric cohort study., Population: Seventy-three patients who underwent radical prostatectomy between 2016-2018., Field Strength/sequence: 3.0T using turbo spin echo (TSE) imaging, single-shot echoplanar diffusion-weighted imaging, and T 1 -weighted high-resolution-isotropic-volume-examination (THRIVE) contrast-enhanced imaging., Assessment: We calculated the probability of extraprostatic extension (EPE) using the PT and MSKCC, as well as the CAPRA score. Three readers with 2-8 years of experience in mpMRI independently staged PCa on imaging., Statistical Tests: Receiver operating characteristics analysis and logistic regression analysis to investigate the per-patient accuracy of mpMRI vs. clinical models vs. mpMRI plus clinical models in predicting stage ≥pT3. The alpha level was 0.05., Results: Median probability for EPE and MSKCCn was 27.3% and 47.0%, respectively. Median CAPRA score was 3. Stage ≥pT3 occurred in 32.9% of patients. Areas under the curve (AUCs) were 0.62 for PT, 0.62 for MSKCCn, 0.64 for CAPRA, and 0.73-0.75 for mpMRI (readers 1-3) (P > 0.05 for all comparisons). Compared with mpMRI, the combination of mpMRI with PT or MSKCCn provided lower AUCs (P > 0.05 for all the readers), while the combination with CAPRA provided significantly higher (P < 0.05) AUCs in the case of readers 1 and 3. On multivariable analysis, mpMRI by reader 1 was the only independent predictor of stage ≥pT3 (odds ratio 7.40). DATA CONCLUSION: mpMRI was more accurate than clinical models and mpMRI plus clinical models in predicting stage ≥pT3, except for the combination of mpMRI and CAPRA in two out of three readers., Level of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1604-1613., (© 2019 International Society for Magnetic Resonance in Medicine.)

Aim: To compare high-resolution computed tomography (HRCT) findings between humoral primary immunodeficiencies (hPIDs) subtypes; to correlate these findings to pulmonary function tests (PFTs)., Methods: We retrospectively identified 52 consecutive adult patients with hPIDs who underwent 64-row HRCT and PFTs at the time of diagnosis. On a per-patient basis, an experienced radiologist recorded airway abnormalities (bronchiectasis, airway wall thickening, mucus plugging, tree-in-bud, and air-trapping) and parenchymal-interstitial abnormalities (consolidations, ground-glass opacities, linear and/or irregular opacities, nodules, and bullae/cysts) found on HRCT. The chi-square test was performed to compare the prevalence of each abnormality among patients with different subtypes of hPIDs. Overall logistic regression analysis was performed to assess whether HRCT findings predicted obstructive and/or restrictive PFTs results (absent-to-mild vs moderate-to-severe)., Results: Thirty-eight of the 52 patients with hPIDs showed common variable immunodeficiency disorders (CVID), while the remaining 14 had CVID-like conditions ( i.e ., 11 had isolated IgG subclass deficiencies and 3 had selective IgA deficiencies). The prevalence of most HRCT abnormalities was not significantly different between CVID and CVID-like patients ( P > 0.05), except for linear and/or irregular opacities (prevalence of 31.6% in the CVID group and 0 in the CVID-like group; P = 0.0427). Airway wall thickening was the most frequent HRCT abnormality found in both CVID and CVID-like patients (71% of cases in both groups). The presence of tree-in-bud abnormalities was an independent predictor of moderate-to-severe obstructive defects at PFTs (Odds Ratio, OR, of 18.75, P < 0.05), while the presence of linear and/or irregular opacities was an independent predictor of restrictive defects at PFTs (OR = 13.00; P < 0.05)., Conclusion: CVID and CVID-like patients showed similar HRCT findings. Tree-in-bud and linear and/or irregular opacities predicted higher risks of, respectively, obstructive and restrictive defects at PFTs., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts of interest related to this article.

Management of chronic diseases in a progressively aging population is a major issue in western industrialized countries and telehealth is one way to ensure the continuity of care in chronic illness. We describe here our personal experience in a telehealth and telecare centre in Italy. Between January 2000 and December 2015, 1635 elderly patients (71% male) with one or more comorbidities have undergone a telehealth program tailored to their specific disease: chronic obstructive pulmonary disease (COPD)/chronic respiratory insufficiency; amyotrophic lateral sclerosis/neuromuscular diseases; chronic heart failure (CHF); post-stroke; and post-cardiac surgery patients discharged from hospital after an acute event. COPD and CHF represent the majority of patients treated (accounting for 80%). Interventions performed by the nurse tutor account for 39-82% of all activities in the five different programs. Specialist second opinion represents 12-27% of the health staff activities. Previously reported results show a reduction of the re-hospitalization rate and costs, and increase in quality of life and patient satisfaction with the service. A multidisciplinary telehealth and telecare integrated approach can provide efficient management for the growing number of complex patients.

RE-START is a multicenter, randomized, prospective, open, controlled trial aiming to evaluate the feasibility and the short- and medium-term effects of an early-start AET program on functional capacity, symptoms and neurohormonal activation in chronic heart failure (CHF) patients with recent acute hemodynamic decompensation. Study endpoints will be: 1) safety of and compliance to AET; 2) effects of AET on i) functional capacity, ii) patient-reported symptoms and iii) AET-induced changes in beta-adrenergic receptor signaling and circulating angiogenetic and inflammatory markers. Two-hundred patients, randomized 1:1 to training (TR) or control (C), will be enrolled. Inclusion criteria: 1) history of systolic CHF for at least 6 months, with ongoing acute decompensation with need of intravenous diuretic and/or vasodilator therapy; 2) proBNP > 1000 pg/mI at admission. Exclusion criteria: 1) ongoing cardiogenic shock; 2) need of intravenous inotropic therapy; 3) creatinine > 2.5 mg/dl at admission. After a 72-hour run-in period, TR will undergo the following 12-day early-start AET protocol: days 1-2: active/passive mobilization (2 sessions/day, each 30 minutes duration); days 3-4: as days 1-2 + unloaded bedside cycle ergometer (3 sessions/day, each 5-10 minutes duration); days 5-8: as days 1-2 + unloaded bedside cycle ergometer (3 sessions/day, each 15-20 minutes duration); days 9-12: as days 1-2 + bedside cycle ergometer at 10-20 W (3 sessions/day, each 15-20 minutes duration). During the same period, C will undergo the same activity protocol as in days 1-2 for TR. All patients will undergo a 6-min WT at day 1, 6, 12 and 30 and echocardiogram, patient-reported symptoms on 7-point Likert scale and measurement of lymphocyte G protein coupled receptor kinase, VEGF, angiopoietin, TNF alfa, IL-1, IL-6 and eNOS levels at day 1, 12 and 30.

Introduction: This review provides a synopsis for clinicians on the use of antiepileptic drugs (AEDs) in the breastfeeding mother., Methods: For each AED, we collected all retrievable data from Hale's "Medications and Mother Milk" (2012), from the LactMed database (2013) of the National Library of Medicine, and from a MedLine Search of relevant studies in the past 10 years., Results: Older AEDs, such as carbamazepine, valproic acid, phenytoin, phenobarbital, primidone are considered to have a good level of safety during lactation, due to the long term clinical experience and the consequent amount of available data from the scientific literature. On the contrary, fewer data are available on the use of new AEDs. Therefore, gabapentin, lamotrigine, oxcarbazepine, vigabatrin, tiagabine, pregabalin, leviracetam and topiramate are compatible with breastfeeding with a less documented safety profile. Ethosuximide, zonisamide and the continue use of clonazepam and diazepam are contraindicated during breastfeeding., Conclusions: Although the current available advice on the use of AEDs during breastfeeding, given by different accredited sources, present some contradictions, most AEDs can be considered safe according to our review.

Background: Exercise rehabilitation after cardiac surgery has beneficial effects, especially on a long-term basis. Rehabilitative programs with telemedicine plus appropriate technology might satisfy the needs of performing rehabilitation at home., Objective: The purpose of this study was to compare exercise capacity after home-based cardiac rehabilitation (HBCR) or in-hospital rehabilitation in patients at low to medium risk for early mortality (EuroSCORE 0-5) following cardiac surgery., Design: A quasi-experimental study was conducted., Methods: At hospital discharge, patients were given the option to decide whether to enroll in the HBCR program. Clinical examinations (electrocardiography, cardiac echo color Doppler, chest radiography, blood samples) of patients in the HBCR group were collected during 4 weeks of rehabilitation, and exercise capacity (assessed using the Six-Minute Walk Test [6MWT]) was assessed before and after rehabilitation. A group of patients admitted to the in-hospital rehabilitation program was used as a comparison group. Patients in the HBCR group were supervised at home by a medical doctor and telemonitored daily by a nurse and physical therapist by video conference. Periodic home visits by health staff also were performed., Results: One hundred patients were recruited into the HBCR group. An equal number of patients was selected for the comparison group. At the end of the 4-week study, the 2 groups showed improvement from their respective baseline values only in the 6MWT. No difference was found in time × group interaction., Limitations: Because patients self-selected to enroll in the HBCR program and because they were enrolled from a single clinical center, the results of the study cannot be generalized., Conclusions: In patients who self-selected HBCR, the program was found to be effective and comparable to the standard in-hospital rehabilitative approach, indicating that rehabilitation following cardiac surgery can be implemented effectively at home when coadministered with an integrated telemedicine service.

The aim of this study is to gain insight into the individual experiences of patients who attempt suicide in order to better understand the reasons for and emotions behind a suicide attempt, thus also gaining insight, through the patients' own input, into the risk and protective factors which might influence possible repeat attempts and the attitude towards the assistance they receive. Two focus groups were conducted involving 17 participants, all hospitalized at the time of research for attempting suicide. The patients proved themselves competent, even expert in indicating reasons for, risk factors of and prevention strategies for suicide. The main findings suggest that the relational factor represents a key point both as a trigger for the suicide attempt and for promoting the communication of the intent or for preventing a repeat suicide attempt, as interpersonal relationships and an empathic environment were, in essence, what was perceived as therapeutic and protective and enabled the expression of thoughts and self-understanding. Accordingly psychotherapy, non-specific relationship 'monitoring' after discharge and tutored self-help groups have been suggested. Feasibility and implementing methods as well as the role of the nurse for such interventions were discussed., (© 2011 Blackwell Publishing.)

Background: Technology and information systems enabling transmission of patients' data and ability to provide and exchange professional support remotely to the general practitioners can improve quality and continuity of care., Design: We set up a programme of primary prevention in 27 patients at risk for cardiovascular diseases by using Telemedicine Service for 6 months., Methods: Telemedicine Service enlisted the involvement of physicians and nurse-tutors. The following cardiovascular activity markers were assessed: (i) cardiovascular risk cards (Framingham Study and Progetto CUORE); (ii) blood pressure; (iii) physical activity (three sessions of bicycle exercise training and calisthenic exercises a week); and (iv) questionnaires on stress and quality of life., Results: Both cardiovascular risk cards showed a statistically significant reduction of the score (p < 0.05). Systolic and diastolic blood pressures showed a statistically significant reduction (128 ± 10 mmHg vs. 121 ± 9 mmHg, p = 0.04; 80 ± 8 mmHg vs. 73 ± 7 mmHg, p = 0.001). There was a noticeable increase in patient compliance for reporting blood pressure data. 89% of patients complied with the physical activity programme. Effort test significantly increased from 11.4 ± 3.5 to 12.7 ± 3.4 min (p = 0.02). There was a significant improvement in physical health (p = 0.04) and 85% of patients were satisfied with the service., Conclusions: A home multidisciplinary programme for primary cardiovascular disease prevention is simple, efficacious, and very well accepted by the patients with the majority of patients showing reduction in cardiovascular risk scores.

PI-2301 is an amino acid copolymer acting as an immunomodulator for the treatment of autoimmune diseases. The present study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics of PI-2301 in a single ascending dose, first-in-human study involving healthy, male adult volunteers. A total of 56 subjects were given a subcutaneous injection of PI-2301 ranging from 0.035 to 60 mg. The only consistent side effect was transient injection site reactions. We describe, for the first time, a pharmacokinetic assay to monitor amino acid copolymer concentration in human serum. PI-2301 was detected in the serum of subjects in the 10-, 30-, and 60-mg cohorts. Maximum serum concentration was achieved between 10 and 30 minutes postdosing with some compound detected 4 hours after dosing. PI-2301's lasting immunological properties were evident by an ex vivo recall assay showing T-cell proliferation and IL-13 production in subjects dosed with 1, 3, or 10 mg of PI-2301, up to 6 months after dosing. A transient increase in chemokine CXCL9 and CXCL10 plasma levels was seen in subjects dosed with 30 or 60 mg of PI-2301. These results are highly consistent with our preclinical findings and suggest that PI-2301 could facilitate the expansion of a favorable immune posture in patients with autoimmune disorders.

During an eight-year period, 358 patients with chronic heart failure (CHF) were enrolled in a six-month home-based telemanagement (HBT) programme. The efficacy of the programme was evaluated in two four-year periods, based on changes in clinical, functional, Quality of Life (QoL) status and rate of hospital readmission. The New York Heart Association (NYHA) class and the number of patients with comorbidities increased significantly in the second period, while the number of patients with beta-blockers decreased significantly (P < 0.01). Following the HBT programme, non-cardiovascular hospital readmission rate and all-cause readmission rate increased by 11% (P < 0.03) and 13% (P < 0.05), respectively. On re-evaluation after six months (238 patients) there was a general improvement in clinical, functional and QoL status and a significant increase in the mean daily dosage of beta-blockers prescribed. Our experience confirms that HBT for patients with CHF is associated with favourable effects on hospital readmission for cardiovascular reasons and on QoL. However, a more comprehensive multidisciplinary approach will probably be required to obtain favourable effects on total morbidity.

The random amino acid copolymer poly(Y,E,A,K)(n) (Copaxone®) is widely used in multiple sclerosis treatment and a second generation copolymer poly(Y,F,A,K)(n) with enhanced efficacy in experimental autoimmune encephalomyelitis in mice has been described. A major mechanism through which copolymers function to ameliorate disease is the generation of immunosuppressive IL-10-secreting regulatory T cells entering the CNS. In addition, the antigen presenting cell to which these copolymers bind through MHC Class II proteins may have an important role. Here, both CCL22 (a Th2 cell chemoattractant) in large amounts and CXCL13 in much smaller amounts are shown to be secreted after administration of YFAK to mice and to a smaller extent by YEAK parallel to their serum concentrations. Moreover, bone marrow-derived macrophages secrete CCL22 in vitro in response to YFAK and to higher concentrations of YEAK. Strikingly, these chemokines are also secreted into serum of MHC Class II -/- mice, indicating that an innate immune receptor on these cells also has an important role. Thus, both the innate and the adaptive immune systems are involved in the mechanism of EAE amelioration by YFAK. The enhanced ability of YFAK to stimulate the innate immune system may account for its enhanced efficacy in EAE treatment.

PI-2301 is an immunomodulator that could be an alternative therapy for MS. A placebo-controlled, multiple-ascending dose, double-blind study was performed in patients with secondary-progressive MS. Treatment was given subcutaneously once weekly for 8 weeks, followed by a 4-week open-label treatment period with active drug. The most common adverse event was transient injection site reactions. Non-significant trend for increases in serum levels of IL-3, IL-13, and CCL22 over time were suggestive of a beneficial T(H)2 immune response in subjects dosed with PI-2301 at 3 and 10 mg. MRI data indicated a non-significant trend for a reduction of lesion numbers in subjects treated with 1 and 3 mg PI-2301., (Copyright 2010 Elsevier B.V. All rights reserved.)

Atrial fibrillation and chronic heart failure often coexist. Asymptomatic atrial fibrillation is common in patients with known atrial fibrillation but also in patients with no history of previous atrial fibrillation. The enhanced diagnostic capabilities of modern implantable devices for cardiac resynchronization therapy allow collecting of data on the clinical status of the patient in addition to information on device performance and cardiac rhythm. We present a paradigmatic case of newly diagnosed atrial fibrillation with hemodynamic consequences detected by the diagnostics of a biventricular implantable cardioverter-defibrillator. We discuss the clinical utility of device-based monitoring and the potential advantages of wireless remote-control systems of implantable devices in the management of heart failure patients.

Background: Chronic heart failure (CHF) remains a common cause of disability, death and hospital admission. Several investigations support the usefulness of programs of disease management for improving clinical outcomes. However, the effect of home-based telemanagement programs on the rate of hospital readmission is still unclear and the cost-effectiveness ratio of such programs is unknown. The aim of the study was to determine whether a home-based telemanagement (HBT) programme in CHF patients decreased hospital readmissions and hospital costs in comparison with the usual care (UC) follow-up programme over a one-year period., Methods and Results: Four hundred-sixty CHF patients (pts), aged 57+/-10 years were randomised to two management strategies: 230 pts to HBT programme and 230 pts to UC programme. The HBT pts received a portable device, transferring, by telephone, a one-lead trace to a receiving station where a nurse was available for interactive teleconsultation. The UC pts were referred to their primary care physicians and cardiologists. The primary objective of the study was one-year hospital readmission for cardiovascular reasons. During one-year follow-up 55 pts (24%) in HBT group and 83 pts (36%) in UC group had at least one readmission (RR=0.56; 95% CI: 0.38-0.82; p=0.01). After adjusting for clinical and demographic characteristics, the HBT group had a significantly lower risk of readmission compared with the UC group (HR=0.50, 95% CI: 0.34-0.73; p=0.01). The intervention was associated with a 36% decrease in the total number of hospital readmissions (HBT group: 91 readmissions; UC group: 142 readmissions) and a 31% decrease in the total number of episodes of hemodynamic instability (101 in HBT group vs 147 in UC group). The rate of hearth failure-related readmission was 19% (43 pts) in HBT group and 32% (73 pts) in UC group (RR=0.49, 95% [CI]: 0.31-0.76; p=0.0001). No significant difference was found on cardiovascular mortality between groups. Mean cost for hospital readmission was significantly lower in HBT group (euro 843+/-1733) than in UC group (euro 1298+/-2322), (-35%, p<0.01)., Conclusions: This study suggests that one-year HBT programme reduce hospital readmissions and costs in CHF patients.

We evaluated the feasibility of a home-based rehabilitation programme, which was designed to resemble an in-hospital rehabilitation programme. Patients who underwent cardiac surgery (EuroSCORE 0-10) followed a one-month home rehabilitation programme supervised by a nurse-tutor and a physiotherapist. Physiotherapy was performed at home with calisthenic exercises and bicycle-ergometer tests. Patients transmitted the recorded ECGs by telephone to a service centre. They also performed a 6-minute walking test and filled in a satisfaction questionnaire at the end of the programme. A total of 47 patients were enrolled in the study. There were 3050 telephone calls, of which 3012 (99%) were scheduled and 38 were unscheduled. No further action was required in 95% of calls. There were 809 sessions for calisthenic exercises and 1039 for exercise training. There was a significant increase in the 6-minute walking test distance at the end of the programme compared to the baseline (404 m vs. 307 m, P < 0.001). Patient satisfaction, as measured in a questionnaire, was about 95% overall. This type of home rehabilitation using telemedicine appears to be worth implementing in selected categories of patients.

A group of patients with chronic heart failure (CHF) were followed by general practitioners (GPs) with a telecardiology system, and a second group of patients were followed by a home-based telemonitoring (HBT) protocol with medical and nursing supervision. The 212 GP patients were older than the 226 HBT patients, mostly women, with CHF secondary to chronic hypertension, less self-sufficient and with a non-optimized therapy. The mean number of telephone calls was 2.6 per patient in the GP group and 16.6 per patient in the HBT group (P<0.001). These preliminary data suggest the applicability and the efficacy of both management models for CHF patients.

Background: Atrial fibrillation (AF) is the most common sustained cardiac tachyarrhythmia and is often an occasional diagnosis in the absence of known cardiac disease. The aim of this study is to describe an Italian patient population with AF followed by their General Practitioners (GPs) using a telecardiology service., Methods: A total of 655 Italian GPs were equipped with a portable electrocardiographer. The ECG tracing of all consecutive patients (7516) received between January and September 2001 was included into the study., Results: AF was detected in 719 patients (9.%) (77+/-12 years). In 448 patients, it was a known chronic condition, while in 271 patients, it was a new diagnosis. In the chronic AF, the principal reason for the teleconsultation was a routine control by the GPs, but an uncontrolled cardiac rate was present in 29% of the cases, while an antiplatelet or anticoagulation therapy was administered in only 46.2% cases. The teleconsultation alone provided a solution to the GPs' requests in 348 patients (77.6%) (154 cases (34.5%) required no further action while 194 patients (43.5%) needed therapy adjustments only), while 47 patients (10.5%) required hospitalization and 51 patients needed further diagnostic tests. In 271 cases, a first evidence of atrial fibrillation was recorded: in 259 patients, GPs requested a teleconsultation in the presence of symptoms (mainly palpitation, dyspnoea and fatigue) and in 12 for routine control; in this case, 121 patients (46.9%) needed Emergency Department (ED) admission, 113 patients (39.1%) needed therapy adjustments and, for 19 patients (7.5%), further diagnostic tests were prescribed., Conclusion: In Italy, many patients, in particular the elderly, with AF are followed by their GPs on a routine basis; a telecardiology service may provide a useful tool in the home management of chronic AF and in the first detection of new cases of AF.

We investigated a home-based intervention based on telecardiology in patients with chronic heart failure (CHF). Two hundred and thirty CHF patients, aged 59 years (SD 9), in stable condition and with optimized therapy were enrolled. The programme consisted of trans-telephonic follow-up and electrocardiogram (ECG) monitoring followed by visits from a paramedical and medical team. The patient could call the centre when required (tele-assistance), while the team could call the patient at prescheduled times (telemonitoring). During the first 12 months, there were 3767 calls (873 ad hoc and 2894 scheduled calls). There were 648 events, including 126 episodes of asymptomatic hypotension and 168 episodes which were not due to cardiological symptoms. No actions were taken by the nurse after 2417 calls (64%). A change in therapy was suggested after 418 calls, hospital admission in 62 patients, further investigations for 243 patients and a consultation with the general practitioner in 41 patients. A total of 2303 one-lead ECG recordings were received (10 per patient); 126 recordings (6%) were diagnosed as pathological in comparison with the baseline one. The one-lead ECG recording was used for titration of beta-blockers in 79 patients (mean dosage 38 mg vs 42 mg, P<0.01). Home telenursing could be an important application of telemedicine and single-lead ECG recording seems to offer additional benefit in comparison with telephone follow-up alone.

Palpitation is a common symptom that sometimes results from a substantial cardiac arrhythmia. We compared the diagnostic yield of trans-telephonic event monitors with those of Holter monitoring in patients with intermittent palpitations. In all, 310 patients were randomly assigned to receive an event recorder or 24-hour Holter monitoring. Event recorders were used for seven days or until two recordings were obtained while symptoms occurred. The main end-point was an electrocardiogram (ECG) recorded during symptoms. The patients with palpitation recorded the one-lead ECG trace and sent it to a telemedicine call centre, where a nurse responded. There were 119 symptomatic patients in the event recorder group and 74 in the Holter group. The total costs were 6019 for event recording and 9605 for Holter monitoring. The average costs were 51 per symptomatic patient detected by event recorder monitoring and 130 per symptomatic patient detected by Holter monitoring. More patients therefore received a clear diagnosis, and more quickly, when using event recording than with Holter monitoring. For this reason, event recorders are preferable to Holter monitors for patients with palpitations.

Chronic heart failure (CHF) remains a common cause of disability. We have investigated the use of home-based telecardiology (HBT) in CHF patients. Four hundred and twenty-six patients were enrolled in the study: 230 in the HBT group and 196 in the usual-care group. HBT consisted of trans-telephonic follow-up and electrocardiogram (ECG) monitoring, followed by visits from the paramedical and medical team. A one-lead ECG recording was transmitted to a receiving station, where a nurse was available for reporting and interactive teleconsultation. The patient could call the centre when assistance was required (tele-assistance), while the team could call the patient for scheduled appointments (telemonitoring). The one-year clinical outcomes showed that there was a significant reduction in rehospitalizations in the HBT group compared with the usual-care group (24% versus 34%, respectively). There was an increase in quality of life in the HBT group (mean Minnesota Living Questionnaire scores 29 and 23.5, respectively). The total costs were lower in the HBT group (107,494 and 140,874, respectively). The results suggest that a telecardiology service can detect and prevent clinical instability, reduce rehospitalization and lower the cost of managing CHF patients.

It has been suggested that the inflammatory cytokine IL-15 plays an important role in the development of several autoimmune diseases, including rheumatoid arthritis. We have generated a unique lytic and antagonistic IL-15 mutant/Fcgamma2a fusion protein (CRB-15) that targets the IL-15R. In the present study we examined the effects of targeting the IL-15R on the prevention and treatment of collagen-induced arthritis (CIA) in mice and probed the possible mechanisms of action of this IL-15 mutant/Fcgamma2a protein. Upon immunization with type II collagen, DBA/1 mice develop severe articular inflammation and destruction. Treatment of DBA/1 mice with a brief course of CRB-15 at the time of type II collagen challenge markedly inhibited the incidence and severity of arthritis. Moreover, in animals with ongoing established arthritis, treatment with CRB-15 effectively blocked disease progression compared with that in control-treated animals. The therapeutic effect of CRB-15 on either disease development or disease progression is remarkably stable, because withdrawal of treatment did not lead to disease relapse. A detailed analysis revealed that treatment with CRB-15 decreased synovitis in the joints; reduced bone erosion and cartilage destruction; reduced in situ production of the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and IL-17; and decreased the responder frequency of autoreactive T cells. Our study suggests that the effective targeting of IL-15R-triggered events with CRB-15 can be of therapeutic importance in the treatment of rheumatoid arthritis.

Objective: The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of high-affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies)., Methods: High-resolution HLA-DR and DQ typing and anti-CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method., Results: Carriership of the individual alleles HLA-DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of anti-CCP antibodies. Carriers of DQ-DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA-DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8-6.0 and OR 13.3, 95% CI 4.6-40.4, respectively). An increased rate of joint destruction was observed in SE+, anti-CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE-, anti-CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti-CCP- patients (1.6 points per year) (P < 0.001), and SE-, anti-CCP- patients (1.6 points per year) (P < 0.001)., Conclusion: HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles.

Background: Palpitations are a common symptom that sometimes results from a substantial cardiac arrhythmia. A 24-hour Holter monitoring is usually used, but the yield of this instrument is low in patients whose symptoms occur infrequently. The aim of this study was to compare the diagnostic yield and the cost-effectiveness of transtelephonic event recorder (TER) with those of Holter monitoring in patients with intermittent palpitations., Methods: Three hundred and ten patients with intermittent palpitations were allocated to the study and randomly assigned to receive a TER or 24-hour Holter monitoring. TER was given to patients until recording was obtained while symptoms occurred or was used at most for 7 days. At enrollment, a basal trace was recorded. Patients with palpitations recorded the one lead ECG trace and sent it by phone (fixed or mobile) to the telemedicine call center where a trained nurse compared the trace with the basal one and checked the patient's symptoms. The cardiologist reported "on-line" all the traces sent in the presence of an arrhythmic event and "stored and forwarded" all the other traces. Standard methods were used for Holter recording and reading., Results: Patients with palpitations during the examination were 119 (76.8%) in the group of TER and 74 (47.8%) in the Holter group (p < 0.000) with an efficacy increase of 29% for TER. In symptomatic patients there were no differences between the two groups about the presence or absence of arrhythmias checked in the ECG traces; the time necessary to make a presence/absence diagnosis of arrhythmias was 2.97 +/- 2.74 days with the event recorder. The total cost of 155 tests made with Holter was altogether 9605.35 Euro (costs per test 61.97 Euro), while the one of TER was 6019.2 Euro (cost par test 38.83 Euro). The cost-effectiveness analysis was 129.80 Euro for Holter and 50.57 Euro for TER, with a saving of 79.23 Euro for every diagnosis made., Conclusions: TER allows to detect intermittent palpitations in real time; it is more useful and effective than Holter; moreover this effectiveness was also confirmed by the cost analysis in which TER resulted less expensive.

We assessed the feasibility of home-based telecardiology for patients with chronic heart failure (CHF). Seventy-four CHF patients were enrolled into a programme of telephone follow-up and single-lead electrocardiography (ECG) monitoring. The patients transmitted their ECG data by fixed telephone line to a receiving station, where a nurse was available for an interactive teleconsultation. Patients were followed up for a mean (SD) of 307 (108) days; 1467 calls were analysed (213 ad hoc consultations and 1254 scheduled consultations). A total of 124 cardiovascular events were recorded. Modifications to therapy were suggested in response to 119 calls; hospital admissions were suggested for 13 patients, further investigations for 7 and a consultation with the patient's general practitioner for 13. No action was taken after 1330 calls. Twenty-two ECG abnormalities were recorded. In 63 patients receiving the beta-blocker carvedilol, the mean dosage increased from 36 to 42 mg. In the previous year there were 1.8 hospitalizations per patient, while in the follow-up period there were 0.2 hospitalizations per patient. Following up CHF patients using a nurse-led telecardiology programme seems to be feasible and useful.

Objective: CD4+,CD25+ T regulatory cells may offer opportunities to intervene in the course of autoimmune disease. We wished to evaluate their potential for influencing systemic and chronic joint inflammation by investigating their involvement in collagen-induced arthritis (CIA)., Methods: We depleted DBA/1 mice of CD25+ regulatory cells by injection of a depleting monoclonal antibody specific for CD25 14 days before a single immunization with type II collagen (CII) in Freund's complete adjuvant. CD4+,CD25+ T cells were adoptively transferred to some groups of mice during immunization. Mice were then scored for signs of arthritis, and blood was taken periodically to measure the amounts of CII-specific antibodies. Splenocytes of treated mice were examined in vitro to determine the effects of depletion on proliferation to CII and control antigens., Results: CD25+ cell-depleted DBA/1 mice had significantly more severe disease than control mice following collagen immunization. The magnified severity was also accompanied by higher antibody titers against collagen, and in vitro tests showed increased proliferation of collagen-specific T cells. Adoptively transferring CD4+,CD25+ T cells into depleted mice was shown to reverse the heightened severity. Control mice, which were depleted and immunized with the neoantigen keyhole limpet hemocyanin (KLH), had neither an increased antibody response toward KLH nor an augmented proliferative response, indicating that CD25+ cell depletion preferentially affects immunity against self antigen., Conclusion: These results establish a link between CD4+,CD25+ regulatory cells and CIA and provide a rationale for investigating CD4+,CD25+ T regulatory cells in the treatment and prevention of arthritis.

Here we report an additional source of variation resulting from genetic polymorphism in HLA-DQbeta1 genes, namely, allelic diversity in the first exon of the HLA-DQB1 locus, which encodes the leader peptide sequence. Six different variants, including a novel polymorphic site, were detected among the DBQ1 haplotypes.