RESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.
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Infecciones por Coronavirus/patología , Neumonía Viral/patología , Síndrome de Respuesta Inflamatoria Sistémica/patología , Autoanticuerpos/sangre , Betacoronavirus/aislamiento & purificación , COVID-19 , Niño , Preescolar , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/virología , Citocinas/metabolismo , Femenino , Humanos , Inmunidad Humoral , Lactante , Masculino , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome Mucocutáneo Linfonodular/patología , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/virología , Análisis de Componente Principal , Proteoma/análisis , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system1,2. The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies3. Somatic and germline gain-of-function mutations in ALK were identified in paediatric neuroblastoma4-7. ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain8,9. ALK is activated by the binding of ALKAL1 and ALKAL2 ligands10-14 to its ECR, but the lack of structural information for the ALK-ECR or for ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-electron microscopy, nuclear magnetic resonance and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a mechanism of RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor-ligand complex. The ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms.
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Quinasa de Linfoma Anaplásico/química , Quinasa de Linfoma Anaplásico/metabolismo , Quinasa de Linfoma Anaplásico/ultraestructura , Sitios de Unión , Membrana Celular/química , Membrana Celular/metabolismo , Microscopía por Crioelectrón , Cristalografía por Rayos X , Citocinas/química , Citocinas/metabolismo , Citocinas/ultraestructura , Activación Enzimática , Humanos , Ligandos , Modelos Moleculares , Complejos Multiproteicos/química , Complejos Multiproteicos/metabolismo , Complejos Multiproteicos/ultraestructura , Resonancia Magnética Nuclear Biomolecular , Unión Proteica , Dominios Proteicos , Multimerización de ProteínaRESUMEN
Recurrence after colorectal cancer resection is rarely documented in the general population while a key clinical determinant for patient survival. We identified 8785 patients with colorectal cancer diagnosed between 2010 and 2013 and clinically followed up to 2020 in 15 cancer registries from seven European countries (Bulgaria, Switzerland, Germany, Estonia, France, Italy, and Spain). We estimated world age-standardized net survival using a flexible cumulative excess hazard model. Recurrence rates were calculated for patients with initially resected stage I, II, or III cancer in six countries, using the actuarial survival method. The proportion of nonmetastatic resected colorectal cancers varied from 58.6% to 78.5% according to countries. The overall 5-year net survival by country ranged between 60.8% and 74.5%. The absolute difference between the 5-year survival extremes was 12.8 points for stage II (Bulgaria vs Switzerland), 19.7 points for stage III (Bulgaria vs. Switzerland) and 14.8 points for Stage IV and unresected cases (Bulgaria vs. Switzerland or France). Five-year cumulative rate of recurrence among resected patients with stage I-III was 17.7%. As compared to the mean of the whole cohort, the risk of developing a recurrence did not differ between countries except a lower risk in Italy for both stage I/II and stage III cancers and a higher risk in Spain for stage III. Survival after colorectal cancer differed across the concerned European countries while there were slight differences in recurrence rates. Population-based collection of cancer recurrence information is crucial to enhance efforts for evidence-based management of colorectal cancer follow up.
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Neoplasias Colorrectales , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Sistema de Registros , Humanos , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/epidemiología , Sistema de Registros/estadística & datos numéricos , Masculino , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/mortalidad , Femenino , Europa (Continente)/epidemiología , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , AdultoRESUMEN
OBJECTIVES: To assess the impact of tocilizumab (TCZ) monotherapy after ultra-short-pulse glucocorticoids (GCs) on clinical manifestations, and vessel inflammation and damage in large vessel-GCA (LV-GCA). METHODS: In this prospective observational study, we enrolled patients with active LV-GCA. All patients received 500 mg per day i.v. methylprednisolone for three consecutive days and weekly s.c. TCZ injections from day 4 until week 52. PET/CT was performed on all patients at baseline and at weeks 24 and 52. The primary end points were the reduction in the PET vascular activity score (PETVAS) at weeks 24 and 52 compared with baseline, and the proportion of patients with relapse-free remission at weeks 24 and 52. The secondary end point was the proportion of patients with new aortic dilation at weeks 24 and 52. RESULTS: A total of 18 patients were included (72% female, mean age 68.5 years). Compared with the baseline value, a significant reduction in the PETVAS was observed at weeks 24 and 52, mean (95% CI) reductions -8.6 (-11.5 to -5.7) and -10.4 (-13.6 to -7.2), P = 0.001 and 0.002, respectively. The proportion of patients with relapse-free remission at weeks 24 and 52 was 10/18 (56%, 95% CI 31-78) and 8/17 (47%, 95% CI 23-72), respectively. At weeks 24 and 52, no patient had shown new aortic dilation. However, 4 patients who had shown aortic dilation at baseline showed a significant increase in aortic diameter (≥5 mm) at week 52. CONCLUSION: TCZ monotherapy after ultra-short-pulse GCs controlled the clinical symptoms of GCA and reduced vascular inflammation. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT05394909.
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Arteritis de Células Gigantes , Glucocorticoides , Humanos , Femenino , Anciano , Masculino , Glucocorticoides/uso terapéutico , Arteritis de Células Gigantes/diagnóstico por imagen , Arteritis de Células Gigantes/tratamiento farmacológico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Resultado del Tratamiento , InflamaciónRESUMEN
OBJECTIVES: To assess the maintenance of efficacy of one year of tocilizumab (TCZ) monotherapy after its discontinuation in large vessel-GCA (LV-GCA). METHODS: 17 patients with active LV-GCA were previously treated with 3 boluses of intravenous methylprednisone and weekly subcutaneous TCZ in monotherapy for 52 weeks. Patients in relapse-free clinical remission at week 52 discontinued TCZ and entered part two, which was a 26-week observational follow-up period. PET/CT was performed in all patients at the end of the 26-week observational period (week 78). End points were the variation in PET vascular activity score (PETVAS) at week 78 compared with baseline and with week 52, and the proportion of patients with relapse-free clinical remission at week 78 and at the end of the follow-up. RESULTS: Compared with baseline, a significant reduction in PETVAS was observed at week 78, mean (95% CI) change -6.6 (-9.5 to -3.7). However, compared with week 52, PETVAS significantly increase 6 months after TCZ discontinuation (week 78), mean (95% CI) change 4.6 (0.7-8.5). The proportion of patients with relapse-free clinical remission at weeks 78 and at the end of the follow-up (median time from TCZ discontinuation 148 weeks) was 11/17 (65%, 95% CI 38-86) and 8/17 (47%, 95% CI 23-72), respectively. Age and sex-adjusted HR (95% CI) for each unit increase of PETVAS indicating subsequent relapse was 1.36 (0.92-2.00). CONCLUSIONS: One year of TCZ monotherapy was effective in maintaining drug-free clinical remission in LV-GCA. Changes in PETVAS early after TCZ discontinuation may predict subsequent relapses. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT05394909.
RESUMEN
AIMS: Tumour necrosis and/or increased mitoses define high-grade papillary thyroid carcinoma (PTC). It is unclear whether angioinvasion is prognostic for PTC. Cut-offs at five or more mitoses/2 mm2 and four or more angioinvasive foci have been empirically defined based upon data from all forms of aggressive non-anaplastic thyroid carcinomas. Performance of tumour necrosis, mitoses and vascular invasion in predicting distant metastases when specifically applied to PTC is undefined. METHODS: We analysed 50 consecutive PTC cases with distant metastases (DM-PTC): 16 synchronous and 34 metachronous. A total of 108 non-metastatic PTC (N-DM-PTC, 15.0-year median follow-up) were used as controls. Invasive encapsulated follicular variant PTC was excluded. Necrosis, mitoses and angioinvasion were quantified. Receiver operating characteristics (ROC) and area under the curve (AUC) analyses determined best sensitivity and specificity cut-offs predictive of distant metastases. RESULTS: Metastases correlated with necrosis (any extent = 43.8% all DM-PTC, 53.1% metachronous DM-PTC versus 5% N-DM-PTC; P < 0.001), mitoses (P < 0.001) and angioinvasion (P < 0.001). Mitoses at five or more per 2 mm2 was the best cut-off correlating with distant metastases: sensitivity/specificity 42.9%/97.2% all DM-PTC (AUC = 0.78), 18.8%/97.2% synchronous DM-PTC (AUC = 0.63), 54.6%/97.2% metachronous DM-PTC (AUC = 0.85). Angioinvasive foci at five or more was the best cut-off correlating with distant metastases: sensitivity/specificity 36.2%/91.7% all DM-PTC (AUC = 0.75), 25%/91.7% synchronous DM-PTC (AUC = 0.79) and 41.9%/91.7% metachronous DM-PTC (AUC = 0.73). Positive/negative predictive values (PPV/NPV) were: necrosis 22.6%/98.2%; five or more mitoses 32.3%/98.2%; five or more angioinvasive foci 11.8%/97.9%. After multivariable analysis, only necrosis and mitotic activity remained associated with DM-PTC. CONCLUSION: Our data strongly support PTC grading, statistically validating World Health Organisation (WHO) criteria to identify poor prognosis PTC. Angioinvasion is not an independent predictor of DM-PTC.
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Necrosis , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Masculino , Neoplasias de la Tiroides/patología , Femenino , Persona de Mediana Edad , Cáncer Papilar Tiroideo/patología , Adulto , Pronóstico , Estudios de Casos y Controles , Anciano , Organización Mundial de la Salud , Invasividad Neoplásica , Carcinoma Papilar/patología , Mitosis , Adulto JovenRESUMEN
OBJECTIVE AND DESIGN: We aimed to identify cytokines whose concentrations are related to lung damage, radiomic features, and clinical outcomes in COVID-19 patients. MATERIAL OR SUBJECTS: Two hundred twenty-six patients with SARS-CoV-2 infection and chest computed tomography (CT) images were enrolled. METHODS: CCL18, CHI3L1/YKL-40, GAL3, ANG2, IP-10, IL-10, TNFα, IL-6, soluble gp130, soluble IL-6R were quantified in plasma samples using Luminex assays. The Mann-Whitney U test, the Kruskal-Wallis test, correlation and regression analyses were performed. Mediation analyses were used to investigate the possible causal relationships between cytokines, lung damage, and outcomes. AVIEW lung cancer screening software, pyradiomics, and XGBoost classifier were used for radiomic feature analyses. RESULTS: CCL18, CHI3L1, and ANG2 systemic levels mainly reflected the extent of lung injury. Increased levels of every cytokine, but particularly of IL-6, were associated with the three outcomes: hospitalization, mechanical ventilation, and death. Soluble IL-6R showed a slight protective effect on death. The effect of age on COVID-19 outcomes was partially mediated by cytokine levels, while CT scores considerably mediated the effect of cytokine levels on outcomes. Radiomic-feature-based models confirmed the association between lung imaging characteristics and CCL18 and CHI3L1. CONCLUSION: Data suggest a causal link between cytokines (risk factor), lung damage (mediator), and COVID-19 outcomes.
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COVID-19 , Neoplasias Pulmonares , Humanos , Interleucina-6 , SARS-CoV-2 , Proteína 1 Similar a Quitinasa-3 , Detección Precoz del Cáncer , Radiómica , Pulmón/diagnóstico por imagen , Citocinas , Quimiocinas CCRESUMEN
BACKGROUND: Exposure to air pollution has been proposed as one of the potential risk factors for leukaemia. Work-related formaldehyde exposure is suspected to cause leukaemia. METHODS: We conducted a nested register-based case-control study on leukaemia incidence in the Viadana district, an industrial area for particleboard production in Northern Italy. We recruited 115 cases and 496 controls, frequency-matched by age, between 1999 and 2014. We assigned estimated exposures to particulate matter (PM10, PM2.5), nitrogen dioxide (NO2), and formaldehyde at residential addresses, averaged over the susceptibility window 3rd to 10th year prior to the index date. We considered potential confounding by sex, age, nationality, socio-economic status, occupational exposures to benzene and formaldehyde, and prior cancer diagnoses. RESULTS: There was no association of exposures to PM10, PM2.5, and NO2 with leukaemia incidence. However, an indication of increased risk emerged for formaldehyde, despite wide statistical uncertainty (OR 1.46, 95%CI 0.65-3.25 per IQR-difference of 1.2 µg/m3). Estimated associations for formaldehyde were higher for acute (OR 2.07, 95%CI 0.70-6.12) and myeloid subtypes (OR 1.79, 95%CI 0.64-5.01), and in the 4-km buffer around the industrial facilities (OR 2.78, 95%CI 0.48-16.13), although they remained uncertain. CONCLUSIONS: This was the first study investigating the link between ambient formaldehyde exposure and leukaemia incidence in the general population. The evidence presented suggests an association, although it remains inconclusive, and a potential significance of emissions related to industrial activities in the district. Further research is warranted in larger populations incorporating data on other potential risk factors.
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Contaminantes Atmosféricos , Contaminación del Aire , Exposición a Riesgos Ambientales , Formaldehído , Leucemia , Material Particulado , Italia/epidemiología , Humanos , Leucemia/epidemiología , Leucemia/inducido químicamente , Leucemia/etiología , Estudios de Casos y Controles , Masculino , Incidencia , Femenino , Persona de Mediana Edad , Contaminantes Atmosféricos/análisis , Exposición a Riesgos Ambientales/efectos adversos , Adulto , Formaldehído/análisis , Formaldehído/toxicidad , Anciano , Material Particulado/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Dióxido de Nitrógeno/análisis , Adulto JovenRESUMEN
BACKGROUND: Asbestos is a known human carcinogen and is causally associated with malignant mesothelioma, lung, larynx and ovarian cancers. METHODS: Cancer risk was studied among a pool of formerly asbestos-exposed workers in Italy. Fifty-two Italian asbestos cohorts (asbestos-cement, rolling-stock, shipbuilding, and other) were pooled and their mortality follow-up was updated to 2018. Standardized mortality ratios (SMRs) were computed for major causes of death considering duration of exposure and time since first exposure (TSFE), using reference rates by region, age and calendar period. RESULTS: The study included 63,502 subjects (57,156 men and 6346 women): 40% who were alive, 58% who died (cause known for 92%), and 2% lost to follow-up. Mortality was increased for all causes (SMR: men = 1.04, 95% confidence interval [CI] 1.03-1.05; women = 1.15, 95% CI 1.11-1.18), all malignancies (SMR: men = 1.21, 95% CI 1.18-1.23; women = 1.29, 95% CI 1.22-1.37), pleural and peritoneal malignancies (men: SMR = 10.46, 95% CI 9.86-11.09 and 4.29, 95% CI 3.66-5.00; women: SMR = 27.13, 95% CI 23.29-31.42 and 7.51, 95% CI 5.52-9.98), lung (SMR: men = 1.28, 95% CI 1.24-1.32; women = 1.26, 95% CI 1.02-1.53), and ovarian cancer (SMR = 1.42, 95% CI 1.08-1.84). Pleural cancer mortality increased during the first 40 years of TSFE (latency), reaching a plateau thereafter. CONCLUSIONS: Analyses by time-dependent variables showed that the risk for pleural neoplasms increased with latency and no longer increases at long TSFE, consistent with with asbestos clearance from the lungs. Peritoneal neoplasm risk increased over all observation time.
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Amianto , Neoplasias Pulmonares , Mesotelioma , Enfermedades Profesionales , Exposición Profesional , Neoplasias Ováricas , Neoplasias Peritoneales , Neoplasias Pleurales , Masculino , Humanos , Femenino , Causas de Muerte , Mesotelioma/etiología , Estudios de Cohortes , Exposición Profesional/efectos adversos , Enfermedades Profesionales/etiología , Materiales de Construcción , Amianto/efectos adversos , Italia/epidemiología , Neoplasias Pulmonares/etiologíaRESUMEN
BACKGROUND: Unsupervised robot-assisted rehabilitation is a promising approach to increase the dose of therapy after stroke, which may help promote sensorimotor recovery without requiring significant additional resources and manpower. However, the unsupervised use of robotic technologies is not yet a standard, as rehabilitation robots often show low usability or are considered unsafe to be used by patients independently. In this paper we explore the feasibility of unsupervised therapy with an upper limb rehabilitation robot in a clinical setting, evaluate the effect on the overall therapy dose, and assess user experience during unsupervised use of the robot and its usability. METHODS: Subacute stroke patients underwent a four-week protocol composed of daily 45 min-sessions of robot-assisted therapy. The first week consisted of supervised therapy, where a therapist explained how to interact with the device. The second week was minimally supervised, i.e., the therapist was present but intervened only if needed. After this phase, if participants learnt how to use the device, they proceeded to two weeks of fully unsupervised training. Feasibility, dose of robot-assisted therapy achieved during unsupervised use, user experience, and usability of the device were evaluated. Questionnaires to evaluate usability and user experience were performed after the minimally supervised week and at the end of the study, to evaluate the impact of therapists' absence. RESULTS: Unsupervised robot-assisted therapy was found to be feasible, as 12 out of the 13 recruited participants could progress to unsupervised training. During the two weeks of unsupervised therapy participants on average performed an additional 360 min of robot-assisted rehabilitation. Participants were satisfied with the device usability (mean System Usability Scale scores > 79), and no adverse events or device deficiencies occurred. CONCLUSIONS: We demonstrated that unsupervised robot-assisted therapy in a clinical setting with an actuated device for the upper limb was feasible and can lead to a meaningful increase in therapy dose. These results support the application of unsupervised robot-assisted therapy as a complement to usual care in clinical settings and pave the way to its application in home settings. TRIAL REGISTRATION: Registered on 13.05.2020 on clinicaltrials.gov (NCT04388891).
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Robótica , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Humanos , Terapia por Ejercicio/métodos , Estudios de Factibilidad , Recuperación de la Función , Rehabilitación de Accidente Cerebrovascular/métodos , Extremidad SuperiorRESUMEN
PURPOSE: We present a comprehensive investigation into the organizational, social, and ethical impact of implementing digital breast tomosynthesis (DBT) as a primary test for breast cancer screening in Italy. The analyses aimed to assess the feasibility of DBT specifically for all women aged 45-74, women aged 45-49 only, or those with dense breasts only. METHODS: Questions were framed according to the European Network of Health Technology Assessment (EuNetHTA) Screening Core Model to produce evidence for the resources, equity, acceptability, and feasibility domains of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) decision framework. The study integrated evidence from the literature, the MAITA DBT trials, and Italian pilot programs. Structured interviews, surveys, and systematic reviews were conducted to gather data on organizational impact, acceptability among women, reading and acquisition times, and the technical requirements of DBT in screening. RESULTS: Implementing DBT could significantly affect the screening program, primarily due to increased reading times and the need for additional human resources (radiologists and radiographers). Participation rates in DBT screening were similar, if not better, to those observed with standard digital mammography, indicating good acceptability among women. The study also highlighted the necessity for specific training for radiographers. The interviewed key persons unanimously considered feasible tailored screening strategies based on breast density or age, but they require effective communication with the target population. CONCLUSIONS: An increase in radiologists' and radiographers' workload limits the feasibility of DBT screening. Tailored screening strategies may maximize the benefits of DBT while mitigating potential challenges.
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Neoplasias de la Mama , Detección Precoz del Cáncer , Mamografía , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Italia , Mamografía/métodos , Persona de Mediana Edad , Anciano , Detección Precoz del Cáncer/métodos , Estudios de FactibilidadRESUMEN
BACKGROUND: Recent studies supported the association between occupational exposure to asbestos and risk of cholangiocarcinoma (CC). Aim of the present study is to investigate this association using an update of mortality data from the Italian pooled asbestos cohort study and to test record linkage to Cancer Registries to distinguish between hepatocellular carcinoma (HCC) and intrahepatic/extrahepatic forms of CC. METHODS: The update of a large cohort study pooling 52 Italian industrial cohorts of workers formerly exposed to asbestos was carried out. Causes of death were coded according to ICD. Linkage was carried out for those subjects who died for liver or bile duct cancer with data on histological subtype provided by Cancer Registries. RESULTS: 47 cohorts took part in the study (57,227 subjects). We identified 639 causes of death for liver and bile duct cancer in the 44 cohorts covered by Cancer Registry. Of these 639, 240 cases were linked to Cancer Registry, namely 14 CC, 83 HCC, 117 cases with unspecified histology, 25 other carcinomas, and one case of cirrhosis (likely precancerous condition). Of the 14 CC, 12 occurred in 2010-2019, two in 2000-2009, and none before 2000. CONCLUSION: Further studies are needed to explore the association between occupational exposure to asbestos and CC. Record linkage was hampered due to incomplete coverage of the study areas and periods by Cancer Registries. The identification of CC among unspecific histology cases is fundamental to establish more effective and targeted liver cancer screening strategies.
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Amianto , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Enfermedades Profesionales , Exposición Profesional , Humanos , Colangiocarcinoma/epidemiología , Colangiocarcinoma/etiología , Exposición Profesional/efectos adversos , Italia/epidemiología , Neoplasias de los Conductos Biliares/epidemiología , Neoplasias de los Conductos Biliares/etiología , Masculino , Amianto/efectos adversos , Estudios de Cohortes , Femenino , Persona de Mediana Edad , Anciano , Enfermedades Profesionales/epidemiología , Enfermedades Profesionales/etiología , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Sistema de RegistrosRESUMEN
Despite the multiple benefits of vaccination, cardiac adverse Events Following COVID-19 Immunization (c-AEFI) have been reported. These events as well as the severe cardiac involvement reported in Multisystem inflammatory syndrome in children (MIS-C) appear more frequent in young adult males. Herein, we firstly report on the inflammatory profiles of patients experiencing c-AEFI in comparison with age, pubertal age and gender matched MIS-C with cardiac involvement. Proteins related to systemic inflammation were found higher in MIS-C compared to c-AEFI, whereas a higher level in proteins related to myocardial injury was found in c-AEFI. In addition, higher levels of DHEAS, DHEA, and cortisone were found in c-AEFI which persisted at follow-up. No anti-heart muscle and anti-endothelial cell antibodies have been detected. Overall current comparative data showed a distinct inflammatory and androgens profile in c-AEFI patients which results to be well restricted on heart and to persist months after the acute event.
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Vacunas contra la COVID-19 , COVID-19 , Miocarditis , Niño , Humanos , Masculino , Adulto Joven , Sistemas de Registro de Reacción Adversa a Medicamentos , Vacunas contra la COVID-19/efectos adversos , Miocarditis/etiología , Síndrome , Vacunación/efectos adversos , Vacunas de ARNmRESUMEN
The size of the latent HIV reservoir is associated with the timing of therapeutic interventions and overall health of the immune system. Here, we demonstrate that T cell phenotypic signatures associate with viral reservoir size in a cohort of HIV vertically infected children and young adults under durable viral control, and who initiated anti-retroviral therapy (ART) <2 years old. Flow cytometry was used to measure expression of immune activation (IA), immune checkpoint (ICP) markers, and intracellular cytokine production after stimulation with GAG peptides in CD4 and CD8 T cells from cross-sectional peripheral blood samples. We also evaluated the expression of 96 genes in sort-purified total CD4 and CD8 T cells along with HIV-specific CD4 and CD8 T cells using a multiplexed RT-PCR approach. As a measure of HIV reservoir, total HIV-DNA quantification by real-time PCR was performed. Poisson regression modeling for predicting reservoir size using phenotypic markers revealed a signature that featured frequencies of PD-1+CD4 T cells, TIGIT+CD4 T cells and HIV-specific (CD40L+) CD4 T cells as important predictors and it also shows that time of ART initiation strongly affects their association with HIV-DNA. Further, gene expression analysis showed that the frequencies of PD-1+CD4 T cells associated with a CD4 T cell molecular profile skewed toward an exhausted Th1 profile. Our data provide a link between immune checkpoint molecules and HIV persistence in a pediatric cohort as has been demonstrated in adults. Frequencies of PD-1+ and TIGIT+CD4 T cells along with the frequency of HIV-specific CD4 T cells could be associated with the mechanism of viral persistence and may provide insight into potential targets for therapeutic intervention.
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Infecciones por VIH/inmunología , VIH-1/fisiología , Linfocitos T/inmunología , Carga Viral/fisiología , Adolescente , Edad de Inicio , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/fisiología , Niño , Estudios de Cohortes , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Humanos , Activación de Linfocitos , Recuento de Linfocitos , Masculino , Linfocitos T/fisiología , Carga Viral/inmunología , Latencia del Virus/fisiologíaRESUMEN
BACKGROUND: The long-term immunologic effects of antiretroviral therapy (ART) in children with perinatally-acquired HIV (PHIV) have not been fully elucidated. Here, we investigated how the timing of ART initiation affects the long-term immune profile of children living with PHIV by measuring immunomodulatory plasma cytokines, chemokines, and adenosine deaminases (ADAs). METHODS: 40 PHIV participants initiated ART during infancy. 39 participant samples were available; 30 initiated ART ≤6 months (early-ART treatment); 9 initiated ART >6 months and <2 years (late-ART treatment). We compared plasma cytokine and chemokine concentrations and ADA enzymatic activities between early-ART and late-ART treatment 12.5 years later and measured correlation with clinical covariates. RESULTS: Plasma concentrations of 10 cytokines and chemokines (IFNγ, IL-12p70, IL-13, IL-17A, IL-IRA, IL-5, IL-6, and IL-9 as well as CCL7, CXCL10), ADA1, and ADA total were significantly higher in late-ART compared to early-ART treatment. Furthermore, ADA1 was significantly positively correlated with IFNγ, IL-17A, and IL-12p70. Meanwhile, total ADA was positively correlated with IFNγ, IL-13, IL-17A, IL-1RA, IL-6, and IL-12p70 as well as CCL7. CONCLUSIONS: Elevation of several pro-inflammatory plasma analytes in late-ART despite 12.5 years of virologic suppression compared to early-ART treatment suggests that early treatment dampens the long-term plasma inflammatory profile in PHIV participants. IMPACT: This study examines differences in the plasma cytokine, chemokine, and ADA profiles 12.5 years after treatment between early (≤6months) and late (>6 months and <2 years) antiretroviral therapy (ART) treatment initiation in a cohort of European and UK study participants living with PHIV. Several cytokines and chemokines (e.g., IFNγ, IL-12p70, IL-6, and CXCL10) as well as ADA-1 are elevated in late-ART treatment in comparison to early-ART treatment. Our results suggest that effective ART treatment initiated within 6 months of life in PHIV participants dampens a long-term inflammatory plasma profile as compared to late-ART treatment.
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Infecciones por VIH , Niño , Embarazo , Femenino , Humanos , Infecciones por VIH/tratamiento farmacológico , Interleucina-17 , Interleucina-13 , Interleucina-6 , Antirretrovirales/uso terapéutico , Citocinas , QuimiocinasRESUMEN
OBJECTIVE: To test the efficacy of self- compared to radiographer-led compression to reduce the average glandular dose without affecting image quality and compliance to follow-up mammography. MATERIALS AND METHODS: Women presenting for mammography for breast cancer follow-up, symptoms, opportunistic screening, or familial risk were asked to participate and, if willing, were randomized to self-compression or radiographer-led compression. Image quality was assessed blindly by two independent radiologists and two radiographers. Pain and discomfort were measured immediately after mammography and their recall was asked when the women participated in the follow-up mammogram, 1 or 2 years later. RESULTS: In total, 495 women (mean age 57 years +/-14) were enrolled, 245 in the self-compression and 250 radiographer-compression arms. Image quality was similar in the two arms (radiologists' judgement p = 0.90; radiographers' judgement p = 0.32). A stronger compression force was reached in the self- than in the radiographer-arm (114.5 vs. 10.25 daN, p < .001), with a 1.7-mm reduction in thickness (p = .14), and almost no impact on dose per exam (1.90 vs. 1.93 mGy, p = .47). Moderate/severe discomfort was reported by 7.8% vs 9.6% (p = .77) and median pain score was 4.0 in both arms (p = .55). Median execution time was 1 min longer with self-compression (10.0 vs. 9.1 min, p < 0.001). No effect on subsequent mammography was detectable (p = 0.47). CONCLUSION: Self-compression achieved stronger compression of the breast, with comparable image quality, but did not substantially reduce glandular dose. The proportion of women who attended follow-up mammography was also similar in the two groups. TRIAL REGISTRATION: clinicaltrials.gov NCT04009278 KEY POINTS: ⢠In mammography, appropriate compression is essential to obtain high image quality and reduce dose. Compression causes pain and discomfort. ⢠Self-compression has been proposed to reach better compression and possibly increase participation in mammography. ⢠In a randomized trial, self-compression reached stronger compression of the breast, with comparable image quality but with no glandular dose reduction or impact on participation in follow-up mammography.
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Neoplasias de la Mama , Mamografía , Femenino , Humanos , Persona de Mediana Edad , Mamografía/métodos , Mama/diagnóstico por imagen , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/complicaciones , Presión , Dolor/etiologíaRESUMEN
OBJECTIVES: A high prevalence of eosinophilic esophagitis (EoE) has been reported in children with repaired esophageal atresia (EA). Topical steroids proved to be an effective and safe therapy in EoE, although not approved in pediatrics. We report the results of the first clinical trial of oral viscous budesonide (OVB) performed in children with EoE after repaired esophageal atresia (EoE-EA). METHODS: This open-label, single-arm, phase 2 clinical trial with randomized pharmacokinetic sampling, was conducted at the Bambino Gesù Children's Hospital between September 2019 and June 2021. EoE-EA patients received an age-banded dose of OVB twice daily for 12 weeks and were endoscopically evaluated. The primary endpoint was the rate of patients achieving histological remission. Secondary endpoints included clinical and endoscopic benefit after treatment, and safety assessments. RESULTS: Eight consecutive EA-EoE patients were enrolled (median age 9.1 years, interquartile range 5.5). Of these, 5 received 0.8 mg and 3 received 1.0 mg twice daily of OVB. Histological remission was obtained in all but 1 patient (87.5%). The clinical score showed significant improvement at the end of treatment in all patients. No endoscopic features of EoE were found after treatment. No treatment-emergent adverse event occurred. CONCLUSION: OVB is an effective, safe, and well-tolerated formulation of budesonide for use in pediatric patients with EoE-EA.
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Esofagitis Eosinofílica , Atresia Esofágica , Niño , Humanos , Lactante , Esofagitis Eosinofílica/patología , Atresia Esofágica/tratamiento farmacológico , Atresia Esofágica/cirugía , Atresia Esofágica/complicaciones , Resultado del Tratamiento , Budesonida/uso terapéutico , Glucocorticoides/uso terapéuticoRESUMEN
BACKGROUND/AIM: Daily air pollution has been linked with mortality from urban studies. Associations in rural areas are still unclear and there is growing interest in testing the role that air pollution has on other causes of death. This study aims to evaluate the association between daily air pollution and cause-specific mortality in all 8092 Italian municipalities. METHODS: Natural, cardiovascular, cardiac, ischemic, cerebrovascular, respiratory, metabolic, diabetes, nervous and psychiatric causes of death occurred in Italy were extracted during 2013-2015. Daily ambient PM10, PM2.5 and NO2 concentrations were estimated through machine learning algorithms. The associations between air pollutants and cause-specific mortality were estimated with a time-series approach using a two-stage analytic protocol where area-specific over-dispersed Poisson regression models where fit in the first stage, followed by a meta-analysis in the second. We tested for effect modification by sex, age class and the degree of urbanisation of the municipality. RESULTS: We estimated a positive association between PM10 and PM2.5 and the mortality from natural, cardiovascular, cardiac, respiratory and nervous system causes, but not with metabolic or psychiatric causes of death. In particular, mortality from nervous diseases increased by 4.55% (95% CI: 2.51-6.63) and 9.64% (95% CI: 5.76-13.65) for increments of 10 µg/m3 in PM10 and PM2.5 (lag 0-5 days), respectively. NO2 was positively associated with respiratory (6.68% (95% CI: 1.04-12.62)) and metabolic (7.30% (95% CI: 1.03-13.95)) mortality for increments of 10 µg/m3 (lag 0-5). Higher associations with natural mortality were found among the elderly, while there were no differential effects between sex or between rural and urban areas. CONCLUSIONS: Short-term exposure to particulate matter was associated with mortality from nervous diseases. Mortality from metabolic diseases was associated with NO2 exposure. Other associations are confirmed and updated, including the contribution of lowly urbanised areas. Health effects were also found in suburban and rural areas.
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Contaminantes Atmosféricos , Contaminación del Aire , Humanos , Anciano , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Dióxido de Nitrógeno/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Material Particulado/toxicidad , Material Particulado/análisis , Ciudades/epidemiología , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , MortalidadRESUMEN
BACKGROUND: Despite being at higher risk of severe disease and pregnancy complications, evidence on susceptibility to SARS-CoV-2 infection in pregnancy is still limited. The aim of the study is to compare the likelihood of undergoing a SARS-CoV-2 test and testing positive for COVID-19 in pregnancy and puerperium with that of the general female population of reproductive age. METHODS: This is a retrospective population-based cohort study including 117,606 women of reproductive age (March 2020-September 2021) with 6608 (5.6%) women having ≥ 1 pregnancy. Women were linked to the pregnancy registry to be classified as "non-pregnant", "pregnant", and "puerperium"; then, according to the national case-based integrated COVID-19 surveillance system, all women undergoing a SARS-CoV-2 test during the study period were identified. The Incidence Rate Ratio was calculated to compare the likelihood of being tested for SARS-CoV-2 in pregnant, puerperium and non-pregnant women among all women included. The likelihood of having a COVID-19 diagnosis was calculated using two comparators (not-pregnant women and the person-time before/after pregnancy) by means of Cox proportional hazards models, adjusting for age and with the cluster option to control standard error calculation in repeated pregnancies. Only first infection and swabs before the first one positive were included. RESULTS: The probability of being tested for SARS-CoV-2 was 4.9 (95% CI: 4.8-5.1) and 3.6 times higher (95%CI: 3.4-3.9) in pregnancy (including spontaneous miscarriages) and in the puerperium, respectively. The Hazard Ratio (HR) of covid-19 diagnosis during pregnancy vs. non-pregnancy was 1.17 (95% CI 1.03-1.33) with similar results when comparing the risk during pregnancy with that of the same women outside pregnancy (puerperium excluded), with an HR of 1.13 (95% CI 0.96-1.33); the excess decreased when excluding the test performed at admission for delivery (HR 1.08 (95%CI 0.90-1.30). In the puerperium, the HR was 0.62 (95% CI 0.41-0.92) comparing women with ≥ 1childbirth with all other women and excluding the first two weeks of puerperium. CONCLUSIONS: Women during pregnancy showed a small increase in the risk of infection, compatible with a higher likelihood of being tested. A lower probability of infection during the puerperium was observed during the entire pandemic period, suggesting likely protective behaviors which were effective in reducing their probability of infection.
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COVID-19 , Complicaciones Infecciosas del Embarazo , Embarazo , Femenino , Humanos , Masculino , COVID-19/diagnóstico , COVID-19/epidemiología , SARS-CoV-2 , Incidencia , Prueba de COVID-19 , Estudios Retrospectivos , Estudios de Cohortes , Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/epidemiologíaRESUMEN
BackgroundUnderstanding the epidemiology of reinfections is crucial for SARS-CoV-2 control over a long period.AimTo evaluate the risk of SARS-CoV-2 reinfection by vaccination status, predominant variant and time after first infection.MethodsWe conducted a cohort study including all residents in the Reggio Emilia province on 31 December 2019, followed up until 28 February 2022 for SARS-CoV-2 first infection and reinfection after 90 days. Cox models were used to compare risk of first infection vs reinfection, adjusting for age, sex, vaccine doses and comorbidities.ResultsThe cohort included 538,516 residents, 121,154 with first SARS-CoV-2 infections and 3,739 reinfections, most in the Omicron BA.1 period. In the pre-Omicron period, three doses of vaccine reduced risk of reinfection by 89% (95%â¯CI:â¯87-90), prior infection reduced risk by 90% (95%â¯CI:â¯88-91), while two doses and infection reduced risk by 98% (95%â¯CI:â¯96-99). In the Omicron BA.1 period, protection estimates were 53% (95%â¯CI:â¯52-55), 9% (95%â¯CI:â¯4-14) and 76% (95%â¯CI:â¯74-77). Before Omicron, protection from reinfection remained above 80% for up to 15 months; with Omicron BA.1, protection decreased from 71% (95%â¯CI:â¯65-76) at 5 months to 21% (95%â¯CI:â¯10-30) at 22 months from the first infection. Omicron BA.1 reinfections showed 48% (95%â¯CI:â¯10-57) lower risk of severe disease than first infections.ConclusionsNatural immunity acquired with previous variants showed low protection against Omicron BA.1. Combined vaccination and natural immunity seems to be more protective against reinfection than either alone. Vaccination of people with prior infection reduced the risk of severe disease.