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Immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy may vary substantially in their clinical presentation, including natural history, outcomes to treatment, and patterns. The application of clinical guidelines for irAE management can be challenging for practitioners due to a lack of common or consistently applied terminology. Furthermore, given the growing body of clinical experience and published data on irAEs, there is a greater appreciation for the heterogeneous natural histories, responses to treatment, and patterns of these toxicities, which is not currently reflected in irAE guidelines. Furthermore, there are no prospective trial data to inform the management of the distinct presentations of irAEs. Recognizing a need for uniform terminology for the natural history, response to treatment, and patterns of irAEs, the Society for Immunotherapy of Cancer (SITC) convened a consensus panel composed of leading international experts from academic medicine, industry, and regulatory agencies. Using a modified Delphi consensus process, the expert panel developed clinical definitions for irAE terminology used in the literature, encompassing terms related to irAE natural history (ie, re-emergent, chronic active, chronic inactive, delayed/late onset), response to treatment (ie, steroid unresponsive, steroid dependent), and patterns (ie, multisystem irAEs). SITC developed these definitions to support the adoption of a standardized vocabulary for irAEs, which will have implications for the uniform application of irAE clinical practice guidelines and to enable future irAE clinical trials.

ObjectiveTo provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs).MethodsThis guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation.ResultsThis guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence.ConclusionApplication of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

BACKGROUND. Immune-related adverse events (irAEs) and their associated morbidity/mortality are a key concern for patients receiving immune checkpoint inhibitors (ICIs). Prospective evaluation of the drivers of irAEs in a diverse pantumor cohort is needed to identify patients at greatest risk and to develop rational treatment and interception strategies. METHODS. In an observational study, we prospectively collected blood samples and performed regular clinical evaluations for irAEs in patients receiving ICI therapy as standard of care for solid tumors. We performed in-parallel analysis of cytokines by Luminex immunoassay and circulating immune cells by cytometry by time-of-flight (CyTOF) at baseline and on treatment to investigate mechanisms of irAEs. RESULTS. We enrolled 111 patients, of whom 40.5% developed a symptomatic irAE (grade > 2). Development of a grade [greater than or equal to] 2 irAE was positively associated with the use of combination ICI and a history of an autoimmune disorder. Early changes in T helper 17 (Th17) (IL-6, IL-17f), type 2 (IL-5, IL-13, IL-25), and type 1 (TNF-[alpha]) cytokine signatures and congruent ontreatment expansions of Th17 and Th2 effector memory (Th2EM) T cell populations in peripheral blood were positively associated with the development of grade [greater than or equal to]2 irAEs. IL-6 levels were also associated with inferior cancer-specific survival and overall survival. CONCLUSIONS. In a diverse, prospective pan-tumor cohort, Th17 and Th2 skewing during early ICI treatment was associated with the development of clinically relevant irAEs but not antitumor responses, providing possible targets for monitoring and therapeutic interventions. FUNDING. Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, the NCI SPORE in Gastrointestinal Cancers (P50 CA062924), NCI grant (R50CA243627 to LD), the NIH Center Core Grant (P30 CA006973), Swim Across America (to MY), NIAMS (K23AR075872 to LC), and imCORE-Genentech grant 137515 (to Johns Hopkins Medicine on behalf of MY)., Introduction Immune checkpoint inhibitors (ICIs) can prolong life for patients with many types of cancers and have become firmly established as a major pillar of contemporary cancer care. However, these [...]

As a result of the COVID-19 pandemic, medical education institutions were suddenly and unexpectedly faced with making significant changes in delivering their clinical assessments to comply with social distancing requirements and limited access to clinical education centres. Seeking a potential solution to these new circumstances, we designed, implemented and evaluated an online virtual OSCE, as a 'proof of concept' intervention study. Our qualitative research involved document analysis of the stages of decision-making and consultation in designing the intervention, and thematic analysis based on the perspectives and experiences of the key stakeholders (final year students, clinical examiners, simulated patients and faculty staff who acted as station assistants), gathered through surveys with Likert-scale questions and free text comments, and online discussion groups which were recorded and transcribed. From our analysis, we identified four themes: optimising assessment design for online delivery, ensuring clinical authenticity, recognising and addressing feelings and apprehensions, and anticipating challenges through incident planning and risk mitigation. Through the data gathered at each stage of the intervention, and the involvement of key stakeholders in the design and evaluation, our study highlights examples of effective practice for future applications of online technologies in assessment, provides guidance for designing and implementing online virtual assessment, and lays a foundation for comparative, longitudinal research on the significant and increasing roles played by technology in healthcare professional education and practice.

As Confissões de Agostinho compõem-se de um conjunto de escritos do hiponense que marcam a espiritualidade ocidental. Os grandes mestres espirituais do Ocidente, devedores à língua latina e à teologia agostiniana, tratam as Confissões como um arquétipo do itinerário humano que se resume na complexa trajetória existencial que visa o desfrute de Deus; isto é, a Contemplatio Dei, como comumente expresso nas narrativas místicas. Concebida desse modo e servindo de inspiração à espiritualidade ocidental, as Confissões de Agostinho, ainda hoje, fornecem variadas perspectivas de análise e um rico material para reflexão. Por isso, este artigo objetiva trazer ao cenário crescente das discussões acerca da mística no Brasil a plausibilidade de tomar as Confissões hermeneuticamente como uma narrativa mística dotada de profundo caráter existencial que se expressa, sobretudo, no X Livro. Tomando o Livro X das Confissões como síntese de um percurso místico que é retratado no conjunto da obra, intenta-se realizar uma leitura hermenêutico-fenomenológica do texto colocando em evidência a Inquietatio Animi como uma das caraterísticas fundamentais para a compreensão do que vem a ser a mística em Agostinho de Hipona. Para isso, realizar-se-ão breves considerações sobre o conceito e as características da mística cristã que emergem de Agostinho, para, então, prosseguir com uma incursão direta na obra do autor, permitindo, na medida do possível, que Agostinho interprete a si mesmo para que, fenomenologicamente, possa emergir da obra em si a Inquietatio Animi como pressuposto e característica necessária da mística.

The CHIVA 2 strategy is a two-step surgical procedure for treating type III venous-venous shunts in the territory of the Greater Saphenous Vein (GSV). The first step consists of disconnecting the incompetent GSV tributary, either N3 or N4. Once a new N2 re-entry perforator vein has developed, or the GSV incompetence has reached the pre-existing N2 re-entry perforator vein, both documented by the re-appearance of GSV reflux during the follow-up, the second step of the CHIVA 2 strategy, i.e. the closure of the saphenous-femoral junction, can be performed. In this paper we addressed the intriguing question of whether it was possible to identify the pre-operative factors able to favourably affect the hemodynamic stability of type III shunts of the GSVs treated by the only first step of the CHIVA 2 strategy. Our data show that the pre-operative GSV anterograde flow, detectable all along the GSV course even soon after the first step of the procedure, plays a pivotal role in ensuring the hemodynamic stability of the treated GSV, which may not need the second step up to 45% of cases.

Background: The introduction of a noninvasive diagnostic algorithm in 2016 led to increased awareness and recognition of cardiac amyloidosis (CA). Objectives: The purpose of this study was to analyze the impact of the introduction of the noninvasive diagnostic algorithm on diagnosis and prognosis in a multicenter Italian CA cohort. Methods: This was a retrospective analysis of 887 CA patients from 5 Italian Cardiomyopathies Referral Centers: 311 light-chain CA, 87 variant transthyretin (TTR)-related CA, 489 wild-type TTR-related CA. Clinical characteristics and outcomes (all-cause mortality and heart failure [HF] hospitalizations) were compared overall and for each CA subtype between patients diagnosed before versus after 2016. Outcomes were further compared by propensity score weighted Kaplan-Meier analysis and Cox regression analysis. Results: CA diagnoses increased after 2016, in particular for wild-type TTR-related CA. Patients diagnosed after versus before 2016 were older, had less frequently a history of HF prior to diagnosis, and NYHA functional class III-IV at diagnosis. Over a median follow-up of 18 months, 172 (86%) patients diagnosed before 2016 died or had an HF hospitalization, versus 300 (44%) diagnosed after 2016. Propensity score weighted Kaplan-Meier analysis showed worse outcomes (P

The article explores the integration of the Digital Twin concept with Federated Learning techniques for monitoring critical infrastructure. This approach allows for local data processing and knowledge transfer between different infrastructures, minimizing the amount of data sent to the cloud. Benefits include enhanced data security, operational efficiency, and more proactive maintenance. Through practical examples, it demonstrates how these technologies can revolutionize the management of critical infrastructure.

Improving the synchronization between the pattern of milk synthesis and nutrient availability throughout the day could enhance production efficiency. In this study, we evaluated the effects of changing feed delivery time on milk production, feeding behavior, and the daily rhythms of blood biomarkers. Eight multiparous Holstein cows housed in a tie-stall barn with controlled environmental conditions were enrolled in a crossover experimental design with three periods of 14 days and three treatments each. Cows were milked twice daily (0530 and 1730 h) and were individually fed with two equal meals of forage and eight equal meals of concentrate during the day. Forage meals were provided at 12-hour intervals either: (i) 5 h before each milking (0030 and 1230 h; BM), (ii) at the end of each milking (0530 and 1730 h; ME), (iii) or 2 h after (0730 and 1930 h; AM). Feed intake and feeding behavior were monitored, and milk production and composition were measured. Blood samples were collected every 4 days at 0700 h and, during the last day of each period, 15 times daily to determine metabolic profiles, hormones, and their daily rhythmicity by the cosinor analysis. Changing forage delivery time did not affect milk yield and dry matter intake. No difference was observed in feeding behavior when expressed relative to the first meal. There were no significant differences in milk component contents and yields. In samples collected at 0700 h, ME had reduced plasma calcium (Ca), magnesium (Mg), and potassium (K) and increased sodium (Na). AM had increased inflammation, as suggested by the greater blood globulin and ceruloplasmin. The patterns of metabolic biomarkers had limited variations when expressed relative to the first forage meal. Nevertheless, the daily rhythms of these biomarkers were remarkably different. Under our conditions, feeding forage meals to cows at different times of the day did not influence productive performance but highlighted the importance of considering the sampling time when interpreting metabolic profiles.

In this contribution we present the achievements of the CUORE experiment so far. It is the first tonne-scale bolometric detector and it is in stable data taking since 2018. We reached to collect about 1800 kg×yr of exposure of which more than 1 ton×year have been analysed. The CUORE detector is meant to search for the neutrinoless double β decay (0νββ) of the 130Te isotope. This is a beyond Standard Model process which could establish the nature of the neutrino to be Dirac or a Majorana particle. It is an alternative mode of the two-neutrinos double β decay, a rare decay which have been precisely measured by CUORE in the 130Te. We found no evidence of the 0νββ and we set a Bayesian lower limit of 2.2 ×1025yr on its half-life. The expertise achieved by CUORE set a milestone for any future bolometric detector, including CUPID, which is the planned next generation experiment searching for 0νββ with scintillating bolometers.

The Cryogenic Underground Observatory for Rare Events (CUORE) is the first cryogenic experiment searching for 0 νββ decay that has been able to reach the one-tonne mass scale. The detector, located at the Laboratori Nazionali del Gran Sasso (LNGS) in Italy, consists of an array of 988 TeO 2 crystals arranged in a compact cylindrical structure of 19 towers. CUORE began its first physics data run in 2017 at a base temperature of about 10 mK and in April 2021 released its 3 rd result of the search for 0 νββ, corresponding to a tonne-year of TeO 2 exposure. This is the largest amount of data ever acquired with a solid state detector and the most sensitive measurement of 0 νββ decay in 130Te ever conducted. We present the current status of CUORE search for 0 νββ with the updated statistics of one tonne-yr. We finally give an update of the CUORE background model and the measurement of the 130Te 2 νββ decay half-life and decay to excited states of 130Xe , studies performed using an exposure of 300.7 kg yr.

The CUORE experiment is a ton-scale array of TeO 2 cryogenic bolometers located at the underground Laboratori Nazionali del Gran Sasso of Istituto Nazionale di Fisica Nucleare (INFN), in Italy. The CUORE detector consists of 988 crystals operated as source and detector at a base temperature of ∼ 10 mK. Such cryogenic temperature is reached and maintained by means of a custom built cryogen-free dilution cryostat, designed with the aim of minimizing the vibrational noise and the environmental radioactivity. The primary goal of CUORE is the search for neutrinoless double beta decay of 130Te , but thanks to its large target mass and ultra-low background it is suitable for the study of other rare processes as well, such as the neutrinoless double beta decay of 128Te. This tellurium isotope is an attractive candidate for the search of this process, due to its high natural isotopic abundance of 31.75%. The transition energy at (866.7 ± 0.7) keV lies in a highly populated region of the energy spectrum, dominated by the contribution of the two-neutrino double beta decay of 130Te. As the first ton-scale infrastructure operating cryogenic TeO 2 bolometers in stable conditions, CUORE is able to achieve a factor > 10 higher sensitivity to the neutrinoless double beta decay of this isotope with respect to past direct experiments.

CUORE Upgrade with Particle IDentification (CUPID) is a foreseen ton-scale array of Li2MoO4 (LMO) cryogenic calorimeters with double readout of heat and light signals. Its scientific goal is to fully explore the inverted hierarchy of neutrino masses in the search for neutrinoless double beta decay of 100Mo. Pile-up of standard double beta decay of the candidate isotope is a relevant background. We generate pile-up heat events via injection of Joule heater pulses with a programmable waveform generator in a small array of LMO crystals operated underground in the Laboratori Nazionali del Gran Sasso, Italy. This allows to label pile-up pulses and control both time difference and underlying amplitudes of individual heat pulses in the data. We present the performance of supervised learning classifiers on data and the attained pile-up rejection efficiency.