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Study objectiveExcessive daytime sleepiness is common with obstructive sleep apnoea and can persist despite efforts to optimise primary airway therapy. The literature lacks recommendations regarding differential diagnosis and management of excessive daytime sleepiness in obstructive sleep apnoea. This study sought to develop expert consensus statements to bridge the gap between existing literature/guidelines and clinical practice.MethodsA panel of 10 international experts was convened to undertake a modified Delphi process. Statements were developed based on available evidence identified through a scoping literature review, and expert opinion. Consensus was achieved through 3 rounds of iterative, blinded survey voting and revision to statements until a predetermined level of agreement was met (≥80 % voting "strongly agree" or "agree with reservation").ResultsConsensus was achieved for 32 final statements. The panel agreed excessive daytime sleepiness is a patient-reported symptom. The importance of subjective/objective evaluation of excessive daytime sleepiness in the initial evaluation and serial management of obstructive sleep apnoea was recognised. The differential diagnosis of residual excessive daytime sleepiness in obstructive sleep apnoea was discussed. Optimizing airway therapy (eg, troubleshooting issues affecting effectiveness) was addressed. The panel recognised occurrence of residual excessive daytime sleepiness in obstructive sleep apnoea despite optimal airway therapy and the need to evaluate patients for underlying causes.ConclusionsExcessive daytime sleepiness in patients with obstructive sleep apnoea is a public health issue requiring increased awareness, recognition, and attention. Implementation of these statements may improve patient care, long-term management, and clinical outcomes in patients with obstructive sleep apnoea.

Abstract Most autoinflammatory diseases are caused by mutations in innate immunity genes. Previously, four variants in the RHO GTPase CDC42 were discovered in patients affected by syndromes generally characterized by neonatal-onset of cytopenia and auto-inflammation, including hemophagocytic lymphohistiocytosis and rash in the most severe form (NOCARH syndrome). However, the mechanisms responsible for these phenotypes remain largely elusive. Here, we show that the recurrent p.R186C CDC42 variant, which is trapped in the Golgi apparatus, elicits a block in both anterograde and retrograde transports. Consequently, it favours STING accumulation in the Golgi in a COPI-dependent manner. This is also observed for the other Golgi-trapped p.*192 C*24 CDC42 variant, but not for the p.Y64C and p.C188Y variants that do not accumulate in the Golgi. We demonstrate that the two Golgi-trapped CDC42 variants are the only ones that exhibit overactivation of the STING pathway and the type I interferon response, and elicit endoplasmic reticulum stress. Consistent with these results, patients carrying Golgi-trapped CDC42 mutants present very high levels of circulating IFNα at the onset of their disease. In conclusion, we report further mechanistic insights on the impact of the Golgi-trapped CDC42 variants. This increase in STING activation provides a rationale for combination treatments for these severe cases.

Abstract Background Artificial intelligence (AI) has become a popular tool for clinical and research use in the medical field. The aim of this study was to evaluate the accuracy and reliability of a generative AI tool on pediatric familial Mediterranean fever (FMF). Methods Fifteen questions repeated thrice on pediatric FMF were prompted to the popular generative AI tool Microsoft Copilot with Chat-GPT 4.0. Nine pediatric rheumatology experts rated response accuracy with a blinded mechanism using a Likert-like scale with values from 1 to 5. Results Median values for overall responses at the initial assessment ranged from 2.00 to 5.00. During the second assessment, median values spanned from 2.00 to 4.00, while for the third assessment, they ranged from 3.00 to 4.00. Intra-rater variability showed poor to moderate agreement (intraclass correlation coefficient range: -0.151 to 0.534). A diminishing level of agreement among experts over time was documented, as highlighted by Krippendorff’s alpha coefficient values, ranging from 0.136 (at the first response) to 0.132 (at the second response) to 0.089 (at the third response). Lastly, experts displayed varying levels of trust in AI pre- and post-survey. Conclusions AI has promising implications in pediatric rheumatology, including early diagnosis and management optimization, but challenges persist due to uncertain information reliability and the lack of expert validation. Our survey revealed considerable inaccuracies and incompleteness in AI-generated responses regarding FMF, with poor intra- and extra-rater reliability. Human validation remains crucial in managing AI-generated medical information.

BackgroundFever is a common symptom in children, but despite existing guidelines, pediatricians may not fully apply recommendations. Fever of Unknown Origin (FUO) is generally referred to as an unexplained prolonged fever. However, a standardized FUO definition and management is missing.ObjectiveTo collect updated data on the approach to fever and FUO among Italian pediatricians.MethodsA cross-sectional anonymous survey was conducted among a large sample of primary care and hospital pediatricians. The panel group formulated and proposed a practical FUO definition, using a modified Delphi approach. A 75% consensus was required to reach an agreement.ResultsAmong 620 respondents, paracetamol was the first-choice antipyretic for 97.7% of participants, followed by ibuprofen; 38.4% prescribed antipyretics based on a specific body temperature rather than on child's discomfort, while physical methods were almost completely abandoned. Alternate treatment was recommended by 19.8% (123/620) of participants, 16.9% (105/620) would prescribe antipyretics to prevent adverse events following immunization. Regarding FUO diagnosis, 58.3% (362/620) considered as cut-off a body temperature above 38°C; the duration required was one week according to 36.45% (226/620) of participants, two weeks according to 35.32% (219/620). The FUO definition proposed by the expert panel reached 81% of consent. Large agreement was observed on first-level laboratory and instrumental investigations in the diagnostic evaluation of FUO, whereas more discrepancies arose on second and third-level investigations. Compared to what participants reported for the treatment of non-prolonged fever, a significant decrease in the prescription of paracetamol as first-choice drug in children with FUO was observed (80.5%; P

Bilateral robotic rehabilitation has proven helpful in the recovery of upper limb motor function in patients with stroke, but its effects on the cortical reorganization mechanisms underlying recovery are still unclear. This pilot Randomized Controlled Trial (RCT) aimed to evaluate the effects on the interhemispheric balance of unilateral or bilateral robotic treatments in patients with subacute stroke, using Quantitative Electroencephalography (qEEG). 19 patients with ischemic stroke underwent a 30-session upper limb neurorehabilitation intervention using a bilateral upper limb exoskeleton. Each patient was randomly assigned to the bilateral (BG, n=10) or unilateral treatment group (UG, n=9). EEG evaluations were performed before (T0) and right after (T $0+\text {)}$ the first treatment session, after 30 treatment sessions (T1), and at 1-week follow-up (T2), in both eyes open and eyes closed conditions. From the acquired EEG data, the pairwise-derived Brain Symmetry Index (pdBSI) was computed. In addition, clinical evaluation was performed at T0 and T1 with validated clinical scales. After the treatment, a significant improvement in clinical and EEG evaluations was observed for both groups, but only the BG showed reduced pdBSI in delta and theta bands. In the cluster of sensorimotor channels, there was no significant difference between groups. The observed changes were not maintained at follow-up. No significant changes were observed in the pdBSI after a single rehabilitation session. Results suggest that balancing of interhemispheric symmetry comes along with a clinical improvement in the upper extremity and that the pdBSI can be used to investigate the mechanisms of neuronal plasticity involved in robotic rehabilitation after stroke.

Staphylococcus aureus (S. aureus) is a Gram-positive bacterium that causes infections ranging from mild superficial cases to more severe, potentially fatal conditions. Many photosensitisers used in photodynamic therapy are more effective against superficial infections due to limitations in treating deeper tissue infections. Recently, attention to this bacterium has increased due to the emergence of multidrug-resistant strains, which complicate antibiotic treatment. As a result, alternative therapies, such as antimicrobial photodynamic therapy (PDT), have emerged as promising options for treating non-systemic infections. PDT combines a photosensitiser (PS) with light and oxygen to generate free radicals that destroy bacterial structures. This systematic review evaluates the effectiveness of PDT delivered via different types of hydrogels in treating wounds, burns, and contamination by S. aureus. Following PRISMA 2020 guidelines, a bibliographic search was conducted in PubMed, Web of Science, and Scopus databases, including articles published in English between 2013 and 2024. Seven relevant studies were included, demonstrating evidence of PDT use against S. aureus in in vitro and in vivo studies. We concluded that PDT can effectively complement antimicrobial therapy in the healing of wounds and burns. The effectiveness of this technique depends on the PS used, the type of hydrogel, and the lesion location. However, further in vivo studies are needed to confirm the safety and efficacy of PDT delivered via hydrogels.

Background/Objectives: Finding innovative digital solutions is fundamental to ensure prompt and continuous care for patients with chronic neurological disorders, whose demand for rehabilitation also in home-based settings is steadily increasing. The aim is to verify the safety and the effectiveness of two telerehabilitation (TR) models in improving recovery from subacute upper limb (UL) disability after stroke, with and without a robotic device. Methods: One hundred nineteen subjects with subacute post-stroke UL disability were assessed for eligibility. Of them, 30 patients were enrolled in the study and randomly assigned to either the Robotic Group (RG), undergoing a 20-session TR program, using a robotic device, or the Non-Robotic Group (NRG), undergoing a 20-session TR program without robotics. Clinical evaluations were measured at baseline (T0) and post-intervention (T1, 5 weeks after baseline), and included assessments of quality of life, motor skills, and clinical/functional status. The primary outcome measure was the World Health Organization Disability Assessment Schedule 2.0, evaluating the change in perceived disability. Results: Statistical analysis shows that patients of both groups improved significantly over time in all domains analyzed (mean decrease from baseline in the WHODAS 2.0 of 6.09 ± 2.62% for the NRG, and of 0.76 ± 2.21% for the RG), with a greater improvement of patients in the NRG in motor (Fugl-Meyer Assessment Upper Extremity—motor function, Box and Block Test) and cognitive skills (Trail Making Test-A). Conclusions: This study highlights the potential of TR programs to transform stroke rehabilitation by enhancing accessibility and patient-centered care, promoting autonomy, improving adherence, and leading to better outcomes and quality of life for stroke survivors.

Chronic respiratory diseases often necessitate lung transplantation due to irreversible damage. Organ engineering offers hope through stem cell-based organ generation. However, the crucial sterilization step in scaffold preparation poses challenges. This study conducted a systematic review of studies that analysed the extracellular matrix (ECM) conditions of decellularised lungs subjected to different sterilisation processes. A search was performed for articles published in the PubMed, Web of Sciences, Scopus, and SciELO databases according to the PRISMA guidelines. Overall, five articles that presented positive results regarding the effectiveness of the sterilisation process were selected, some of which identified functional damage in the ECM. Was possible concluded that regardless of the type of agent used, physical or chemical, all of them demonstrated that sterilisation somehow harms the ECM. An ideal protocol has not been found to be fully effective in the sterilisation of pulmonary scaffolds for use in tissue and/or organ engineering.

Chronic respiratory diseases often necessitate lung transplantation due to irreversible damage. Organ engineering offers hope through stem cell-based organ generation. However, the crucial sterilization step in scaffold preparation poses challenges. This study conducted a systematic review of studies that analysed the extracellular matrix (ECM) conditions of decellularised lungs subjected to different sterilisation processes. A search was performed for articles published in the PubMed, Web of Sciences, Scopus, and SciELO databases according to the PRISMA guidelines. Overall, five articles that presented positive results regarding the effectiveness of the sterilisation process were selected, some of which identified functional damage in the ECM. Was possible concluded that regardless of the type of agent used, physical or chemical, all of them demonstrated that sterilisation somehow harms the ECM. An ideal protocol has not been found to be fully effective in the sterilisation of pulmonary scaffolds for use in tissue and/or organ engineering.

ObjectiveInflammation has been associated with an increased risk for cancer development, while innate immune system activation could counteract the risk for malignancies. Familial Mediterranean fever (FMF) is a severe systemic inflammatory condition and also represents the archetype of innate immunity deregulation. Therefore, the aim of this study is to investigate the risk for cancer development in FMF.MethodsThe risk ratio (RR) for malignancies was separately compared between FMF patients and fibromyalgia subjects, Still’s disease patients and Behçet’s disease patients. Clinical variables associated with cancer development in FMF patients were searched through binary logistic regression.Results580 FMF patients and 102 fibromyalgia subjects, 1012 Behçet’s disease patients and 497 Still’s disease patients were enrolled. The RR for the occurrence of malignant neoplasms was 0.26 (95% Confidence Interval [CI.] 0.10-0.73, p=0.006) in patients with FMF compared to fibromyalgia subjects; the RR for the occurrence of malignant cancer was 0.51 (95% CI. 0.23-1.16, p=0.10) in FMF compared to Still’s disease and 0.60 (95% CI. 0.29-1.28, p=0.18) in FMF compared to Behçet’s disease. At logistic regression, the risk of occurrence of malignant neoplasms in FMF patients was associated with the age at disease onset (β1 = 0.039, 95% CI. 0.001-0.071, p=0.02), the age at the diagnosis (β1 = 0.048, 95% CI. 0.039-0.085, p=0.006), the age at the enrolment (β1 = 0.05, 95% CI. 0.007-0.068, p=0.01), the number of attacks per year (β1 = 0.011, 95% CI. 0.001- 0.019, p=0.008), the use of biotechnological agents (β1 = 1.77, 95% CI. 0.43-3.19, p=0.009), the use of anti-IL-1 agents (β1 = 2.089, 95% CI. 0.7-3.5, p=0.002).ConclusionsThe risk for cancer is reduced in Caucasic FMF patients; however, when malignant neoplasms occur, this is more frequent in FMF cases suffering from a severe disease phenotype and presenting a colchicine-resistant disease.

Background Rilonacept, a once‐weekly interleukin‐1 alpha and beta cytokine trap, reduced pericarditis recurrence in the phase 3 study, RHAPSODY (Rilonacept Inhibition of Interleukin‐1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study). The RHAPSODY long‐term extension further explored recurrent pericarditis natural history and treatment duration decision‐making during 24 additional months of open‐label rilonacept treatment. Methods and Results Seventy‐four patients commenced the long‐term extension, with a median (maximum) total rilonacept duration of 22 (35) months. Individually, 18 months after the most proximal pericarditis recurrence, investigators decided to continue rilonacept on study, suspend rilonacept for off‐treatment observation (rescue allowed), or discontinue the study. The annualized incidence of pericarditis recurrence on rilonacept up to the 18‐month decision milestone was 0.04 events/patient‐year versus 4.4 events/patient‐year prestudy while on oral therapies. At the 18‐month decision milestone, 64% (33/52) continued rilonacept, 15% (8/52) suspended rilonacept for observation, and 21% (11/52) discontinued the study. Among the 33 patients (1/33; 3.0%) continuing rilonacept (median time to recurrence could not be estimated due to too few events), a single recurrence occurred 4 weeks after a treatment interruption. Among patients suspending rilonacept, 75% (6/8) experienced recurrence (median time to recurrence, 11.8 weeks [95% CI, 3.7 weeks to not estimable]). There was a 98% reduction in risk of pericarditis recurrence among patients continuing rilonacept treatment after the 18‐month decision milestone versus those suspending treatment for observation (hazard ratio, 0.02; P

Abstract Background Ataxia-telangiectasia (A-T) is a rare autosomal recessive DNA repair disorder, characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, recurrent sinopulmonary infections, radiation sensitivity, premature aging and predisposition to cancer. Although the association with autoimmune and chronic inflammatory conditions such as vitiligo, thrombocytopenia and arthritis has occasionally been reported, an onset with articular involvement at presentation is rare. Case presentation We herein report the case of a 7-year-old Caucasian girl who was admitted to the Rheumatology Department with a history of febrile chough and polyarthritis which led initially to the suspicion of an autoinflammatory disease. She had overt polyarthritis with knees deformities and presented with severe pneumonia. A chest Computed Tomography (CT) scan showed bilateral bronchiectasis, parenchymal consolidation and interstitial lung disease; rheumatoid factor and type I interferon signature resulted negative, therefore excluding COatomer Protein subunit Alpha (COPA) syndrome. A diagnosis of sarcoidosis had been suspected based on histological evidence of granulomatous liver inflammation, but ruled out after detecting normal angiotensin converting enzyme and chitotriosidase blood levels. Based on her past medical history characterized by at least six episodes of pneumonia in the previous 4 years, immunological phenotyping was performed. This showed complete IgA and IgE deficiency with defective antigen-specific antibodies to Pneumococcal, Tetanus toxin and Hemophilus Influenzae B vaccines. Additionally, low numbers of B cells and recent thymic emigrants (RTE) were found (CD4Ra 1.4%), along with a low CD4+/CD8 + T cells ratio (

Systemic autoinflammatory diseases (SAIDs) are disorders of innate immunity, which are characterized by unprovoked recurrent flares of systemic inflammation often characterized by fever associated with clinical manifestations mainly involving the musculoskeletal, mucocutaneous, gastrointestinal, and nervous systems. Several conditions also present with varied, sometimes prominent, involvement of the vascular system, with features of vasculitis characterized by variable target vessel involvement and organ damage. Here, we report a systematic review of vasculitis and vasculopathy associated with inborn errors of immunity.