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Omega-3 polyunsaturated fatty acids (PUFAs) represent valuable dietary adjuncts for subjects with hypertriglyceridemia and at increased risk of cardiovascular disease, including subjects with type 1 diabetes (T1D). However, the exact role of omega-3 PUFAs in the regulation of glucose homeostasis and chronic complications in patients with diabetes remains uncertain. Herein, we report a 3-year follow-up of an athlete adolescent with T1D who started to use continuous glucose monitoring (CGM) two years after the diagnosis, and initiated omega-3 PUFA supplementation four years after the clinical onset of T1D. CGM metrics related to a 18-month period of omega-3 PUFA supplementation (50 mg/Kg/day of EPA and DHA) was compared to CGM metrics referring to a 18-month period prior to the nutrition intervention. Omega-3 PUFA supplementation resulted in a significant reduction of mean glucose and glucose variability, along with a significant increase in Time in range (TIR) 70-180 mg/dL. No significant changes were observed in daily insulin requirements between the two study periods. Future studies will be of assistance to better understand the exact impact of omega-3 PUFAs on the regulation of glucose homeostasis in patients with type 1 and its complications.

The coronavirus SARS-CoV-2 is cause of a global pandemic of a pneumonia-like disease termed Coronavirus Disease 2019 (COVID-19). COVID-19 presents a high mortality rate, estimated at 3.4%. More than 1 out of 4 hospitalized COVID-19 patients require admission to an Intensive Care Unit (ICU) for respiratory support, and a large proportion of these ICU-COVID-19 patients, between 17% and 46%, have died. In these patients COVID-19 infection causes an inflammatory response in the lungs that can progress to inflammation with cytokine storm, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), thromboembolic events, disseminated intravascular coagulation, organ failure, and death. Mesenchymal Stem Cells (MSCs) are potent immunomodulatory cells that recognize sites of injury, limit effector T cell reactions, and positively modulate regulatory cell populations. MSCs also stimulate local tissue regeneration via paracrine effects inducing angiogenic, anti-fibrotic and remodeling responses. MSCs can be derived in large number from the Umbilical Cord (UC). UC-MSCs, utilized in the allogeneic setting, have demonstrated safety and efficacy in clinical trials for a number of disease conditions including inflammatory and immune-based diseases. UC-MSCs have been shown to inhibit inflammation and fibrosis in the lungs and have been utilized to treat patients with severe COVID-19 in pilot, uncontrolled clinical trials, that reported promising results. UC-MSCs processed at our facility have been authorized by the FDA for clinical trials in patients with an Alzheimer’s Disease, and in patients with Type 1 Diabetes (T1D). We hypothesize that UC-MSC will also exert beneficial therapeutic effects in COVID-19 patients with cytokine storm and ARDS. We propose an early phase controlled, randomized clinical trial in COVID-19 patients with ALI/ARDS. Subjects in the treatment group will be treated with two doses of UC-MSC (100 x 106 cells). The first dose will be infused within 24 hours following study enrollment. A second dose will be administered 72 ± 6 hours after the first infusion. Subject in the control group will receive infusion of vehicle (DPBS supplemented with 1% HSA and 70 U/kg unfractionated Heparin, delivered IV) following the same timeline. Subjects will be evaluated daily during the first 6 days, then at 14, 28, 60, and 90 days following enrollment (see Schedule of Assessment for time window details). Safety will be determined by adverse events (AEs) and serious adverse events (SAEs) during the follow-up period. Efficacy will be defined by clinical outcomes, as well as a variety of pulmonary, biochemical and immunological tests. Success of the current study will provide a framework for larger controlled, randomized clinical trials and a means of accelerating a possible solution for this urgent but unmet medical need. The proposed early phase clinical trial will be performed at the University of Miami (UM), in the facilities of the Diabetes Research Institute (DRI), UHealth Intensive Care Unit (ICU) and the Clinical Translational Research Site (CTRS) at the University of Miami Miller School of Medicine and at the Jackson Memorial Hospital (JMH).

Type 1 diabetes, which affects 1.25 million American children and adults, and more than 20 million people around the world, is a challenging chronic disease caused by the body’s inability to make insulin. Among its most severe forms is brittle diabetes. People with brittle diabetes frequently experience large swings in blood sugar that can quickly move from too high to too low or vice versa. Severely low blood sugar, called hypoglycemia, can cause sudden and unexpected seizures, coma, heart attacks, and even death. Insulin is the main treatment for this common disease. But it isn’t a cure. A type of cell transplant that comes close to a cure for some people with type 1 diabetes, a technique pioneered and tested in the United States, is now available in many countries but is still deemed an experimental procedure in the U.S., making it almost impossible to get. More than a decade ago, the United Kingdom’s National Health Service approved islet cell transplantation for type 1 diabetes — an approval based on an extensive review of the evidence generated by clinical trials conducted in the United States. Our federal dollars supported that research, and this treatment ought to be available to U.S. citizens. Islet cell transplantation is not a panacea for all forms of type 1 diabetes. And transplantation of any organ, including islet cells, requires the use of anti-rejection drugs that can have a range of adverse side effects. Nevertheless, individuals with severe brittle diabetes who are fully informed of the risks and benefits should have the ability to access this lifesaving treatment option. We fully understand the FDA’s efforts to rein in companies marketing unapproved stem cell products that have little or no evidence to support their use and that may put patients at risk. Yet the FDA should stay equally focused on its commitment to approving evidence-based transformative treatments for devastating diseases and conditions, including brittle diabetes.

Background: Wolfram Syndrome 1 (WS1) has been characterized on the basis of mutation in the WFS1 gene encoding a calcium storage wolframin endoplasmatic reticulum transmembrane glycoprotein. Patients and Methods: We observed a WS 10-years old female subject, with Type 1 diabetes-mellitus (DM), that had compound heterozygous WSF1 mutations but without other symptoms generally observed in WS subjects, such as optic atrophy or neurodegeneration. Results: Decreased copper, ceruloplasmin, and transferrin levels, pointing to a copper deficiency, were associated with a new c.1870-3A>G mutation in the ATP7B gene, while lower calcium levels were associated with WSF1 mutations. An omega-3 fatty acids therapy was administrated to the subject in the attempt to ameliorate diabetes symptoms, restored copper deficiency, and normal calcium levels. Conclusions: This specific case report provides new insights into the potential interplay of ATP7B mutation in shaping a milder WS clinical picture.

Chronic inflammation has been linked to the progression of type 1 diabetes (T1D). Supplementation with vitamin D and omega-3 fatty acids, which have anti-inflammatory properties, may slow or stop the progression of T1D. A field study is underway to assess the relationship between these nutrients and T1D progression among auto-antibody positive individuals who have not been diagnosed with T1D. The T1D Prevention Field Study is currently recruiting participants to complete online health surveys and home blood-spot tests for 25-hydroxyvitamin D [25(OH)D], Omega-3 Index, AA:EPA Ratio, high-sensitivity C-reactive protein, and HbA1c every three to four months for 5 years. Participants (or their parents/guardians) are given information about the importance of achieving a 25(OH)D level between 40-60 ng/ml and an AA:EPA Ratio between 1.5-3.0 to reduce inflammation. However, participants are free to choose their own supplement or dietary regimens. Data analysis will focus on associations between vitamin D and omega-3 status and progression of T1D. Initial enrollment in the T1D Prevention Field Study includes 103 participants from fifteen countries; total enrollment is expected to reach at least 400 participants by the end of 2022. The field study approach allows for cost-effective research that capitalizes on new technologies for recruitment, data collection, and blood level testing from home. However, some challenges have arisen. Many individuals are reading the open source protocols and some choose to supplement and test on their own so incentives may be needed to increase enrollment. Additionally, some participants do not have access to auto-antibody testing or are unable to get access to their test results; therefore, there is a need to provide blood spot auto-antibody testing through the field study.

Previous studies in humans with type 1 diabetes mellitus (T1D) and in nonobese diabetic mice have investigated the beneficial immunomodulatory potential of aerobic physical activity. Performing high volume of aerobic exercise may favorably regulate autoimmunity in diabetes. We tested whether increased physical activity is a self-sufficient positive factor in T1D subjects. During a 3-month observational period, active (six males; 40.5 ± 6.1 years; BMI: 24.5 ± 2.1) and sedentary (four males, three females; 35.9 ± 8.9 years; BMI: 25.7 ± 3.8) T1D individuals on insulin pump therapy were studied for metabolic, inflammatory, and autoimmune parameters. At baseline and at the end of a 3-month period, glycosylated hemoglobin (HbA1c), autoantibodies (anti-GAD, anti-ZnT8, anti-IA2, and ICA) and proinflammatory cytokines (IL-6 and TNF-α) were evaluated. During the third month of the period, physically active T1D patients showed a significant reduction in the average glucose levels (-9%, p = 0.025, by CGM) compared to the first month values, and even their hyperglycemic episodes (>180 mg/dl) diminished significantly (-24.2%, p = 0.032 vs. first month). Moreover, active T1D subjects exhibited an improved body composition with respect to sedentary controls. No significant changes were detected as to the autoimmune and inflammatory profiles. This study confirms the beneficial role of physical exercise associated with insulin pump therapy in order to improve metabolic control in individuals with T1D. These preliminary positive observations need to be challenged in a prolonged interventional follow-up.

Giant cell arteritis (GCA), also known as temporal arteritis, is the most common form of vasculitis in the elderly. While initially described as involving the temporal arteries, GCA can also affect the aorta and its major branches. Despite the increased use of imaging modalities and the availability of temporal artery biopsy, diagnosing GCA remains challenging. GCA should be considered a spectrum, with diagnostic methodologies tailored to the prevalent symptoms. The sensitivity and specificity of different diagnostic approaches can vary depending on the clinical setting. Timing in diagnosing GCA is crucial to prevent serious complications, such as blindness and cerebrovascular ischemic events. While the prompt initiation of glucocorticoids (GCs) has reduced the incidence of major ischemic events, an uncertain diagnosis may expose the patient to unnecessary harm, such as complications from overtreatment or organ damage due to inadequate control of vasculitis. This narrative review will summarize the most widely available diagnostic techniques for GCA and outline our approach for cases where the diagnosis may be uncertain., Competing Interests: Declaration of competing interest none declared., (Copyright © 2025. Published by Elsevier B.V.)

Type 1 diabetes mellitus (T1DM) is a growing global health concern that affects approximately 8.5 million individuals worldwide. T1DM is characterized by an autoimmune destruction of pancreatic β cells, leading to a disruption in glucose homeostasis. Therapeutic intervention for T1DM requires a complex regimen of glycaemic monitoring and the administration of exogenous insulin to regulate blood glucose levels. Advances in continuous glucose monitoring and algorithm-driven insulin delivery devices have improved the quality of life of patients. Despite this, mimicking islet function and complex physiological feedback remains challenging. Pancreatic islet transplantation represents a potential functional cure for T1DM but is hindered by donor scarcity, variability in harvested cells, aggressive immunosuppressive regimens and suboptimal clinical outcomes. Current research is directed towards generating alternative cell sources, improving transplantation methods, and enhancing cell survival without chronic immunosuppression. This Review maps the progress in cell replacement therapies for T1DM and outlines the remaining challenges and future directions. We explore the state-of-the-art strategies for generating replenishable β cells, cell delivery technologies and local targeted immune modulation. Finally, we highlight relevant animal models and the regulatory aspects for advancing these technologies towards clinical deployment., Competing Interests: Competing interests: A.G. is a co-founder of Continuity Biosciences LLC, and an inventor of intellectual property licensed by the same company. A.J.G. is an inventor of intellectual property related to technologies for cell therapy in T1DM owned in part by the Georgia Tech Research Corporation, is a co-founder, sits on the Board of Directors, and owns equity interest in iTolerance Inc. H.S. is an inventor on a patent licensed by iTolerance Inc, is a co-founder of the Company, and serves on the scientific advisory board of the Company. M. Ma is a co-founder and equity holder of AvantGuard and Persista Bio. J.O. is co-founder, owns stock equity, and serves on the scientific advisory board of Regenerative Medical Solutions Inc., is a clinical trial investigator for Vertex Pharmaceuticals Inc., and is a member of DSMB for Sernova Corp. J.R.M. is an inventor on related patents and patent applications, was employed at Sana Biotechnology, and has stocks and options in Sana Biotechnology. T.A.D. is a scientific founder of Encellin Inc., a cell therapy device company. K.P. discloses interest in Procyon Technologies LLC. M.C.N. has a sponsored research agreement with Universal Cells Inc., and a patent licensed to Sernova Corp. H.A.R. holds patents in the regenerative medicine space and served as SAB member of Sigilon Therapeutics, Prellis Biologics and consults or consulted for Sigilon Therapeutics, Eli Lilly, Minutia, Guidepoint Global, Axon Advisors and Tolerance Bio. C.R. is scientific adviser to Novo Nordisk, Vertex Pharma and iTolerance, and is a founding scientist of Lipogems International and AION Healthspan. M.C.P. is scientific founder of Vicapsys Life Sciences Inc. All other authors declare no competing interests., (© 2024. Springer Nature Limited.)

Background: Vascular inflammation persists in temporal artery biopsy (TAB) of giant cell arteritis (GCA) patients even after prolonged glucocorticoid (GC) therapy. We aimed to evaluate the histological impact of adding tocilizumab (TCZ) to GCs., Methods: We enrolled all consecutive GCA patients with an inflammed TAB at diagnosis who were treated with TCZ and GCs for ≥6 months and followed from December 2017 to December 2023. Within 2 weeks, all patients underwent a second TAB, positron emission 18-fluorodeoxyglucose tomography/CT (PET/CT) and vessel colour Doppler ultrasonography (CDUS). Results were compared with pretreatment findings., Results: 13 patients repeated TAB after a median TCZ treatment of 2.4 years (Q1-Q3: 1.2-3.9 years). The first TAB showed transmural inflammation (TMI) in 11/13 patients (84.6%), inflammation limited to adventitia (ILA) in one patient (7.7%) and small vessel vasculitis (SVV) in another (7.7%). On repeated TABs, five patients (38.5%) still showed some degree of inflammation. Among the 11 patients with initial TMI, 2 had ILA, 1 had TMI, 1had SVV and 1 had vasa vasorum vasculitis at the second TAB. Nine patients had active vasculitis at baseline PET/CT, and three (33.3%) still showed activity at the last PET/CT, with a relevant reduction in mean PET vascular activity score (-6.5; 95% CI 1.54 to 11.45; p=0.017). The repeated quantitative CDUS revealed altered parameters suggestive of vasculitis in temporal arteries in about one-third of the patients., Conclusion: Our study, using pathological and imaging assessments, revealed that after TCZ and GCs, over one-third of patients still presented with vascular inflammation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Managing metabolism for optimal training, performance, and recovery in medium-to-high-level endurance runners involves enhancing energy systems through strategic nutrient intake. Optimal carbohydrate intake before, during, and after endurance running can enhance glycogen stores and maintain optimal blood glucose levels, influencing various physiological responses and adaptations, including transitory post-endurance inflammation. This randomized trial investigates the impact of a high-dose 2:1 maltodextrin-fructose supplementation to medium-to-high-level endurance runners immediately before, during, and after a 15 km run at 90% VO 2max intensity on post-exercise inflammatory stress., Methods: We evaluated inflammatory biomarkers and lipidomic profiles before the endurance tests and up to 24 h after. We focused on the effects of high-dose 2:1 maltodextrin-fructose supplementation on white blood cell count, neutrophil number, IL-6, cortisol, and CRP levels, as well as polyunsaturated fatty acids, ω-3 index, and AA/EPA ratio., Results: This supplementation significantly reduced inflammatory markers and metabolic stress. Additionally, it may enhance the post-activity increase in blood ω-3 fatty acid levels and reduce the increase in ω-6 levels, resulting in a lower trend of AA/EPA ratio at 24 h in the treated arm., Conclusions: Adequate carbohydrate supplementation may acutely mitigate inflammation during a one-hour endurance activity of moderate-to-high intensity. These effects could be beneficial for athletes engaging in frequent, high-intensity activities.

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Giant cell arteritis (GCA) is a common vasculitis affecting patients aged 50 and older. GCA leads to chronic inflammation of large/medium-sized vessel walls with complications such as permanent vision loss and risk of stroke and aortic aneurysms. Early diagnosis is crucial and relies on temporal artery biopsy (TAB) and ultrasound imaging of temporal and axillary arteries. However, these methods have limitations. Serum biomarkers as autoantibodies have been reported but with inconclusive data for their use in the clinical setting. Additionally, C-reactive protein and erythrocyte sedimentation rate are non-specific and limited in reflecting disease activity, particularly in patients treated with IL-6 inhibitors. This study aimed to identify serum autoantibodies as new diagnostic biomarkers for GCA using a human protein array., Methods: One commercial and one proprietary human protein array were used for antibody profiling of sera from patients with GCA (n=55), Takayasu (TAK n=7), and Healthy Controls (HC n=28). The identified candidate autoantigens were purified and tested for specific autoantibodies by ELISA., Results: Antibodies against two proteins, VSIG10L (V-Set and Immunoglobulin Domain Containing 10 Like) and DCBLD1 (discoidin), were identified and found to be associated with GCA, with an overall prevalence of 43-57%, respectively, and high specificity as individual antibodies. A control series of TAK sera tested negative., Conclusions: Detecting GCA-specific autoantibodies may offer a new, non-invasive tool for improving our diagnostic power in GCA. Even though cell-mediated immune responses are crucial for GCA pathogenesis, this finding opens the way for investigating the additional role of humoral immune responses in the disease.

Mesenchymal stem cells (MSCs) are a promising therapy to potentially treat diabetes given their potent anti-inflammatory and immune-modulatory properties. While these regenerative cells have shown considerable promise in cell culture, their clinical translation has been challenging. In part, this can be attributed to these cells not reaching the pancreas to exert their regenerative effects following conventional intravenous (IV) injection, with the majority of cells being trapped in the lungs in the pulmonary first-pass effect. In the present study, we will therefore examine whether direct delivery of MSCs to the pancreas via an intra-arterial (IA) injection can improve their therapeutic efficacy. Using a mouse model, in which repetitive low doses of STZ induced a gentle, but progressive, hyperglycemia, we tested bone marrow-derived MSCs (BM-MSCs) which we have shown are enriched with pro-angiogenic and immunomodulatory factors. In cell culture studies, BM-MSCs were shown to preserve islet viability and function following exposure to proinflammatory cytokines (IFN-γ, IL-1β, and TNF-α) through an increase in pAkt. When tested in our animal model, mice receiving IV BM-MSCs were not able to mitigate the effects of STZ, however those which received the same dose and batch of cells via IA injection were able to maintain basal and dynamic glycemic control, to similar levels as seen in healthy control animals, over 10 days. This study shows the importance of considering precision delivery approaches to ensure cell-based therapies reach their intended targets to enable them to exert their therapeutic effects., (© The Author(s) 2024. Published by Oxford University Press.)

Pathological studies have demonstrated that the adventitial layer is markedly thickened in Takayasu (TAK) as compared to large vessel giant cell arteritis (LV-GCA). An ultrasound (US) examination of the arterial vessels allows the determination of intima media thickness (IMT) and of adventitial layer thickness (extra media thickness (EMT)). No previous study has evaluated if there are differences in EMT thickness between TAK and LV-GCA. In this cross-sectional retrospective study of stored ultrasound (US) imaging, we have compared common carotid artery (CCA) EMT and IMT in a series of consecutive TAK and LV-GCA patients. US examination CCA IMT and EMT were significantly higher in TAK as compared to LV-GCA. With ROC curve analysis, we have found that an EMT > 0.76 mm has high sensitivity and specificity for TAK CCA examination. The percentage of CCA at EMT > 0.76 mm and the total arterial wall thickening were significantly higher in TAK group examinations. EMT thickness correlated with disease duration and IMT in the TAK group, as well as with the IMT and ESR values in the LV-GCA group. Upon multivariate logistic regression analysis, factors independently associated with TAK CCA were EMT > 0.76 mm and age. No significant variation in IMT and EMT could be demonstrated in subsequent US CCA examinations.

Systemic vasculitides comprise a collection of rare and heterogeneous disorders capable of impacting any organ and system, posing a considerable burden of mortality and comorbidity. As with previous annual reviews of this series, this review will offer a critical overview of the latest literature on pathogenesis, biomarkers, and treatment options in both small- and large-vessel vasculitis.

Objectives: To describe the clinical findings, response to therapy and course of patients with transmural eosinophilic infiltration at temporal artery biopsy (TAB)., Methods: The study consisted of a retrospective cohort of 254 consecutive GCA patients with evidence of transmural inflammation at TAB seen at the Santa Maria Nuova Hospital over a 28-year period. The findings of the 22 patients with eosinophilic infiltration (≥ 20 eosinophils/hpf) at TAB were compared with those of 232 patients without. Among these 232 patients, we sampled 42 GCA patients matched for age, sex and follow-up duration to the 22 with eosinophilic infiltration, to compare allergic manifestations., Results: GCA patients with eosinophilic infiltration compared to those without presented more frequently cranial symptoms (p = 0.052), headaches (p = 0.005), abnormalities of TAs at physical examination (p = 0.045), jaw claudication (p = 0.024), and systemic manifestations (p = 0.016) and had higher CRP levels at diagnosis (p = 0.001). Regarding histological lesions, a severe transmural inflammation, laminar necrosis and intraluminal acute thrombosis were more frequently observed in patients with eosinophilic infiltration (p = 0.066, p < 0.001, and p = 0.010, respectively). Long-term remission and flares were similar in the two groups. When 21 GCA patients with eosinophilic infiltration were compared to 42 without, blood eosinophilic counts at diagnosis were normal and no patients had evidence or developed allergic manifestations and/or clinical findings of systemic necrotizing vasculitis., Conclusion: Patients with transmural eosinophilic infiltration represent a subset of GCA with cranial disease and more severe inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Accurate clinical assessment of disease activity in Takayasu arteritis (TAK) can be challenging. 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) can directly measure vascular inflammation. This study details the development of a new type of disease activity index called the Takayasu's Arteritis Integrated Disease Activity Index (TAIDAI)., Methods: Clinical symptoms for TAIDAI were identified from a literature review. Each symptom was paired with FDG-PET findings in corresponding arterial territories. Constitutional symptoms were paired with acute phase reactant levels. One point was given for each clinical symptom paired with supporting FDG-PET or laboratory abnormalities and summed into the TAIDAI score. A TAIDAI of ≥1 defined active disease. To assess performance of TAIDAI, face validity, content validity, and sensitivity to change were evaluated within a prospective observational cohort study of patients with TAK., Results: Seventeen clinical symptoms were paired with imaging or laboratory abnormalities. In a cohort of 96 patients contributing 204 study visits, TAIDAI showed excellent sensitivity (96.3%) and good specificity (79.2%) compared to physician's clinical assessment. TAIDAI significantly correlated with physician global assessment, PET Vascular Activity Score, patient global assessment, and acute phase reactant levels. In patients treated with either tumor necrosis factor inhibitors or tocilizumab, a TAIDAI of 0 was achieved in 21 (91%) of 23 patients who met a predefined definition of clinical response., Conclusion: TAIDAI is new type of disease activity index in TAK in which clinical symptoms are integrated with specific laboratory and imaging findings. TAIDAI should be validated in future randomized controlled trials in TAK., (© 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objectives: To investigate potential associations between the two functional C-reactive protein (CRP) gene polymorphisms at position 3872C>T (rs1205) and 4741G>C (rs3093068) and susceptibility, clinical expression, laboratory and pathological findings, and outcomes of giant cell arteritis (GCA) in a Nothern Italian population., Methods: One hundred and seventy Italian patients with biopsy-proven GCA resident in Reggio Emilia area, Italy, and 200 healthy controls from the same geographic area were genotyped for rs1205 and rs3093068 CRP gene polymorphisms by molecular methods. The patients were subgrouped on the basis of the presence or absence of clinical manifestations, histological and laboratory findings, and outcomes., Results: The distribution of rs1205 genotype was significantly different between GCA patients and controls (p=0.018). Homozygosity for T allele was significantly more frequent in GCA patients compared to controls [p=0.006; odds ratio (OR): 2.28 (95% CI: 1.1, 4.8)]. The distribution of rs3093068 genotype differed significantly between GCA patients and controls (p=0.010). Allele C and the carriers of the C allele (C/C+C/G) of rs3093068 genotype were significantly less frequent in GCA patients compared to controls [p=0.002, OR: 0.39 (95% CI: 0.24-0.73); p=0.002, OR: 0.35 (95% CI: 0.17-0.70), respectively]. No significant associations were found between the two polymorphisms and baseline clinical manifestations. The carriers of the allele C of rs3093068 genotype had significantly higher CRP values at diagnosis (13.2±5.0 vs. 8.3±6.0 mg/dl, p=0.007). Homozygosity for T allele of rs1205 genotype had a significantly more frequent eosinophil infiltration of the temporal artery wall (21.4% vs. 6.0%) (p=0.010, OR 4.28;1.31-13.98) than patients carrying the allele C. Carriers of the allele T of rs1205 genotype had lower glucocorticoid (GC) treatment duration (p=0.041), lower cumulative total GC dose (p=0.017), and higher prevalence of long-term remission (p=0.024)., Conclusions: CRP gene rs1205 and rs3093068 polymorphisms influence GCA susceptibility and its outcomes.

Spontaneous bacterial peritonitis (SBP) is a severe complication in patients with decompensated liver cirrhosis and is commonly treated with broad spectrum antibiotics. However, the rise of antibiotic resistance requires alternative therapeutic strategies. As recently shown, human amnion-derived mesenchymal stem cells (hA-MSCs) are able, in vitro, to promote bacterial clearance and modulate the immune and inflammatory response in SBP. Our results highlight the upregulation of FOXO1, CXCL5, CXCL6, CCL20, and MAPK13 in hA-MSCs as well as the promotion of bacterial clearance, prompting a shift in the immune response toward a Th17 lymphocyte phenotype after 72 h treatment. In this study, we used an in vitro SBP model and employed omics techniques (next-generation sequencing) to investigate the mechanisms by which hA-MSCs modify the crosstalk between immune cells in LPS-stimulated ascitic fluid. We also validated the data obtained via qRT-PCR, cytofluorimetric analysis, and Luminex assay. These findings provide further support to the hope of using hA-MSCs for the prevention and treatment of infective diseases, such as SBP, offering a viable alternative to antibiotic therapy.

Objectives: Age is the strongest risk factor of giant cell arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multimarker algorithm in temporal artery biopsies (TABs) of GCA patients., Methods: 75(+) TABs from GCA patients, 22(-) TABs from polymyalgia rheumatica (PMR) patients and 10(-) TABs from non-GCA/non-PMR patients were retrospectively retrieved and analysed. Synovial tissue specimens from patients with inflammatory arthritis and aorta tissue were used as disease control samples. Senescent cells and their histological origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype by triple costaining. GCA or PMR artery culture supernatants were applied to fibroblasts, HUVECs and monocytes with or without IL-6R blocking agent to explore the induction of IL-6-associated cellular senescence., Results: Senescent cells were present in GCA arteries at higher proportion compared with PMR (9.50% vs 2.66%, respectively, p<0.0001) and were mainly originated from fibroblasts, macrophages and endothelial cells. IL-6 was expressed by senescent fibroblasts, and macrophages while MMP-9 by senescent fibroblasts only. IL-6(+) senescent cells were associated with the extension of vascular inflammation (transmural inflammation vs adventitia limited disease: 10.02% vs 4.37%, respectively, p<0.0001). GCA but not PMR artery culture supernatant could induce IL-6-associated senescence that was partially inhibited by IL-6R blockade., Conclusions: Senescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk, suggesting a potential implication in disease pathogenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To assess the effectiveness and safety of the 26-week tapering regimen of glucocorticoids (GC) used in the GiACTA trial in a prospective cohort of treatment-naive, biopsy-proven GCA patients., Methods: Patients with a new diagnosis of biopsy-proven GCA enrolled in the GC arm of the START project (molecular stratification of patients with GCA to tailor GC and tocilizumab therapy) were included. All patients were treated with the 26-week taper regimen of GC used in the GiACTA trial. The primary endpoint was the rate of relapse-free remission at week 52. The secondary endpoints were the proportion of patients with incident aortic damage, cumulative GC doses and GC-related adverse events (AE)., Results: 22 patients were included between December 2018 and February 2022. At week 52, 10 patients (45 %, 95 % CI 24-68) were in relapse-free remission. After a median (IQR) follow-up of 35 (22-40) months, 7 patients (32 %, 95 % CI 14-55) were in relapse-free remission. 18 patients with baseline large-vessel imaging underwent CT angiography at the end of the follow-up. No patients had evidence of new aortic dilation, significant progression of aortic damage or large vessel stenosis. 15/22 patients (68 %) had at least one relapse during follow-up. No patients developed visual or cerebrovascular manifestations during relapses. 15/22 (68 %) patients had at least one GC-related AE., Conclusions: A 26 week taper regimen of GC was effective and safe in inducing and maintaining remission in a sizeable proportion of newly diagnosed GCA patients. However, the frequency of GC-related adverse events was high., Competing Interests: Declaration of Competing Interest The authors declare there is no conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Islet transplantation (ITx) shows promise in treating T1D, but the role of islet autoantibodies on graft survival has not been clearly elucidated. We aimed to analyze the effect of GAD65 and IA2 autoantibody status on graft survival and attainment of insulin independence in subjects with T1D who underwent ITx., Method: We conducted a retrospective cohort study on 47 ITx recipients from 2000 to 2018. Islet infusion was performed via intrahepatic portal (n=44) or onto the omentum via laparoscopic approach (n=3). Immunosuppression involved anti-IL2 receptor antibody, anti-TNF, and dual combinations of sirolimus, tacrolimus, or mycophenolate mofetil (Edmonton-like) in 38 subjects (80.9%). T-cell depletion induction with Edmonton-like maintenance was used in 9 subjects (19%). GAD65 and IA2 autoantibodies were assessed pre-transplant and post-transplant (monthly) until graft failure, and categorized as persistently negative, persistently positive, or seroconverters. Graft survival was analyzed using U-Mann-Whitney test, and Quade's nonparametric ANCOVA adjusted for confounders. Kaplan-Meier and Log-Rank tests were employed to analyze attainment of insulin independence. P value <0.05 indicated statistical significance., Results: ITx recipients with persistent autoantibody negativity (n = 21) showed longer graft function (98 [61 - 182] months) than those with persistent autoantibody positivity (n = 18; 38 [13 - 163] months), even after adjusting for immunosuppressive induction protocol (P = 0.027). Seroconverters (n=8) had a median graft survival time of 73 (7.7 - 167) months, which did not significantly differ from the other 2 groups. Subjects with persistently single antibody positivity to GAD65 (n = 8) had shorter graft survival compared to negative islet autoantibody (GAD65/IA2) subjects (n = 21; P = 0.016). Time of graft survival did not differ in subjects with single antibody positivity to IA2. The proportion of insulin independence attainment was similar irrespective of autoantibody status., Conclusion: The persistence of islet autoantibodies, as markers of islet autoimmunity, may represent an underappreciated contributing factor to the failure of transplanted β cells. Whether induction with T-cell depletion may lead to improved graft survival, independent of islet autoantibody status, could not be evaluated in our cohort. Larger prospective studies are needed to further address the role of islet autoantibody status on islet graft survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lemos, Poggioli, Ambut, Bozkurt, Alvarez, Padilla, Vendrame, Ricordi, Baidal and Alejandro.)

Human pancreatic plasticity is implied from multiple single-cell RNA sequencing (scRNA-seq) studies. However, these have been invariably based on static datasets from which fate trajectories can only be inferred using pseudotemporal estimations. Furthermore, the analysis of isolated islets has resulted in a drastic underrepresentation of other cell types, hindering our ability to interrogate exocrine-endocrine interactions. The long-term culture of human pancreatic slices (HPSs) has presented the field with an opportunity to dynamically track tissue plasticity at the single-cell level. Combining datasets from same-donor HPSs at different time points, with or without a known regenerative stimulus (BMP signaling), led to integrated single-cell datasets storing true temporal or treatment-dependent information. This integration revealed population shifts consistent with ductal progenitor activation, blurring of ductal/acinar boundaries, formation of ducto-acinar-endocrine differentiation axes, and detection of transitional insulin-producing cells. This study provides the first longitudinal scRNA-seq analysis of whole human pancreatic tissue, confirming its plasticity in a dynamic fashion., Competing Interests: Declaration of interests Drs. J.D.-B. and R.L.P. are named inventors in the patent titled Compositions, systems and methods for obtaining insulin-producing cells (US patent no. 11,466,255 B2; October 11, 2022). Drs. J.D.-B. and R.L.P. are also named inventors in the patents titled Enhanced oxygen cell culture platforms (patent no. 8,551,770; July 11, 2013) and Enhanced oxygen cell culture platforms (patent no. 9,175,254; September 17, 2015). The University of Miami and Dr. J.D.-B. et al. hold the rights to intellectual property used in the study and may financially benefit from the commercialization of the intellectual property., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Extracellular (e)ATP, a potent proinflammatory molecule, is released by dying/damaged cells at the site of inflammation and is degraded by the membrane ectonucleotidases CD39 and CD73. In this study, we sought to unveil the role of eATP degradation in autoimmune diabetes. We then assessed the effect of soluble CD39 (sCD39) administration in prevention and reversal studies in NOD mice as well as in mechanistic studies. Our data showed that eATP levels were increased in hyperglycemic NOD mice compared with prediabetic NOD mice. CD39 and CD73 were found expressed by both α- and β-cells and by different subsets of T cells. Importantly, prediabetic NOD mice displayed increased frequencies of CD3+CD73+CD39+ cells within their pancreata, pancreatic lymph nodes, and spleens. The administration of sCD39 into prediabetic NOD mice reduced their eATP levels, abrogated the proliferation of CD4+- and CD8+-autoreactive T cells, and increased the frequency of regulatory T cells, while delaying the onset of T1D. Notably, concomitant administration of sCD39 and anti-CD3 showed a strong synergism in restoring normoglycemia in newly hyperglycemic NOD mice compared with monotherapy with anti-CD3 or with sCD39. The eATP/CD39 pathway plays an important role in the onset of T1D, and its targeting might represent a potential therapeutic strategy in T1D., (© 2023 by the American Diabetes Association.)

Herein, we describe an unusually prolonged duration (31 months) of the clinical remission phase in a 22-year-old Italian man with new-onset type 1 diabetes. Shortly after the disease diagnosis, the patient was treated with calcifediol (also known as 25-hydroxyvitamin D3 or calcidiol), coupled with low-dose basal insulin, to correct hypovitaminosis D and to exploit the anti-inflammatory and immunomodulatory properties of vitamin D. During the follow-up period, the patient retained a substantial residual β-cell function and remained within the clinical remission phase, as evidenced by an insulin dose-adjusted glycated hemoglobin value <9. At 24 months, we detected a peculiar immunoregulatory profile of peripheral blood cells, which may explain the prolonged duration of the clinical remission sustained by calcifediol as add-on treatment to insulin.

Prior studies of anti-CD40 ligand (CD40L)-based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation. AT-1501 monotherapy led to long-term graft survival in both islet and kidney transplant models, confirming its immunosuppressive potential. Furthermore, AT-1501-based regimens after islet transplant resulted in higher C-peptide, greater appetite leading to weight gain, and reduced occurrence of cytomegalovirus reactivation compared with conventional immunosuppression. These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate models, warranting further testing in clinical trials.

Omega-3 polyunsaturated fatty acids (PUFA) have demonstrated anti-inflammatory properties, while Omega-6 have pro-inflammatory effects, and the balance between the two is an important aspect of healthy nutrition. Over the last 30 years, however, the Western diet has shifted largely from Omega-3 to Omega-6 consumption. Uncontrolled aberrant and chronic inflammation is a leading component of many common diseases, including arthritis, cardiovascular diseases, neurodegenerative diseases, cancer, obesity, autoimmune diseases, and infective diseases. Eicosanoids derived from Omega-6 participate in the inflammatory process, while Omega-3 PUFA have the opposite effect. Many favorable effects of Omega-3 are believed to result from their anti-inflammatory properties, but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also have inhibitory effects on immune cells and reduce proinflammatory cytokine release. All these mechanisms can be beneficial in autoimmunity. No effective preventions or definite cures for autoimmune diseases are yet known because pathophysiology is also unclear. Omega-3 fatty acid supplementation is associated with a significant reduction in disease activity in several autoimmune diseases, like type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). Studies of viral diseases, including COVID-19, show improvement in symptom severity, recovery prognosis, and probability of survival with the use of Omega-3. Finally, the evidence of the beneficial effect of Omega-3 on metabolic diseases associated with aging is persuasive; various studies have demonstrated that their consumption improves lipids, fatty liver disease, obesity, cognitive function, and cardiovascular complications of chronic kidney disease (CKD). Omega-3 PUFA have also been shown to support an anti-inflammatory effect in older age and to have favorable effects on age-related disease's complications, frailty, and mortality. A healthy Omega-6/3 PUFA ratio should be targeted for the modulation of low-grade inflammation, as well as for the prevention of immune dysregulation and complications of uncontrolled inflammation triggered by infections, development, and progression of autoimmune disorders, and the consequences of oxidative stress due to aging. There is still a need for randomized clinical studies to validate current evidence supporting supplementation with correct doses of Omega-3 PUFA in autoimmune and chronic disease prevention.