Lifelong Therapy Research Articles

Nucleic acid amplification testing using dried blood spots to confirm the diagnosis of HIV-1 in adults

BackgroundThe WHO HIV testing algorithm for high prevalence populations recommends the use of three different serologic assays, though this approach may lead to diagnostic misclassification. The study objective was to compare dried blood spot (DBS)-based HIV-1 nucleic acid detection methods to determine their suitability to confirm the diagnosis of HIV-1 in adults generally with suppressed or low-level plasma HIV-1 RNA. MethodsFour methods were evaluated: Cepheid Xpert HIV-1 Qual Assay (Xpert), Hologic Aptima HIV-1 Quant Dx assay (Aptima), Roche Cobas Ampliprep/Cobas TaqMan HIV-1 test, v.2.0 (CAP/CTM) with guanidinium-based sample pre-extraction buffer (SPEX), or CAP/CTM with phosphate-buffered saline (PBS). Testing was performed on 163 DBS samples collected from participants with HIV-1 in the AIDS Clinical Trial Group (ACTG) A5230 study (73 samples) and the Peninsula AIDS Research Cohort (PARC) study (90 samples). ResultsXpert and SPEX CAP/CTM [96.9 % (158/163):95.7 % (156/163); P = 0.75) showed similar sensitivity. However, PBS CAP/CTM and Aptima demonstrated significantly lower sensitivity, 68.2 % (107/157) and 69.2 % (99/143), respectively, compared to Xpert and SPEX CAP/CTM (P < 0.0001 for all comparisons). Overall agreement between Xpert and SPEX CAP/CTM was 93.9 % (153/163), including 152 DBS samples in which both methods detected HIV-1 nucleic acids. ConclusionsXpert and SPEX CAP/CTM provide sensitive performance for the detection of HIV-1 nucleic acids using DBS collected from adults living with HIV-1, including those with suppressed virus loads. Given the cost and side-effects associated with inappropriate life-long antiretroviral therapy, these assays may play a role in diagnosing HIV-1 infection in individuals with suspected false-positive serologic testing.

Survival of a Patient Following Initial LVAD Implantation and Two Successive LVAD Exchanges: case report

Abstract Background Initially conceptualized as a bridge to heart transplantation, the Left Ventricular Assist Device (LVAD) has become an important option for improving survival in patients with severe heart failure and poor prognosis. Case summary We report the case of a patient suffering from severe chronic heart failure, complicated by ST-elevation myocardial infarction (STEMI) due to left main coronary artery (LMCA) stenosis (NYHA IV, INTERMACS profile 1). Despite support with veno-arterial extracorporeal membrane oxygenation (VA-ECMO), inotropes and catecholamine therapy, the patient´s cardiac function did not recover sufficiently. Consequently, the decision was made to proceed with LVAD implantation as destination therapy. The initial LVAD implantation was uneventful, and the patient received anticoagulant therapy according to standard operating procedure (SOP). However pump thrombosis occurred on the first postoperative day, necessitating an LVAD exchange. Following an extended stay in the cardiac surgery intensive care unit (ICU), the patient was eventually discharged. Approximately 15 months later, the patient developed a driveline infection, involving most of the intrapericardial components of the LVAD. A second LVAD exchange was required and the patient received a third LVAD. To mitigate the risk of recurrent infection, suppressive antibiotic therapy with ampicillin/sulbactam was initiated. Discussion This is the first reported case of a patient surviving three LVAD implantations and highlights an instance of off-label use of lifelong antibiotic therapy following a driveline infection.

Identifying and optimizing critical process parameters for large-scale manufacturing of iPSC derived insulin-producing β-cells

BackgroundType 1 diabetes, an autoimmune disorder leading to the destruction of pancreatic β-cells, requires lifelong insulin therapy. Islet transplantation offers a promising solution but faces challenges such as limited availability and the need for immunosuppression. Induced pluripotent stem cells (iPSCs) provide a potential alternative source of functional β-cells and have the capability for large-scale production. However, current differentiation protocols, predominantly conducted in hybrid or 2D settings, lack scalability and optimal conditions for suspension culture.MethodsWe examined a range of bioreactor scaleup process parameters and quality target product profiles that might affect the differentiation process. This investigation was conducted using an optimized High Dimensional Design of Experiments (HD-DoE) protocol designed for scalability and implemented in 0.5L (PBS-0.5 Mini) vertical wheel bioreactors.ResultsA three stage suspension manufacturing process is developed, transitioning from adherent to suspension culture, with TB2 media supporting iPSC growth during scaling. Stage-wise optimization approaches and extended differentiation times are used to enhance marker expression and maturation of iPSC-derived islet-like clusters. Continuous bioreactor runs were used to study nutrient and growth limitations and impact on differentiation. The continuous bioreactors were compared to a Control media change bioreactor showing metabolic shifts and a more β-cell-like differentiation profile. Cryopreserved aggregates harvested from the runs were recovered and showed maintenance of viability and insulin secretion capacity post-recovery, indicating their potential for storage and future transplantation therapies.ConclusionThis study demonstrated that stage time increase and limited media replenishing with lactate accumulation can increase the differentiation capacity of insulin producing cells cultured in a large-scale suspension environment.

Stem cell exosomes: new hope and future potential for relieving liver fibrosis.

Liver fibrosis is a chronic liver injury resulting from factors like viral hepatitis, autoimmune hepatitis, non-alcoholic steatohepatitis, fatty liver disease, and cholestatic liver disease. Liver transplantation is currently the gold standard for treating severe liver diseases. However, it is limited by a shortage of donor organs and the necessity for lifelong immunosuppressive therapy. Mesenchymal stem cells (MSCs) can differentiate into various liver cells and enhance liver function when transplanted into patients due to their differentiation and proliferation capabilities. Therefore, it can be used as an alternative therapy for treating liver diseases, especially for liver cirrhosis, liver failure, and liver transplant complications. However, due to the potential tumorigenic effects of MSCs, researchers are exploring a new approach to treating liver fibrosis using extracellular vesicles (exosomes) secreted by stem cells. Many studies show that exosomes released by stem cells can promote liver injury repair through various pathways, contributing to the treatment of liver fibrosis. In this review, we focus on the molecular mechanisms by which stem cell exosomes affect liver fibrosis through different pathways and their potential therapeutic targets. Additionally, we discuss the advantages of exosome therapy over stem cell therapy and the possible future directions of exosome research, including the prospects for clinical applications and the challenges to be overcome.

Hyperacute thrombosis of a vertebral artery stent with a single missed dose of a P2Y12 inhibitor and poor stent wall apposition: illustrative case.

Iatrogenic vertebral artery injury during surgery can cause pseudoaneurysm, hemorrhage, thrombosis, ischemia, or death. Strategies to prevent cerebrovascular embolic complications include surgical ligation, endovascular stenting, and/or antiplatelet therapy. A 73-year-old female with a known right vertebral artery occlusion underwent a C2-3 laminectomy, complicated by left vertebral artery injury and occlusion with subsequent posterior circulation ischemia. She underwent immediate angioplasty and stenting of the injured artery with undersized drug-eluting stents. Dual antiplatelet therapy of aspirin 81 mg daily and ticagrelor 90 mg twice daily was initiated. On two occasions, more than 6 months after stenting, holding a single ticagrelor dose led to in-stent thrombosis and embolic stroke within hours of the missed dose. Lifelong therapy with ticagrelor was favored over further procedural intervention. It is recommended to prioritize optimal wall stent apposition with oversized stents in patients without collateral circulation. The risk of thromboembolism due to poorly apposed stents is very high, even in delayed (> 6 months) settings. Stent construct revision or bypass grafting may not be feasible or desirable options. For patients without wall apposition, endothelialization may not occur, necessitating lifelong P2Y12 inhibitor therapy to prevent recurrent thromboembolic events. https://thejns.org/doi/10.3171/CASE24296.

Non-Surgical Management of Methicillin-Sensitive Staphylococcus Aureus Bacteremia-Related Mediastinitis.

Acute mediastinitis is rarely caused by haematogenous spread of a remote infection. In this respect, since the only medical therapy is usually unsuccessful, treating acute mediastinitis with no source of infection detected is very challenging and management not standardized. In this case report, we describe non-surgical management experience of acute mediastinitis caused by methicillin-sensitive Staphylococcus aureus. In a 79-year-old man judged not eligible for cardiac surgery, we attempted the infection source control through vacuum-assisted closure therapy, together with antimicrobial therapy. We observed gradual clinical, laboratory and radiologic improvements: reduced swelling and normalization of the white blood cell count and C-reactive protein level were associated with reduction in size of a periaortic abscess. We managed a clinical condition with high mortality risk with chronic antimicrobial therapy alone, a strategy that is rarely considered. With this medical strategy we achieved an optimal response to a clinical picture that does not allow any other approach. Mediastinitis is a rare but severe infection with a high mortality rate.Chronic antimicrobial therapy can be an effective strategy in high surgical risk patients.The present case demonstrates good tolerability of lifelong antibiotic therapy.

A cost-effectiveness analysis of RefluxStop against relevant therapeutic alternatives for chronic gastroesophageal reflux disease in Sweden

ABSTRACT Introduction The standard treatment for gastroesophageal reflux disease (GERD) is proton pump inhibitors (PPIs). In selected cases, Nissen fundoplication is offered as a surgical treatment option, but alternative endoscopic and minimally invasive surgical alternatives are emerging. RefluxStop is a new technology for the treatment of GERD. Research design and methods A cost-effectiveness analysis of RefluxStop in comparison to PPI therapy and Nissen fundoplication in the Swedish healthcare setting was conducted using a Markov model and available comprehensive population and clinical trial-based long-term data. Benefits were measured in quality-adjusted life-years (QALYs). Uncertainty was determined by deterministic and probabilistic sensitivity analyses. Results The base case incremental cost-effectiveness ratios (ICERs) for RefluxStop in comparison to PPIs and Nissen fundoplications were SEK 48,152 (€ 4,531) and SEK 62,966 (€ 5,925) per QALY gained, respectively. At a cost-effectiveness threshold of SEK 500,000 per QALY gained, RefluxStop has a high likelihood of being cost-effective, with probabilities of 96% and 100% against Nissen fundoplication and PPIs, respectively. The results of the model remained robust with sensitivity analysis. Conclusions RefluxStop may offer a highly cost-effective long-term treatment alternative for chronic GERD patients over lifelong PPI therapy, but also in comparison with laparoscopic Nissen fundoplication.

Bone impairment in atypical hemolytic and uremic syndrome treated by long-term eculizumab.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy, related to complement dysregulation, including Factor H deficiency (FH) treated by lifelong eculizumab therapy. Its long-term tolerance is not yet fully described. We report two patients with genetic FH deficiency receiving long-term eculizumab and displaying a peculiar bone phenotype. First case is a 13-year-old girl, presenting with bone pains, arthritis, and deformities, for which X-rays and MRI described multifocal osteochondritis. Bone biopsy revealed an active remodeling bone (many areas of bone formation and resorption) and C3c accumulation on immunohistochemical staining. The second patient is an 11-year-oldgirl, displaying mechanical bone pains, for which bone scintigraphy found hypofixation of wrists and ankles. These findings could be consistent with a side effect of eculizumab, as C3c accumulation may result from the downstream C5-blockade. Alternatively, bone alterations could be due to the absence of FH, as described in murine models. Further investigations are required to characterize bone disease in aHUS.

Evaluation of the Effect of Diet Adherence on Nutritional Status and Metabolic Control in Children with Phenylketonuria Consuming a Phenylalanine-Restricted Diet: A Single-Center Study

Objective: The aim of this study was to determine the dietary habits of patients with phenylketonuria (PKU) in different age groups, to assess energy, protein and phenylalanine intakes, and to evaluate dietary compliance and its effect on metabolic control. Material and Methods: The study, conducted between 1 March 2022 and 30 September 2022, the study involved 20 children aged 2-18 diagnosed with PKU at the Department of Pediatric Metabolism Outpatient Clinic of Ankara Bilkent City Hospital. Participants were evaluated for diet compliance and had their blood phenylalanine and tyrosine levels were measured. Results: Among the 20 patients, 42.9% (n=9) were female and 57.1% (n=11) were male, with a mean age of 4.7±3.22 years. Age distribution was 70% (n=14) aged 2-6, 20% (n=4) aged 6-10, and 10% (n=2) aged 10-13. Patients attended four follow-ups over six months. A moderate negative correlation was found between daily dietary phenylalanine and blood phenylalanine levels in the first and last controls, and a high negative correlation in the 2nd and 3rd controls (p=0.006, p&amp;lt;0.001, p&amp;lt;0.001, p=0.013). A positive moderate correlation was found between the frequency of daily amino acid mixture consumption and diet compliance (p=0.025). Increased meal frequency improved diet compliance. No significant relationship was found between blood phenylalanine levels and amino acid mixture consumption, diet compliance, or daily amino acid mixture consumption frequency. Conclusion: In PKU, nutritional habits, daily phenylalanine intake and amino acid mixture consumption frequency impact dietary compliance and metabolic control. Lifelong medical nutrition therapy requires multidisciplinary team support, frequent follow-ups and adherence to the recommended diet.

5103 Synthroid Absorption Conundrum: A Case Deciphered

Abstract Disclosure: H. Nadeem: None. O. Alzohaili: None. Hypothyroidism is a disorder requiring lifelong Synthroid therapy. Untreated patients have high morbidity rate and suffer from weight gain, cold intolerance, fatigue and constipation. Inadequate therapeutic outcomes may result in the case of malabsorption, like GI tract conditions, medication interactions and dietary ingredients. Here, we describe the case of a 50-year-old woman who despite compliance to therapy, had refractory hypothyroidism. Complexity of unexplained Synthroid malabsorption is highlighted, emphasizing the importance of managing and optimizing thyroid hormone replacement therapy. A 50-year-old woman with a history of papillary carcinoma s/p thyroidectomy and radioactive iodine therapy came in with fatigue, weight gain and constipation. Despite taking Synthroid 150 mcg, thyroid function tests (TFTs) remained high with TSH 150 uIU/mL and fT4 0.25 ng/dL. Her dose was gradually increased until it reached 1800 mcg yet repeat TFTs showed refractory hypothyroidism with TSH 179 uIU/mL, fT4 0.8 ng/dL. Compliance was addressed to which she demonstrated strict adherence, while avoiding concurrent intake of food, supplements or medications interfering with the absorption. Autoimmune conditions were ruled out and no dietary patterns affecting absorption were identified. A thyroid absorption test was then performed, during which 2100 mcg of Synthroid were given orally in the AM, and thyroid hormones were measured for 8 hours. She was found to have a TSH in 200s uIU/mL and fT4 &amp;lt;0.10 ng/dL, deeming her to have refractory hypothyroidism. She was seen by GI and had an EGD/ colonoscopy, revealing no abnormalities. In a follow up visit, she was still complaining of the same symptoms, periorbital edema, and mild confusion. Her TSH was still elevated at 225 uIU/mL. She was then started on IV 500 mcg of weekly Synthroid infusions and after several weeks, she reported symptoms improvement. Subsequent TFTs showed a progress in TSH, now 26.6 uIU/mL, with fT4 1 ng/dL, indicating successful management of Synthroid malabsorption. During this process, she had a nutritional assessment and was consistently having hyperlipidemia with LDL 243 mg/dL. She was compliant with Praluent and max dose of atorvastatin 80 mg, but LDL only decreased to 134 mg/dL after adjusting her thyroid hormone levels. With nonadherence being the top cause of medication non responsiveness, ruling out causes of malabsorption is vital. In this case, compliance, nutritional assessment, medication interactions, GI abnormalities, autoimmune conditions were all addressed and no interfering factors were identified. IV treatment with unexplained thyroid hormone malabsorption was the effective treatment, ultimately improving outcomes. With the hope to transition her to oral medication, the possibility of it happening is still not clear. More research is necessary to discover the underlying causes in such an exceptional case. Presentation: 6/2/2024

12575 Exploring Patient And Parent Perceptions Of Administering Hydrocortisone Injection During Adrenal Crisis: A Cross-Sectional Study

Abstract Disclosure: S.V. Llahana: None. J. Anhony: Employee; Self; Solution Medical LLC. Background: Adrenal insufficiency (AI) necessitates lifelong glucocorticoid replacement therapy for most patients, with parenteral hydrocortisone crucial for managing adrenal crisis, a potentially life-threatening complication. Despite this, approximately 1 in 6-12 patients are hospitalised at least once a year, while 1 in 200 patients die from a potentially preventable adrenal crisis. While timely self-administration of hydrocortisone mitigates these risks, the complexity of current injection devices, requiring up to 20 steps to administer, often impedes effective self-treatment. Evidence shows that although 70% of patients possess emergency hydrocortisone injection kits, only 19% have received training for self-administration. Aim: This study aimed to investigate the experiences and perceptions of patients with AI and their caregivers regarding the usage of Solu-Cortef Act-O-Vial (parenteral hydrocortisone) for adrenal crisis management. Methods: A cross-sectional online survey was conducted, involving participants recruited through USA-based patient advocacy groups, CARES Foundation and Adrenal Insufficiency United. Participants provided insights into factors influencing their ability to manage adrenal crisis using Solu-Cortef Act-O-Vial. Content analysis generated themes, which were quantitatively analyzed using SPSS descriptive statistics and correlations. Results: The survey encompassed 689 patients and caregivers. Content analysis revealed eighteen themes across three domains: patient-based factors, external influences, and emotional aspects. Predominant themes, identified by over 80% of participants, included the complexity of the hydrocortisone device, the necessity for assistance during adrenal crisis episodes, and emotional distress due to fear associated with injection. Conclusion: This study underscores the necessity for a simpler injection device to enhance patient self-confidence and self-administration ability. Heightened awareness among healthcare professionals and the public regarding adrenal crisis is imperative for timely management and prevention of avoidable hospital admissions. Presentation: 6/3/2024

7936 Type 1 Diabetes Therapeutic Compound MSB-61: Using RNA Sequencing To Identify The Mechanism

Abstract Disclosure: P. Khan: None. K. Corbin: None. N. Ajmal: None. S. Bergmeir: None. G. Gu: None. X. Tong: None. C.S. Nunemaker: None. Abstract Type 1 diabetes (T1D) is a chronic autoimmune disease in which loss of insulin-producing beta-cells leads to hyperglycemia due to which patients eventually require lifelong insulin therapy to maintain normal glycemic control. Insulin remains the gold standard and the only effective treatment for T1D since its discovery 100 years ago. Protecting the pancreatic beta cells from cytokine-induced cell death and restoring insulin secretion are important to treat T1D, two properties that are currently lacking in present therapies. Our lab identified a chemical compound MSB-61 that increases insulin release and protects pancreatic islets against T1D-associated cytokines and endoplasmic reticulum (ER) stress. This study aims to identify the mechanism of action of MSB-61 in protecting pancreatic islets from ER stress-induced cell death. To achieve this aim pancreatic islets obtained from CD-1 strain mice were exposed for one hour to 50uM MSB-61 or vehicle control. After treatment, RNA was collected for RNA sequencing. In addition to RNA extraction for sequencing, MSB-61's ability to secrete insulin was verified by performing ELISA on control,10 and 50uM MSB-61-treated islets, and the activity of protection from cell death was assessed by performing cell death assay on islets treated with ER stressors in the presence and absence of 10 and 50uM MSB-61. Using Genialis, a bioinformatics service, we evaluated 57,010 genes (including non-coding transcripts) in our RNA sequencing data set. The DESeq2 technique of data analysis allowed us to identify 350 differentially expressed genes (DEGs), of which 251 were upregulated and 74 were downregulated. After removing non-coding/undefined transcripts and genes with &amp;lt;5 counts per million, a total of 117 genes remained; 108 up and 9 down. According to the String database (string-db.org), many of the top DEGs formed a common network of genes associated with cell death protection and insulin secretion. A key component of that gene network is a stress-responsive orphan nuclear receptor with known protective effects in beta cells. Testing this orphan nuclear receptor as a possible direct or indirect target of MSB-61 for cell death prevention can aid in identifying the genes and pathways targeted by MSB-61, allowing us to improve our approaches to T1D treatment and develop better medications. Presentation: 6/3/2024

Prospective study on the impact of different antithrombotic therapies on subclinical leaflet thickening and its temporal dynamics in transcatheter aortic valves—The NOTION-4 trial

Transcatheter aortic valve replacement (TAVR) has become the standard-of-care treatment for a majority of patients with severe, symptomatic aortic stenosis. The post-procedural anti-thrombotic therapeutic management is still a topic of debate and could affect the incidence of HALT, a phenomenon which can be assessed by four-dimensional computed tomography (4DCT). The NOTION-4 trial is a randomized controlled trial comprising TAVR patients with no indication for oral anticoagulant (OAC) therapy, comparing lifelong single anti-platelet therapy (standard arm) versus early 3-month direct oral anticoagulant (DOAC) therapy followed by single anti-plateletet therapy (experimental arm). The incidence of HALT and clinical endpoints will be evaluated in both groups at 3 months, 1 year and 5 years after randomization. The primary endpoint is the number of patients with at least one bioprosthetic aortic valve leaflet with HALT as assessed by cardiac 4DCT imaging at 1 year. The trial is powered for superiority testing and started enrollment in 2021. In total, 324 patients will be included. The last patient is expected to be enrolled by the end of 2024 and the primary endpoint is to be presented in 2026. The NOTION-4 trial aims to study whether an early 3-month DOAC therapy after TAVR can result in a sustained lower incidence of HALT in transcatheter aortic valves. This trial holds the potential to give valuable insights into whether early OAC therapy should be integrated in future guidelines for post-TAVR anti-thrombotic therapeutic management. NOTION-4, ClinicalTrials.gov ID NCT06449469, https://clinicaltrials.gov/study/NCT06449469.

8733 Adrenal Crisis In A Patient Diagnosed With Primary Adrenal Insufficiency Following COVID-Vaccination

Abstract Disclosure: A. Hayat: None. N. Aslam: None. Primary adrenal insufficiency, or Addison's disease, is characterized by the inadequate production of cortisol and often requires lifelong hormone replacement therapy. COVID-19 vaccines have demonstrated overall safety, but this report explores a unique case of adrenal crisis post-vaccination in a patient with pre-existing adrenal insufficiency. A 38-year-old female, diagnosed with primary adrenal insufficiency, received her second dose of a COVID-19 vaccine. Within 48 hours after vaccine administration , she presented to the emergency department with severe fatigue, hypotension, nausea, and abdominal pain. Clinical examination and laboratory tests confirmed an adrenal crisis, with markedly decreased cortisol levels, hyponatremia, hyperkalemia, and an elevated ACTH level. The patient was promptly treated with intravenous hydrocortisone and saline fluids. Close monitoring of vital signs and cortisol levels was maintained, with a gradual tapering of hydrocortisone as the patient's symptoms improved. The importance of stress-dose steroids during illness or vaccination in patients with adrenal insufficiency is underscored. This case highlights that the Healthcare providers should be aware of this rare but severe complication and consider appropriate monitoring and stress-dose steroid coverage in susceptible populations. Presentation: 6/3/2024

8439 Targeting Interferon Gamma-Mediated CXCL16-CXCR6 Chemokine-Receptor Interactions As A Strategy To Prevent Immune Checkpoint Inhibitor Autoimmune Diabetes

Abstract Disclosure: S. Wang: None. N. Huang: None. J.G. Ortega: None. J. Lee: None. K. Kimbrell: None. J. Nguyen: None. J. Olay: None. E. McCarthy: None. E. Peluso: None. H. Chen: None. M.G. Lechner: None. Autoimmune diabetes mellitus is a rare but life-threatening side effect of immune checkpoint inhibitor (ICI) cancer therapy. Checkpoint inhibitors increase immune activation by blocking regulatory molecules on T cells, including programmed death protein (PD1). As a result of this heightened immune activation, patients can develop autoimmunity in healthy tissues, known as immune related adverse events (IRAEs). ICI-associated diabetes mellitus (ICI-T1DM) is an IRAE that results in autoimmune destruction of insulin-producing pancreatic beta-cells. Patients with ICI-T1DM require life-long insulin therapy and more than half present initially with diabetic ketoacidosis. Unfortunately, the mechanism of this IRAE is not fully understood. Anti-PD1 antibody treatment (10mg/kg/dose, twice weekly, i.p.) of male and female non-obese diabetic (NOD) mice leads to autoimmune infiltrates in multiple tissues, including accelerated insulitis and DM. Single cell RNA sequencing of islet infiltrating immune cells from ICI-treated mice previously showed a role for CD8+ T cells and cytokine interferon gamma (IFNγ) in the development of ICI-T1DM. Using CellChat to perform receptor-ligand interaction analysis of these data, we identified both CD8+ and CD4+ T cells as the primary source of IFNγ in immune infiltrates and islet myeloid cells as the primary target. Furthermore, CellChat analysis showed increased receptor-ligand interactions between T cell receptor CXCR6 and its chemokine CXCL16, as well as CXCR3 and chemokines CXCL9 and CXCL10. In vitro IFNγ stimulation of myeloid cells induced strong expression of CXCL16, 9, and 10, suggesting a potential mechanism by which effector T cells are recruited to islets during ICI therapy. Immunophenotyping of islet-infiltrating immune cells indeed showed increased IFNγ+CXCR6+ effector CD8+ cells in anti-PD1 treated mice compared to isotype-treated controls. Moreover, these IFNγ+CXCR6+CD8+ T cells stained positively for the NRP-V7 mimotope tetramer, a known antigen for CD8+ T cells in spontaneous autoimmune diabetes in NOD mice, suggesting this as an antigen-specific population contributing to the immunopathogenesis of ICI-T1DM. Finally, genetic deletion of CXCR6 in NOD mice delayed the onset of autoimmune diabetes during anti-PD1 treatment in female (p=0.0162) but not male mice (p=0.3656). In summary, these data further elucidate the cellular mechanisms by which IFNγ and chemokine signaling pathways drive the development of ICI-T1DM and identify the CXCR6-CXCL16 axis as a potential therapeutic target to prevent this IRAE in checkpoint inhibitor-treated cancer patients. Presentation: 6/2/2024

Unravelling the Role of Gut and Oral Microbiota in the Pediatric Population with Type 1 Diabetes Mellitus

Type 1 Diabetes Mellitus (T1DM) is a chronic autoimmune disease that results in the destruction of pancreatic β cells, leading to hyperglycaemia and the need for lifelong insulin therapy. Although genetic predisposition and environmental factors are considered key contributors to T1DM, the exact causes of the disease remain partially unclear. Recent evidence has focused on the relationship between the gut, the oral cavity, immune regulation, and systemic inflammation. In individuals with T1DM, changes in the gut and oral microbial composition are commonly observed, indicating that dysbiosis may contribute to immune dysregulation. Gut dysbiosis can influence the immune system through increased intestinal permeability, altered production of short chain fatty acids (SCFAs), and interactions with the mucosal immune system, potentially triggering the autoimmune response. Similarly, oral dysbiosis may contribute to the development of systemic inflammation and thus influence the progression of T1DM. A comprehensive understanding of these relationships is essential for the identification of biomarkers for early diagnosis and monitoring, as well as for the development of therapies aimed at restoring microbial balance. This review presents a synthesis of current research on the connection between T1DM and microbiome dysbiosis, with a focus on the gut and oral microbiomes in pediatric populations. It explores potential mechanisms by which microbial dysbiosis contributes to the pathogenesis of T1DM and examines the potential of microbiome-based therapies, including probiotics, prebiotics, synbiotics, and faecal microbiota transplantation (FMT). This complex relationship highlights the need for longitudinal studies to monitor microbiome changes over time, investigate causal relationships between specific microbial species and T1DM, and develop personalised medicine approaches.

TNF-α inhibitors for type 1 diabetes: exploring the path to a pivotal clinical trial.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas. This destruction leads to chronic hyperglycemia, necessitating lifelong insulin therapy to manage blood glucose levels. Typically diagnosed in children and young adults, T1D can, however, occur at any age. Ongoing research aims to uncover the precise mechanisms underlying T1D and to develop potential interventions. These include efforts to modulate the immune system, regenerate β-cells, and create advanced insulin delivery systems. Emerging therapies, such as closed-loop insulin pumps, stem cell-derived β-cell replacement and disease-modifying therapies (DMTs), offer hope for improving the quality of life for individuals with T1D and potentially moving towards a cure. Currently, there are no disease-modifying therapies approved for stage 3 T1D. Preserving β-cell function in stage 3 T1D is associated with better clinical outcomes, including lower HbA1c and decreased risk of hypoglycemia, neuropathy, and retinopathy. Tumor Necrosis Factor alpha (TNF-α) inhibitors have demonstrated efficacy at preserving β-cell function by measurement of C-peptide in two clinical trials in people with stage 3 T1D. However, TNF-α inhibitors have yet to be evaluated in a pivotal trial for T1D. To address the promising clinical findings of TNF-α inhibitors in T1D, Breakthrough T1D convened a panel of key opinion leaders (KOLs) in the field. The workshop aimed to outline an optimal clinical path for moving TNF-α inhibitors to a pivotal clinical trial in T1D. Here, we summarize the evidence for the beneficial use of TNF-α inhibitors in T1D and considerations for strategies collectively identified to advance TNF-α inhibitors beyond phase 2 clinical studies for stage 3 T1D.

Cardiorenal Benefit of Tirzepatide in Type 1 Diabetes: A Case Report

Abstract Patients with type 1 diabetes (T1D) who are obese are at risk of cardiovascular disease, renal diseases, and other complications. Unfortunately, there is currently no cure for T1D, necessitating individuals with this condition to rely on lifelong insulin therapy. Tirzepatide, a dual-acting glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist, has recently been approved for treating type 2 diabetes. We report the case of a 38-year-old male who presented with T1D, stage 2 chronic kidney disease, obesity, and other comorbidities. He was prescribed tirzepatide 2.5 mg initially, followed by titration up to 5 mg. A significant reduction in blood glucose levels, weight, and microalbumin levels was observed. Additionally, the systolic blood pressure level was also seen to improve. These results highlight new indications of tirzepatide in managing T1D and obesity. However, further studies are warranted to explore its efficacy and safety in patients with T1D.

Natural biomaterials in the management of the aortic valve pathology. Biomedical and clinical aspects: A review.

Heart valve diseases are a prevalent cardiovascular pathology worldwide, affecting nearly 2.5% of the population. Degenerative aortic stenosis is the most common form of heart valve disease. The treatment options include surgical or transcatheter procedures. There are two main categories of valve prostheses available: mechanical heart valves constructed from synthetic materials and bioprosthetic heart valves made from natural biomaterials. The choice of valve type depends on various factors, including the underlying medical condition, suitability for anticoagulation, valve durability, and the patient's age and preferences. Mechanical heart valves have the advantage of long-term durability. However, patients receiving mechanical implants are subjected to lifelong anticoagulation therapy with an increased risk of thromboembolism and bleeding. Natural biomaterials do not require long-term anticoagulation. However, they experience degenerative changes leading to structural valve deterioration that may require reoperation. The purpose of this article is to review the role of natural biological materials used for aortic valve replacement or repair, assess their biomedical and clinical advantages and limitations, and analyze the direction and perspectives of future development.

Transplant-Acquired Food Allergy in Children.

Organ transplantation in children is a vital procedure for those with end-stage organ failure, but it has been linked to the development of post-transplant allergies, especially food allergies. This phenomenon, known as transplant-acquired food allergy (TAFA), is becoming increasingly recognized, though its mechanisms remain under investigation. Pediatric transplant recipients often require lifelong immunosuppressive therapy to prevent graft rejection, which can alter immune function and heighten the risk of allergic reactions. Our review aimed to gather the latest evidence on TAFA. We conducted a PubMed search from 25 June to 5 July 2024, using specific search terms, identifying 143 articles. After screening, 36 studies were included: 24 retrospective studies, 1 prospective study, 2 cross-sectional researches, and 9 case reports/series. Most studies focused on liver transplants in children. The prevalence of food allergies ranged from 3.3% to 54.3%. Tacrolimus, alongside corticosteroids, was the most commonly used immunosuppressive therapy. In addition to food allergies, some patients developed atopic dermatitis, asthma, and rhinitis. Allergic symptoms typically emerged within a year post-transplant, with common allergens including milk, eggs, fish, nuts, soy, wheat, and shellfish. Both IgE-mediated and non-IgE-mediated reactions were observed, with treatment often involving the removal of offending foods and the use of adrenaline when necessary. Consistent immunological monitoring, such as skin prick tests and IgE level assessments, is essential for early detection and management of allergies in these patients. Understanding the link between transplantation and allergy development is crucial for improving long-term outcomes for pediatric transplant recipients.