Successful hematopoietic stem cell transplantation in a 4-1BB deficient patient with EBV-induced lymphoproliferation.

Complete remission from recurrent EBV-positive lymphoma is not mandatory before HSCT to achieve long-term cure in a patient suffering from a recently described immunodeficiency affecting the T-cell coactivation molecule 4-1BB.

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. OBJECTIVE: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. CONCLUSIONS: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.

Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation.

BACKGROUND: The gene AK2 encodes the phosphotransferase adenylate kinase 2 (AK2). Human variants in AK2 cause reticular dysgenesis, a severe combined immunodeficiency with agranulocytosis, lymphopenia, and sensorineural deafness that requires hematopoietic stem cell transplantation for survival. OBJECTIVE: We investigated the mechanisms underlying recurrent sinopulmonary infections and hypogammaglobulinemia in 15 patients, ranging from 3 to 34 years of age, from 9 kindreds. Only 2 patients, both of whom had mildly impaired T-cell proliferation, each had a single clinically significant opportunistic infection. METHODS: Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function. RESULTS: We identified 2 different homozygous variants in AK2. AK2G100S and AK2A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but 1 patient had intact hearing. The patients' B cells had severely impaired proliferation and in vitro immunoglobulin secretion. With activation, the patients' B cells exhibited defective mitochondrial respiration and impaired regulation of mitochondrial membrane potential and quality. Although activated T cells from the patients with opportunistic infections demonstrated impaired mitochondrial function, the mitochondrial quality in T cells was preserved. Consistent with the capacity of activated T cells to utilize nonmitochondrial metabolism, these findings revealed a less strict cellular dependence of T-cell function on AK2 activity. Chemical inhibition of ATP synthesis in control T and B cells similarly demonstrated the greater dependency of B cells on mitochondrial function. CONCLUSIONS: Our patients demonstrate the in vivo sequelae of the cell-specific requirements for the functions of AK2 and mitochondria, particularly in B-cell activation and antibody production.

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.

BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency.

BACKGROUND: The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8+ T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells. OBJECTIVE: We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in 2 unrelated patients. METHODS: Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed. RESULTS: The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8+ T cells had reduced proliferation, impaired expression of IFN-γ and perforin, and diminished cytotoxicity against allogeneic and HLA-matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients' activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients' defective CD8+ T-cell activation and cytotoxicity against EBV-infected B cells in vitro. CONCLUSION: This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists: Exploring Their Impact on Diabetes, Obesity, and Cardiovascular Health Through a Comprehensive Literature Review.

Glucagon-like peptide-1 receptor agonists (GLP-1-RAs) are a novel class of medications promising for treating type 2 diabetes mellitus (T2DM) and obesity-related conditions such as cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). This comprehensive literature review examines available research on these medications, focusing on their mechanisms of action, clinical effectiveness, safety profiles, and socioeconomic implications. A comprehensive search was performed using the PubMed, EMBASE, and Cochrane Library databases. Although initially developed for glucose management, these drugs have also demonstrated efficacy in promoting weight loss and reducing the risk of CVD. GLP-1-RAs function similarly to naturally occurring incretins. They stimulate insulin secretion in response to glucose levels, inhibit glucagon release, delay stomach emptying, and generate a sense of fullness via brain pathways. Head-to-head clinical studies have indicated that GLP-1-RAs outperform conventional antidiabetic medicines in terms of glycemic management and weight reduction. According to cardiovascular outcome studies, various drugs in this category have been found to reduce the frequency of severe adverse cardiovascular events. A common side effect is gastrointestinal toxicity, which can be mitigated by gradually increasing the dose. Personalized treatment is likely because the effectiveness, safety, and dose regimens of currently available GLP-1-RAs differ. GLP-1-RAs are a superior choice for patients with T2DM, especially those who already have CVD or require weight-control support. The high cost of these drugs creates hurdles to access and fair healthcare. Current research mainly focuses on increasing therapeutic uses and producing orally delivered medicines with greater potency and bioavailability. Integrating GLP-1-RAs into clinical practice can enhance patient outcomes and reduce the community burden of cardiometabolic disease.

Case report: A late and isolated presentation of meningoencephalomyelitis uncovers a novel pathogenic variant in the CIITA gene.

Background: Bare lymphocyte syndrome type II (BLS II) is a rare form of severe combined immunodeficiency caused by mutations in the CIITA gene, which regulates major histocompatibility complex class II (MHC II) expression. Objective: We report the case of a Saudi boy with a novel mutation in the CIITA gene who presented with acute and late meningoencephalomyelitis, resulting in severe neurodevelopmental regression. Methods: We reviewed the patient's clinical and laboratory data obtained from medical records and performed a literature search on BLS II. Results: The patient presented with acute meningoencephalomyelitis confirmed by MRI findings and was later found to carry a homozygous pathogenic variant in the CIITA gene p.(Leu473Hisfs*15). The patient had no MCH II expression, confirming the genetic diagnosis of autosomal recessive BLS II. Surprisingly, the patient's prior clinical history was unremarkable for significant infections or autoimmunity. Conclusions: We report a case with a novel CIITA gene mutation presenting atypically with a late and isolated severe infection. Isolated severe meningoencephalomyelitis may be a manifestation of primary immunodeficiency.

Investigation of composed charged particles with suspension of ternary hybrid nanoparticles in 3D-power law model computed by Galerkin algorithm.

Transport of heat visualizes a vital role in many industrial developments. Current study is discussing the role of Joule heating, solar thermal radiation, heat generation/absorption, reactions (homogeneous and heterogeneous) with variable thermal conductivity on partially ionized power law material past over a three-dimensional heated stretched surface. The power law model is assumed to have the thermal characteristics of ethylene glycol material. The phenomenon of momentum and energy balance is derived in Cartesian coordinates and developed PD (partial differential)-equations. Swimming pools, solar collectors, food processing, electronic gadgets, cooling systems, magnetic field measurement, computer chips, thermal enhancement, semiconductor characterization, nuclear fusion research and other physical applications are examples of ongoing research. The principle of boundary layer simplified the governing problem. The complex coupled PD (partial differential)-equations have been converted into ordinary differential equations OD (ordinary differential)-equations by using appropriate similarity transformation. The converted boundary value problem is complex and highly nonlinear which does not have the exact solution. The approximate solution is computed numerically via finite element scheme (FES) which is coded in MAPLE 18.0 symbolic package. The convergence of the scheme is established through grid independent survey and the solution is plotted against numerous involved parameters. Thermal performance produced by [Formula: see text]-[Formula: see text]-[Formula: see text]/EG is higher thermal performance produced by [Formula: see text]-[Formula: see text]/EG. Ion slip and Hall forces are responsible for generating Joule heating mechanism that is responsible for reduction of velocity curve and generating shear stresses. Hence, tangential stresses are declined against increasing [Formula: see text] and [Formula: see text].

Analyzing Cardiovascular Characteristics of Patients Initially Diagnosed with Breast Cancer in Saudi Arabia.

Introduction Cancer is a condition where abnormal cells proliferate uncontrollably, leading to metastasis, which can be related to death. Breast cancer is the most prevalent type among women worldwide. Early detection with screening mammography has contributed to the decline in breast cancer incidence and mortality. Breast cancer patients are more likely to develop cardiovascular disease, with elderly patients dying from complications. Understanding the patients' cardiovascular status prior to treatment is essential. The study's objective was to evaluate the cardiovascular characteristics of women with breast cancer at diagnosis within the designated time frame of one year. Methodology This was a retrospective study that focused on patients in Taif City, Saudi Arabia, who were initially diagnosed with primary breast cancer over a span of one year. The inclusion criteria encompassed eligible patients, while those not meeting the criteria were excluded. Data extraction from patients' records was conducted, and the analysis was executed using IBM SPSS Statistics for Windows, Version 26.0 (Released 2019; IBM Corp., Armonk, New York, United States). Results This study analyzed the cardiovascular attributes of breast cancer patients, focusing on 136 female cases. The study found significant patterns concerning cardiovascular risk factors in breast cancer patients, categorized by menopausal status. Premenopausal female cases had a mean age of 43.09 ± 8.31 years, while postmenopausal patients had an average age of 58.07 ± 11.70 years. Postmenopausal patients had a higher prevalence of overweight/obesity, irregular menstrual cycles, type II diabetes, hypertension, and hyperlipidemia compared to their premenopausal counterparts. No significant differences were found between the two groups regarding low-density lipoprotein (LDL) cholesterol levels, axillary lymph node metastasis, or distant metastasis. This study emphasized the importance of regular check-ups for menopausal women to detect potential health complications early. Conclusion In summary, breast cancer is a global health concern, and understanding its impact on the cardiovascular system is crucial for comprehensive patient care. A study in Saudi Arabia found associations between cardiovascular risk factors and menopausal status in breast cancer patients. Postmenopausal patients had more prevalent risk factors, emphasizing the need for proactive assessment and management. Age-appropriate screenings and interventions are essential. Integrated healthcare approaches should consider the interplay between breast cancer and cardiovascular health, with medical professionals vigilant in evaluating and addressing risk factors to mitigate complications and optimize long-term outcomes.

The Effect of High Altitude on Short-Term Outcomes of Post-hemorrhoidectomy.

Background Hemorrhoids are caused by the distal displacement of the hemorrhoidal cushions and venous distention. Hemorrhoidal illness is still a prevalent issue. Hemorrhoidal symptoms affect 5% of the general population and 50% of people over the age of 50. Surgical therapy ensures satisfactory results that are much better than those obtained with conservative treatments, particularly for grade III and IV hemorrhoids. Objectives This study aims to compare postoperative complications of hemorrhoidectomy among patients who live in a high-altitude region (Taif) and a sea-level (low-altitude level) region (Jeddah). Methods This retrospective study was conducted among patients who underwent hemorrhoidectomy between January 2019 and January 2022 in Taif and Jeddah, Saudi Arabia. Simple random sampling was used to select the study population, and data were collected from patient files. Data analysis was conducted using IBM SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, NY). Results A total of 135 patients were included in this study. Most of our patients were males (73.3%). Patients from Jeddah represented more than half of the study population, and 45.2% were from Taif. The majority of low-altitude area patients require less than a week to return to normal activities (54.1%), whereas the majority of high-altitude area patients (59%) require more than a week (P = 0.047). 94.1% of participants felt pain on Day 1, and 54.1% had pain on Day 7. According to our findings, approximately one-fourth of patients (25.2%) developed recurrent hemorrhoids, and 27.4% experienced recurrent hemorrhoid symptoms. When we compared low-altitude regions and high-altitude regions in postoperative complications of hemorrhoidectomy, we found that urinary retention was most common in the high-altitude regions (37.7%). Conclusion Our results found that urinary retention was the most common complication in the high-altitude region. Early return to regular activity with less postoperative pain on Day 7 was a significant finding among low-altitude area patients.

Acceptance, Awareness, Attitude, and Practices Toward Heart Transplantation: A Saudi Based Survey.

Introductions: The awareness of brain death and heart donation (HD) among the Saudi population remains limited, coupled with negative attitudes toward heart donation, resulting in a significant gap between the demand for donor hearts and the available supply. This study aimed to comprehensively understand the current perceptions, attitudes, and practices of the Saudi population regarding HD, as well as identify the obstacles. The ultimate goal was to strengthen the local donor pool. Methods: A cross-sectional study was conducted from March to May 2023, employing a self-administered internet survey. The survey collected demographic information, assessed awareness, attitudes, and practices related to HD, and was completed by 1820 participants from various regions in Saudi Arabia. Data was analyzed using SPSS version 25 (SPSS Inc., Chicago, Illinois, USA). Chi-square test, Independent-samples t-test, one way analysis of variance test (ANOVA) and Spearman correlation coefficient was performed with the significance level set at p < 0.05. Results: A significant portion of the population (out of 1820 participants) lacked organ donation cards and were uncertain about the registration process. Participants displayed a moderate level of knowledge about HD, with roughly half holding unfavorable attitudes toward HD. A considerable percentage of participants 62.0% were unwilling to register as heart donors, but a majority (79.9%) were willing to contribute by disseminating information about HD. The study identified significant associations between knowledge scores and several factors, including age (p = 0.002), career (p = 0.000), possession of an organ donation card (p = 0.000), and a history of transplantation or organ donation among relatives (p = 0.000). A significant relationship was observed between attitude scores and several factors, including career (p = 0.001), Saudi region (p = 0.025), possession of an organ donation card (p = 0.000), and a history of transplantation or organ donation among relatives (p = 0.000). Conclusion: The study highlights the urgent need for increased awareness to bolster the number of local heart donors. The involvement of healthcare professionals and social campaigns is essential to enhance public knowledge and potentially boost the willingness of individuals to become donors.

Early Cytokine Signatures of Hospitalized Mild and Severe COVID-19 Patients: A Prospective Observational Study.

Background: The severe manifestation of coronavirus disease 2019 (COVID-19) is known to be mediated by several cytokines and chemokines. The study aimed to compare the early cytokine profile of mild and severe COVID-19 patients to that with COVID-19-like symptoms and tested negative for Severe Acute Respiratory Syndrome Coronavirus-2 in the Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) test. Methods: This was a prospective, observational study on COVID-19 patients admitted to King Khalid University Hospital, King Saud University Medical City from June to November 2020. Clinical and biochemical data were collected from hospital charts. Blood samples were collected at the time of hospital admission to measure cytokines. A Cytokine and Growth Factor High-Sensitivity Array was used to quantitatively measure cytokines. Results: The study included 202 RT-PCR-positive individuals and 61 RT-PCR-negative individuals. C-Reactive protein (CRP) and Interleukin-10 (IL-10) levels were found significantly elevated in the RT-PCR positive group compared to the RT-PCR negative group (p=0.001). Patients with severe COVID-19 had significantly longer median hospital stays than those with mild COVID-19 cases (7 vs 6 days). They also had higher CRP and Vascular Endothelial Growth Factor (VEGF) levels and lower Interleukin-4 (IL-4) levels compared to the mild cases. CRP, interleukin-6, IL-10, VEGF, and Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly elevated in men and IL-10 was significantly higher and interleukin-8 was significantly lower in women compared to negative controls. Elevated Interferon-É£ (IFN-γ) and IL-10 levels were seen in mild COVID-19 cases and elevated level of MCP-1 was seen in severe COVID-19 cases when categorized according to the length of stay in the hospital. Conclusion: CRP and IL-10 levels were elevated in the RT-PCR positive group. People with severe COVID-19 had higher CRP and VEGF levels and lower IL-4 levels. Elevated IFN-γ and IL-10 levels were seen in mild COVID-19 cases and elevated level of MCP-1 was seen in severe COVID-19 cases when categorized according to the length of stay in the hospital.

Association Between Cardiovascular Disease and Chronic Kidney Disease Prevalence and Characteristics in Saudi Arabia.

Introduction Cardiovascular disease (CVD), including coronary artery disease (CAD), is a leading global cause of death. Chronic kidney disease (CKD) is a significant risk factor, particularly in data-scarce Saudi Arabia, due to shared risk factors. A study aims to assess the CVD-CKD relationship, identifying clinical characteristics and risk factors to improve prevention and care in this context, filling a knowledge gap in Saudi Arabia's healthcare map. Methodology It is a single-center retrospective study aimed at evaluating the relationship between cardiovascular disease and chronic kidney disease, conducted between January 2023 and October 2023. Data was sourced from patient files using a data sheet based on a previous study. The data was cleaned in MS Excel (Redmond, USA) and analyzed in IBM Corp. Released 2022. IBM SPSS Statistics for Windows, Version 29.0. Armonk, NY: IBM Corp. Results Our study contains predominantly males (61%), aged 61-80 (54.1%), with a normal body mass index (BMI) (<25) (61.5%) and a high prevalence of smoking (72.3%). Diabetes, hypertension, and smoking were prevalent risk factors. The relationship between CAD severity, renal dysfunction, and ejection fraction (EF) was explored, emphasizing the association between declining renal function and more advanced CAD stages, as well as the decline in estimated glomerular filtration rate (eGFR) with decreasing EF. Age, smoking, CAD, and decreasing EF were linked to renal dysfunction, while smoking, stroke history, peripheral vascular disease (PVD), BMI, and decreasing EF were associated with CAD stage severity. Conclusion Our study explored that as CAD severity increases, renal function decreases, showing both CVD and CKD connected with each other, and a similar correlation occurs between decreasing EF and decreasing eGFR, revealing significant associations with various risk factors. Further research is warranted to explore potential interventions aimed at mitigating the synergistic impact of CVD and CKD on patient morbidity and mortality.