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Abstract Background and aim Heart failure is still a leading cause of mortality and morbidity. Assist devices are reserved for advanced heart failure patients with no other therapeutic options. We aim in this paper to describe the characteristics and outcome of Lebanese left ventricular assist device (LVAD) patients. Results From 2010 till December 2019, 78 patients were implanted with assist devices at the Beirut cardiac Institute, 82 pumps were used. To the most recent follow up after 10 years, 26 patients died (34%). 24 patients of 35 (68%) survived more than 5 years. Seven patients only (9%) died during one month of surgery. One year mortality was 19% (15 patients). The leading cause of early mortality was infection, whereas cerebrovascular accidents CVA were the leading cause of late mortality. Pump thrombosis occurred in 12% of the cases. The most serious long term complication was haemorrhagic CVA. Only seven patients (9%) received heart transplantation, with a mean time on support prior to transplantation of 1303 ± 213 days. Conclusion In this manuscript we reported the characteristics and outcome of the largest population of LVAD patients in Lebanon. The survival rate was 81% at one year. These findings were comparable to the international registries except for rates of heart transplantation. More efforts should be made to encourage organ donation in Lebanon.

Background and objectives: In Kuwait, information regarding public knowledge and attitudes towards organ donation are scanty. This study aimed to evaluate public knowledge and attitude regarding organ donation and determine factors which predict them. Methods: This cross-sectional study was conducted among 630 participants recruited from 27 randomly selected public cooperative societies and private supermarkets in Kuwait. A self-administered questionnaire was used to collect data. Results: The prevalence rate of knowledge about organ donation was 68%, with a significantly higher rate among females than males (73% vs. 63%, respectively, p = 0.01). A composite score of knowledge was also higher among females than males (8.4 ± 5.8 vs. 6.8 ± 5.8, respectively, p = 0.001). In multivariate analysis, female gender (OR = 1.7; 95% CI =1.2, 2.4) and an educational level of bachelor’s degree or higher (OR = 2.6, 95% CI = 1.7, 3.9) were significant predictors of the knowledge. Among the barriers, more females than males mentioned about the fear of the operative procedures (p

T follicular helper (Tfh) cells abundantly express the immunoreceptor programmed cell death protein 1 (PD-1), and the impact of PD-1 deficiency on antibody (Ab)-mediated immunity in mice is associated with compromised Tfh cell functions. Here, we revisited the role of the PD-1-PD-L1 axis on Ab-mediated immunity. Individuals with inherited PD-1 or PD-L1 deficiency had fewer memory B cells and impaired Ab responses, similar to Pdcd1 -/- and Cd274 -/- Pdcd1lg2 -/- mice. PD-1, PD-L1, or both could be detected on the surface of human naive B cells following in vitro activation. PD-1- or PD-L1-deficient B cells had reduced expression of the transcriptional regulator c-Myc and c-Myc-target genes in vivo, and PD-1 deficiency or neutralization of PD-1 or PD-L1 impeded c-Myc expression and Ab production in human B cells isolated in vitro. Furthermore, B cell-specific deletion of Pdcd1 prevented the physiological accumulation of memory B cells in mice. Thus, PD-1 shapes optimal B cell memory and Ab-mediated immunity through B cell-intrinsic and B cell-extrinsic mechanisms, suggesting that B cell dysregulation contributes to infectious and autoimmune complications following anti-PD-1-PD-L1 immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: This study investigates the efficacy and feasibility of electrical stimulation (E-Stim) on sensory fibers of the plantar region during hemodialysis sessions, aiming to improve mobility in patients with diabetes by providing a connection between E-Stim and enhanced mobility with minimal patient effort required., Research Design and Methods: Participants aged ≥18 years with diabetes undergoing hemodialysis and able to walk at least 10 m with or without aid were recruited and divided into an intervention group receiving 1-h intradialytic E-Stim three times a week and a control group using an identical nonfunctional device for 12 weeks. Gait, physical activity, patient-reported outcomes, and the technology acceptance model were assessed to evaluate the intervention's effectiveness and acceptance., Results: Out of 117 initial participants, 97 completed the study. Significant improvements were observed in the intervention group compared with the control group in gait performance (stride time at dual-task and fast walking), physical activity (stand to walk and sit to stand), quality of life, plantar numbness, and cognitive function after 12 weeks. The intervention group showed that magnitudes of improvement on gait performance and physical activity metrics were associated with enhancements in quality of life and cognitive function, respectively. The intervention group also reported higher usefulness and usage satisfaction, with a greater willingness to continue using E-Stim at home., Conclusions: The 12-week intradialytic E-Stim intervention is a feasible and effective method to enhance gait performance, physical activity level, cognitive function, and other patient-reported outcomes in patients undergoing hemodialysis, representing a practical, low-risk therapy option for those unable to engage in traditional exercise programs., (© 2024 by the American Diabetes Association.)

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αβ T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αβ T cells, autoimmune conditions were more frequent in these patients compared with the general population.

De novo aortic regurgitation (AR) presents a great challenge following left ventricular assist device (LVAD) implantation and requires valve replacement in some cases. Patients with LVAD are frequently those who underwent multiple previous sternotomies or suffer from multiple comorbidities. Thus, they are at high surgical risk for further sternotomy. Transcatheter aortic valve implantation (TAVI) previously approved for treatment of severe aortic stenosis is also used for this category of patients. Here, we report the case of a young female patient supported with heart mate II LVAD who presented with severe de novo AR. The patient was successfully treated with TAVI using Myval trancatheter heart valve (THV) in our center. To our knowledge, our patient is the first to be treated with such type of valve using TAVI procedure in LVAD supported patients., Competing Interests: No conflict of interest to declare., (© The Author(s) 2023. Published by Oxford University Press.)

Older adults with diabetes receiving hemodialysis have impaired gait speed and balance compared to the general population, which have been associated with increased risks of falls and mortality. This study evaluated the effectiveness of a game-based intradialytic exercise training program (iExergame) on improving gait speed and balance. This was a single-blind randomized controlled trial. The intervention group (IG) received iExergame training using real-time audiovisual feedback with wearable inertial sensors. The control group (CG) received conventional training without any technology. Both trainings were intradialytic, non-weight-bearing, and used ankle range of motion. Gait and balance parameters were collected at baseline and 4-week follow-up. Data from 70 adults (age 64.2 ± 9.0 years) were analyzed. Compared to the CG, the IG showed greater changes between baseline and 4-week follow-up in several parameters. Gait parameters included faster speeds and longer stride lengths, particularly during dual task walking (p < 0.050). Balance parameters included reductions in center of mass (p = 0.004), ankle (p < 0.001), and hip (p = 0.010) sways during semi-tandem stance, particularly in users of assistive devices. iExergame training could improve gait speed and balance in this population and might be an option to increase intradialytic exercise adherence while reducing burdens of exercise administration., (© 2023. Springer Nature Limited.)

Background: This cross-sectional study aimed to compare physical activity levels, plantar sensation, and fear of falling between individuals with diabetes undergoing hemodialysis, with or without walking aids., Methods: Sixty-four participants were recruited, with 37 not using walking aids (age = 65.8 ± 0.7 years, 46% female) and 27 using walking aids (age = 69.2 ± 1.2 years, 63% female). Physical activity was measured using validated pendant sensors over two consecutive days. Concern for falling and plantar numbness were assessed using the Falls Efficacy Scale-International and vibration perception threshold test, respectively., Findings: Participants using walking aids exhibited a greater fear of falling (84% vs. 38%, p < 0.01) and fewer walking bouts (p < 0.01, d = 0.67) and stand-to-walk transitions (p < 0.01, d = 0.72) compared to those not using walking aids. The number of walking bouts was negatively correlated with concern for falling scores (ρ = -0.35, p = 0.034) and vibration perception threshold (R = -0.411, p = 0.012) among individuals not using walking aids. However, these correlations were not significant among those using the walking aid. There was no significant group difference in active behavior (walking + standing %) and sedentary behavior (sitting + lying %)., Interpretation: Those undergoing hemodialysis often lead sedentary lives, with mobility affected by fear of falling and plantar numbness. Using walking aids can help, but it doesn't guarantee more walking. A combined psychosocial and physical therapy approach is key for managing fall concerns and improving mobility., Competing Interests: Declaration of Competing Interest None of the authors declared conflict of interest relevant to the scope of this study., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Impaired mobility is a debilitating consequence of hemodialysis. We examined the efficacy of intradialytic-plantar-electrical-nerve-stimulation (iPENS) to promote mobility among diabetes patients undergoing hemodialysis.., Methods: Adults with diabetes undergoing hemodialysis received either 1-h active iPENS, (Intervention-Group) or non-functional iPENS (Control-Group) during routine hemodialysis for 12 weeks (3 sessions/week). Participants and care-providers were blinded. Mobility (assessed using a validated pendant-sensor) and neuropathy (quantified by vibration-perception-threshold test) outcomes were assessed at baseline and 12 weeks., Results: Among 77 enrolled subjects (56.2 ± 2.6 years old), 39 were randomly assigned to the intervention group, while 38 were assigned to the control group. No study-related adverse events and dropouts were reported in the intervention group. Compared to the control group, significant improvements with medium to large effect sizes were observed in the intervention group at 12 weeks for mobility-performance metrics, including active-behavior, sedentary-behavior, daily step counts, and sit-to-stand duration variability (p < 0.05), Cohen's d effect size (d = 0.63-0.84). The magnitude of improvement in active-behavior was correlated with improvement in the vibration-perception-threshold test in the intervention group (r = - 0.33, p = 0.048). A subgroup with severe-neuropathy (vibration-perception-threshold > 25 V) showed a significant reduction in plantar numbness at 12 weeks compared to baseline (p = 0.03, d = 1.1)., Conclusions: This study supports feasibility, acceptability, and effectiveness of iPENS to improve mobility and potentially reduce plantar numbness in people with diabetes undergoing hemodialysis. Considering that exercise programs are not widely used in hemodialysis clinical practice, iPENS may serve as a practical, alternative solution to reduce hemodialysis-acquired weakness and promote mobility., (© 2023. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Background: Allergic disorders are the consequence of IgE sensitization to allergens. Population studies have shown that certain human leukocyte antigen (HLA) alleles are associated with increased or decreased risk of developing allergy., Objective: We aimed to characterize the relationship between HLA class II allelic diversity and IgE sensitization in an understudied Arab population., Methods: We explored associations between IgE sensitization to 7 allergen mixes and mesquite (comprising 41 food or aeroallergens) and 45 common classical HLA class II alleles in a well-defined cohort of 797 individuals representing the general adult population of Qatari nationals and long-term residents. To do so, we performed HLA calling from whole genome sequencing data at 2-field resolution using 2 independent algorithms. We then applied 3 different regression models to assess either each allergen mix independently, in the context of IgE sensitization to other allergens tested, or polysensitization., Results: More than half (n = 447) of the study participants showed IgE sensitization to at least 1 allergen, most of them (n = 400) to aeroallergens (Phadiatop). We identified statistically significant negative and positive associations with 24 HLA class II alleles. These have been reported to confer risk or protection from variety of diseases; however, only a few have previously been associated with allergy in other populations., Conclusions: Our study reveals several new risk and protective genetic markers for allergen-specific IgE sensitization. This is a first and essential step toward a better understanding of the origins of allergic diseases in this understudied population., (© 2023 The Author(s).)

Early-career researchers must acquire the skills necessary to effectively search and extract information from biomedical literature. This ability is for instance crucial for evaluating the novelty of experimental results, and assessing potential publishing opportunities. Given the rapidly growing volume of publications in the field of biomedical research, new systematic approaches need to be devised and adopted for the retrieval and curation of literature relevant to a specific theme. In this context, we present a hands-on training curriculum aimed at retrieval, profiling, and visualization of literature associated with a given topic. The curriculum was implemented in a workshop in January 2021. Here we provide supporting material and step-by-step implementation guidelines with the ISG15 gene literature serving as an illustrative use case. Workshop participants can learn several skills, including: 1) building and troubleshoot PubMed queries in order to retrieve the literature associated with a gene of interest; 2) identifying key concepts relevant to given themes (such as cell types, diseases, and biological processes); 3) measuring the prevalence of these concepts in the gene literature; 4) extracting key information from relevant articles, and 5) developing a background section or summary on the basis of this information. Finally, trainees can learn to consolidate the structured information captured through this process for presentation via an interactive web application., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Al Ali F et al.)

Introduction Epileptogenesis has been considered one of the most prevalent diseases affecting significant numbers of individuals worldwide. Since vitamin B12 has been reported to possess antiepileptic effects, this supports that vitamin B12 deficiency is correlated to seizure occurrence. Hence, this study aimed to evaluate the neuroprotective effects of vitamin B12 injection on pentylenetetrazole (PTZ)-induced rats. Methods The study was performed using 40 adult female Sprague-Dawley rats (~250 g). A 45 mg/kg PTZ was intraperitoneally injected into rat models to induce seizure effects. Different groups of rat models received methyl vitamin B12 therapy at different dosages, a low dosage of 45 µg/kg and a high dosage of 85 µg/kg, at different pre-treatment periods, one day and two weeks prior to PTZ injection. A control group, which received only PTZ injection, served as a reference. The seizure latency, seizure intensity, and differences in the quality of seizures and their characteristics, from simple twitches to complete seizures, were observed after 30 minutes of PTZ injection. Results In general, the latency to convulsion significantly increased when vitamin B12 pre-treatment was employed. The longest latency time (LT) of 520.63±73.83 seconds was observed when a high dosage of vitamin B12 at 85 µg/kg was injected one day prior to PTZ inoculation, which was significantly higher than that of the control group at 176.88±62.67 seconds (P<0.001). Moreover, the duration of convulsion significantly decreased in which the lowest duration time (DT) of 7.00±4.68 seconds was observed when a high dosage of vitamin B12 at 85 µg/kg was injected two weeks prior to PTZ inoculation, which was significantly lower than that of the control group at 257.75±41.93 seconds (P<0.001). Lastly, the percentage of the population with PTZ-induced convulsion generally decreased after vitamin B12 pre-treatment in which majority showed more of simple less aggressive twitches rather than tonic-clonic seizures. Conclusion The results showed that vitamin B12 pre-treatment alleviates the seizure occurrence among PTZ-kindled rat models. These findings then suggest that vitamin B12 is a potential strategy and treatment for epilepsy and other related epileptogenesis activities., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Fakhroo et al.)

Patients with autosomal recessive (AR) IL-12p40 or IL-12Rβ1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium -inducible IFN-γ immunity in both Vδ2 + γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F-dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ-dependent immunity to Mycobacterium in at least two lymphocyte subsets.

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity., Competing Interests: Declaration of interests J.-L.C. serves on the scientific advisory boards of ADMA Biologics Inc., Kymera Therapeutics, and Elixiron Immunotherapeutics., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia with a concomitant expansion of CD4-CD8- double-negative (DN) αβ and Vδ2- γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES- phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients' T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients' total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ-producing T cell subsets, thereby underlying TB., (© 2022 Ogishi et al.)

Introduction: Artificial intelligence (AI) and its applications are among the most discussed modern technologies today. Despite the rapidly expanding use of AI in medicine, and specifically in dermatology, only a few studies have studied the attitude of physicians toward AI., Objective: To recognize the attitudes towards AI among dermatologists in the Kingdom of Saudi Arabia., Methods: A cross-sectional survey was done among dermatologists in Saudi Arabia. Questionnaires were distributed through several online channels., Results: Overall, 103 dermatologists filled out the survey. The majority saw very strong or strong potential for AI in the automated detection of skin diseases based on dermatological clinical images (50.9%), dermoscopic images (66.6%) and within dermatopathology (66.6%). In regard to results of attitudes towards AI, 56.6% and 52. 8% agreed that AI will revolutionize medicine and dermatology, respectively. However, many of the respondents disagreed that AI will replace physicians (41.5%) and human dermatologists (39.6%) in the future. Age did not impact the overall attitude of dermatologists., Conclusion: Dermatologists in Saudi Arabia showed an optimistic attitude towards AI in dermatology and medicine. However, dermatologists believe that AI will not replace humans in the future.

Introduction: In this study, we aimed at exploring the morphologic and quantitative abnormalities in the peripheral blood counts of coronavirus disease 2019 (COVID-19) patients., Methods: A cohort of 131 COVID-19 patients was recruited at University Hospital Sharjah (UHS), UAE. Their peripheral blood smears were examined for morphological evaluation. Also, their clinical laboratory investigations and radiological findings were retrieved from the medical records. Our cohort consisted of 63 males and 68 females with an age of 63.6 ± 18.6 years., Results: The presence of atypical lymphocytes was observed in around 80% of the recruited COVID-19 patients. Further, monocytes with toxic cytoplasmic vacuoles were identified in 55% of the cases. Neutrophil-associated changes, including pseudo-Pelger-Huët, bands, and long nuclear endoplasm, were reported in around 25-35% of the patients. RBCs associated changes such as microcytic and hypochromic RBCs, as well as targetoid, dacrocytes, ovalocytes, echinocytes/burr cells, and schistocytes, were described. According to disease severity, RBCs chromicity was found to be significantly different between stable and critical patients. COVID-19 patients with CO-RADS 5 showed a similar change in RBCs as well as a decrease in the neutrophils with hypogranular cytoplasm., Conclusion: Peripheral blood smear assessment in COVID-19 patients could provide information about the disease state and pulmonary involvement., 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 © 2022 Elemam, Talaat, Bayoumi, Zein, Georgy, Altamimi, Alkhayyal, Habbal, Al Ali, ElKhider, Ahmed, Abusnana and Bendardaf.)

The atmospheric reaction of a series of furan compounds (furan (F), 2-methylfuran (2-MF), 3-methylfuran (3-MF), 2,5-dimethylfuran (2,5-DMF), and 2,3,5-trimethylfuran (2,3,5-TMF)) with nitrate radical (NO 3 ) has been investigated using the relative rate kinetic method in the CHamber for the Atmospheric Reactivity and the Metrology of the Environment (CHARME) simulation chamber at the laboratoire de Physico-Chimie de l'Atmosphere (LPCA) laboratory (Dunkerque, France). The experiments were performed at (294 ± 2) K atmospheric pressure and under dry conditions (relative humidity, RH < 2%) with proton transfer mass reaction-time of flight-mass spectrometer (PTR-ToF-MS) for the chemical analysis. The following rate coefficients (in units cm 3 molecule -1 s -1 ) were determined: furan, k (F) = (1.51 ± 0.38) × 10 -12 , 2-methylfuran, k (2-MF) = (1.91 ± 0.32) × 10 -11 , 3-methylfuran, k (3-MF) = (1.49 ± 0.33) × 10 -11 , 2,5-dimethylfuran, k (2,5-DMF) = (5.82 ± 1.21) × 10 -11 , and 2,3,5-trimethylfuran, k (2,3,5-TMF) = (1.66 ± 0.69) × 10 -10 . The uncertainty on the measured rate coefficient (Δ k FC ) includes both the uncertainty on the measurement and that on the rate coefficient of the reference molecule. To our knowledge, this work represents the first determination for the rate coefficient of the 2,3,5-TMF reaction with NO 3 . This work shows that the reaction between furan and methylated furan compounds with nitrate radical (NO 3 ) is the dominant removal pathway during the night with lifetimes between 0.5 and 55 min for the studied molecules.

Background and Objectives: The heterogeneity of the coronavirus disease of 2019 (COVID-19) lies within its diverse symptoms and severity, ranging from mild to lethal. Acute respiratory distress syndrome (ARDS) is a leading cause of mortality in COVID-19 patients, characterized by a hyper cytokine storm. Autoimmunity is proposed to occur as a result of COVID-19, given the high similarity of the immune responses observed in COVID-19 and autoimmune diseases. Here, we investigate the level of autoimmune antibodies in COVID-19 patients with different severities., Results: Initial screening for antinuclear antibodies (ANA) IgG using ELISA revealed that 1.58% (2/126) and 4% (5/126) of intensive care unit (ICU) COVID-19 cases expressed strong and moderate ANA levels, respectively. An additional sample was positive with immunofluorescence assays (IFA) screening. However, all the non-ICU cases (n=273) were ANA negative using both assays. Samples positive for ANA were further confirmed with large-scale autoantibody screening by phage immunoprecipitation-sequencing (PhIP-Seq). The majority of the ANA-positive samples showed "speckled" ANA pattern by microscopy and revealed autoantibody specificities that targeted proteins involved in intracellular signal transduction, metabolism, apoptotic processes, and cell death by PhIP-Seq; further denoting reactivity to nuclear and cytoplasmic antigens., Conclusion: Our results further support the notion of routine screening for autoimmune responses in COVID-19 patients, which might help improve disease prognosis and patient management. Further, results provide compelling evidence that ANA-positive individuals should be excluded from being donors for convalescent plasma therapy in the context of COVID-19., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Allelic diversity of human leukocyte antigen (HLA) class II genes may help maintain humoral immunity against infectious diseases. In this study, we investigated germline genetic variation in classical HLA class II genes and employed a systematic, unbiased approach to explore the relative contribution of this genetic variation in the antibody repertoire to various common pathogens. We leveraged a well-defined cohort of 800 adults representing the general Arab population in which genetic material is shared because of the high frequency of consanguineous unions. By applying a high-throughput method for large-scale antibody profiling to this well-defined cohort, we were able to dissect the overall effect of zygosity for classical HLA class II genes, as well as the effects associated with specific HLA class II alleles, haplotypes and genotypes, on the antimicrobial antibody repertoire breadth and antibody specificity with unprecedented resolution. Our population genetic studies revealed that zygosity of the classical HLA class II genes is a strong predictor of antibody responses to common human pathogens, suggesting that classical HLA class II gene heterozygosity confers a selective advantage. Moreover, we demonstrated that multiple HLA class II alleles can have additive effects on the antibody repertoire to common pathogens. We also identified associations of HLA-DRB1 genotypes with specific antigens. Our findings suggest that HLA class II gene polymorphisms confer specific humoral immunity against common pathogens, which may have contributed to the genetic diversity of HLA class II loci during hominine evolution., 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 © 2022 Khan, Rahman, Ahmed, Al Ali, Jithesh and Marr.)

Coronavirus Disease (COVID-19) was declared a pandemic by WHO in March 2020. Since then, additional novel coronavirus variants have emerged challenging the current healthcare system worldwide. There is an increased need for hospital care, especially intensive care unit (ICU), for the patients severely affected by the disease. Most of the studies analyzed COVID-19 infected patients in the hospitals and established the positive correlation between clinical parameters such as high levels of D-dimer, C-reactive protein, and ferritin to the severity of infection. However, little is known about the course of the ICU admission. The retrospective study carried out at University Hospital Sharjah, UAE presented here reports an integrated analysis of the biochemical and radiological factors among the newly admitted COVID-19 patients to decide on their ICU admission. The descriptive statistical analysis revealed that patients with clinical presentations such as acute respiratory distress syndrome (ARDS) (p<0.0001) at the time of admission needed intensive care. The ROC plot indicated that radiological factors including high chest CT scores (>CO-RADS 4) in combination with biochemical parameters such as higher levels of blood urea nitrogen (>6.7 mg/dL;66% sensitivity and 75.8% specificity) and ferritin (>290 μg/mL, 71.4% sensitivity and 77.8% specificity) may predict ICU admission with 94.2% accuracy among COVID-19 patients. Collectively, these findings would benefit the hospitals to predict the ICU admission amongst COVID-19 infected patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive., Objectives: To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C., Methods: Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured., Results: We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency., Conclusions: Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients., (© 2022. The Author(s).)

Introduction: Diabetes mellitus (DM) is a leading cause of end-stage kidney disease (ESKD). We provide the first description of DM prevalence, related outcomes, and the hemoglobin A1c (HbA1c)/mortality relationship in national hemodialysis (HD) patient samples across the Gulf Cooperation Council (GCC) countries., Methods: We analyzed data from the prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) in the GCC (2012-2018, N  = 2274 HD patients ≥18 years old). Descriptive statistics were calculated, and all-cause mortality was analyzed for patients with DM versus without DM and by HbA1c levels in patients with DM by Cox regression with progressive confounder adjustments., Results: DM in the GCC ranged from 45% to 74% in patients with HD by country. Patients with DM were 13 years older (59.9 vs. 46.7 years) and had greater body mass index (BMI), shorter median years on dialysis (1.5 vs. 3.0 years), and higher comorbidity burden. In patients with DM, insulin use was 26% to 50% across countries, with variable oral antidiabetic drug use (2%-32%); median HbA1c levels were 6.1% to 7.5% across countries. Patients with DM (vs. without DM) had higher crude death rates (15.6 vs. 6.2 deaths per 100 patient-years, mean follow-up 1.3 years) and adjusted mortality (hazard ratio [HR] = 1.72 [95% CI 1.23-2.39]). In patients with DM, mortality was lowest at HbA1c 6.5% to 7.5%, with mortality particularly elevated at high HbA1c >9% (HR = 2.13 [95% CI 1.10-4.10])., Conclusion: Patients with DM in the GCC have high comorbidity burden and mortality rates despite a relatively young mean age. In GCC countries, a holistic strategy for improving diabetes care and outcomes for HD patients is needed at the primary, secondary, and tertiary levels., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Purpose: Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency; however, the extent to which immune signaling and host defense are impaired is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM&#95;006282.2:c.871C > T, p.Arg291*) identified in a pediatric patient by comparing his innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls., Methods: The genetic etiology was verified by whole genome and Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA, and flow cytometry. Antibody responses were assessed by ELISA and phage immunoprecipitation-sequencing., Results: The patient exhibited partial loss of STK4 expression and complete loss of STK4 function combined with recurrent viral and bacterial infections, notably persistent Epstein-Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient's whole blood and PBMC samples indicated dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis as well as impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpes virus antigens., Conclusion: Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells., (© 2021. The Author(s).)

Introduction: Anemia management in dialysis is challenging. Keeping hemoglobin levels within a tight range is difficult. A new program (anemia nurse manager [ANM]) was started for better anemia management. This study aimed to compare traditional anemia management with the new ANM model regarding the achievement of better hemoglobin targets (range, 10-12 g/dL), avoidance of extreme hemoglobin levels ( < 9 or >13 g/dL), and evaluation of the cost-effectiveness of the new model., Methods: This retrospective observational study compared traditional anemia management with management involving our new ANM model. Patients on hemodialysis in all ambulatory dialysis clinics in Qatar were included. The study included three phases: phase 1 (observation): June 2015 to August 2015, 460 patients; phase 2 (pilot): September 2015 to May 2016, 211 patients; and phase 3 (expansion in two phases): June 2016 to February 2017 and October 2017 to June 2018, 610 patients. Hemoglobin, iron saturation, and ferritin were evaluated according to the protocol., Results: In this study, 55% of the patients achieved the target hemoglobin in phase 1 compared with 75% in phase 2 ( p  = 0.0007). The hemoglobin level within the target range was sustained at 72% ± 5% of patients in phase 3. The achievement rate of the target hemoglobin level increased from 56% (May 2015) to 72% (July 2018) ( p  < 0.001). The proportion of patients with extreme hemoglobin declined from 10.7% in phase 1 to 6.4% in phase 2 and sustained at 8% afterward. Reducing the doses of erythropoietin stimulating agents, owing to the use of the ANM model, saved costs by approximately 11%., Conclusions: The ANM model was able to achieve and maintain hemoglobin levels within the target range and decrease extreme hemoglobin levels. These outcomes improved patient care by avoiding high hemoglobin (increase thrombosis, cancer recurrence, stroke, and death) and low hemoglobin (weakness, poor quality of life, and need for transfusion) levels. The ANM model was cost effective even after including the salaries of nurses. This model can be considered in other aspects of patient care in dialysis., (© 2021 Hamad, Ezzat, Ghonimi, Ibrahim, Ramadan, Noor, Yasin, Ismail, Al-Ali, licensee HBKU Press.)

In this study, we investigated the prevalence of sexual dysfunction among males with advanced chronic kidney disease and the effect of treating hyperprolactinemia among these patients. In this prospective study, patients were assessed with history, physical examination, hormonal assessment, and two questionnaires, IIEF and AIPE. Patients with hyperprolactinemia received treatment with cabergoline 0.5 mg once per week for 6 months and were re-evaluated. A total of 102 patients were included in this study, 75 (73.53%) were on hemodialysis, 13 (12.75%) on peritoneal dialysis and 14 (13.73%) on medical treatment alone. Ninety (88.24%) patients had premature ejaculation, 85 (83.33%) had anything from mild-to-moderate-to-severe erectile dysfunction. The incidence of hypogonadism and hyperprolactinemia was 34.4%. Patients treated with cabergoline (n = 26) showed a significant increase in LH levels (p = .003) and a significant decrease in prolactin levels (p = .003). Testosterone levels and the incidence of erectile dysfunction or premature ejaculation did not improve significantly. There is a high incidence of sexual dysfunction among patients. Treatment of hyperprolactinemia is effective in correcting prolactin levels, but does not improve erectile dysfunction or premature ejaculation. Therefore, treating hyperprolactinemia is not an overall effective treatment for erectile dysfunction in these patients., (© 2021 The Authors. Andrologia published by Wiley-VCH GmbH.)

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants ( p = 3.5 × 10 -5 ). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection ( n =2, 5 and 38 years), or moderate ( n =1, 5 years), severe ( n =1, 27 years), or critical ( n =1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10 -4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract., (Copyright © 2021, American Association for the Advancement of Science.)

Background: Wasting is a common complication of kidney failure that leads to weight loss and poor outcomes. Recent experimental data identified parathyroid hormone (PTH) as a driver of adipose tissue browning and wasting, but little is known about the relations among secondary hyperparathyroidism, weight loss, and risk of mortality in dialysis patients., Methods: We included 42,319 chronic in-centre haemodialysis patients from the Dialysis Outcomes and Practice Patterns Study phases 2-6 (2002-2018). Linear mixed models were used to estimate the association between baseline PTH and percent weight change over 12 months, adjusting for country, demographics, comorbidities, and labs. Accelerated failure time models were used to assess 12 month weight loss as a mediator between baseline high PTH and mortality after 12 months., Results: Baseline PTH was inversely associated with 12 month weight change: 12 month weight loss >5% was observed in 21%, 18%, 18%, 17%, 15%, and 14% of patients for PTH ≥600 pg/mL, 450-600, 300-450, 150-300, 50-150, and <50 pg/mL, respectively. In adjusted analyses, 12 month weight change compared with PTH 150-299 pg/mL was -0.60%, -0.12%, -0.10%, +0.15%, and +0.35% for PTH ≥600, 450-600, 300-450, 50-150, and <50 pg/mL, respectively. This relationship was robust regardless of recent hospitalization and was more pronounced in persons with preserved appetite. During follow-up after the 12 month weight measure [median, 1.0 (interquartile range, 0.6-1.7) years; 6125 deaths], patients with baseline PTH ≥600 pg/mL had 11% [95% confidence interval (CI), 9-13%] shorter lifespan, and 18% (95% CI, 14-23%) of this effect was mediated through weight loss ≥2.5%., Conclusions: Secondary hyperparathyroidism may be a novel mechanism of wasting, corroborating experimental data, and, among chronic dialysis patients, this pathway may be a mediator between elevated PTH levels and mortality. Future research should determine whether PTH-lowering therapy can limit weight loss and improve longer term dialysis outcomes., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4 + T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4 + T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity., Competing Interests: Declaration of interests L.D.N. receives compensation as Chief Editor of Frontiers in Immunology. T.W. serves on advisory boards for MSD (Merck Sharp and Dohme). J.-L.C. serves on the scientific advisory boards of ADMA Biologics Inc., Kymera Therapeutics, and Elixiron Immunotherapeutics. All other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Patients with end-stage renal disease treated with dialysis have poor quality of life (QOL). Improving QOL in these patients with multiple comorbidities is a large challenge. We performed a cross-sectional study to evaluate the prevalence and associated factors of depression and sleep disorders in this population. Our primary aim was to evaluate QOL measures in dialysis patients in Qatar through a series of validated questionnaires mainly concerning depression and sleep disorders. Our secondary aim was to study the associations of age, sex, and comorbid conditions with the QOL measures. We hypothesized that end-stage renal disease (ESRD) patients on dialysis would have disturbed QOL due to both ESRD and dialysis and comorbidities. This prospective cross-sectional study included adult ESRD patients receiving either hemodialysis (HD) or peritoneal dialysis (PD) in the main tertiary dialysis unit in Qatar. We administered two surveys to evaluate depression (the Center for Epidemiologic Studies Depression Scale, http://www.bmedreport.com/archives/7139) and sleep disorders (the Pittsburgh Sleep Quality Index, https://www.sleep.pitt.edu/instruments/). We also reviewed patient demographics, comorbidities, and laboratory test results to evaluate any associated factors. We randomly studied 253 patients (62% on HD and 38% on PD). Overall, 48% of patients had depression, while 83.8% had sleep disorders. The PD had more poor sleepers than the HD group (89.1% versus (vs.) 75%, p =0.003). Most of our dialysis patients had poor sleep, but it was more significant in the elderly group 109 (90%) than in the young group 103 (78%) ( p =0.009). Patients with diabetes mellitus (DM) had significantly more prevalence of poor sleep (131 (88.5%)) than those without DM (81 (77.1%), p =0.01). More female patients had depression than male patients (52% vs. 25%, p < 0.0001; odds ratio: 3.27 (95% confidence interval: 1.9-5.6), p < 0.0001). This is the first study in Qatar to evaluate depression and sleep disorders in patients on dialysis therapy., Competing Interests: All authors declare no conflicts of interest., (Copyright © 2021 Fadwa Al-Ali et al.)

Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria., Competing Interests: The authors declare no competing interest.

Background: End-stage kidney disease (ESKD) patients on maintenance renal replacement therapy (RRT) have far lower life spans than those of the general population. No previous studies have been performed to assess the mortality of dialysis patients in the State of Qatar. We designed this study to assess the mortality of dialysis patients in Qatar and the impact of dialysis modality., Methods: All chronic ambulatory dialysis patients (both on hemodialysis (HD) and peritoneal dialysis (PD) between 2014 and 2016) were included in the study, whereas patients undergoing dialysis for less than 3 months were excluded. We reviewed patients' demographics, comorbidities, and general laboratory investigations through our electronic record system and collected and analyzed them. We identified patients who died during that period and compared them to those who survived. We performed a subanalysis for HD versus PD patients who died., Results: The total number of deceased dialysis patients was 164, with an overall crude mortality rate of 6.4%. They were significantly older than those who survived ( p  = 0.0001). The mortality rate was significantly higher in female than in male patients (51.2% and 38.9%, respectively) ( p  = 0.004) but significantly lower in PD than HD patients (1.36%, PD; 5.0%, HD ;   p  = 0.007). It was also significantly higher in natives than in the expats (60.3% and 39.6%, respectively)  (p  = 0.0008); however, no significant differences were noted between deceased natives and expats in most demographic and laboratory characteristics. The most common cause of patient death was CVD (62 patients, 37.8%), followed by sepsis (44 patients, 26.8%). Diabetes, cerebrovascular accident, and dyslipidemia were more common in HD deceased patients than in PD patients (80.6%, 47%, and 59%, respectively, in HD patients vs 68.5%, 42%, and 31%, respectively, in PD patients). Albumin and potassium levels in deceased PD patients were significantly lower than in HD patients ( p  = 0.001)., Conclusion: Our study found that the high-risk population had a significant mortality, which was higher in HD than PD patients. This is the first study to look at these outcomes in Qatar. We identified multiple mortality associated factors, such as comorbid conditions and old age. We believe that improving treatment and close monitoring for comorbid conditions in the dialysis population might improve survival., (© 2021 Ghonimi, Hamad, Iqbal, Yasin, Ali, Ismail, Aziz, Al-Ali, licensee HBKU Press. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.)

With the increasing prevalence of obesity and type 2 diabetes, fatty liver disease associated with metabolic dysfunction is a global health problem, especially because it is one of the earliest consequences of obesity and it precedes diabetes development. Fatty liver disease associated with metabolic dysfunction is of particular concern in the Middle East and north Africa, where its prevalence is greater than that in the rest of the world. Despite the magnitude of the problem, no regional guidelines have been developed to address this disease. This Review describes suggestions of redefining fatty liver disease associated with metabolic dysfunction, including its terminology and criteria for diagnosis. Experts have raised serious concerns on the current nomenclature, which labels the disease as non-alcoholic fatty liver disease (NAFLD), and its diagnostic criteria. The panel reached a consensus that the disease should be renamed as metabolic-associated fatty liver disease (MAFLD) and that the disease should be diagnosed by positive criteria. The aim is now to work with authorities across the region to implement these proposed changes and reflect them in health-care policy and to improve health care for patients in this region., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2 + γδ T lymphocytes, and of Mycobacterium-non reactive classic T H 1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8 + αβ T and non-classic CD4 + αβ T H 1 ∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2 + γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8 + αβ T, and CD4 + αβ T H 1 ∗ cells unable to compensate for this deficit., Competing Interests: Declaration of Interests L.H.G. serves on the Board of Directors of GlaxoSmithKline Pharmaceutical Company and the Analog Device Corporation and formerly served on the Boards of Bristol Myers Squibb Pharmaceutical Company and the Waters Corporation. She is also on the Scientific Advisory Boards of Abpro, Kaleido, and Repare biotechnology companies. J.-L.C. serves on the Scientific Advisory Boards of ADMA Biologics Inc., Celgene, and Kymera Therapeutics, Inc. He also consults for Elixiron Immunotherapeutics. Other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) has collected data since 2012 in all six Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and United Arab Emirates). We report the relationship of PTH with mortality in this largest GCC cohort of patients on hemodialysis studied to date., Methods: Data were from randomly selected national samples of hemodialysis facilities in GCC-DOPPS phases 5 and 6 (2012-2018). PTH descriptive findings and case mix-adjusted PTH/mortality Cox regression analyses were based on 1825 and 1422 randomly selected patients on hemodialysis, respectively., Results: Mean patient age was 55 years (median dialysis vintage, 2.1 years). Median PTH ranged from 259 pg/ml (UAE) to 437 pg/ml (Kuwait), with 22% having PTH <150 pg/ml, 24% with PTH of 150-300 pg/ml, 34% with PTH 301-700 pg/ml, and 20% with PTH >700 pg/ml. Patients with PTH >700 pg/ml were younger; on dialysis longer; less likely to be diabetic; have urine >200 ml/d; be prescribed 3.5 mEq/L dialysate calcium; had higher mean serum creatinine and phosphate levels; lower white blood cell counts; and more likely to be prescribed cinacalcet, phosphate binders, or IV vitamin D. A U-shaped PTH/mortality relationship was observed with more than two- and 1.5-fold higher adjusted HR of death at PTH >700 pg/ml and <300 pg/ml, respectively, compared with PTH of 301-450 pg/ml., Conclusions: Secondary hyperparathyroidism is highly prevalent among GCC patients on hemodialysis, with a strong U-shaped PTH/mortality relationship seen at PTH <300 and >450 pg/ml. Future studies are encouraged for further understanding this PTH/mortality pattern in relationship to unique aspects of the GCC hemodialysis population., Competing Interests: B. Bieber, R. Pisoni, and B. Robinson report receiving grants from Amgen, during the conduct of the study. E. Fouly reports receiving salary from his company, Amgen, during the conduct of the study, which was supported by Amgen. In addition, E. Fouly’s company, Amgen, has licensed patents for cinacalcet and etelcalcetide, which are drugs used to treat sHPT and are thus related to the topic of this paper. This project was carried out as part of the DOPPS Program which receives global support from a large consortium of funders listed at https://www.dopps.org/AboutUs/Support.aspx. All such grants were made to Arbor Research Collaborative for Health and not to coauthors directly. All remaining authors have nothing to disclose., (Copyright © 2020 by the American Society of Nephrology.)

Cognitive impairment is prevalent but still poorly diagnosed in hemodialysis adults, mainly because of the impracticality of current tools. This study examined whether remotely monitoring mobility performance can help identifying digital measures of cognitive impairment in hemodialysis patients. Sixty-nine diabetes mellitus hemodialysis patients (age = 64.1±8.1years, body mass index = 31.7±7.6kg/m2) were recruited. According to the Mini-Mental State Exam, 44 (64%) were determined as cognitive-intact, and 25 (36%) as cognitive-impaired. Mobility performance, including cumulated posture duration (sitting, lying, standing, and walking), daily walking performance (step and unbroken walking bout), as well as postural-transition (daily number and average duration), were measured using a validated pendant-sensor for a continuous period of 24-hour during a non-dialysis day. Motor capacity was quantified by assessing standing balance and gait performance under single-task and dual-task conditions. No between-group difference was observed for the motor capacity. However, the mobility performance was different between groups. The cognitive-impaired group spent significantly higher percentage of time in sitting and lying (Cohens effect size d = 0.78, p = 0.005) but took significantly less daily steps (d = 0.69, p = 0.015) than the cognitive-intact group. The largest effect of reduction in number of postural-transition was observed in walk-to-sit transition (d = 0.65, p = 0.020). Regression models based on demographics, addition of daily walking performance, and addition of other mobility performance metrics, led to area-under-curves of 0.76, 0.78, and 0.93, respectively, for discriminating cognitive-impaired cases. This study suggests that mobility performance metrics could be served as potential digital biomarkers of cognitive impairment among hemodialysis patients. It also highlights the additional value of measuring cumulated posture duration and postural-transition to improve the detection of cognitive impairment. Future studies need to examine potential benefits of mobility performance metrics for early diagnosis of cognitive impairment/dementia and timely intervention., Competing Interests: Author TT is an employee of the Hamad Medical Co. Doha, Qatar' and 'Author Bijan Najafi is a handling editor on the PLOS ONE Digital Health Technology Call for Papers'. This does not affect our adherence to PLOS ONE policies on sharing data and materials.

Regular exercise can reduce depression. However, the uptake of exercise is limited in patients with end-stage renal disease undergoing hemodialysis. To address the gap, we designed a gamified non-weight-bearing intradialytic exercise program (exergame). The intradialytic exergame is virtually supervised based on its interactive feedback via wearable sensors attached on lower extremities. We examined the effectiveness of this program to reduce depression symptoms compared to nurse-supervised intradialytic exercise in 73 hemodialysis patients (age = 64.5 ± 8.7years, BMI = 31.6 ± 7.6kg/m 2 ). Participants were randomized into an exergame group (EG) or a supervised exercise group (SG). Both groups received similar exercise tasks for 4 weeks, with three 30 min sessions per week, during hemodialysis treatment. Depression symptoms were assessed at baseline and the fourth week using the Center for Epidemiologic Studies Depression Scale. Both groups showed a significant reduction in depression score (37%, p < 0.001, Cohen's effect size d = 0.69 in EG vs. 41%, p < 0.001, d = 0.65 in SG) with no between-group difference for the observed effect ( p > 0.050). The EG expressed a positive intradialytic exercise experience including fun, safety, and helpfulness of sensor feedback. Together, results suggested that the virtually supervised low-intensity intradialytic exergame is feasible during routine hemodialysis treatment. It also appears to be as effective as nurse-supervised intradialytic exercise to reduce depression symptoms, while reducing the burden of administrating exercise on dialysis clinics.

Background: Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 ( Nos2 ) are susceptible to the related murine CMV infection., Methods: We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally., Results: We found a homozygous frameshift mutation in NOS2 encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all NOS2 variants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001., Conclusions: These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.)., (Copyright © 2020 Massachusetts Medical Society.)