Search

High offset liners help to restore soft tissue tension after primary total hip arthroplasty (THA). However, prior research has reported increased rates of aseptic loosening when using offset components. The purpose of this study was to examine the postoperative complication and revision rates of neutral vs offset acetabular liners at our institution. Two hundred eight primary THAs in 206 patients performed between 2016 and 2018 using neutral or offset liners were reviewed. All patients had a minimum 2-year clinical follow-up (mean, 3.3 years; range, 2.0-5.7 years). Postoperative complications and revision surgeries were reviewed. All offset liners were 4 mm in thickness. Twelve (10.0%) complications occurred in the neutral liner group, and 13 (14.8%) complications occurred in the offset liner group. Two cases of aseptic loosening occurred in the neutral liner group, with no cases reported in the offset liner group. Nine cases (7.5%) in the neutral group required revision surgery, whereas 3 cases in the offset group required revision surgery. Chi-square analysis found no difference between the groups in the rate of postoperative complications, χ 2 (1, N=208)=1.09 ( P >.05), or the rate of revision, χ 2 (1, N=208)=1.56 ( P >.05). We found no significant differences between the neutral and offset groups regarding the rates of postoperative complications, aseptic loosening, or revision surgery. Our findings suggest that contemporary high offset liners, up to 4 mm, are safe and effective when attempting to restore native hip mechanics after THA. [ Orthopedics . 202x;4x(x):xx–xx.]

Background: Data concerning impact of COVID-19 on children with rheumatic disorders in developing countries are limited. Methods: We conducted a retrospective analysis, examining the medical records of 49 children (15 males, 34 females) with rheumatologic disorders who got infected with SARS-CoV2. They were recruited, over a period of 17 months, from the Children’s Hospitals of Ain Shams, Mansoura and Assiut Universities in Egypt. Data recorded were the type and duration of rheumatologic, antirheumatic treatment received, and COVID-19 presentation including severity, and outcome. Complete blood count (CBC), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), lactate dehydrogenase enzyme (LDH), serum ferritin, and Ddimer levels were recorded. Results: Our series included 25 SLE, 16 JIA, two polyarteritis nodosa, two dermatomyositis, two mixed connective tissue disease, one systemic sclerosis, and one HSP patients. They had median (IQR) age of 13 (10-14) years. Twenty-nine (59.2%) patients had active disease flare. Fortyone (83.7%) patients were on corticosteroids, and 35 (71.4%) were on add-on immunosuppressives. Twenty-nine patients were hospitalized with median (IQR) admission duration of 25 (14-38) days. They included 8 mild/asymptomatic, 4 moderate, 6 severe, and 11 critical COVID-19 cases. Seven cases with critical COVID-19 passed away with mortality rate of 14.3 %. The deceased cases had higher neutrophil/lymphocyte ratio (p=0.003), higher CRP levels (p= 0.041) and higher D-dimer (p=0.001) and ferritin levels (0.002) as compared to survivors. Conclusion: Although reported to be milder in children, COVID-19 seems to have higher mortality among children with rheumatic disorders compared to rates reported in the general population. We could not find evidence for the impact of immunosuppressive treatment on COVID-19 related mortality, yet our findings need to be validated by wider scale prospective studies.

Purpose Inborn errors of immunity (IEI) comprise a heterogeneous group of monogenic disorders with wide spectrum of clinical manifestations. The aim of this study is to describe epidemiologic, clinical, and genetic features of patients with inborn errors of immunity in Mansoura University Children’s Hospital, a tertiary care center in Egypt. Methods We included patients seen during the period between 2014–2022. Data collected included sociodemographic, clinical features, laboratory investigations, management, and outcome. Results We enrolled 184 patients. The male/female ratio was 1.8:1. The age of onset of symptoms ranged between 2 and 24 months. The age at diagnosis ranged between 12 and 33.5 months with a diagnostic delay range of 0 to 213 months. One hundred and fifteen patients (62.5%) were born to consanguineous parents and family history was positive in 59 patients (32.1%). The most common category was immunodeficiencies affecting cellular and humoral immunity with Seventy-seven patients (41.8%). A causative mutation was identified in 106 patients (57.6% of all cases) with a diagnostic yield of 82.8%. The overall case fatality rate was 48 patients (26.1%). Conclusion Despite a single centre study, this data set may act as a nidus for setting up a national registry of IEIs disorders in Egypt. This study indicates that PIDs are not uncommon in Egypt and that immunodeficiencies affecting cellular and humoral immunity is the most common category. Introduction of wide-scale genetic tests allow early diagnosis and treatment that improve the quality of life.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Introduction Early recognition of an anaphylaxis event is crucial for instituting lifesaving management. We sought to explore knowledge and practice towards anaphylaxis in a sample of physicians from ten Egyptian governorates. Methods An eighteen question-based questionnaire was developed by expert allergists to evaluate the knowledge and practice towards anaphylaxis, based on the World Allergy Organization guidelines for the assessment and management of anaphylaxis. The questionnaires were distributed, and the answered forms collected via emails, and data were tabulated, and analysed. Results In this cross-sectional study, a total of 242 physicians completed the survey (183 (75.6%) paediatricians, 32 (13.2%) internists, 22 (9.1%) intensivists and five (2.1%) anaesthetists). Only 91 participants (37.6%) identified all the four proposed anaphylaxis clinical scenarios while 70, 45 and 36 identified three, two and one scenario, respectively. Loss of consciousness and abdominal symptoms were not recognised as possible presentations of anaphylaxis by 64.5% and 80.2% of the participants, respectively. Epinephrine was considered the first line treatment by 98 (40.5%), corticosteroids by 77 (31.8%) and antihistamines by 25 (10.3%). 75 (31%) responders identified the right dose of epinephrine while 119 (49.2%) identified the proper route. Concerning practice, 83 physicians (39.2%) used epinephrine for all cases of anaphylaxis, 88 (41.5%) used it for refractory cases only whereas 41 (19.3%) did not use epinephrine at all. Discussion Our survey shows that the knowledge of Egyptian physicians and their practice towards anaphylaxis are still inadequate. The current situation reinforces the need to disseminate and encourage the adoption of the international guidelines for anaphylaxis diagnosis and treatment.

BackgroundWe previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants wasTLR7, with an OR of 27.68 (95%CI:1.5-528.7,P=1.1×10−4), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2],P=2.1×10−4). Adding the recently reportedTYK2COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4];P=3.4×10−3). When these 14 loci andTLR7were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0],P=4.7×10−7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9],P=0.02). Finally, the patients with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years;P=1.68×10−5).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Background:Coronavirus disease 2019 (COVID-19) is responsible for significant lung disease in adults. Despite mild manifestations in most children, multisystem inflammatory syndrome (MIS-C) associated with COVID-19 is well described in older children with cardiac manifestations. However, MIS-C-related cardiac manifestations are not as well described in younger children.Methods:The study is a retrospective analysis of MIS-C patients under the age of 5 years admitted between May and November 2020 to a single centre. Included cases fulfilled the case definition of MIS-C according to Royal College of Pediatrics and Child Health criteria with laboratory, electrocardiogram, or echocardiographic evidence of cardiac disease. Collected data included patients’ demographics, laboratory results, echocardiographic findings, management, and outcomes.Results:Out of 16 MIS-C cases under 5 years of age, 10 (62.5%) had cardiac manifestations with a median age of 12 months, 9 (90%) were previously healthy. Cardiac manifestations included coronary arterial aneurysms or ectasia in five (50%) cases, two (20%) with isolated myopericarditis, coronary ectasia with myocarditis in two (20%), and supraventricular tachycardia in one (10%). Intravenous immunoglobulins were given in all cases with coronary involvement or myocarditis. The median duration of hospitalisation was 7 (6–14) days; two (20%) cases with cardiac disease were mechanically ventilated and mortality in MIS-C cases below 5 years was 12.5%. Normalisation of systolic function occurred in half of the affected cases within 1 week and reached 100% by 30 days of follow-up.Conclusions:MIS-C associated with SARS-CoV-2 has a high possibility of serious associated cardiac manifestations in children under the age of 5 years with mortality and/or long-term morbidities such as coronary aneurysms even in previously healthy children.

Background: Hypertrophic scar (HTS) formation after burn remains a major issue for burned patients and is considered a huge problem for clinicians because the hypertrophic scar is painful, reddish, elevated, pruritic, and aesthetically unacceptable. Objective: To evaluate the therapeutic efficacy of Cybele Scagel phonophoresis on the treatment of hypertrophic scar post burn cases. Patients and methods: Thirty patients who had hypertrophic scar after wound closure with ages ranged from 20 to 45 years were selected randomly and divided into two equal groups in number (15 patients each). Group A (study group): received Cybele scagel phonophoresis, 3 sessions per week for 8 weeks (24 sessions), while patients in group B (control group): received topical cybele scagel for 8 weeks. Methods of assessment before and after the study included Modified Vancouver scar scale (VSS) to assess hypertrophic scar characteristics (height, vascularity, pigmentation and pliability) and digital imaging for visual assessment of the scars. Results: the results of the study showed that between groups comparison, there was no significant difference in VSS between both groups pre-treatment (p > 0.05). Comparison between group A and group B post-treatment revealed a significant decrease in VSS of the group A compared to that of group B (p > 0.05). Conclusion: It could be concluded that Cybele Scagel phonophoresis is an effective and safe modality that can be used for improving appearance of post burn hypertrophic scar.

Background About 25–50% of multisystem inflammatory syndrome in children (MIS-C) patients meet the criteria for diagnosis of Kawasaki disease (KD). The differentiation of both conditions is so challenging on clinical practice as the management of both is time dependant and precise diagnosis is fundamental. Method Data were collected from children Results 72 patients with MIS-C and 18 with KD were included in the study. Patients with MIS-C had a higher prevalence of abdominal pain (p = 0.02), vomiting (p = 0.03), and cervical lymphadenopathy (p = 0.02) compared with KD cases. MIS-C patients had higher liver enzymes (aspartate aminotransferase (AST) (p = 0.04), alanine aminotransferase (ALT) (p = 0.03), serum creatinine (p = 0.03), and lower platelet count nadir (p = 0.02) than KD. Four variables were detected in the regression analysis model, and the independent predictors were utilized to generate a scoring model that distinguished MIS-C from KD with an area under the curve of 0.70. Conclusion This study constructed a prediction model for differentiation of MIS-C from KD based on clinical and laboratory profiles. This model will be valuable to guide clinicians in the treatment decisions. Key Points• Children with MIS-C are more likely to have gastrointestinal symptoms, cervical lymphadenopathy, and respiratory involvement than KD patients.• Elevated liver enzymes and lower platelet count are more pronounced laboratory findings in MIS-C than KD.• This study constructed a prediction model for differentiation of MIS-C from KD based on clinical and laboratory profiles. This model will be valuable to guide clinicians in the treatment decisions.

Introduction Respiratory conditions are the most common reason for admission of newborns to a neonatal care unit. The index of contractility (ICON) can be used to measure the thoracic fluid content (TFC) in neonates which is a significant parameter in cases presented with transient tachypnea of newborn (TTN). Objective The objective was to compare TFC between newborn infants with TTN compared with other causes of respiratory distress (RD). We tested the hypothesis that TFC would be higher in infants with TTN. Study Design In total, 105 newborns were enrolled at the delivery room and were categorized into three groups: TTN, other causes of RD, and control, according to physical examination and Chest X-Ray. TFC was measured within the first 6 hours for all infants and at 24 and 48 hours for the first two groups. Results Demographic data showed higher male participants and use of antenatal steroid therapy in RD groups. TFC within the first 6 hours was higher in RD groups. However, TFC at 24 hours of ≤24 mL/kg, and TFC drop rate at 24 hours of >12% are statistically significant discriminators of TTN from non-TTN, with sensitivity and specificity of 97.1 and 47.1%, and 60 and 82.4%, respectively (Fig 1 and 2). Conclusion ICON can be used in conjunction with clinical parameters and CXR as a tool for differentiation between TTN and other causes of RD within the first 24 hours of life by using the cutoff value of TFC at 24 hours and TFC drop rate. This will allow earlier and optimum management of different causes of RD. Key Points

Software defined networks are an emerging category of networks in which the data plane and control plane are separated. This separation of planes opens the door for designing sophisticated routing algorithms that would overwhelm the computing power of traditional networking nodes. In this paper, we consider the possibility of introducing node trust into the routing problem. There are many ways for measuring node trust. However, in this paper, we focus on denial of service attacks. We develop a hybrid method for detecting denial of service attacks and incorporate this information in routing decisions so that nodes that are part of a botnet can be quickly identified and excluded from the network. The proposed method is flexible enough to allow nodes that have been suspected of participating in a denial of service attack to be “rehabilitated” if they cease their malicious behavior. The technique is also able to detect the start of a second attack while another one is on-going. Our results indicate that the proposed method for detecting denial of service attacks performs better than non-hybrid techniques.

Photonic networks and software-defined networks are two promising technologies to improve network-on-chips performance, scalability, and resource utilization. Several architectures suffer from scaling limitations, high-power consumption, and noise interference drawbacks. In this paper, an enhanced photonic network-on-chip architecture called (SD-PNoC) is presented. The proposed architecture based on a hybrid hardware-software approach, and a Software-Defined Management Orchestrator (SDMO) to separate the network control and data forwarding planes. This orchestrator has hosted on the upper hardware router as a virtual layer capable of dynamic management. It reconfigures data forwarding paths and allows dynamic execution of different algorithms in real-time, as it scales the proposed topology based on both applications and the network requirements. The proposed SD-PNoC architecture, hierarchical communication protocols, and orchestrator management policies were implemented, simulated, and tested using a customized Phoenix-SIM framework in the OMNIT++ simulation environment. Numerous simulation experiments under different conditions have been performed and have proven that the performance of the proposed architecture is better than that of the conventional electronic network on chip (ENoC). Furthermore, simulation results without using the management policies showed that the latency is reduced by 46% and 25.5% for the $4\times 4$ and $8\times 8$ network structures, respectively. While the power consumption is reduced by 76.5% and 78.5% for the $4\times 4$ and $8\times 8$ network structures, respectively. Besides, the chip area is reduced by 33.4%. Moreover, simulation results of SDMO with using the management policies for the $8\times 8$ network structures increased the enhancement of latency from 25.5% to 37.3% and the power consumption from 78.5% to approximately 80%, which assure the ability of the proposed architecture to remarkably enhance the overall performance of complex network-on-chip structures.

Background Post hematopoietic cell transplantation (HCT) autoimmune cytopenia (AIC) is a potentially life-threatening complication, but studies focusing on large cohorts of patients transplanted for primary immunodeficiency are lacking. Objectives This study sought to determine the incidence, risk factors, and outcomes of post-HCT AIC and B-lymphocyte function following rituximab. Methods We retrospectively studied 502 children with primary immunodeficiency who were transplanted at our center between 1987 and 2018. Results Thirty-six patients (9%) developed post-HCT AIC, with a median onset of 6.5 months post-HCT. On univariate analysis, pre-HCT AIC, mismatched donor, alemtuzumab, anti-thymocyte antiglobulin, and acute and chronic graft versus host disease were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (subdistribution hazard ratio, 9.0; 95% CI, 1.50-54.0; P = .02) was independently associated with post-HCT AIC. Corticosteroid and high-dose intravenous immunoglobulin achieved remission in 50% (n = 18), additional rituximab led to remission in 25% (n = 9), and the remaining 25% were treated with a combination of various modalities including sirolimus (n = 5), bortezomib (n = 3), mycophenolate mofetil (n = 2), splenectomy (n = 2), and second HCT (n = 3). The mortality of post-HCT AIC reduced from 25% (4 of 16) prior to 2011 to 5% (1 of 20) after 2011. The median follow-up of 5.8 years (range, 0.4 to 29.1 years) showed that 26 of 30 survivors (87%) were in complete remission, and 4 were in remission with ongoing sirolimus and low-dose steroids. Of the 17 who received rituximab, 7 had B-lymphocyte recovery, 5 had persistent low B-lymphocyte count and remained on intravenous immunoglobulin replacement, 2 had second HCT, and 3 died. Conclusions The frequency of post HCT AIC in our cohort was 9%, and the most significant risk factors for its occurrence were the presence of graft versus host disease and the use of alemtuzumab.

Objective To explore early features that can predict colchicine resistance in familial Mediterranean fever (FMF) patients. Methods It included FMF cases who fulfilled the Yalcinkaya–Ozen criterion and were on colchicine for at least 6 months. Data were collected from medical files and interpreted with respect to clinical parameters, incluing the auto-inflammatory diseases activity index (AIDAI) and FMF severity score. FMF50 score assessed the treatment response. Laboratory findings and genetic analysis of Mediterranean fever (MEFV) mutations were evaluated according to the standard technique. Patients were classified into two groups according to their response to colchicine. Both groups were compared, and significant variables were entered into a logistic regression model to detect independent predictors. The diagnostic accuracy of these predictors was assessed using the receiver operating characteristic curve. Results In all, 120 FMF children were included. After the exclusion of 16 non-compliant patients (13.3%), colchicine responders were 66 (63.4%) (group I) and colchicine-resistant cases (group II) were 38 (36.5%). The fever duration after colchicine, number of attacks before/after colchicine, skin rash/erysipelas-like erythema, myalgia/protracted febrile myalgia, AIDAI before/after treatment, FMF severity score, and the maximum colchicine dose were higher in group II. Furthermore, high C-reactive protein and neutropenia were frequent in group II. However, different MEFV mutations, including M694V were similar between the two groups. Eight variables were detected in the regression analysis model, and independent predictors were utilized to generate a scoring model. Conclusion This study constructed a prediction model for colchicine nonresponse based on clinical and laboratory profiles. This model will be valuable for the treatment decisions of FMF children.

Human inborn errors of immunity (IEI) are a group of 485 distinct genetic disorders affecting children and adults. Signs and symptoms of IEI are heterogeneous, and accurate diagnosis can be challenging and depends on the available human expertise and laboratory resources. The Middle East and North Africa (MENA) region has an increased prevalence of IEI because of the high rate of consanguinity with a predominance of autosomal recessive disorders. This area also exhibits more severe disease phenotypes compared with other regions, probably due to the delay in diagnosis. The MENA-IEI registry network has designed protocols and guidelines for the diagnosis and treatment of IEI, taking into consideration the variable regional expertise and resources. These guidelines are primarily meant to improve the care of patients within the region, but can also be followed in other regions with similar patient populations.

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD., Alborz University of Medical Sciences, This work was supported by the vice chancellor for research, Alborz University of Medical Sciences.

We report a female patient presenting with generalized pustular psoriasis and hypogammaglobulinemia due to digenic mutations in IL-36RA and SEC61A1. The patient presented with recurrent fevers, elevated inflammatory markers, hepatosplenomegaly, and recurrent sinopulmonary infections in the context of hypogammaglobulinemia which improved on immunoglobulin replacement. This report demonstrates how digenic inheritance leads to complex phenotypes, and illustrates the importance of following an unbiased approach to identifying variants, especially in patients with atypical clinical presentations.

Background Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. Methods We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. Results We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). Conclusions This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation., Karolinska Institute, Open access funding provided by Karolinska Institute.

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

T follicular helper (Tfh) cell migration into germinal centers (GCs) is essential for the generation of GC B cells and antibody responses to T cell–dependent (TD) antigens. This process requires interactions between lymphocyte function–associated antigen 1 (LFA-1) on Tfh cells and ICAMs on B cells. The mechanisms underlying defective antibody responses to TD antigens in DOCK8 deficiency are incompletely understood. We show that mice selectively lacking DOCK8 in T cells had impaired IgG antibody responses to TD antigens, decreased GC size, and reduced numbers of GC B cells. However, they developed normal numbers of Tfh cells with intact capacity for driving B cell differentiation into a GC phenotype in vitro. Notably, migration of DOCK8-deficient T cells into GCs was defective. Following T cell receptor (TCR)/CD3 ligation, DOCK8-deficient T cells had impaired LFA-1 activation and reduced binding to ICAM-1. Our results therefore indicate that DOCK8 is important for LFA-1–dependent positioning of Tfh cells in GCs, and thereby the generation of GC B cells and IgG antibody responses to TD antigen.

Introduction Despite efforts, primary immunodeficiency disorders (PIDs) are still under estimated. Predominantly antibody deficiencies (PADs) account for approximately two-thirds of all PIDs. We sought to screen for immunoglobulin deficiency among Egyptian infants and children presenting with unusually recurrent, severe and/ or persistent infections. Methods We conducted a cross sectional study that included 75 children presenting with clinical history and/or features suggestive of immunodeficiency. They were enrolled from Children’s Hospitals of Ain Shams and Mansoura Universities. They were subjected to clinical evaluation and measurement of serum immunoglobulin (Ig) levels: IgA, IgG and IgM (by nephelometry) and IgE (by ELISA). Results Patients’ ages ranged between 0.5-14 years (median (IQR): 2(0.83-3) with male to female ratio 2:1. Pneumonia was the most common infection (84%) followed by gastroenteritis (64%). Eleven patients (14.7%) had allergic manifestations and three (4%) had suppurative lung disease. Duration of infections per year ranged 3-150 days (median (IQR): 65(60-90), with average of 5 times hospitalization per year. Eighteen (24%) patients had failure to thrive and 21 patients (28%) had absent BCG scar. According to immunological evaluation, 7 patients (9.3%) had combined immunodeficiency, 4 (5%) had agammaglobulinemia, 2 (2.5%) had hypogammaglobulinemia, 2 (2.5%) had Hyper-immunoglobulin E syndrome and one had HIV infection. Patients without B cell defects had significantly higher frequency infection and hospitalization per year compared to those with B cell defects (p = 0.017 and 0.019 respectively). Conclusion: Primary immunodeficiency disorders are not rare. The awareness of families and primary health care physicians is crucial in the establishment of early diagnosis and initiation of appropriate therapy.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may present with some systemic lupus erythematosus (SLE) manifestations intermingled with Kawasaki disease features. These emerging presentations were dubbed under the umbrella term ‘multisystem inflammatory syndrome in children (MIS-C)’. A one and half-year-old girl, admitted to Mansoura University Children’s Hospital (MUCH) with fever, bad general condition, vomiting, widespread maculopapular, vasculitic rash, hands and feet oedema, oral ulceration, arthralgia and lymphadenopathy. Moreover, bicytopenia, positive antinuclear, anti–double-stranded DNA antibodies and low C3 qualified her as a case of juvenile SLE. Despite the child received the initial therapy of immunosuppressive medication, her general condition deteriorated with fever persistence and rash exacerbation. At that time, the skin of her hands and feet started to peel. Thus, an expanded study for other alternatives was obligatory; SARS-CoV-2 infection testing revealed positive IgG serology, and retesting for lupus autoantibodies turned negative. HRCT chest showed bilateral basal consolidation with ground-glass appearance. Furthermore, Echo exhibited coronary artery dilation with thrombus inside. This evolution raised the concern for COVID-related MIS-C syndrome. This report provides a model of COVID-19 heterogeneity with protean immune-related manifestations. This case has a unique presentation that necessities its description, in order to provide a nidus for future studies in this new entity.

Cyclophosphamide (CP) is an anti-neoplastic drug, which is widely used for treating cancer and non-malignant tumors. One of the major side effects of CP is hemorrhagic cystitis. Spirulina (Arthrospira platensis; Sp) is a blue-green algae with the ability to attenuate oxidative stress, which may be utilized for alleviating side effects of chemotherapeutic drugs in the clinic. The aim of the present study was to evaluate the ability of Sp, to protect mice from cyclophosphamide-induced urotoxicity and hemorrhagic cystitis due to its antioxidant properties. Adult female mice were orally administered Sp (600 g/kg body weight/day) over nine days as well as a single dose of CP (40 mg/kg body weight) intraperitoneally either four days previously (CP + Sp group) or four days after the start of Sp intake (Sp + CP group); two further groups were treated with either Sp or CP only, respectively. The results showed that CP induced hemorrhagic cystitis in mice, with levels of malondialdehyde (MAD) significantly increased and those of glutathione (GSH) decreased compared with the control group (P