There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of ...developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.
We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.
An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.
We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.
This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
THOC6 variants are the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, ...which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants reduce the binding affinity of ALYREF to THOC5 without affecting the protein expression of TREX members, implicating impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for key signaling pathways known to regulate the transition from proliferative to neurogenic divisions during human corticogenesis. Together, these findings implicate altered RNA processing in the developmental biology of TIDS neuropathology.
Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections ...that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.
We report an algorithm to detect structural variation and indels from 1 base pair (bp) to 1 Mbp within exome sequence data sets. Splitread uses one end-anchored placements to cluster the mappings of ...subsequences of unanchored ends to identify the size, content and location of variants with high specificity and sensitivity. The algorithm discovers indels, structural variants, de novo events and copy number-polymorphic processed pseudogenes missed by other methods.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Crimean-Congo Hemorrhagic Fever Virus (CCHFV) causes a life-threatening disease with up to a 40% mortality rate. With no approved medical countermeasures, CCHFV is considered a public health priority ...agent. The non-neutralizing mouse monoclonal antibody (mAb) 13G8 targets CCHFV glycoprotein GP38 and protects mice from lethal CCHFV challenge when administered prophylactically or therapeutically. Here, we reveal the structures of GP38 bound with a human chimeric 13G8 mAb and a newly isolated CC5-17 mAb from a human survivor. These mAbs bind overlapping epitopes with a shifted angle. The broad-spectrum potential of c13G8 and CC5-17 and the practicality of using them against Aigai virus, a closely related nairovirus were examined. Binding studies demonstrate that the presence of non-conserved amino acids in Aigai virus corresponding region prevent CCHFV mAbs from binding Aigai virus GP38. This information, coupled with in vivo efficacy, paves the way for future mAb therapeutics effective against a wide swath of CCHFV strains.
Web service composition is an inevitable aspect of Web services technology, which solves complex problems by combining available basic services and ordering them to best suit the problem ...requirements. Automatic composition gives us flexibility of selecting best candidate services at composition time satisfying QoS requirements; this would require the user to define constraints for selecting and composing candidate Web services. In this work, a Web service composition approach is presented in which a rich set of constraints can be defined on the composite service. The output of the framework is the schedule of Web service composition in which how and when services are executed is defined. The basic properties of the proposed approach is converting Web service composition problem into a constraint satisfaction problem in order to find the best solution that meets all criteria defined by user and providing semantic compatibility and composability during composition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Traumatic brain injury (TBI) is a multifaceted condition that causes mortality and disability worldwide. Limited data are available on the factors associated with the decision for the withdrawal of ...life-sustaining treatment (WLST) for patients with TBI. In the present study, we aimed to determine the risk factors and attitudes affecting neurosurgeons when deciding on WLST for patients with TBI using a multicenter survey.
An online questionnaire was applied worldwide and shared using social media platforms and electronic mail to ∼5000 neurosurgeons. The social media group “Neurosurgery Cocktail” was used to post a link to the questionnaire. In addition, randomly chosen neurosurgery clinics around the world were sent the survey via electronic mail.
Of the participants, 17.22% had decided on WLST after TBI for >26 patients. Neurosurgeons with more WLST decisions were older, had had more clinical experience and intensive care unit (ICU) training, and were better prepared to involve the family members of TBI patients in their decision-making compared with those with fewer WLST decisions. The respondents stated that the patient's family, ICU consultants, and themselves played the most influential role in the WLST decisions, with the hospital administration, social workers, spiritual caregivers, and nurses having lesser roles. The current and presenting Glasgow coma scale scores, pupillary response, advanced patient age, candidates for a vegetative state, and impaired neurological function were significant factors associated with the WLST decision.
To the best of our knowledge, the present study is the first to evaluate neurosurgeons concerning their opinions and behaviors regarding WLST decisions after TBI. Increased patient age, Glasgow coma scale score, pupillary response, the presence of comorbidities, candidacy for a vegetative state, and impaired neurological function were the main factors contributing to the decision for WLST. We also found that the family, ICU consultants, and the attending neurosurgeon had the most effective roles in the decisions regarding WLST.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recently autosomal recessively inherited mutations in the gene encoding Jagunal homolog 1 (JAGN1) was described as a novel disease-causing gene of severe congenital neutropenia (SCN)
JAGN1
-mutant ...neutrophils were characterized by abnormality in endoplasmic reticulum structure, absence of granules, abnormal N-glycosylation of proteins and susceptibility to apoptosis. These findings imply the role of JAGN1 in neutrophil survival. Here, we report two siblings with a homozygous mutation in
JAGN1
gene, exhibiting multisystemic involvement.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
•MIDD prevalence is considered higher in MENA region due to consanguineous marriages.•The most prevalent defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%).•The infections, autoimmunity and organomegaly were common initial & overall symptoms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cisplatin, an effective chemotherapeutic agent, is used for the treatment of several types of cancers. However, cisplatin has some severe side effects such as nephrotoxicity. On the other hand, ...molsidomine, a NO donor, has anti-oxidative and vasodilator effects.
The aim of this study was to estimate the protective effects of molsidomine on cisplatin-induced nephrotoxicity.
Thirty-two rats were randomly divided into 4 groups as follows: (1) control; (2) received a single-dose intraperitoneal (i.p.) injection of 5 mg/kg cisplatin; (3) received single i.p. dose of molsidomine (4 mg/kg/day) for 3 consecutive days before cisplatin treatment; (4) received single i.p. dose of molsidomine (4 mg/kg/day) for 3 consecutive days. The specific biochemical markers, including antioxidants, and the histopathological alterations were evaluated.
Cisplatin significantly increased malondialdehyde (MDA) and myeloperoxidase (MPO) levels and decreased glutathione peroxidase (GPX) level. Molsidomine significantly decreased MPO level nearly to control level; however, its ameliorating effects on MDA, SOD, CAT and GPX did not reach to significant levels. Cisplatin-induced elevation of blood-urea-nitrogen and serum-creatinine were diminished after molsidomine administration. Cisplatin also induced severe tubular degeneration, nuclear condensation, apoptosis and scattered patchy inflammation in the histological examination. Molsidomine improved all of these histological damages.
In this study, the beneficial effect of molsidomine against cisplatin nephrotoxicity has been evaluated for the first time.
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