A Registry Study of 240 Patients with X-Linked Agammaglobulinemia Living in the USA.

PURPOSE: To understand the natural history and clinical outcomes for patients with X-linked agammaglobulinemia (XLA) in the United States utilizing the United States Immunodeficiency Network (USIDNET) patient registry. METHODS: The USIDNET registry was queried for data from XLA patients collected from 1981 to 2019. Data fields included demographics, clinical features before and after diagnosis of XLA, family history, genetic mutation in Bruton's tyrosine kinase (BTK), laboratory findings, treatment modalities, and mortality. RESULTS: Data compiled through the USIDNET registry on 240 patients were analyzed. Patient year of birth ranged from 1945 to 2017. Living status was available for 178 patients; 158/178 (88.8%) were alive. Race was reported for 204 patients as follows: White, 148 (72.5%); Black/African American, 23 (11.2%); Hispanic, 20 (9.8%); Asian or Pacific Islander, 6 (2.9%), and other or more than one race, 7 (3.4%). The median age at last entry, age at disease onset, age at diagnosis, and length of time with XLA diagnosis was 15 [range (r) = 1-52 years], 0.8 [r = birth-22.3 years], 2 [r = birth-29 years], and 10 [r = 1-56 years] years respectively. One hundred and forty-one patients (58.7%) were < 18 years of age. Two hundred and twenty-one (92%) patients were receiving IgG replacement (IgGR), 58 (24%) were on prophylactic antibiotics, and 19 (7.9%) were on immunomodulatory drugs. Eighty-six (35.9%) patients had undergone surgical procedures, two had undergone hematopoietic cell transplantation, and two required liver transplantation. The respiratory tract was the most affected organ system (51.2% of patients) followed by gastrointestinal (40%), neurological (35.4%), and musculoskeletal (28.3%). Infections were common both before and after diagnosis, despite IgGR therapy. Bacteremia/sepsis and meningitis were reported more frequently before XLA diagnosis while encephalitis was more commonly reported after diagnosis. Twenty patients had died (11.2%). The median age of death was 21 years (range = 3-56.7 years). Neurologic condition was the most common underlying co-morbidity for those XLA patients who died. CONCLUSIONS: Current therapies for XLA patients reduce early mortality, but patients continue to experience complications that impact organ function. With improved life expectancy, more efforts will be required to improve post-diagnosis organ dysfunction and quality of life. Neurologic manifestations are an important co-morbidity associated with mortality and not yet clearly fully understood.

INDIAMAN-20 (INstant DIAgnosis of 20 Major ANomalies) protocol: application of IOTA diagnostic strategy to fetal anomalies.

OBJECTIVES: To compile a list of instant diagnoses of major fetal anomalies, and to present their sonographic descriptors and test them in a retrospective series of fetuses with congenital anomalies managed at our center. METHODS: The first step was to identify major anomalies that meet the following criteria: (1) can be diagnosed directly and unequivocally on the basis of a set of descriptors evident on a single sonographic view; (2) are among those more commonly diagnosed in utero; (3) represent major lethal or life-threatening malformations or anomalies for which no or only palliative surgery can be performed. For each of these anomalies, a sonographic descriptor was produced. The second step was to test the descriptors of the instant diagnoses in all cases with these anomalies evaluated since January 2000 in our Fetal Medicine Unit, retrieved from our electronic database. For each congenital anomaly-sonographic descriptor pair we then evaluated the presence vs absence of an unequivocal relationship between anomaly and descriptor, assessing: whether a particular descriptor in a set reference plane identified unequivocally the anomaly, i.e. the same descriptor could not be found in any other malformation; and whether a particular anomaly presented the corresponding descriptor in all cases. Finally, we evaluated whether the sonographic descriptors could be applied in all trimesters or only selectively, considering the natural history of the 20 instant diagnoses. RESULTS: Of the 20 instant diagnoses, five involved the central/peripheral nervous system (exencephaly/anencephaly, alobar/semilobar holoprosencephaly, cephalocele, open spinal dysraphism, complete agenesis of corpus callosum), five involved the heart (hypoplastic left heart syndrome, complete atrioventricular septal defect, severe Ebstein's anomaly, critical aortic stenosis, transposition of the great arteries), five involved the abdominal wall (left-sided congenital diaphragmatic hernia, exomphalos, gastroschisis, body-stalk anomaly) or gastrointestinal tract (duodenal atresia), and five involved the remaining systems (three urinary (autosomal recessive polycystic kidney disease, multicystic dysplastic kidney, lower urinary tract obstruction), two skeletal (transverse limb defect, radial ray defect)). All of the descriptors were found to identify unequivocally the related malformations, whereas four of the malformations were not associated with their reference descriptors in every case. For example, congenital diaphragmatic hernia (left-sided) presented without the stomach in the thorax in 42/93 (45.2%) cases. Due to the natural history of the condition, not all signs were recognizable in the first trimester, some becoming evident only from the second trimester onwards. CONCLUSION: We have defined sonographic descriptors that enable an unequivocal instant diagnosis for a list of 20 major congenital anomalies: the 'INDIAMAN-20' (INstant DIAgnosis of Major ANomalies) protocol. We believe that using this approach may facilitate focused training of less experienced operators and that it may be incorporated into artificial intelligence and deep learning protocols, further boosting the instant prenatal recognition of these lethal or life-threatening malformations. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

The mammalian SKIV2L RNA exosome is essential for early B cell development.

The SKIV2L RNA exosome is an evolutionarily conserved RNA degradation complex in the eukaryotes. Mutations in the SKIV2L gene are associated with a severe inherited disorder, trichohepatoenteric syndrome (THES), with multisystem involvement but unknown disease mechanism. Here, we reported a THES patient with SKIV2L mutations showing severe primary B cell immunodeficiency, hypogammaglobulinemia, and kappa-restricted plasma cell dyscrasia but normal T cell and NK cell function. To corroborate these findings, we made B cell-specific Skiv2l knockout mice (Skiv2lfl/flCd79a-Cre), which lacked both conventional B-2 and innate-like B-1 B cells in the periphery and secondary lymphoid organs. This was linked to a requirement of SKIV2L RNA exosome activity in the bone marrow during early B cell development at the pro-B cell to large pre-B cell transition. Mechanistically, Skiv2l-deficient pro-B cells exhibited cell cycle arrest and DNA damage. Furthermore, loss of Skiv2l led to substantial out-of-frame V(D)J rearrangement of immunoglobulin heavy chain and severely reduced surface expression of µH, both of which are crucial for pre-BCR signaling and proliferative burst during early B cell development. Together, our data demonstrated a crucial role for SKIV2L RNA exosome in early B cell development in both human and mice by ensuring proper V(D)J recombination and Igh expression, which serves as the molecular basis for immunodeficiency associated with THES.

Computational Metabolomics Tools Reveal Metabolic Reconfigurations Underlying the Effects of Biostimulant Seaweed Extracts on Maize Plants under Drought Stress Conditions.

Drought is one of the major abiotic stresses causing severe damage and losses in economically important crops worldwide. Drought decreases the plant water status, leading to a disruptive metabolic reprogramming that negatively affects plant growth and yield. Seaweed extract-based biostimulants show potential as a sustainable strategy for improved crop health and stress resilience. However, cellular, biochemical, and molecular mechanisms governing the agronomically observed benefits of the seaweed extracts on plants are still poorly understood. In this study, a liquid chromatography-mass spectrometry-based untargeted metabolomics approach combined with computational metabolomics strategies was applied to unravel the molecular 'stamps' that define the effects of seaweed extracts on greenhouse-grown maize (Zea mays) under drought conditions. We applied mass spectral networking, substructure discovery, chemometrics, and metabolic pathway analyses to mine and interpret the generated mass spectral data. The results showed that the application of seaweed extracts induced alterations in the different pathways of primary and secondary metabolism, such as phenylpropanoid, flavonoid biosynthesis, fatty acid metabolism, and amino acids pathways. These metabolic changes involved increasing levels of phenylalanine, tryptophan, coumaroylquinic acid, and linolenic acid metabolites. These metabolic alterations are known to define some of the various biochemical and physiological events that lead to enhanced drought resistance traits. The latter include root growth, alleviation of oxidative stress, improved water, and nutrient uptake. Moreover, this study demonstrates the use of molecular networking in annotating maize metabolome. Furthermore, the results reveal that seaweed extract-based biostimulants induced a remodeling of maize metabolism, subsequently readjusting the plant towards stress alleviation, for example, by increasing the plant height and diameter through foliar application. Such insights add to ongoing efforts in elucidating the modes of action of biostimulants, such as seaweed extracts. Altogether, our study contributes to the fundamental scientific knowledge that is necessary for the development of a biostimulants industry aiming for a sustainable food security.

Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic.

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro-a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.

Health-Related Quality of Life in 91 Patients with X-Linked Agammaglobulinemia.

PURPOSE: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency (PID) caused by a defect in the gene encoding for Bruton tyrosine kinase (BTK). In the absence of a functional BTK, patients have low or absent circulating B cells and low or absent serum immunoglobulin. Despite gammaglobulin replacement and prompt use of antimicrobial agents, patients with XLA continue to experience infectious and non-infectious complications throughout their lifetime. The purpose of this study was to understand self-perceived health status of US-based patients with XLA, and examine the associations amongst clinical characteristics, treatment experience, and quality of life (QoL). METHODS: A 46 and 68 question survey, developed by the Immune Deficiency Foundation (IDF) and a Short Form-12item v2® (SF-12v2®) for adults and SF-10™ for children to assess QoL, were mailed by IDF to patients in 2017 and 2018. Those that self-identified as having XLA or males with agammaglobulinemia were selected for analysis. Mean physical and mental composite scores (PCS and MCS) from SF-12v2® and mean physical health component (PHS) and psychological health summary (PSS) from SF-10™ scores were compared to the US normative data. RESULTS: Ninety-one patients completed the surveys: 58 (63.7%) adults and 33 (36.3%) children. For the combined surveys, the overall median age at time of the survey was 28.5 years (yrs); Inter-Quartile-Range (IQR) 13-49.5 yrs; the median age at diagnosis was 2 yrs (IQR = 0-4 yrs) and the median number of years with XLA diagnosis was 23 (IQR 10.75-40yrs). Amongst adult patients, physical scores were noted to be below the general adult population but did not reach statistical significance. In contrast, 2 or more chronic conditions impacted both physical and mental QoL (p < .001) and hospitalization was associated with significantly decreased physical health QoL (p < .001); three or more infections in the past 12 months exhibited impact on physical health although was not found to be statistically significant. Adult patients with public insurance fared worse in mental health domains compared to those with combined public and private or those with private alone (p = 0.001). Employment status did not impact QoL. None of these variables met statistical significance nor demonstrated impact within the pediatric population in either physical or mental domains of health. CONCLUSION: Our study provides further insight into what factors impact both physical and mental domains of health amongst patients with XLA. Early detection to prevent the development of associated morbidity, as well as vigilant care to prevent hospitalizations and infections, can limit the impact this disease may have on the overall well-being of XLA patients.

Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease.

Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. The SKIV2L RNA exosome is cytoplasmic RNA degradation machinery that was thought to be essential for preventing the self-RNA-mediated interferon (IFN) response. Here, we demonstrate the physiological function of SKIV2L in mammals. We found that Skiv2l deficiency in mice disrupted epidermal and T cell homeostasis in a cell-intrinsic manner independently of IFN. Skiv2l-deficient mice developed skin inflammation and hair abnormality, which were also observed in a SKIV2L-deficient patient. Epidermis-specific deletion of Skiv2l caused hyperproliferation of keratinocytes and disrupted epidermal stratification, leading to impaired skin barrier with no appreciable IFN activation. Moreover, Skiv2l-deficient T cells were chronically hyperactivated and these T cells attacked lesional skin as well as hair follicles. Mechanistically, SKIV2L loss activated the mTORC1 pathway in both keratinocytes and T cells. Both systemic and topical rapamycin treatment of Skiv2l-deficient mice ameliorated epidermal hyperplasia and skin inflammation. Together, we demonstrate that mTORC1, a classical nutrient sensor, also senses cytoplasmic RNA quality control failure and drives autoinflammatory disease. We also propose SKIV2L-associated trichohepatoenteric syndrome (THES) as a new mTORopathy for which sirolimus may be a promising therapy.

Soil Salinity, a Serious Environmental Issue and Plant Responses: A Metabolomics Perspective.

The effects of global warming have increasingly led to devastating environmental stresses, such as heat, salinity, and drought. Soil salinization is a serious environmental issue and results in detrimental abiotic stress, affecting 7% of land area and 33% of irrigated lands worldwide. The proportion of arable land facing salinity is expected to rise due to increasing climate change fuelled by anthropogenic activities, exacerbating the threat to global food security for the exponentially growing populace. As sessile organisms, plants have evolutionarily developed mechanisms that allow ad hoc responses to salinity stress. The orchestrated mechanisms include signalling cascades involving phytohormones, kinases, reactive oxygen species (ROS), and calcium regulatory networks. As a pillar in a systems biology approach, metabolomics allows for comprehensive interrogation of the biochemistry and a deconvolution of molecular mechanisms involved in plant responses to salinity. Thus, this review highlights soil salinization as a serious environmental issue and points to the negative impacts of salinity on plants. Furthermore, the review summarises mechanisms regulating salinity tolerance on molecular, cellular, and biochemical levels with a focus on metabolomics perspectives. This critical synthesis of current literature is an opportunity to revisit the current models regarding plant responses to salinity, with an invitation to further fundamental research for novel and actionable insights.

Metabolomics-Guided Elucidation of Plant Abiotic Stress Responses in the 4IR Era: An Overview.

Plants are constantly challenged by changing environmental conditions that include abiotic stresses. These are limiting their development and productivity and are subsequently threatening our food security, especially when considering the pressure of the increasing global population. Thus, there is an urgent need for the next generation of crops with high productivity and resilience to climate change. The dawn of a new era characterized by the emergence of fourth industrial revolution (4IR) technologies has redefined the ideological boundaries of research and applications in plant sciences. Recent technological advances and machine learning (ML)-based computational tools and omics data analysis approaches are allowing scientists to derive comprehensive metabolic descriptions and models for the target plant species under specific conditions. Such accurate metabolic descriptions are imperatively essential for devising a roadmap for the next generation of crops that are resilient to environmental deterioration. By synthesizing the recent literature and collating data on metabolomics studies on plant responses to abiotic stresses, in the context of the 4IR era, we point out the opportunities and challenges offered by omics science, analytical intelligence, computational tools and big data analytics. Specifically, we highlight technological advancements in (plant) metabolomics workflows and the use of machine learning and computational tools to decipher the dynamics in the chemical space that define plant responses to abiotic stress conditions.

The Growing Need to Understand Very Early Onset Inflammatory Bowel Disease.

Very Early Onset Inflammatory Bowel Disease (VEO-IBD) represents a cohort of inflammatory bowel disease (IBD) patients diagnosed before 6 years of age. Unlike IBD diagnosed at older ages, VEO-IBD can be associated with underlying primary immunodeficiencies. VEO-IBD has been linked to monogenic variations in over 70 genes involved in multiple pathways of immunity. As sequencing technologies and platforms evolve and become readily available, an increasing number of genes linked to VEO-IBD have emerged. Although monogenic defects are rare in VEO-IBD, diagnosis of these variants can often dictate specific treatment. In this mini-review, we set out to describe monogenic variants previously characterized in multiple patients in the literature that contribute to VEO-IBD, diagnostic tools, unique treatment modalities for specific genetic diagnoses, and future directions in the field of VEO-IBD. Although this mini-review is by no means comprehensive of all the novel monogenic variants linked to VEO-IBD, we hope to provide relevant information that is readily accessible to clinicians and educators.

Serum IgG Profiling of Toddlers Reveals a Subgroup with Elevated Seropositive Antibodies to Viruses Correlating with Increased Vaccine and Autoantigen Responses.

PURPOSE: The human antibody repertoire forms in response to infections, the microbiome, vaccinations, and environmental exposures. The specificity of such antibody responses was compared among a cohort of toddlers to identify differences between seropositive versus seronegative responses. METHODS: An assessment of the serum IgM and IgG antibody reactivities in 197 toddlers of 1- and 2-years of age was performed with a microfluidic array containing 110 distinct antigens. Longitudinal profiling was done from years 1 to 2. Seropositivity to RNA and DNA viruses; bacteria; live attenuated, inactive, and subunit vaccines; and autoantigens was compared. A stratification was developed based on quantitative variations in the IgG responses. Clinical presentations and previously known genetic risk alleles for various immune system conditions were investigated in relation to IgG responses. RESULTS: IgG reactivities stratified toddlers into low, moderate, and high responder groups. The high group (17%) had elevated IgG responses to multiple RNA and DNA viruses (e.g., respiratory syncytial virus, Epstein-Barr virus, adenovirus, Coxsackievirus) and this correlated with increased responses to live attenuated viral vaccines and certain autoantigens. This high group was more likely to be associated with gestational diabetes and an older age. Genetic analyses identified polymorphisms in the IL2RB, TNFSF4, and INS genes in two high responder individuals that were associated with their elevated cytokine levels and clinical history of eczema and asthma. CONCLUSION: Serum IgG profiling of toddlers reveals correlations between the magnitude of the antibody responses towards viruses, live attenuated vaccines, and certain autoantigens. A low responder group had much weaker responses overall, including against vaccines. The serum antibody screen also identifies individuals with IgG responses to less common infections (West Nile virus, parvovirus, tuberculosis). The characterization of the antibody responses in combination with the identification of genetic risk alleles provides an opportunity to identify children with increased risk of clinical disease.

Clinical effectiveness of non-TMS neurostimulation in depression: Clinical trials from 2010 to 2020.

OBJECTIVE: Treatment for major depressive disorder (MDD) have evolved, although there is still a strong unmet need for more effective and tolerable options. The present study summarizes and discusses recent evidence regarding the non-transcranial magnetic stimulation (non-TMS) neurostimulation treatment for MDD. METHODS: The authors reviewed non-TMS neurostimulation clinical trials for MDD between 2010 and 2020. Electroconvulsive therapy was not included in this review. A systematic review was performed in MEDLINE database through PubMed, the Cochrane Collaboration's Clinical Trials Register (CENTRAL), PsycINFO and Thomson Reuters's Web of Science. RESULTS: Only 20 articles met the inclusion criteria. Randomized controlled trials demonstrated efficacy of transcranial direct current stimulation (tDCS) in five of seven trials. tDCS augmented with sertraline, fluoxetine, citalopram and escitalopram was superior to placebo and to tDCS only. A comparative trial demonstrated that the duration of tDCS sessions can modulate the effectiveness of this treatment. Open trials indicated that deep brain stimulation, epidural cortical stimulation, trigeminal nerve stimulation, magnetic seizure therapy and vagus nerve stimulation may be effective in treatment-resistant depression. CONCLUSION: This review confirmed the efficacy of tDCS in MDD. Despite new evidence showing effectiveness for other non-TMS neurostimulation, their effectiveness is still unclear. Non-TMS neurostimulation RCTs with large samples and head-to-head studies comparing non-TMS neurostimulation and gold standard pharmacological treatments are still lacking.

Lipopolysaccharide perception in Arabidopsis thaliana: Diverse LPS chemotypes from Burkholderia cepacia, Pseudomonas syringae and Xanthomonas campestris trigger differential defence-related perturbations in the metabolome.

Lipopolysaccharides (LPSs) are microbe-associated molecular pattern molecules (MAMPs) from Gram-negative bacterial pathogens that potentially contain three different MAMPs (the O-polysaccharide chain, the oligosaccharide core and lipid A). LPSs was purified from Burkholderia cepacia, Pseudomonas syringae and Xanthomonas campestris and electrophoretically profiled. Outcomes of the interactions of the three different LPS chemotypes with Arabidopsis thaliana, as reflected in the induced defence metabolites, profiled at 12 h and 24 h post elicitation, were investigated. Plants were pressure-infiltrated with LPS solutions and methanol-based extractions at different time points were performed for untargeted metabolomics using ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Multivariate data modelling and chemometric analysis were applied to generate interpretable biochemical information from the multidimensional data sets. The three LPSs triggered differential metabolome changes in the plants as apparent from chromatographically distinct MS chromatograms. Unsupervised and supervised multivariate data models exhibited time- and treatment-related variations, and revealed discriminating metabolite variables. Heat map models comparatively displayed the up-regulated pathways affecting the metabolomes and Venn diagrams indicated up-regulated and shared metabolites among the three LPS treatments. The altered metabolomes reflect the up-regulation of metabolites from not only the glucosinolate pathway, but also from the shikimate-phenylpropanoid-flavonoid -, terpenoid - and indolic/alkaloid pathways, as well as oxygenated fatty acids. Distinct phytochemical profiles, especially at the earlier time point, suggest differences in the perception of the three LPS chemotypes, associated with the molecular patterns within the tripartite lipoglycans.

Correction: Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT.

The original version of this article unfortunately contained the missing author, Caridad Martinez. The authors would like to correct the list. We apologize for any inconvenience that this may have caused. The correct author list is shown above.

FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans.

We report on 2 patients with compound heterozygous mutations in forkhead box N1 (FOXN1), a transcription factor essential for thymic epithelial cell (TEC) differentiation. TECs are critical for T cell development. Both patients had a presentation consistent with T-/loB+NK+ SCID, with normal hair and nails, distinct from the classic nude/SCID phenotype in individuals with autosomal-recessive FOXN1 mutations. To understand the basis of this phenotype and the effects of the mutations on FOXN1, we generated mice using CRISPR-Cas9 technology to genocopy mutations in 1 of the patients. The mice with the Foxn1 compound heterozygous mutations had thymic hypoplasia, causing a T-B+NK+ SCID phenotype, whereas the hair and nails of these mice were normal. Characterization of the functional changes due to the Foxn1 mutations revealed a 5-amino acid segment at the end of the DNA-binding domain essential for the development of TECs but not keratinocytes. The transcriptional activity of this Foxn1 mutant was partly retained, indicating a region that specifies TEC functions. Analysis of an additional 9 FOXN1 mutations identified in multiple unrelated patients revealed distinct functional consequences contingent on the impact of the mutation on the DNA-binding and transactivation domains of FOXN1.

Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT.

INTRODUCTION: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking. METHODS: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016. RESULTS: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT. CONCLUSIONS: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

An essential role for the Zn2+ transporter ZIP7 in B cell development.

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

Pharmacological and Neuromodulatory Treatments for Panic Disorder: Clinical Trials from 2010 to 2018.

OBJECTIVE: Treatment for panic disorder (PD) have evolved, although there is still a strong unmet need for more effective and tolerable options. The present study summarizes and discusses recent evidence regarding the pharmacological and neuromodulatory treatment of PD. METHODS: MEDLINE, Cochrane Library, PsycINFO and Thomson Reuters's Web of Science were searched for clinical trials published between 2010 and 2018. We included all prospective experimental studies including randomized controlled trials (RCT) and other clinical trials with more than 10 patients. RESULTS: Only 11 articles met the inclusion criteria, including 4 RCT, 3 open clinical trials and 5 comparative clinical trials. RCT demonstrated efficacy of transcranial magnetic stimulation (TMS) in only one of two trials. Neither pindolol nor d-fenfluramine were effective in blocking flumazenil-induced panic attacks. Augmentation with quetiapine was not superior to placebo. Open trials indicated that escitalopram, vortioxetine and TMS may be effective. Comparative trials did not demonstrate superiority from any drug, but confirmed tranylcypromine, paroxetine, clonazepam and alprazolam as effective options. CONCLUSION: The current study confirmed the efficacy of tranylcypromine, paroxetine, clonazepam, alprazolam and escitalopram. Vortioxetine and TMS, with duration of 4 or more weeks, also seems to be effective. Quetiapine, pindolol and d-fenfluramine were not considered effective compounds.

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome.

Chromosome 22q11.2 deletion syndrome (22q11.2del) is a complex, multi-organ disorder noted for its varying severity and penetrance among those affected. The clinical problems comprise congenital malformations; cardiac problems including outflow tract defects, hypoplasia of the thymus, hypoparathyroidism, and/or dysmorphic facial features. Additional clinical issues that can appear over time are autoimmunity, renal insufficiency, developmental delay, malignancy and neurological manifestations such as schizophrenia. The majority of individuals with 22q11.2del have a 3 Mb deletion of DNA on chromosome 22, leading to a haploinsufficiency of ~106 genes, which comprise coding RNAs, noncoding RNAs, and pseudogenes. The consequent haploinsufficiency of many of the coding genes are well described, including the key roles of T-box Transcription Factor 1 (TBX1) and DiGeorge Critical Region 8 (DGCR8) in the clinical phenotypes. However, the haploinsufficiency of these genes alone cannot account for the tremendous variation in the severity and penetrance of the clinical complications among those affected. Recent RNA and DNA sequencing approaches are uncovering novel genetic and epigenetic differences among 22q11.2del patients that can influence disease severity. In this review, the role of coding and non-coding genes, including microRNAs (miRNA) and long noncoding RNAs (lncRNAs), will be discussed in relation to their bearing on 22q11.2del with an emphasis on TBX1.