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In addition to being a vital organ for gas exchange, the lung is a crucial immune organ continuously exposed to the external environment. Genetic defects that impair immune function, called inborn errors of immunity (IEI), often have lung disease as the initial and/or primary manifestation. Common types of lung disease seen in IEI include infectious complications and a diverse group of diffuse interstitial lung diseases. Although lung damage in IEI has been historically ascribed to recurrent infections, contributions from potentially targetable autoimmune and inflammatory pathways are now increasingly recognized. This article provides a practical guide to identifying the diverse pulmonary disease patterns in IEI based on lung imaging and respiratory manifestations, and integrates this clinical information with molecular mechanisms of disease and diagnostic assessments in IEI. We cover the entire IEI spectrum, including immunodeficiencies and immune dysregulation with monogenic autoimmunity and autoinflammation, as well as recently described IEI with pulmonary manifestations. Although the pulmonary manifestations of IEI are highly relevant for all age groups, special emphasis is placed on the pediatric population, because initial presentations often occur during childhood. We also highlight the pivotal role of genetic testing in the diagnosis of IEI involving the lungs and the critical need to develop multidisciplinary teams for the challenging evaluation of these rare but potentially life-threatening disorders. [ABSTRACT FROM AUTHOR]

Autoimmune cytopenias (AICs) regularly occur in profoundly IgG-deficient patients with common variable immunodeficiency (CVID). The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear. We sought to determine reactivity, clonality, and provenance of AIC-associated IgM autoantibodies in patients with CVID. We used glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan-binding profiles were used to identify autoreactive clones across B-cell subsets, specifically circulating marginal zone (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes, and responses of tonsillar MZ B cells to different T H - cell subsets were determined by confocal microscopy, RNA-sequencing, and cocultures, respectively. Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen–recognizing B-cell receptors were highly enriched among CVID+AIC circulating MZ B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL-10/IL-21–secreting FOXP3−CD25hi T follicular helper (Tfh) cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3+ regulatory T cells, and rare FOXP3−CD25+ cells that represented likely CD25hi Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25hi Tfh cells greatly outnumbered regulatory cells. Our findings indicate that glycan-reactive IgM autoantibodies produced outside of germinal centers may contribute to the autoimmune pathogenesis of CVID. [ABSTRACT FROM AUTHOR]

Prior studies have reported that renal insufficiency occurs in a small percentage of patients with predominantly antibody deficiency (PAD) and in about 2% of patients with common variable immunodeficiency. The goal of our study was to understand and evaluate the prevalence and type of renal complications in patients with PAD in the United States Immunodeficiency Network (USIDNET) cohort. We hypothesized that there is an association between certain renal complications and severity of immunophenotype in patients with PAD. We performed a query of patients with PAD from the USIDNET cohort with renal complications. Patients with documented renal disease such as chronic kidney disease (CKD), nephrolithiasis, nephritis, and renal failure syndrome were included. We compared immunophenotype, flow cytometry findings, and immunoglobulin levels of patients with PAD accompanied by renal complications with those of the total USIDNET cohort of patients with PAD. We determined that 140 of 2071 patients with PAD (6.8%) had renal complications. Of these 140 patients, 50 (35.7%) had CKD, 46 (32.9%) had nephrolithiasis, 18 (12.9 %) had nephritis, and 50 (35.7%) had other renal complications. Compared with the total USIDNET cohort of patients with PAD, patients with CKD had lower absolute lymphocyte counts, CD3+ T-cell counts, CD4+ T-cell counts, CD19+ B-cell counts, CD20+ B-cell counts, and CD27+IgD– B-cell counts (P <.05 for all). Patients with nephritis had lower absolute lymphocyte counts, CD19+ B-cell counts, CD27+ B-cell counts, and IgE levels (P <.05 for all) than patients with PAD without renal disease. We determined that 6.8% of the USIDNET cohort of patients with PAD had a documented renal complication. Compared with the overall cohort of patients with PAD, those patients with nephritis and CKD had a more severe immunophenotype. [ABSTRACT FROM AUTHOR]

Identification of biomarkers associated with immune-mediated diseases in 22q11.2 deletion syndrome is an evolving field. We sought to use a carefully phenotyped cohort to study immune parameters associated with autoimmunity and atopy in 22q11.2 deletion syndrome to define biomarkers associated with immune-mediated disease in this syndrome. Chart review validated autoimmune disease and atopic condition diagnoses. Laboratory data were extracted for each subcohort and plotted according to age. A random-effects model was used to define statistical significance. CD19, CD4, and CD4/45RA lymphocyte populations were not different from the general cohort for patients with atopic conditions. CD4/45RA T cells were significantly lower in the subjects with immune thrombocytopenia compared with the general cohort, and CD4 T-cell counts were lower in patients with autoimmune thyroid disease. The mechanisms of autoimmunity in cytopenias may be distinct from those of solid-organ autoimmunity in 22q11.2 deletion syndrome. This study identifies potential biomarkers for risk stratification among commonly obtained laboratory studies. [ABSTRACT FROM AUTHOR]

Most patients with childhood-onset immune dysregulation, polyendocrinopathy, and enteropathy have no genetic diagnosis for their illness. These patients may undergo empirical immunosuppressive treatment with highly variable outcomes. We sought to determine the genetic basis of disease in patients referred with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked–like (IPEX-like) disease, but with no mutation in FOXP3 ; then to assess consequences of genetic diagnoses for clinical management. Genomic DNA was sequenced using a panel of 462 genes implicated in inborn errors of immunity. Candidate mutations were characterized by genomic, transcriptional, and (for some) protein analysis. Of 123 patients with FOXP3 -negative IPEX-like disease, 48 (39%) carried damaging germline mutations in 1 of the following 27 genes: AIRE , BACH2 , BCL11B , CARD11 , CARD14 , CTLA4 , IRF2BP2 , ITCH , JAK1 , KMT2D , LRBA , MYO5B , NFKB1 , NLRC4 , POLA1 , POMP , RAG1 , SH2D1A , SKIV2L , STAT1 , STAT3 , TNFAIP3 , TNFRSF6/FAS , TNRSF13B/TACI , TOM1 , TTC37 , and XIAP. Many of these genes had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene could have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation. Many childhood disorders now bundled as "IPEX-like" disease are caused by individually rare, severe mutations in immune regulation genes. Most genetic diagnoses of these conditions yield clinically actionable findings. Barriers are lack of testing or lack of repeat testing if older technologies failed to provide a diagnosis. [ABSTRACT FROM AUTHOR]

The fusion of nuclear vesicles bound to chromatin in xenopus egg extracts was examined, and the ratio function of Ca2+ during nuclear envelope organization was studied in vitro. The assumption that fusion needs Ca2+ mobilization through IP3 receptors was tested. 5 mM BAPTA, a Ca2+ buffer that suppresses cytosolic (Ca2+) gradients, impairs fusion. In an IP3-reversible fashion, heparin, a powerful antagonist of IP3 receptors, obstructed fusion autonomously. Nuclear vesicle fusion may be controlled by phosphoinositide signaling.

As construction moves towards modularization and prefabrication, adhered joints have become increasingly prevalent across civil infrastructure, particularly in automotive, naval, aerospace, engineered wood, and concrete industries. Adhered joints offer the benefits of easier application and continuity of the connection without inducing additional residual stress in the connections in the ways that traditional bolted and welded connections do. However, these benefits are largely ignored in the steel industry. This paper discusses the success of structural adhesives in heavy structural settings, highlighting the opportunities for adhered joints in heavy structural connections. A review of test standards and research on steel-to-steel connections was performed and revealed that the performance assessment of structural adhesives should be standardized. A database of available adhesives appropriate for steel-to-steel connections was compiled and analyzed herein and indicates that for increased use of structural adhesives by the steel industry, uniformity in reporting of physical and mechanical properties of adhesives by adhesive manufacturers is necessary. From this database, preliminary statistical-analysis based design objectives for adhesive steel-to-steel connections were established. • Relevant research and standards on adhered steel-to-steel joints is reviewed. • Limit states for adhered steel connection design are discussed. • A database of commercially available structural adhesives is compiled and analyzed. • There is currently no uniformity in adhesive property reporting by manufacturers. • Performance based objectives are developed based on available adhesive data. [ABSTRACT FROM AUTHOR]

Background: Dentists are high prescribers of antibiotics for both treatment and prevention of infection, although there are few guidelines to aid clinicians. Given the worldwide concerns about unnecessary use of antibiotics, there is a need for a better understanding of dentists' use of these drugs for antibiotic prophylaxis (AP) to prevent distant site infections (i.e., infective endocarditis and prosthetic joint infection).Objective: The aim of this study was to develop and implement an effective, self-reporting, cross-sectional, survey instrument that optimized the response rate and maximized reliability and validity for determining the beliefs and behaviors of a large and nationally representative group of generalist and specialist dentists concerning their use of AP.Study Design: A 15-question survey (58 items) was developed in a structured process by a multidisciplinary team and configured for automated online dissemination to 3584 national Dental Practice-Based Research Network (DPBRN; hitherto referred to as "Network") practitioners. The implementation phase consisted of 3 waves of greater than 1000 Network members. Additionally, 47 randomly selected dentists were surveyed twice to assess test-retest reliability.Results: Of 3584 eligible Network members, 2169 (60.5%) completed the survey. The age and geographic distributions of responders was similar to those of dentists in the 2019 American Dental Association census. Furthermore, test-retest weighted kappa values for the survey were acceptable (median 0.56; interquartile range 0.42-0.64).Conclusions: We developed a highly structured survey with a high response rate and good reliability that will allow us to obtain unique data on dentists' beliefs and practices regarding AP prescribing. [ABSTRACT FROM AUTHOR]

Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional T H cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. Although CD4+ T H cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency–associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs. [ABSTRACT FROM AUTHOR]

Background The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy. Objective We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID−AIC). Methods We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID−AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID. Results We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID−AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID−AIC. Moreover, IgG+ B cells from patients with CVID+AIC expressed VH4-34 -encoded antibodies with unmutated Ala-Val-Tyr and Asn-His-Ser motifs, which recognize both erythrocyte I/i self-antigens and commensal bacteria. Conclusions Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG+ B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens. [ABSTRACT FROM AUTHOR]

Abstract Patients with common variable immunodeficiency (CVID) have a higher incidence of rheumatologic disorders. To delineate this clinical association, we investigated the phenotypic features of patients with CVID affected by these conditions. Methods We conducted a retrospective analysis of 870 pediatric and adult patients with CVID included in the United States Immunodeficiency Network (USIDNET) registry. Outcomes included clinical characteristics (age, gender, ethnicity, rheumatologic diagnosis, and comorbidities), infectious history and basic immunophenotype (serum immunoglobulin levels, CD19+ B cells, and CD4/CD8 ratio) in patients with CVID and rheumatologic disorders compared to those with non-inflammatory CVID. Demographic and clinical data were compared using chi-square, Fisher's exact or Wilcoxon-Mann-Whitney tests. Non-parametric tests, single and multiple logistic regression models were used to evaluate the relationship between CVID-associated rheumatologic disorders and basic immunophenotypic parameters (IgA, IgM, CD19+ B-cell counts, and CD4/CD8 ratios). Results Physician-reported rheumatic diseases were present in 5.9% of patients with CVID (n = 51) included in the registry. Although CVID affects both sexes equally, and patients are of predominantly White-Caucasian ethnicity, there were more females (3.3:1 female to male ratio) and increased proportion of non-white patients in the rheumatologic disease group (p < 0.05). Specific disorders included: inflammatory arthritis (n = 18), Sjogren's syndrome (n = 11), SLE (n = 8), Raynaud's syndrome (n = 8), vasculitis (n = 9), MCTD (n = 3), and other (n = 5). In about one-third of patients, a rheumatologic condition was associated with an additional inflammatory complication or malignancy. In regards to the immunophenotype parameters compared (CD19+ B-cell counts, CD4/CD8 ratio, IgA, and IgM), no significant differences were demonstrated between the two groups. Conclusion Our findings highlight the coexistence of primary antibody immunodeficiencies and systemic rheumatologic disorders, describe the spectrum of rheumatologic manifestations, and contrast differences in relevant demographic, clinical and immunophenotype parameters in the largest registry of CVID patients in the U.S. In spite of its limitations, our study details the intersection of systemic autoimmunity and CVID and provides valuable insights into these two groups of disorders. Further delineating the link between systemic autoimmunity and humoral immunodeficiencies can provide novel insights into the immune abnormalities underlying these related conditions. [ABSTRACT FROM AUTHOR]

Acute respiratory tract viral infections (ARTIs) cause significant morbidity and mortality. CD8 T cells are fundamental to host responses, but transcriptional alterations underlying anti-viral mechanisms and links to clinical characteristics remain unclear. CD8 T cell transcriptional circuitry in acutely ill pediatric patients with influenza-like illness was distinct for different viral pathogens. Although changes included expected upregulation of interferon-stimulated genes (ISGs), transcriptional downregulation was prominent upon exposure to innate immune signals in early IFV infection. Network analysis linked changes to severity of infection, asthma, sex, and age. An influenza pediatric signature (IPS) distinguished acute influenza from other ARTIs and outperformed other influenza prediction gene lists. The IPS allowed a deeper investigation of the connection between transcriptional alterations and clinical characteristics of acute illness, including age-based differences in circuits connecting the STAT1/2 pathway to ISGs. A CD8 T cell-focused systems immunology approach in pediatrics identified age-based alterations in ARTI host response pathways. [ABSTRACT FROM AUTHOR]

Monogenic lupus is rare, but its study has contributed immensely to a better understanding of the pathogenesis of systemic lupus erythematosus. The first forms identified were inherited complement deficiencies, which predisposed to lupus due to impaired tolerance, and aberrant clearance of apoptotic bodies and immune complexes. In recent years, several new monogenic disorders with a lupus-like phenotype have been described. These include forms that affect nucleic acid repair, degradation and sensing ( TREX1 , DNASE1L3 ), the type I interferon (IFN) pathway ( SAMHD1 , RNASEH2ABC , ADAR1 , IFIH1 , ISG15, ACP5, TMEM173 ) and B cell development checkpoints ( PRKCD ; RAG2 ). Pathways informed by these newly described disorders have continued to improve our understanding of systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

Background & Aims Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed at 5 years of age or younger, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development. Methods Patients with VEO-IBD and parents (when available) were recruited from the Children’s Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (age, 3 wk to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by postprocessing and variant calling. After functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency less than 0.1%, and scaled combined annotation-dependent depletion scores of 10 or less. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n = 45) or adult-onset Crohn’s disease (n = 20) and healthy individuals (controls, n = 145) were obtained from the University of Kiel, Germany, and used as control groups. Results Four hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling more than 1 Mbp of coding sequence, were selected from the whole-exome data. Our analysis showed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19 . Conclusions In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants. [ABSTRACT FROM AUTHOR]

Background Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients. Objective We sought to seek novel associations of genes and genetic variants with CVID. Methods We performed association analyses in a discovery cohort of 164 patients with CVID and 19,542 healthy control subjects genotyped on the Immuno BeadChip from Illumina platform; replication of findings was examined in an independent cohort of 135 patients with CVID and 2,066 healthy control subjects, followed by meta-analysis. Results We identified 11 single nucleotide polymorphisms (SNPs) at the 16p11.2 locus associated with CVID at a genome-wide significant level in the discovery cohort. The most significant SNP, rs929867 ( P = 6.21 × 10 −9 ), is in the gene fused-in-sarcoma (FUS) , with 4 other SNPs mapping to integrin CD11b (ITGAM) . Results were confirmed in our replication cohort. Conditional association analysis suggests a single association signal at the 16p11.2 locus. A strong trend of association was also seen for 38 SNPs ( P < 5 × 10 −5 ) in the MHC region, supporting that this is a genuine CVID locus. Interestingly, we found that 80% of patients with the rare ITGAM variants have reduced switched memory B-cell counts. Conclusion We report a novel association of CVID with rare variants at the FUS/ITGAM (CD11b) locus on 16p11.2. The association signal is enriched for promoter/enhancer markers in the ITGAM gene. ITGAM encodes the integrin CD11b, a part of complement receptor 3, a novel candidate gene implicated here for the first time in the pathogenesis of CVID. [ABSTRACT FROM AUTHOR]

Very early onset inflammatory bowel disease (VEO-IBD), diagnosed <6 years old, can be genetically and phenotypically distinct and more refractory than older-onset IBD. Identified causal monogenic defects have been targeted therapeutically in a small subset of VEO-IBD1; however, for most of these children, treatment strategies, such as phenotypic profiles, are critically needed to improve outcomes. [ABSTRACT FROM AUTHOR]

Background: Dedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse. DOCK8 activates cell division cycle 42, which, together with Wiskott-Aldrich syndrome protein, coordinates F-actin reorganization. Although abnormalities in T- and B-cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. Objectives: We sought to understand the role of DOCK8 in NK cell function to determine whether NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. Methods: A cohort of DOCK8-deficient patients was assembled, and patients'' NK cells, as well as NK cell lines with stably reduced DOCK8 expression, were studied. NK cell cytotoxicity, F-actin content, and lytic immunologic synapse formation were measured. Results: DOCK8-deficient patients'' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content. Conclusions: DOCK8 deficiency results in severely impaired NK cell function because of an inability to form a mature lytic immunologic synapse through targeted synaptic F-actin accumulation. This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy. [Copyright &y& Elsevier]

Allogeneic hematopoietic cell transplantation (HCT) has been used for 40 years to ameliorate or cure primary immune deficiency (PID) diseases, including severe combined immunodeficiency (SCID) and non-SCID PID. There is a critical need for evaluation of the North American experience of different HCT approaches for these diseases to identify best practices and plan future investigative clinical trials. Our survey of incidence and prevalence of PID in North American practice sites indicates that such studies are feasible. A conference of experts in HCT treatment of PID has recommended (1) a comprehensive cross-sectional and retrospective analysis of HCT survivors with SCID; (2) a prospective study of patients with SCID receiving HCT, with comparable baseline and follow-up testing across participating centers; (3) a pilot study of newborn screening for SCID to identify affected infants before compromise by infection; and (4) studies of the natural history of disease in patients who do or do not receive HCT for the non-SCID diseases of Wiskott-Aldrich syndrome and chronic granulomatous disease. To accomplish these goals, collaboration by a consortium of institutions in North America is proposed. Participation of immunologists and HCT physicians having interest in PID and experts in laboratory methods, clinical outcomes assessment, databases, and analysis will be required for the success of these studies. [Copyright &y& Elsevier]

Abstract: Resilience has been described as positive adaptation despite significant adversity. While the evidence cited as determinant of resilience varies across studies, most researchers consider adolescents and young adults who perform well in school; maintain a job; exhibit hope and optimism; engage in positive, nurturing, long-term relationships; and do not have evidence of psychopathology to indeed be resilient. A significant number of children, adolescents, and adults exposed to childhood abuse, poverty, and other substantial stressors exhibit these characteristics. The factors that predict resilience and the role of the primary care nurse practitioner (NP) in fostering positive adaptation are explored in this paper. [Copyright &y& Elsevier]

Velocardiofacial syndrome (VCFS) is characterized by conotruncal cardiac defects, palatal defects, and dysmorphic facies. VCFS is considered part of the spectrum of chromosome 22q11.2 deletion syndrome. Although the immunodeficiency was once thought to occur in patients with the clinical phenotype of DiGeorge syndrome, it is now known that any patient with chromosome 22q11.2 deletion syndrome may have a T cell defect. Fortunately, the majority of patients with chromosome 22q11.2 deletion syndrome have a mild to moderate immunodeficiency. These patients may develop recurrent infections or autoimmune disease, but infections are seldom life threatening. Less than 1% have the most serious form of the immunodeficiency requiring bone marrow or thymus transplantation. [Copyright &y& Elsevier]

Streams depend on riparian forests to supply many important functions such as delivery of large woody debris (LWD), organic matter, and nutrients into the aquatic ecosystem and to provide shade to help maintain cool water. Both forests and streams are dynamic, and inputs from the riparian forest are constantly replenished as organic matter and nutrients are processed and transported. Forest stand dynamics have been intensively studied and foresters have developed a good understanding of tree growth and mortality to support commercial forest management. In recent years, the relationships between aquatic functions and adjacent forest stand characteristics have been increasingly quantified by ecologists. Management of riparian forests to protect aquatic functions and water quality has received considerable attention in the Pacific Northwest and elsewhere. For scientific knowledge to be useful to decision-makers, the complex set of riparian relationships, increasingly well understood individually, need to be collectively and objectively linked in a form that can be easily used by scientists and non-scientists alike to develop management strategies for riparian forests. In this paper we describe an analytical system that quantitatively links widely used forest growth forecasting systems for coastal Pacific Northwest forest types to the riparian ecological functions of large woody debris recruitment and shade. The riparian aquatic interaction simulator (RAIS), with its user-friendly interface, allows managers to forecast aquatic functions for up to 300 years. RAIS provides these forecasts over a range of critical input variables and produces realistic estimates of riparian functions when compared with published research. RAIS is available at http://www.weyerhaeuser.com/rais.html [Copyright &y& Elsevier]

Introduction Acute kidney injury (AKI) is a frequent occurrence within the first 100 days post HCT. The incidence varies widely, reports ranging from 27-70%. The development of targeted strategies to reduce this risk is limited by multiple risk features of HCT. Methods We analyzed urine samples and clinical data from children (2-19 yrs) undergoing their first allogeneic HCT and enrolled in a prospective cohort study at the Children's Hospital of Philadelphia (CHOP) and Cincinnati Children's Hospital (CCHMC). Urine was collected at baseline and monthly for the first 4 months, frozen, and later analyzed by ELISA for the chemoattractant cytokines CXCL10 and CXCL9. Data were analyzed as raw concentrations and also adjusted for urine creatinine. AKI was defined as a 1.5x increase of serum creatinine from the day of urine sample collection (±1 day) compared to the pre-HCT baseline. Generalized estimating equations, accounting for repeated measures, tested the association between the urinary biomarkers and AKI. Results 36 subjects received HCT at CHOP and 141 subjects received HCT at CCHMC (Table). Overall, 35% of patients at CHOP and 16% of those at CCHMC developed AKI in the first 4 months after HCT. Acute graft versus host disease occurred in 21/36 (58%) and 50/141 (35%) at CHOP and CCHMC, respectively. Dialysis was required in 1/36 (2.7%) at CHOP and 14/141 (9%) at CCHMC. Raw urine CXCL10 and CXCL9 concentrations were significantly higher among children who developed AKI compared with children who did not develop AKI. CXCL10 adjusted for creatinine was also significantly associated with AKI (p<0.01). In the CHOP discovery cohort, the odds ratio (OR) of developing AKI with a raw CXCL9 concentration >200 pg/ml was 4.6 (95% CI 1.7-12.6; p<0.01). The OR of developing AKI with a raw CXCL10 concentration >0 pg/ml was 4.7 (95% CI 1.7-12.7; p<0.01). In the validation cohort, the OR of developing AKI with a CXCL9 concentration >200 pg/ml was 2.65 (95% CI 1.2-6.0; p<0.05) and the OR of developing AKI with a CXCL10 concentration >0 pg/ml was 2.2 (95% CI 1.3-3.9; p<0.01). Conclusions AKI is common in the first 4 months after HCT, although the risk varied across centers. Higher urine concentrations of CXCL9 and CXCL10 were significantly associated with AKI. This data supports a potential role for inflammation in the pathogenesis of AKI after HCT. [ABSTRACT FROM AUTHOR]