Role of standard HLA mismatch in modifying associations between non-pharmacologic risk factors and solid organ malignancy after kidney transplantation.

BACKGROUND: Human leukocyte antigen mismatch(es) (HLA-mm) between donors and recipients has not been extensively studied either as a risk factor for solid organ malignancy (SOM) or as a modifier of associations between nonpharmacologic risk factors and SOM in kidney transplant recipients (KTRs). METHODS: In a secondary analysis from a previous study, 166,256 adult KTRs in 2000-2018 who survived the first 12 months post-transplant free of graft loss or malignancy were classified into 0, 1-3, and 4-6 standard HLA-mm cohorts. Multivariable cause-specific Cox regressions analyzed the risks of SOM and all-cause mortality (ac-mortality) in 5 years following the first KT year. Comparisons of associations between SOM and risk factors in HLA mismatch cohorts were made by estimating the ratios of adjusted hazard ratios. RESULTS: Compared with 0 HLA-mm, 1-3 HLA-mm was not associated, and 4-6 HLA-mm was equivocally associated with increased risk of SOM [hazard ratio, (HR) = 1.05, 95%, confidence interval (CI) = 0.94-1.17 and HR = 1.11, 95% CI = 1.00-1.34, respectively]. Both 1-3 HLA-mm and 4-6 HLA-mm were associated with increased risk of ac-mortality compared with 0 HLA mm [hazard ratio (HR) = 1.12, 95%, Confidence Interval (CI) = 1.08-1.18) and (HR = 1.16, 95% CI = 1.09-1.22), respectively]. KTR's history of pre-transplant cancer, age 50-64, and >/=65 years were associated with increased risks of SOM and ac-mortality in all HLA mismatch cohorts. Pre-transplant dialysis >2 years, diabetes as the primary renal disease, and expanded or standard criteria deceased donor transplantation were risk factors for SOM in the 0 and 1-3 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. KTRs male sex or history of previous kidney transplant was a risk factor for SOM in the 1-3 and 4-6 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. CONCLUSION: Direct association between SOM and the degree of HLA mismatching is equivocal and limited to the 4-6 HLA-mm stratum; however, the degree of HLA mismatching has significant modifying effects on the associations between specific nonpharmacologic risk factors and SOM in KTRs.

Developing Drugs for Prevention of Chemotherapy-Induced Nausea and Vomiting: Draft Guidance from the FDA.

The administration of preventative therapy for chemotherapy-induced nausea and vomiting (CINV) is an essential component of the treatment plan for many patients with cancer. In May 2021, the FDA issued a draft guidance for industry to facilitate the clinical development of drugs for the prevention of CINV in adults. FDA guidance has a vital role in the regulatory dialogue between the Agency and external stakeholders. Sharing the FDA's current recommended approach can expedite drug development and ultimately the availability of safe and effective therapies to patients in need. In addition, guidance documents may be leveraged to facilitate communication between regulatory agencies, the academic community, patient advocacy groups, and the pharmaceutical industry. The draft guidance for industry Chemotherapy-Induced Nausea and Vomiting: Developing Drugs for Prevention (May 2021) outlines the FDA's current recommendations regarding clinical development programs for drugs for the prevention of CINV and the required attributes of patients for enrollment, aspects of trial design, and efficacy assessments. This article provides an overview of the recommendations contained in the draft guidance.

Association of HLA mismatch and MTOR inhibitor regimens with malignancy and mortality after kidney transplantation.

Background The association of mammalian target of rapamycin inhibitors (MTORI) with malignancies and mortality in kidney transplant recipients (KTR) with different degrees of human leukocyte antigen mismatch (HLA-mm) at transplant has not been previously studied. Methods Our observational cohort study included 166, 256 adult KTRs in 2000-2018. Immunosuppression in the first post-transplant year were MTORIs in 13,056 (7.85%) and non-MTORIs in 153,200 (92.15%). We used Cox multivariable regression models to determine the cause-specific hazard ratio (HRcs) of non-melanoma skin cancer (NMSC),solid organ malignancies (SOM)] and all-cause death (deathac); and the HR of the composite outcomes of NMSC or deathac and SOM or deathac associated with MTORI versus non-MTORI regimens in the overall study sample and the 0, 1-3, and 4-6 HLA-A, B and DR mm subgroups. Results NMSC risk was lower with MTORI than non-MTORI in all HLA-mm subgroups [(0 mm, HRcs = 0.67; 95% CI = 0.46-0.97, 1-3 mm, HRcs = 0.73; 95% CI = 0.61-0.87, 4-6 mm, HRcs = 0.69; 95% CI = 0.62-0.76)]. SOM risks were similar between regimens in the 0 HLA mm subgroup (HRcs = 1.10 (95% CI = 0.78-1.57) and lower with MTORI than non-MTORI in the 1-3, and 4-6 HLA-mm subgroups, [(HR = 0.84; (95% CI = 0.71-0.99), and (HR = 0.86; 95% CI = 0.78-0.94); respectively]. Risks of deathac and composite outcomes (NMSC or deathac and SOM or deathac) were higher with MTORI than non-MTORI in almost all HLA-mm subgroups. Conclusion MTORIs are associated with protection from NMSC and SOM in almost all HLA-mm subgroups ca; however, their association with increased all-cause mortality in adult kidney transplant recipients needs further investigation.

Concordance between gene expression in peripheral whole blood and colonic tissue in children with inflammatory bowel disease.

BACKGROUND: Presenting features of inflammatory bowel disease (IBD) are non-specific. We hypothesized that mRNA profiles could (1) identify genes and pathways involved in disease pathogenesis; (2) identify a molecular signature that differentiates IBD from other conditions; (3) provide insight into systemic and colon-specific dysregulation through study of the concordance of the gene expression. METHODS: Children (8-18 years) were prospectively recruited at the time of diagnostic colonoscopy for possible IBD. We used transcriptome-wide mRNA profiling to study gene expression in colon biopsies and paired whole blood samples. Using blood mRNA measurements, we fit a regression model for disease state prediction that was validated in an independent test set of adult subjects (GSE3365). RESULTS: Ninety-eight children were recruited [39 Crohn's disease, 18 ulcerative colitis, 2 IBDU, 39 non-IBD]. There were 1,118 significantly differentially (IBD vs non-IBD) expressed genes in colon tissue, and 880 in blood. The direction of relative change in expression was concordant for 106/112 genes differentially expressed in both tissue types. The regression model from the blood mRNA measurements distinguished IBD vs non-IBD disease status in the independent test set with 80% accuracy using only 6 genes. The overlap of 5 immune and metabolic pathways in the two tissue types was significant (p<0.001). CONCLUSIONS: Blood and colon tissue from patients with IBD share a common transcriptional profile dominated by immune and metabolic pathways. Our results suggest that peripheral blood expression levels of as few as 6 genes (IL7R, UBB, TXNIP, S100A8, ALAS2, and SLC2A3) may distinguish patients with IBD from non-IBD.

Development and user evaluation of a rare disease gene prioritization workflow based on cognitive ergonomics.

Objective: The clinical diagnosis of genetic disorders is undergoing transformation, driven by whole exome sequencing and whole genome sequencing (WES/WGS). However, such nucleotide-level resolution technologies create an interpretive challenge. Prior literature suggests that clinicians may employ characteristic cognitive processes during WES/WGS investigations to identify disruptions in genes causal for the observed disease. Based on cognitive ergonomics, we designed and evaluated a gene prioritization workflow that supported these cognitive processes. Materials and Methods: We designed a novel workflow in which clinicians recalled known genetic diseases with similarity to patient phenotypes to inform WES/WGS data interpretation. This prototype-based workflow was evaluated against the common computational approach based on physician-specified sets of individual patient phenotypes. The evaluation was conducted as a web-based user study, in which 18 clinicians analyzed 2 simulated patient scenarios using a randomly assigned workflow. Data analysis compared the 2 workflows with respect to accuracy and efficiency in diagnostic interpretation, efficacy in collecting detailed phenotypic information, and user satisfaction. Results: Participants interpreted genetic diagnoses faster using prototype-based workflows. The 2 workflows did not differ in other evaluated aspects. Discussion: The user study findings indicate that prototype-based approaches, which are designed to model experts' cognitive processes, can expedite gene prioritization and provide utility in synergy with common phenotype-driven variant/gene prioritization approaches. However, further research of the extent of this effect across diverse genetic diseases is required. Conclusion: The findings demonstrate potential for prototype-based phenotype description to accelerate computer-assisted variant/gene prioritization through complementation of skills and knowledge of clinical experts via human-computer interaction.

Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability.

Over the last decades, a growing spectrum of monogenic disorders of human magnesium homeostasis has been clinically characterized, and genetic studies in affected individuals have identified important molecular components of cellular and epithelial magnesium transport. Here, we describe three infants who are from non-consanguineous families and who presented with a disease phenotype consisting of generalized seizures in infancy, severe hypomagnesemia, and renal magnesium wasting. Seizures persisted despite magnesium supplementation and were associated with significant intellectual disability. Whole-exome sequencing and conventional Sanger sequencing identified heterozygous de novo mutations in the catalytic Na+, K+-ATPase α1 subunit (ATP1A1). Functional characterization of mutant Na+, K+-ATPase α1 subunits in heterologous expression systems revealed not only a loss of Na+, K+-ATPase function but also abnormal cation permeabilities, which led to membrane depolarization and possibly aggravated the effect of the loss of physiological pump activity. These findings underline the indispensable role of the α1 isoform of the Na+, K+-ATPase for renal-tubular magnesium handling and cellular ion homeostasis, as well as maintenance of physiologic neuronal activity.

Well-defined and reliable clinical outcome assessments for pediatric Crohn disease: a critical need for drug development.

OBJECTIVES: The aim of the present study was to identify areas for further development of clinical outcome assessment (COA) in pediatric Crohn disease (CD). METHODS: The study analyzed the measurement properties of all existing COA tools for pediatric CD in literature and published registration trials of approved drugs for pediatric CD based on criteria described in Food and Drug Administration guidance for patient-reported outcome (PRO) development. RESULTS: The Pediatric Crohn's Disease Activity Index (PCDAI) and its derivatives (abbreviated, short, modified, and weighted PCDAIs) were reviewed. The Crohn's Disease Activity Index (CDAI) and Harvey-Bradshaw index (HBI), designed for adult patients, have been adapted for use in a few pediatric CD studies. The use of PCDAI as an endpoint in Remicade and Humira trials led to the Food and Drug Administration-approved indication in pediatric CD. Common issues in measurement properties of COA tools included the absence of direct patient or caregivers' input to generate the items measuring signs and symptoms; absence of evidence demonstrating correlation with clinically relevant inflammation observed with endoscopic measures; lack of standardization in measurement, age-appropriate interviewer script, and response rating criteria for the physician interviewer. CONCLUSIONS: Available evidence indicates that CDAI, HBI, and 5 versions of the PCDAI lack adequate measurement properties for use as a primary endpoint for phase 3 trials intended to support approval of products intended to treat pediatric CD. In order to facilitate pediatric drug development, a well-defined, reliable, sensitive, and globally recognized PRO that measures signs and symptoms in children with CD and that can be used in conjunction with endoscopy-based endpoints and/or biomarkers is sorely needed.

Potential role of IGF-1 z score to predict permanent linear growth impairment in children with IBD.

In this pilot study, we analyzed serum insulin-like growth factor 1 (IGF-1)- and IGF-binding protein-3-for-age z scores from 54 inflammatory bowel disease children with no, temporary, or permanent growth impairment. Although our findings did not reach statistical significance, patients with permanent linear growth impairment had lower IGF-1-for-age z scores (-1.76 [-2.25 to -0.43]) compared with those with no or temporary growth impairment (-0.84 [-1.49 to -0.3]) and -1.16 [-1.59 to -1.51], respectively). IGF-binding protein-3 levels were similar across the 3 groups. In the absence of significant inflammation and malnutrition, lower IGF-1-for-age z scores may help distinguish patients likely to have permanent growth impairment from those whose growth impairment is likely to be temporary.

Elevated subclinical double-stranded DNA antibodies and future proliferative lupus nephritis.

BACKGROUND AND OBJECTIVES: Elevated anti-double-stranded DNA (dsDNA) antibody and C-reactive protein are associated with proliferative lupus nephritis (PLN). Progression of quantitative anti-dsDNA antibody in patients with PLN has not been compared with that in patients with systemic lupus erythematosus (SLE) without LN before diagnosis. The temporal relationship between anti-dsDNA antibody and C-reactive protein elevation has also not been evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This case-control Department of Defense Serum Repository (established in 1985) study compared longitudinal prediagnostic quantitative anti-dsDNA antibody and C-reactive protein levels in 23 patients with biopsy-proven PLN (Walter Reed Army Medical Center, 1993-2009) with levels in 21 controls with SLE but without LN matched for patient age, sex, race, and age of serum sample. The oldest (median, 2601 days; 25%, 1245 days, 75%, 3075 days), the second to last (368; 212, 635 days), and the last (180; 135, 477 days) serum sample before diagnosis were analyzed. RESULTS: More patients with PLN had an elevated anti-dsDNA antibody level than did the matched controls at any point (78% versus 5%; P<0.001), <1 year (82% versus 8%; P<0.001), 1-4 years (53% versus 0%; P<0.001), and >4 years (33% versus 0%; P=0.04) before diagnosis. A rate of increase >1 IU/ml per year (70% versus 0%; P<0.001) was most specific for PLN. The anti-dsDNA antibody levels increased before C-reactive protein did in most patients with an antecedent elevation (92% versus 8%; P<0.001). CONCLUSIONS: Elevated anti-dsDNA antibody usually precedes both clinical and subclinical evidence of proliferative LN, which suggests direct pathogenicity. Absolute anti-dsDNA antibody level and rate of increase could better establish risk of future PLN in patients with SLE.

Association of linear growth impairment in pediatric Crohn's disease and a known height locus: a pilot study.

The etiology of growth impairment in Crohn's disease (CD) has been inadequately explained by nutritional, hormonal, and/or disease-related factors, suggesting that genetics may be an additional contributor. The aim of this cross-sectional study was to investigate genetic variants associated with linear growth in pediatric-onset CD. We genotyped 951 subjects (317 CD patient-parent trios) for 64 polymorphisms within 14 CD-susceptibility and 23 stature-associated loci. Patient height-for-age Z-score < -1.64 was used to dichotomize probands into growth-impaired and nongrowth-impaired groups. The transmission disequilibrium test (TDT) was used to study association to growth impairment. There was a significant association between growth impairment in CD (height-for-age Z-score < -1.64) and a stature-related polymorphism in the dymeclin gene DYM (rs8099594) (OR = 3.2, CI [1.57-6.51], p = 0.0007). In addition, there was nominal over-transmission of two CD-susceptibility alleles, 10q21.1 intergenic region (rs10761659) and ATG16L1 (rs10210302), in growth-impaired CD children (OR = 2.36, CI [1.26-4.41] p = 0.0056 and OR = 2.45, CI [1.22-4.95] p = 0.0094, respectively). Our data indicate that genetic influences due to stature-associated and possibly CD risk alleles may predispose CD patients to alterations in linear growth. This is the first report of a link between a stature-associated locus and growth impairment in CD.

Final adult height of children with inflammatory bowel disease is predicted by parental height and patient minimum height Z-score.

BACKGROUND: This study was designed to elucidate the contribution of parental height to the stature of children with inflammatory bowel disease (IBD), who often exhibit growth impairment. Accordingly, we compared patients' final adult heights and target heights based on measured parental heights and examined predictors of final adult height in pediatric IBD patients. METHODS: We prospectively analyzed the growth of 295 patients diagnosed between ages 1 and 18 (211 Crohn's disease [CD], 84 ulcerative colitis [UC]) and their family members (283 mothers, 231 fathers, 55 siblings). RESULTS: Twenty-two percent had growth impairment (height for age Z-score <-1.64, equivalent to <5th percentile on growth curve) in more than 1 measurement since diagnosis; most growth-impaired patients had CD (88% CD versus 12% UC). Parents of the growth-impaired group had lower mean height Z-scores compared to parents of nongrowth-impaired patients (-0.67 versus 0.02 for mothers [P < 0.001]; -0.31 versus 0.22 for fathers [P = 0.002]). For 108 patients who reached adult heights and had available parental heights, the growth-impaired group continued to demonstrate lower adult height Z-scores (-1.38 versus 0.07; P < 0.001). Adult heights were within 1 SD of target heights even for the growth-impaired group. Only 11.3% remained persistently growth-impaired in adulthood. Multivariate regression analysis demonstrated lower parental height and minimum patient height Z-score as significant predictors of lower final adult height in IBD. CONCLUSIONS: Parental height is a powerful determinant of linear growth even in the presence of chronic inflammation, and should be an integral part of the evaluation of growth in IBD children.

Established genetic risk factors do not distinguish early and later onset Crohn's disease.

BACKGROUND: Early-onset disease is frequently examined in genetic studies because it is presumed to contain a more severe subset of patients under a higher influence of genetic effects. In light of the dramatic success of Crohn's disease (CD) gene discovery efforts, we aimed to characterize the contribution of established common risk variants to pediatric CD. METHODS: Using 35 confirmed CD risk alleles, we genotyped 384 parent-child trios (mean age of onset 11.7 years) along with 321 healthy controls. We performed association tests on the independent pediatric cohort and compared results to those previously published.1 We also computed a weighted CD genetic risk score for each affected person. Six variants not previously validated in children (at 5q33, 1q24, 7p12, 12q12, 8q24, and 1q32) were significantly associated with pediatric CD (P < 0.03). RESULTS: We detected no significant association between risk score and age at onset through age 30. This analysis illustrates that the genetic effect of established CD risk variants is similar in early and later onset CD. CONCLUSIONS: These results motivate joint analyses of genome-wide association data in early and late onset cohorts and suggest that, rather than established risk variants, independent variants or environmental exposures should be sought as modulators of age of onset.

Upper gastrointestinal tract eosinophilic disorders: pathobiology and management.

Patients with eosinophilic esophagitis present with symptoms similar to those from gastroesophageal reflux disease along with dense esophageal eosinophilia (normal gastric and duodenal biopsies) that persist despite aggressive acid blockade. The dramatic increase in prevalence of eosinophilic esophagitis over the past several years provides clinicians with a new explanation for previously unexplained dysphagia, food impaction, vomiting, and abdominal pain. As a product of this recognition, an increasing number of basic and translational studies are building a new understanding of the pathogenesis of esophageal eosinophilia. This review addresses recent studies that define clinical features, genetic predisposition, pathogenetic mechanisms, and treatment options for eosinophilic esophagitis.