Citations

Importance Sudden infant death syndrome (SIDS) remains a leading cause of death during the first year of life. The etiology of SIDS is complex and remains largely unknown. Objective To evaluate whether siblings of children who died of SIDS have a higher risk of SIDS compared with the general pediatric population. Design, Setting, and Participants This register-based cohort study used Danish nationwide registers. Participants were all infants (<1 year) in Denmark between January 1, 1978, and December 31, 2016, including siblings of children who died of SIDS. Siblings were followed up from the index cases’ date of SIDS, date of birth, or immigration, whichever came first, and until age 1 year, emigration, developing SIDS, death, or study end. The median (IQR) follow-up was 1 (1-1) year. Data analysis was conducted from January 2017 to October 2022. Main Outcomes and Measures Standardized incidence ratios (SIRs) of SIDS were calculated with Poisson regression models relative to the general population. Results In a population of 2 666 834 consecutive births (1 395 199 [52%] male), 1540 infants died of SIDS (median [IQR] age at SIDS, 3 [2-4] months) during a 39-year study period. A total of 2384 younger siblings (cases) to index cases (first sibling with SIDS) were identified. A higher rate of SIDS was observed among siblings compared with the general population, with SIRs of 4.27 (95% CI, 2.13-8.53) after adjustment for sex, age, and calendar year and of 3.50 (95% CI, 1.75-7.01) after further adjustment for mother’s age (<29 years vs ≥29 years) and education (high school vs after high school). Conclusions and Relevance In this nationwide study, having a sibling who died of SIDS was associated with a 4-fold higher risk of SIDS compared with the general population. Shared genetic and/or environmental factors may contribute to the observed clustering of SIDS. The family history of SIDS should be considered when assessing SIDS risk in clinical settings. A multidisciplinary genetic evaluation of families with SIDS could provide additional evidence.

231 Background: The recent development of KRAS G12C inhibitors underscores the potential to target KRAS mutations. Right-sided and left-sided colon tumors (RT and LT) exhibit different molecular features. We characterize the prevalence of KRAS-variants, interrelation with primary tumor location, and association with immune biomarkers in CRC. Methods: We retrospectively reviewed CRC tumors of all stages (with known sidedness) that underwent NGS with the Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Bivariate analyses were performed to compare KRAS alterations, immune biomarkers, and co-mutations by tumor location. P-values comparing individual co-mutations between groups were adjusted for false discovery (FDR). Results: A total of 3,391 CRC were analyzed (RT: n = 442 [13%], transverse: n = 116 [3%], LT; n = 2,833 [84%]) of which 1486 (44%) tumors harbored KRAS mutations. Overall, KRAS mutations were more frequent in RT compared to transverse tumors and LT (52% vs 41% vs 43%, p<0.001, respectively). The most frequent KRAS mutation variants observed were G12D (29 %), G12V (22%), G13D (16%), and G12C (5.7%). There was no significant difference in the prevalence of KRAS variant types between LT and RT (p=0.5). Significant differences in genomic co-mutations with various KRAS variants were observed in the following genes: TP53, FBXW7, and NF1 (FDR- P<0.05). RT and transverse tumors were more likely have MSI-H and TMB-H (>10 mut/mb) status than LT (MSI-H: 18% vs 22% vs 2.2% and TMB-H (20% vs 22% vs 3%, P<0.001), respectively. CRC tumors harboring G13D variants were more likely to be associated with and MSI-H and TMB-H status (and 7.7% and 8.5%) compared to G12D (2.8 % and 3.9 %), G12V (1.8 % and 2.1%), and G12C (0% and 2.4%); P = 0.003 and 0.001. Conclusions: The most frequent KRAS mutation variants observed in CRC tumors were G12D, G12V, G13D, and G12C. There was no significant difference in the prevalence of KRAS variant types between tumors of the left vs right colon. CRC tumors that harbored G13D variants were significantly more likely to be associated with MSI-H and TMB-H status. [Table: see text]

Abstract Atopic dermatitis (AD) is the most common skin inflammatory disease. Dysregulation of innate and adaptive immune systems plays a major role in the pathophysiology of AD. JAKi (Janus Kinase Inhibitors) reduce the production of pro‐inflammatory cytokines and represent a promising novel treatment for AD. To assess and summarize the overall efficacy and safety of topial JAKi in the treatment of AD in adults and pediatrics, a broad search was performed on Ovid Medline, Ovid Embase, Cochrane Library, Web of Sciences, Scopus, CINAHL and Google Scholar until 14 June 2022. After screening, 19 studies remained for the final review. The current systematic review was conducted according to PRISMA, and the protocol was registered in PROSPERO (ID #CRD42022303321). Topical delgocitinib, tofacitinib, ruxolitinib, cerdulatinib and ifidancitinib are effective in treating AD and significantly improve EASI, IGA, pruritus‐NRS score and some other indexes in adults. Moreover, topical delgocitinib was observed to have a great efficacy in the treatment of AD in paediatrics. All topical JAKi showed minimal risk of mild‐to‐moderate adverse effects. Available topical JAKi are effective and safe modalities in treating AD. Nevertheless, further studies with longer duration and head‐to‐head comparative trials are necessary to find the best option with the least adverse effects.

Background Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis. Methods A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls. Results sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9–3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5–0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7–1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for IL2RA , IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls. Conclusion Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.

AbstractATP6AP1‐CDG is an X‐linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1‐CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N‐glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N‐glycan profiles. The aberrant N‐linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high‐mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1‐CDG patients, these results demonstrate that fractionated plasma N‐glycan profiling could be a valuable tool in diagnosis and disease monitoring.

PURPOSE: Testing for pathogenic variants can aid in oncologic risk stratification and identification of targeted therapies. Despite known disparities in access to prostate cancer (PCa) care, little has been written about access to germline genetic testing (GGT) for Black men and other historically marginalized populations. This systematic review sought to delineate racial/ethnic disparities in GGT for PCa. METHODS: This systematic review identified articles published from January 1996 through May 2021 in PubMed, Web of Science, and Embase. We included studies that reported rates of GGT in men with PCa in the United States by race/ethnicity as reflective of routine clinical care or research. A narrative synthesis was performed. RESULTS: Of 4,309 unique records, 91 studies examining 50 unique study populations met inclusion criteria. Of these, four populations included men who received GGT through routine clinical care, accounting for 4,415 men (72.6% White and 7.2% Black). The other 46 populations included men who received GGT as part of a research study, accounting for 30,824 men (64.3% White and 21.6% Black). Of these 46 research populations, 19 used targeted methods to increase recruitment from a specific demographic. CONCLUSION: Most studies that report GGT rates by race/ethnicity are in research settings. Many of these studies used targeted recruitment methods and subsequently have a greater proportion of Black men than clinical and US population–based studies. Other historically marginalized populations are not well represented. There remains a knowledge gap regarding the extent of racial disparities in the use of GGT, particularly in the clinical setting.

Purpose To analyze the current literature regarding risk factors associated with medial ulnar collateral ligament (MUCL) injury in baseball players and to serve as a robust source for identifying modifiable risk factors that once optimized, have the potential to reduce injury risk. Methods Comprehensive search of the available literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. Studies were included if they evaluated risk factors for MUCL injuries in the elbow of baseball players. Risk of bias assessment was performed via Methodological Index for Non‐randomized Studies (MINORS) scoring system. The Oxford Centre for Evidence‐Based Medicine was used to determine level of evidence. Variables of interest; player age, position, shoulder motion, humeral retrotorsion, joint laxity, strength, balance, geography, velocity, pitch count, pitch types, throwing volumes, and throwing mechanics were recorded. Results Twenty‐one studies were included in this systematic review. MINORS scores ranged from 75 to 87%, and variables demonstrated significant heterogeneity. Performance‐based risk factors for MUCL injury included: increased pitch count (both annual and per game), higher percentage of fastballs thrown, smaller pitch repertoire, and/or a loss of pitching velocity. Biomechanical studies demonstrated the relationship between decreased shoulder range of motion (total ROM, ER, IR, and abduction), increased humeral retrotorsion, increased elbow valgus opening in the throwing arm, lower Y‐Balance score, and increased lateral release position to increased MUCL injury. Conclusions Risk factors for MUCL injury can generally be categorized into 4 primary groups: 1) various player demographics and characteristics, 2) throwing too hard (high velocity), 3) throwing too much (pitch count/volume), and 4) throwing with poor mechanics. In this systematic review, the most significant nonmodifiable risk factors for MUCL injuries included: increased glenohumeral retrotorsion and elbow valgus opening. The most consistent modifiable risk factors included: total shoulder range of motion, pitch count, pitch selection, Y balance score, and lateral release position. Pitch velocity was inconsistent in literature, but most studies found this as a risk for injury. These risk factors may serve as appropriate targets for future evidence‐based injury mitigation strategies. Level of Evidence Level IV, systematic review of Level II‐IV studies.

Abstract Objectives To explore current management practices for PMR by general practitioners (GPs) and rheumatologists including implications for clinical trial recruitment. Methods An English language questionnaire was constructed by a working group of rheumatologists and GPs from six countries. The questionnaire focused on: 1: Respondent characteristics; 2: Referral practices; 3: Treatment with glucocorticoids; 4: Diagnostics; 5: Comorbidities; and 6: Barriers to research. The questionnaire was distributed to rheumatologists and GPs worldwide via members of the International PMR/Giant Cell Arteritis Study Group. Results In total, 394 GPs and 937 rheumatologists responded to the survey. GPs referred a median of 25% of their suspected PMR patients for diagnosis and 50% of these were returned to their GP for management. In general, 39% of rheumatologists evaluated patients with suspected PMR &gt;2 weeks after referral, and a median of 50% of patients had started prednisolone before rheumatologist evaluation. Direct comparison of initial treatment showed that the percentage prescribing &gt;25 mg prednisolone daily for patients was 30% for GPs and 12% for rheumatologists. Diagnostic imaging was rarely used. More than half (56%) of rheumatologists experienced difficulties recruiting people with PMR to clinical trials. Conclusion This large international survey indicates that a large proportion of people with PMR are not referred for diagnosis, and that the proportion of treatment-naive patients declined with increasing time from referral to assessment. Strategies are needed to change referral and management of people with PMR, to improve clinical practice and facilitate recruitment to clinical trials.

Genome-wide fragmentation patterns in cell-free DNA (cfDNA) in plasma are strongly influenced by cellular origin due to variation in chromatin accessibility across cell types. Such differences between healthy and cancer cells provide the opportunity for development of novel cancer diagnostics. Here, we investigated whether analysis of cfDNA fragment end positions and their surrounding DNA sequences reveals the presence of tumor-derived DNA in blood. We performed genome-wide analysis of cfDNA from 521 samples and analyzed sequencing data from an additional 2147 samples, including healthy individuals and patients with 11 different cancer types. We developed a metric based on genome-wide differences in fragment positioning, weighted by fragment length and GC content [information-weighted fraction of aberrant fragments (iwFAF)]. We observed that iwFAF strongly correlated with tumor fraction, was higher for DNA fragments carrying somatic mutations, and was higher within genomic regions affected by copy number amplifications. We also calculated sample-level means of nucleotide frequencies observed at genomic positions spanning fragment ends. Using a combination of iwFAF and nine nucleotide frequencies from three positions surrounding fragment ends, we developed a machine learning model to differentiate healthy individuals from patients with cancer. We observed an area under the receiver operative characteristic curve (AUC) of 0.91 for detection of cancer at any stage and an AUC of 0.87 for detection of stage I cancer. Our findings remained robust with as few as 1 million fragments analyzed per sample, demonstrating that analysis of fragment ends can become a cost-effective and accessible approach for cancer detection and monitoring.