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Introduction: Pediatric pelvic and acetabular fractures are rare but potentially devastating injuries and significant management variation exists across the United States. This study sought to elucidate treatment decision-making trends, involvement of adult trauma fellowship-trained surgeons in pediatric care, and pre- and postoperative transfer patterns., Methods: Pediatric orthopaedic surgeons who serve as trauma liaisons at 20 PTCs were surveyed regarding training, practice volume, and factors contributing to institutional management of pelvic and acetabular injuries. Five clinical scenarios of pelvic ring and acetabular fractures that varied by injury pattern, age, and sex were presented. Descriptive statistics were used to summarize the results., Results: Eighteen institutions responded to the survey (90% response rate, 16 Level, 1 PTC). All surgeons were pediatric fellowship-trained (77.7% in practice >5 y). The four most common factors affecting whether surgeons independently managed both pelvic ring and acetabular fractures were patient age, fracture characteristics, displacement and need for surgery. The majority reported managing <10 acetabular (72.2%) but >10 pelvic ring (77.8%) injuries per year. In the clinical scenarios, patients <10 were more likely to have treatment decisions made by a pediatric orthopaedic surgeon. Older patients were more likely to be transferred to another institution for surgery but were often transferred back to the PTC postoperatively. In all clinical scenarios other than posterior hip dislocation, a trauma fellowship-trained surgeon was more likely to be the operative surgeon, even when the patient was not transferred., Conclusions: There is substantial variation in the management of pediatric and adolescent pelvic and acetabular fractures. Even at tertiary care PTCs, volumes are low, and trauma fellowship-trained surgeons are often involved in decision-making and operative management. Age and injury pattern seem to play a large role in variation, and patient transfers between facilities are common., Level of Evidence: V., Competing Interests: J.S. is a consultant for OrthoPediatrics. I.S. is a consultant for OrthoPediatrics. W.T. is currently receiving grants from the National Institutes of Health and the Gillette Foundation. The remaining authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The authors have no conflicts of interest.

Background and Objectives: There are few specialists that serve adults with neurodevelopmental disabilities (NDD), and most adults with NDD receive care from providers without specialty training in NDD. Care for this population is highly variable, and patient and caregiver priorities in this age group are not well known. We aimed to explore individual and caregiver values around adult neurodevelopmental care., Methods: In this qualitative study, a qualitative analyst conducted 22 semistructured virtual interviews from September 2021 to February 2022 with randomly selected adults with NDD and/or their caregivers. Each individual with NDD had at least one appointment in the adult NDD clinic, which started in October 2020. Interviews were recorded and professionally transcribed. An inductive codebook was developed and reconciled through an iterative process; transcripts were coded in Atlas.ti with 20% double-coding. Major themes were developed through team discussion., Results: Most interviewees were caregivers of patients with NDD (12); 9 interviews were with patient/caregiver dyads; 1 interview was with a patient alone. Three main themes emerged from the interviews. (1) Value in providers who are curious, engaged, and knowledgeable about NDD-related conditions, which individuals and caregivers referred to as "Unicorn Providers." (2) Value in a connected and coordinated web of care. (3) Value in comfortable and adaptable clinic spaces. They value clinical environments that foster patient success during visits., Discussion: The need for adult neurodevelopmental care is growing as more individuals with NDD are living into adulthood. Better understanding of patient and caregiver values can help shape this emerging field to meet the needs of this unique, often overlooked and underserved, population., Competing Interests: The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Background: As patients with neurodevelopmental disorders (NDDs) transition from pediatric to adult health care systems, they often have difficulty finding physicians to address their NDD-related needs. In response to this care gap, we established a new consultation clinic within a behavioral neurology clinic in an adult neurology department to address the neurodevelopmental concerns of these adult patients., Objective: To characterize the population of adult patients with NDDs seen in the adult NDD clinic in its first year., Method: Data were obtained by a retrospective chart review of all patients with NDDs seen in the adult NDD clinic from September 2020 through December 2021., Results: Of the 86 patients who were seen in the adult NDD clinic, the average age was 34 years (SD = 15, range = 18-74 years). Developmental diagnoses included intellectual disability (63%), autism spectrum disorder (47%), Down syndrome (15%), cerebral palsy (9%), and other genetic disorders (26%). Comorbidities addressed included behavioral concerns (34%), anxiety (29%), seizure disorders (22%), and depression (15%). Behavioral and/or mental health concerns prompted 65% of the initial clinic visits. The most common recommendation made was to begin or increase exercise (59%), followed by facilitating connection to community, social, and employment resources., Conclusion: Adults with NDDs have diagnoses, comorbidities, and concerns that are similar to, but also distinct from, those addressed in other adult neurology clinics. This study addresses the need for, and feasibility of, caring for the diverse population of adults with NDDs in an adult neurology setting., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Many physicians feel uncomfortable caring for patients with intellectual and developmental disabilities (IDD). While some residency training programs include lecture content on IDD, few provide structured experiences with individuals with IDD. One strategy for improving comfort is "contact theory:" increasing interactions with "dissimilar" people can lead to decreased negative attitudes toward that population., Objective: Evaluate the impact of an interactive session on resident physicians' comfort with adults with IDD., Methods: Small groups of resident physicians and artists with IDD collaborated on art projects during the noon conference. A prospective pre-post-intervention survey, including the validated Interaction with Disabled Persons Scale (IDP), evaluated residents' comfort with patients with IDD before and after the session., Results: 53 residents completed both pre- and post-conference surveys. Mean IDP scores decreased from 78.7 (10.9) to 75.8 (9.5; p  < 0.01), indicating decreasing discomfort. The mean level of comfort interacting with individuals with IDD increased from uncomfortable 3.6 (1.2), before the intervention, to comfortable 4.4 (1.2) after the intervention ( p  = <0.01). The mean level of comfort treating individuals with IDD increased from uncomfortable 3.5 (1.1) to comfortable 4.1 (1.3) after the intervention ( p  < 0.01)., Discussion: Providing resident physicians with real-life connections with people with IDD was associated with increased comfort. If statistically significant improvements occurred after one session, future studies should evaluate if additional experiences with people with IDD could have more substantial, lasting impacts on future doctors' comfort with and willingness to care for patients with IDD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sanders, Williams, Thompson and Shapiro.)

Background: Whenever the kidney standard allocation (SA) algorithms according to the Eurotransplant (ET) Kidney Allocation System or the Eurotransplant Senior Program fail, rescue allocation (RA) is initiated. There are 2 procedurally different modes of RA: recipient oriented extended allocation (REAL) and competitive rescue allocation (CRA). The objective of this study was to evaluate the association of patient survival and graft failure with RA mode and whether or not it varied across the different ET countries., Methods: The ET database was retrospectively analyzed for donor and recipient clinical and demographic characteristics in association with graft outcomes of deceased donor renal transplantation (DDRT) across all ET countries and centers from 2014 to 2021 using Cox proportional hazards methods., Results: Seventeen thousand six hundred seventy-nine renal transplantations were included (SA 15 658 [89%], REAL 860 [4.9%], and CRA 1161 [6.6%]). In CRA, donors were older, cold ischemia times were longer, and HLA matches were worse in comparison with REAL and especially SA. Multivariable analyses showed comparable graft and recipient survival between SA and REAL; however, CRA was associated with shorter graft survival. Germany performed 76% of all DDRTs after REAL and CRA and the latter mode reduced waiting times by up to 2.9 y., Conclusions: REAL and CRA are used differently in the ET countries according to national donor rates. Both RA schemes optimize graft utilization, lead to acceptable outcomes, and help to stabilize national DDRT programs, especially in Germany., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: There is limited guidance for whether repeat magnetic resonance imaging (MRI) studies are clinically impactful among children with acute hematogenous osteomyelitis (AHO) who fail to improve as expected. This study aimed to determine whether repeat MRIs changed management among children with AHO and identify clinical characteristics predictive of which patients benefit from repeat MRIs., Methods: Children admitted to a quaternary care pediatric hospital with AHO were identified during a 9-year period. Patients with chronic symptoms, non-hematogenous infections, or significant contributing comorbidities were excluded. Medical records were retrospectively reviewed for all MRIs performed 3 weeks before admission to 24 months after discharge. An MRI was considered clinically impactful if it identified a new infectious process (eg, abscess not seen on the initial MRI) or if it resulted in surgical intervention within 24 hours. Bivariable comparisons of categorical variables were performed, and multivariable logistic regression was used to assess the clinical factors of impactful repeat MRIs., Results: Among the 239 included patients, 41 (17%) had more than 1 MRI performed during their clinical course, the majority of whom (53.7%) had a repeat MRI that impacted care. Patients who underwent repeat MRIs had longer hospitalizations (7 vs. 5 d, P <0.01), were more likely to have C-reactive protein (CRP) levels >20 mg/dL (41% vs. 10%, P <0.01), and were more likely to have a delayed transition to oral antimicrobials (8.4 vs. 3.3 d, P <0.01). Peak CRP >20 mg/dL and prolonged bacteremia were found to be associated with increased odds of having an impactful repeat MRI, with adjusted odds ratios of 3.9 ( P =0.007) and 3.4 ( P =0.03), respectively., Conclusions: When used judiciously among ill children with complicated AHO, repeat MRI can be clinically impactful. Prospective studies are needed to better define which children with AHO benefit from repeat MRI., Level of Evidence: Level II evidence-this is a retrospective cohort study interested in determining the clinical utility of repeat magnetic resonance imaging studies for children with osteomyelitis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Repeated exposure to sensitizing events can activate HLA-specific memory B cells, leading to the production of donor-specific memory B cell antibodies (DSAm) that pose a risk for antibody-mediated rejection (ABMR) in kidney transplant recipients (KTRs). This single-center retrospective study aimed to identify DSAm and assess their association with outcomes in a cohort of KTRs with pretransplant serum donor-specific antibodies (DSA)., Methods: We polyclonally activated pretransplant peripheral blood mononuclear cells (PBMCs) from 60 KTRs in vitro, isolated and quantified IgG from the culture supernatant using ELISA, and analyzed the HLA antibodies of eluates with single antigen bead (SAB) assays, comparing them to the donor HLA typing for potential DSAm. Biopsies from 41 KTRs were evaluated for rejection based on BANFF 2019 criteria., Results: At transplantation, a total of 37 DSAm were detected in 26 of 60 patients (43%), of which 13 (35%) were found to be undetectable in serum. No significant association was found between pretransplant DSAm and ABMR (P=0.53). Similar results were observed in a Kaplan-Meier analysis for ABMR within the first year posttransplant (P=0.29). Additionally, MFI levels of DSAm showed no significant association with ABMR (P=0.28)., Conclusion: This study suggests no significant association between DSAm and biopsy-proven clinical ABMR. Further prospective research is needed to determine whether assessing DSAm could enhance existing immunological risk assessment methods for monitoring KTRs, particularly in non-sensitized KTRs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Altulea, van den Born, Diepstra, Bungener, Terpstra, Hepkema, Lammerts, Heeringa, Heidt, Otten, Reteig, Karahan, Berger and Sanders.)

Background: Podcasts have become increasingly utilized in medical education over the past decade, especially in orthopaedic surgery. Compared with more traditional learning tools, podcasts are easily accessible, free, and capable of use while multitasking. Despite these apparent benefits, the effectiveness of podcasts as a dissemination tool for emerging peer-reviewed literature is not well understood. The Peds Ortho Podcast is the official podcast of Pediatric Orthopedic Society of North America that highlights recently published peer-reviewed articles through author interviews and executive summaries of featured articles. The purpose of this study was to compare the distribution of the Peds Ortho Podcast to traditional media by comparing electronic access statistics between the podcast episodes and the journal articles they summarize., Methods: Podcast episodes were reviewed to catalog the abstracts and articles discussed therein. Because podcasts and articles utilize different electronic metrics to track distribution, we established a common metric of an "access," which we defined as an "intent to consume the media." For articles, we defined an "access" as the largest value of a publisher's online metrics, be it abstract views, full text views, or article downloads. For podcast episodes, we defined an "access" as any play >0 seconds. Access data were analyzed using independent samples t test and analyses of variance., Results: Eighty episodes of the Peds Ortho Podcast have featured 333 published, peer-reviewed articles to date, with 303 included in the final analysis with available article metrics. There were significantly more mean electronic accesses per podcast episode than featured articles (1236 vs. 482, P <0.001). Podcast consumption greatly varies in the first 30 days following episode release; however, recent episodes have a substantial proportion of accesses soon after publication., Conclusions: Given that podcast electronic access is greater than traditional media, podcasts appear to be a valuable tool for health care providers and trainees. Podcasts serve a complementary role to traditional media by quickly disseminating main points and raising awareness of emerging research., Competing Interests: R.C.C Clement, J. B. H., J.S.S, and C.R.L. Jr. are all co-hosts of the Peds Ortho Podcast, which might pose a conflict of interest in connection with the submitted article. The remaining authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Case: We report a case in the United States of a 12-year-old girl with multidrug-resistant tuberculous (MDR-TB) osteomyelitis of the hand managed with surgical debridement and second-line anti-TB therapy. The disease course was complicated by dissemination and multifocal progression., Conclusion: Despite early intervention, multidrug resistance makes TB treatment challenging and facilitated progression to disseminated disease in this case. We review the difficulties in diagnosis and treatment of pediatric MDR-TB., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C294)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes including CYP3A4 in vitro. Here, we investigated the effect of genetic variants in TSPYL on CYP3A4 activity using data from a clinical study and a human liver bank. Five SNVs (rs3828743, rs10223646, rs6909133, rs1204807, and rs1204811) in TSPYL were selected because of a reported effect on CYP3A4 expression in vitro or suggested clinical effect. For the clinical study, whole blood concentrations, clinical data, and DNA were available from 295 kidney transplant recipients participating in the prospective MECANO study. A multivariate pharmacokinetic model adjusted for body weight, steroid treatment, and CYP3A4 genotype was used to assess the effect of the genetic variants on cyclosporine clearance. In multivariate analysis, homozygous carriers of rs3828743 had a 18% lower cyclosporin clearance compared to the wild-type and heterozygous patients (28.72 vs. 35.03 L/h, p = 0.018) indicating a lower CYP3A4 activity and an opposite direction of effect compared to the previously reported increased CYP3A4 expression. To validate, we tested associations between rs3828743 and CYP3A4 mRNA and protein expression as well as enzyme activity with data from a liver bank (n = 150). No association with any of these end points was observed. In conclusion, the totality of evidence is not in support of a significant role for TSPYL SNV rs3828743 in explaining variability in CYP3A4 activity., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level., (© 2024 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

In kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of those scores in relation to transplant outcome is unknown. In a large Dutch kidney transplant cohort, Ellipro scores of pretransplant donor antibodies that can be assigned to known eplets (donor epitope specific HLA antibodies [DESAs]) were compared between early graft failure and long surviving deceased donor transplants. We did not observe a significant Ellipro score difference between the two cohorts, nor significant differences in graft survival between transplants with DESAs having high versus low total Ellipro scores. We conclude that Ellipro scores cannot be used to identify DESAs associated with early versus late kidney graft loss in deceased donor transplants., (© 2023 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27 + memory B cells of patients with active AAV was performed, revealing an upregulated NF-κB-associated gene signature. NF-κB signaling pathways act downstream of various B cell surface receptors, including the BCR, CD40, BAFFR and TLRs, and are essential for B cell responses. Here we demonstrate that novel pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signaling) and inhibitor-of-κB-kinase-β (IKKβ, canonical NF-κB signaling) can effectively inhibit NF-κB signaling in B cells, whereas T cell responses were largely unaffected. Moreover, both inhibitors significantly reduced B cell proliferation, differentiation and production of antibodies, including proteinase-3 (PR3) autoantibodies, in B lineage cells of AAV patients. These findings indicate that targeting NF-κB, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement., Competing Interests: Declaration of competing interest “The authors have declared that no conflict of interest exists”., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Clinical care pathways (CPs) integrate best evidence into the local care delivery context to promote efficiency and patient safety. However, the impact of CPs on diagnostic performance remains poorly understood. The objectives of this study were to evaluate adherence to a musculoskeletal infection (MSKI) diagnostic CP and identify recurrent failure points leading to missed diagnostic opportunities (MDOs)., Methods: Retrospective chart review was performed from January 2018 to February 2022 for children 6 months to 18 years of age who had an unplanned admission for MSKI after being evaluated and discharged from the pediatric emergency department (PED) for related complaints within the previous 10 days. MDOs were identified using the Revised Safer Dx. Demographic and clinical characteristics of children with and without MDOs were compared using bivariate descriptive statistics. An improvement team reviewed the diagnostic trajectories of MDOs for deviations from the MSKI CP and developed a fishbone diagram to describe contributing factors to CP deviations., Results: The study identified 21 children with and 13 children without MSKI-associated MDOs. Children with MDOs were more likely to have an initial C-reactive protein value > 2 mg/dL (90.0% vs. 0%, p = 0.01) and returned to care earlier than children without MDOs (median 2.8 days vs. 6.7 days, p = 0.004). Factors contributing to MDOs included failure to obtain screening laboratory tests, misinterpretation of laboratory values, failure to obtain orthopedic consultation, and failure to obtain definitive imaging., Conclusion: Several recurrent deviations from an MSKI diagnostic CP were found to be associated with MDOs. Future quality improvement efforts to improve adherence to this MSKI CP may prevent MDOs., (Copyright © 2023. Published by Elsevier Inc.)

T-cell-mediated help to B cells is required for the development of humoral responses, in which the cytokine interleukin (IL)-21 is key. Here, we studied the mRNA-1273 vaccine-induced SARS-CoV-2-specific memory T-cell IL-21 response, memory B cell response, and immunoglobulin (Ig)G antibody levels in peripheral blood at 28 days after the second vaccination by ELISpot and the fluorescent bead-based multiplex immunoassay, respectively. We included 40 patients with chronic kidney disease (CKD), 34 patients on dialysis, 63 kidney transplant recipients (KTR), and 47 controls. We found that KTR, but not patients with CKD and those receiving dialysis, showed a significantly lower number of SARS-CoV-2-specific IL-21 producing T cells than controls (P < .001). KTR and patients with CKD showed lower numbers of SARS-CoV-2-specific IgG-producing memory B cells when compared with controls (P < .001 and P = .01, respectively). The T-cell IL-21 response was positively associated with the SARS-CoV-2-specific B cell response and the SARS-CoV-2 spike S1-specific IgG antibody levels (both Pearson r = 0.5; P < .001). In addition, SARS-CoV-2-specific B cell responses were shown to be IL-21 dependent. Taken together, we show that IL-21 signaling is important in eliciting robust B cell-mediated immune responses in patients with kidney disease and KTR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Acute hematogenous osteomyelitis (AHO) is a relatively common condition in children, and identifying the offending pathogen with blood or tissue cultures aids in diagnosis and medical management while reducing treatment failure. Recent 2021 AHO clinical practice guidelines from the Pediatric Infectious Disease Society recommend obtaining routine tissue cultures, particularly in cases with negative blood cultures. The purpose of this study was to identify variables associated with positive tissue cultures when blood cultures are negative., Methods: Children with AHO from 18 pediatric medical centers throughout the United States through the Children's ORthopaedic Trauma and Infection Consortium for Evidence-based Study were evaluated for predictors of positive tissue cultures when blood cultures were negative. Cutoffs of predictors were determined with associated sensitivity and specificity., Results: One thousand three children with AHO were included, and in 688/1003 (68.6%) patients, both blood cultures and tissue cultures were obtained. In patients with negative blood cultures (n=385), tissue was positive in 267/385 (69.4%). In multivariate analysis, age ( P <0.001) and C-reactive protein (CRP) ( P =0.004) were independent predictors. With age >3.1 years and CRP >4.1 mg/dL as factors, the sensitivity of obtaining a positive tissue culture when blood cultures were negative was 87.3% (80.9-92.2%) compared with 7.1% (4.4-10.9%) if neither of these factors was present. There was a lower ratio of methicillin-resistant Staphylococcus aureus in blood culture-negative patients who had a positive tissue culture 48/188 (25.5%), compared with patients who had both positive blood and tissue cultures 108/220 (49.1%)., Conclusion: AHO patients with CRP ≤ 4.1 mg/dL and age under 3.1 years are unlikely to have clinical value from tissue biopsy that exceeds the morbidity associated with this intervention. In patients with CRP > 4.1 mg/dL and age over 3.1 years, obtaining a tissue specimen may add value; however, it is important to note that effective empiric antibiotic coverage may limit the utility of positive tissue cultures in AHO., Level of Evidence: Level III-Retrospective comparative study., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Existing classification systems may not adequately describe the injury patterns seen pelvic ring and acetabular fractures in the skeletally immature population. Pediatric patients, once stabilized, are often transferred for these injuries. We evaluated which commonly used systems correlate with clinical management in pediatric patients, including transfer patterns based on injury severity., Methods: A retrospective review of patients aged 1 to 15 treated for traumatic pelvic or acetabular fractures over a 10-year period at an academic level I Pediatric Trauma Center reviewed demographic, radiographic, and clinical data., Results: A total of 188 pediatric patients (average age 10.1 y) were included. Increasing injury severity based on classification Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA P <0.001; Young and Burgess P <0.001; Torode/Zieg P <0.001), increasing Injury Severity Score ( P =0.0017), and decreasing hemoglobin levels ( P =0.0144) were significantly associated with operative management. Injury characteristics did not differ between patients who were transferred versus patients who were brought in directly from the field. Air transport was significantly associated with surgical treatment, pediatric intensive care unit admission, polytrauma, and Torode/Zieg classification ( P =0.036, <0.0001, 0.0297, 0.0003, respectively)., Conclusions: Although not fully descriptive of skeletally immature fracture patterns, the AO/OTA and Young and Burgess classification systems adequately assess the severity of pelvic rings and injuries in pediatric patients and predict management patterns. The Torode and Zieg classification also predicts management. In a large cohort, air transport was significantly associated with surgical treatment, need for pediatric intensive care unit stay, the presence of an additional injury, and instability in the Torode and Zieg classification. These findings suggest that air transfers are being utilized to expedite advanced-level care in more severe injuries. Further studies with long-term follow-up are required to assess the clinical outcomes of both nonoperatively and operatively treated pediatric pelvic fractures and to guide both triage and treatment decisions for these rare but severe injuries., Level of Evidence: Level III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Cytokines are regulators of the immune response against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the contribution of cytokine-secreting CD4 + and CD8 + memory T cells to the SARS-CoV-2-specific humoral immune response in immunocompromised kidney patients is unknown. Here, we profiled 12 cytokines after stimulation of whole blood obtained 28 days post second 100 μg mRNA-1273 vaccination with peptides covering the SARS-CoV-2 spike (S)-protein from patients with chronic kidney disease (CKD) stage 4/5, on dialysis, kidney transplant recipients (KTR), and healthy controls. Unsupervised hierarchical clustering analysis revealed two distinct vaccine-induced cytokine profiles. The first profile was characterized by high levels of T-helper (Th) 1 (IL-2, TNF-α, and IFN-γ) and Th 2 (IL-4, IL-5, IL-13) cytokines, and low levels of Th 17 (IL-17A, IL-22) and Th 9 (IL-9) cytokines. This cluster was dominated by patients with CKD, on dialysis, and healthy controls. In contrast, the second cytokine profile contained predominantly KTRs producing mainly Th 1 cytokines upon re-stimulation, with lower levels or absence of Th 2 , Th 17 , and Th 9 cytokines. Multivariate analyses indicated that a balanced memory T cell response with the production of Th 1 and Th 2 cytokines was associated with high levels of S1-specific binding and neutralizing antibodies mainly at 6 months after second vaccination. In conclusion, seroconversion is associated with the balanced production of cytokines by memory T cells. This emphasizes the importance of measuring multiple T cell cytokines to understand their influence on seroconversion and potentially gain more information about the protection induced by vaccine-induced memory T cells., (© 2023. The Author(s).)

Background and Objectives: Individuals with intellectual and/or developmental disabilities (IDD) experience worse health outcomes compared with peers without a disability partly due to difficulties accessing age-appropriate health care. Provider discomfort with interacting and caring for individuals with IDD is a primary barrier to accessing care. The objectives of this study were to describe resident physicians' education, experiences, and comfort levels regarding individuals with IDD and to identify predictors of higher comfort levels with this patient population., Methods: In this cross-sectional study, we surveyed medical trainees in 7 residency programs in Boston, Massachusetts on their education, experiences, and comfort levels regarding individuals with IDD. The comfort level was assessed directly on a 6-point Likert scale. The relationship between comfort regarding people with IDD and several candidate explanatory variables was explored with Spearman and partial Spearman correlations ( r s )., Results: The estimated survey response rate was 49%. Of 423 resident physicians included in the study, 96% reported they had treated a patient with IDD, while only 25% reported having formal education on caring for this population. On a scale of 1-6, with higher numbers corresponding to greater comfort, the mean comfort level treating individuals with IDD was 3.73 (CI 3.61-3.85). In bivariant analyses, the amount of prior experience with people with IDD had a moderate, positive correlation with increased comfort levels treating individuals with IDD ( r s = 0.42, p < 0.01). The following characteristics had a weak, positive correlation with increased comfort levels: training in a pediatric-focused residency specialty ( r s = 0.18, p < 0.01), number of hours of formal education on caring for people with IDD ( r s = 0.15, p < 0.01), and age ( r s = 0.12, p = 0.03). Only the amount of prior experience with this patient population remained positively correlated with higher comfort levels when the other variables were controlled for ( r s = 0.38, p < 0.01)., Discussion: Prior experience with individuals with IDD predicted higher comfort levels with this population. This study supports the need for increased opportunities for medical trainees to engage with people with IDD to improve resident physicians' comfort caring for this patient population., Competing Interests: The authors report no disclosures. Go to Neurology.org/NE for full disclosures., (© 2023 American Academy of Neurology.)

Background: Although current clinical practice guidelines from the American Academy of Orthopaedic Surgeons suggest that Type II and III supracondylar humerus (SCH) fractures be treated by closed reduction and pin fixation, controversy remains as to whether type IIa fractures with no rotation or angular deformity require surgery. The purpose of our study was to prospectively compare radiographic and functional outcomes of type IIa SCH fractures treated with or without surgery., Methods: Between 2017 and 2019, 105 patients between 2 and 12 years of age presenting with type IIa SCH fractures and without prior elbow trauma, neuromuscular or metabolic conditions, were prospectively enrolled. Ten orthopaedic surgeons managed the patients with 5 preferring surgical treatment and 5 preferring an initial attempt at nonoperative treatment. Patients in the nonoperative cohort were managed with a long-arm cast and close radiographic follow-up. Patients underwent a standardized protocol, including 3 to 4 weeks of casting, bilateral radiographic follow-up 6 months postinjury, and telephone follow-up at 6, 12, and 24 months., Results: Ninety-nine patients met the inclusion criteria (45 nonoperative and 54 operatives). Of the nonoperative patients, 4 (9%) were converted to surgery up to their first clinical follow-up. No differences were identified between the cohorts with respect to demographic data, but patients undergoing surgery had on average 6 degrees more posterior angulation at the fracture site preoperatively (P<0.05). At the final clinical follow-up (mean=6 mo), the nonoperative group had more radiographic extension (176.9 vs 174.4 degrees, P=0.04) as measured by the hourglass angle, but no other clinical or radiographic differences were appreciated. Complications were similar between the nonoperative and operative groups: refracture (4.4 vs 5.6%), avascular necrosis (2.2 vs 1.9%) and infection (0 vs 1.9%) (P>0.05). Patient-reported outcomes at a mean of 24 months showed no differences between groups., Conclusion: Contrary to American Academy of Orthopaedic Surgeons guidelines, about 90% of patients with type IIa supracondylar fractures can be treated nonoperatively and will achieve good radiographic and functional outcomes with mild residual deformity improving over time. Patients treated nonoperatively must be monitored closely to assess for early loss of reduction and the need for surgical intervention., Competing Interests: The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: There is no consensus if nor when a native nephrectomy should be performed in the workup for kidney transplantation in ADPKD patients. In our PKD Expertise Center, a restrictive approach is pursued in which nephrectomy is performed only in patients with severe complaints, i.e., in case of serious volume-related complaints, lack of space for the allograft, recurrent cyst infections, persistent cyst bleedings, or chronic refractory pain. We analyzed in a retrospective cohort study whether this approach is justified., Methods: All ADPKD patients who received kidney transplantation between January 2000 and January 2019 were reviewed. Patients were subdivided into three groups: no nephrectomy (no-Nx), nephrectomy performed before (pre-Tx), or after kidney transplantation (post-Tx). Simultaneous nephrectomy together with transplantation were not performed in our center., Results: 391 patients (54 ± 9 years, 55% male) were included. The majority of patients did not undergo a nephrectomy (n = 257, 65.7%). A nephrectomy was performed pre-Tx in 114 patients (29.2%). After Tx, nephrectomy was performed in only 30 patients (7.7%, median 4.4 years post-Tx). Surgery-related complication rates did not differ between both groups (38.3% pre-Tx vs. 27.0% post-Tx, p = 0.2), nor were there any differences in 10-year patient survival (74.4% pre-Tx vs. 80.7% post-Tx vs. 67.6% no-Nx, p = 0.4), as well as in 10-year death-censored graft survival (84.4% pre-Tx vs. 85.5% post-Tx vs. 90.0% no-Nx, p = 0.9)., Conclusions: This study indicates that with a restrictive nephrectomy policy in the workup for kidney transplantation, only a part of ADPKD patients need a native nephrectomy., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Objective: The authors examined how the COVID-19 pandemic affected the behavioral health of people with intellectual and developmental disabilities (IDD)., Methods: A modified version of the Coronavirus Health Impact Survey-Adapted for Autism and Related Neurodevelopmental Conditions was sent to the authors' clinical networks and IDD-affiliated organizations from March to June 2021., Results: In total, 437 people with IDD or their caregivers responded to the survey. Diagnoses included intellectual disability (51%) and autism spectrum disorder (48%). More than half (52%) of respondents reported worsened mental health. Losing access to services correlated with declining mental health. Interventions suggested to improve behavioral health included more time with friends and family (68%), more time outdoors (61%), and access to community activities (59%)., Conclusions: COVID-19 affected the behavioral health of individuals with IDD. Survey results highlight the opportunity to leverage physical activity and pandemic-safe social supports as accessible means to mitigate gaps in services.

Introduction: It is unclear whether polyomavirus BK (BKPyV) microribonucleic acid (miRNA) measurement has additional diagnostic and predictive value in kidney transplant recipients (KTR) as compared to current methods of monitoring BKPyV DNA loads., Patients and Methods: A retrospective, longitudinal study was performed in 30 KTR with BKPyV viruria (n = 10), BKPyV viremia (n = 10), or BKPyV-associated neuropathy (BKPyVAN) (n = 10). Bkv-miR-B1-3p and 5p and BKPyV DNA load were measured in urine and plasma and compared using receiver operating characteristic (ROC) curves., Results: Levels of Bkv-miR-B1-3p and 5p and BKPyV DNA correlated strongly. Overall, mostly analog courses of urinary and plasma miRNA and DNA loads were observed. Areas under the ROC curves were not significantly different between miRNAs and DNA. Only, in contrast to BKPyV DNA load, BKPyV miRNA levels increased from 6 to 12 months in the viremia group, while in the BKPyVAN group, a decline was seen in both DNA and miRNA., Conclusions: In this study, we could not demonstrate an additional value of BKPyV miRNA detection compared to BKPyV DNA monitoring in the early phase after kidney transplantation. We did observe significant differences between the viremia and the BKPyVAN groups during follow-up. This study was performed with a small number of patients and therefore results should be verified in a larger patient cohort. Furthermore, future studies with larger patient groups are necessary to elucidate final clinical value of these data., (© 2022 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Studies have shown that coronavirus disease 2019 (COVID-19) vaccination is associated with a lower humoral response in vulnerable kidney patients. Here, we investigated the T-cell response following COVID-19 vaccination in kidney patients compared with controls., Methods: Patients with chronic kidney disease (CKD) stage G4/5 [estimated glomerular filtration rate <30 mL/min/1.73 m2], on dialysis, or living with a kidney transplant and controls received 2 doses of the mRNA-1273 COVID-19 vaccine. Peripheral blood mononuclear cells were isolated at baseline and 28 d after the second vaccination. In 398 participants (50% of entire cohort; controls n = 95, CKD G4/5 n = 81, dialysis n = 78, kidney transplant recipients [KTRs] n = 144)' SARS-CoV-2-specific T cells were measured using an IFN-γ enzyme-linked immune absorbent spot assay., Results: A significantly lower SARS-CoV-2-specific T-cell response was observed after vaccination of patients on dialysis (54.5%) and KTRs (42.6%) in contrast to CDK G4/5 (70%) compared with controls (76%). The use of calcineurin inhibitors was associated with a low T-cell response in KTRs. In a subset of 20 KTRs, we observed waning of the cellular response 6 mo after the second vaccination, which was boosted to some extent after a third vaccination, although T-cell levels remained low., Conclusion: Our data suggest that vaccination is less effective in these patient groups, with humoral nonresponders also failing to mount an adequate cellular response, even after the third vaccination. Given the important role of T cells in protection against disease and cross-reactivity to SARS-CoV-2 variants, alternative vaccination strategies are urgently needed in these high-risk patient groups., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Objective: To develop standardization for nomenclature, diagnostic work up and diagnostic criteria for cases of neurocognitive regression in Down syndrome., Background: There are no consensus criteria for the evaluation or diagnosis of neurocognitive regression in persons with Down syndrome. As such, previously published data on this condition is relegated to smaller case series with heterogenous data sets. Lack of standardized assessment tools has slowed research in this clinical area., Methods: The authors performed a two-round traditional Delphi method survey of an international group of clinicians with experience in treating Down syndrome to develop a standardized approach to clinical care and research in this area. Thirty-eight potential panelists who had either previously published on neurocognitive regression in Down syndrome or were involved in national or international working groups on this condition were invited to participate. In total, 27 panelists (71%) represented nine medical specialties and six different countries reached agreement on preliminary standards in this disease area. Moderators developed a proposed nomenclature, diagnostic work up and diagnostic criteria based on previously published reports of regression in persons with Down syndrome., Results: During the first round of survey, agreement on nomenclature for the condition was reached with 78% of panelists agreeing to use the term Down Syndrome Regression Disorder (DSRD). Agreement on diagnostic work up and diagnostic criteria was not reach on the first round due to low agreement amongst panelists with regards to the need for neurodiagnostic testing. Following incorporation of panelist feedback, diagnostic criteria were agreed upon (96% agreement on neuroimaging, 100% agreement on bloodwork, 88% agreement on lumbar puncture, 100% agreement on urine studies, and 96% agreement on "other" studies) as were diagnostic criteria (96% agreement)., Conclusions: The authors present international consensus agreement on the nomenclature, diagnostic work up, and diagnostic criteria for DSRD, providing an initial practical framework that can advance both research and clinical practices for this condition., Competing Interests: JDS receives research support from the National Institutes of Health, the Race to Erase MS Foundation, and the Thrasher Society. He also serves as a consultant to UCB on myelin oligodendrocyte glycoprotein antibody spectrum disorders. GG receives part-time salary support from the Centers for Disease Control and Prevention for acute flaccid myelitis disease surveillance. DA is supported by the Fondo de Investigaciones Sanitarias (FIS grant PI19/00634, from the Ministerio de Economía y Competitividad (Instituto de Salud Carlos III) and co-funded by The European Regional Development Fund (ERDF) “A way to make Europe” and the. Fondation Jérôme Lejeune (grant no. 2021a-2069). The Adult Down Syndrome Outpatient unit at Hospital Universitario de La Princesa is grateful to Licenciado don Jesús Coronado Hinojosa for his financial support of the research endeavors of our unit. BS occasionally consults on the topic of Down syndrome through Gerson Lehrman Group. He receives remuneration from Down syndrome nonprofit organizations for speaking engagements and associated travel expenses. BS receives annual royalties from Woodbine House, Inc., for the publication of his book, Fasten Your Seatbelt: A Crash Course on Down Syndrome for Brothers and Sisters. Within the past 2 years, he has received research funding from F. Hoffmann-La Roche, Inc., and LuMind Research Down Syndrome Foundation to conduct clinical trials for people with Down syndrome. BS is occasionally asked to serve as an expert witness for legal cases where Down syndrome is discussed. He serves in a nonpaid capacity on the Honorary Board of Directors for the Massachusetts Down Syndrome Congress and the Professional Advisory Committee for the National Center for Prenatal and Postnatal Down Syndrome Resources. BS has a sister with Down syndrome. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Santoro, Patel, Kammeyer, Filipink, Gombolay, Cardinale, Real de Asua, Zaman, Santoro, Marzouk, Khoshnood, Vogel, Tanna, Pagarkar, Dhanani, Ortega, Partridge, Stanley, Sanders, Christy, Sannar, Brown, McCormick, Van Mater, Franklin, Worley, Quinn, Capone, Chicoine, Skotko and Rafii.)

Tissue-specific nonhuman leukocyte antigen (HLA) antigens can play crucial roles in allograft immunity and have been shown to trigger humoral responses leading to rejection of HLA-matched kidney allografts. Interest in the role of endothelial-specific antigens has grown over the past years, and several case reports have been described in which antibodies reacting with endothelial cells (ECs) are associated with rejection. Such antibodies escape the detection in conventional crossmatch tests as they do not react with lymphocytes. However, due to the heterogeneity of endothelial cells from different vascular beds, it remains difficult to draw organ-specific conclusions from studies describing endothelial crossmatch assays. We present a case of a 69-year-old male patient whose kidney allograft was rejected as hyperacute, despite the absence of pretransplant HLA-specific antibodies. To place findings from previous studies in a kidney-related context, we performed crossmatch assays with primary renal endothelial cells. The patient's serum was reactive with primary renal ECs, demonstrated by antibody binding and complement-dependent cytotoxicity. Antibodies from this patient did not react with lymphocytes nor were HLA donor-specific antibodies (DSAs) found. Two years later, the patient successfully received a second kidney transplant after treatment with rituximab and plasmapheresis before and after transplantation. We demonstrated that the removal of antibodies against non-HLA EC-specific molecules can be monitored using a primary renal EC crossmatch test, possibly contributing to a successful transplantation outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lammerts, Born, Huberts-Kregel, Gomes-Neto, Daha, Hepkema, Sanders, Pol, Diepstra and Berger.)

Single-kidney glomerular filtration rate (GFR) increases after living kidney donation due to compensatory hyperfiltration and structural changes. The implications of inter-individual variability in this increase in single-kidney GFR are unknown. Here, we aimed to identify determinants of the increase in single-kidney GFR at three-month postdonation, and to investigate its relationship with long-term kidney function. In a cohort study in 1024 donors, we found considerable inter-individual variability of the early increase in remaining single-kidney estimated GFR (eGFR) (median [25th-75th percentile]) 12 [8-18] mL/min/1.73m 2 . Predonation eGFR, age, and cortical kidney volume measured by CT were the main determinants of the early postdonation increase in single-kidney eGFR. Individuals with a stronger early increase in single-kidney eGFR had a significantly higher five-year postdonation eGFR, independent of predonation eGFR and age. Addition of the postdonation increase in single-kidney eGFR to a model including predonation eGFR and age significantly improved prediction of a five-year postdonation eGFR under 50 mL/min/1.73m 2 . Results at ten-year follow-up were comparable, while accounting for left-right differences in kidney volume did not materially change the results. Internal validation using 125 I-iothalamate-based measured GFR in 529 donors and external validation using eGFR data in 647 donors yielded highly similar results. Thus, individuals with a more pronounced increase in single-kidney GFR had better long-term kidney function, independent of predonation GFR and age. Hence, the early postdonation increase in single-kidney GFR, considered indicative for kidney reserve capacity, may have additional value to eGFR and age to personalize follow-up intensity after living kidney donation., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

To date, human leukocyte antigens (HLA) have been the major focus in the approach to acute and chronic antibody-mediated rejection (AMBR) in solid-organ transplantation. However, evidence from the clinic and published studies has shown that non-HLA antibodies, particularly anti-endothelial cell antibodies (AECAs), are found either in the context of AMBR or synergistically in the presence of donor-specific anti-HLA antibodies (DSA). Numerous studies have explored the influence of AECAs on clinical outcomes, yet the determination of the exact clinical relevance of non-HLA antibodies in organ transplantation is not fully established. This is due to highly heterogeneous study designs including differences in testing methods and outcome measures. Efforts to develop reliable and sensitive diagnostic non-HLA antibody tests are continuously made. This is essential considering the technical difficulties of non-HLA antibody assays and the large variation in reported incidences of antibodies. In addition, it is important to take donor specificity into account in order to draw clinically relevant conclusions from non-HLA antibody assays. Here, we provide an overview of non-HLA solid-phase and cell-based crossmatch assays for use in solid-organ transplantation that are currently available, either in a research setting or commercially., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lammerts, Altulea, Hepkema, Sanders, Born and Berger.)

Background: The primary purpose of this analysis was to compare supracondylar humerus fracture (SCHF) treatment patterns at a single quaternary pediatric hospital relative to the American Academy of Orthopedic Surgeons (AAOS) appropriate use treatment recommendation(s)., Methods: Among all fractures included in the cohort (n=571), the observed treatment approach was evaluated relative to the AAOS "Appropriate" treatment recommendation(s). The proportion, and corresponding 95% confidence interval, of cases that agreed with the "Appropriate" treatment recommendation was estimated. Demographics and clinical characteristics among cases that were managed in accordance with the "Appropriate," "May be Appropriate," or "Rarely Appropriate" were compared., Results: All fractures were treated according to the "Appropriate," "May be Appropriate," or "Rarely Appropriate" AAOS treatment guidelines. The observed treatment among fractures included in the cohort agreed with AAOS "Appropriate" recommendations in 92.1% [95% confidence interval (CI): 89.6%-94.2%] of the cases. Fracture type differed significantly between patients treated according to AAOS "Appropriate" recommendations compared to those treated according to "May be Appropriate," or "Rarely Appropriate" recommendation., Conclusions: The treatment approach implemented at a single level 1 trauma center was in concordance with the appropriate use criteria treatment recommendations in a significant majority of cases. Fractures not treated according to "Appopriate" recommendations were primarily type IIA injuries, and were treated with closed reduction and casting instead of the recommended closed reduction and percutaneous pinning., Level of Evidence: Level III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Living donor kidney transplantation is currently the preferred treatment for patients with end-stage renal disease. The psychosocial evaluation of kidney donor candidates relies mostly on the clinical viewpoint of transplant professionals because evidence-based guidelines for psychosocial donor eligibility are currently lacking. However, the accuracy of these clinical risk judgements and the potential added value of a systematic self-reported screening procedure are as yet unknown. The current study examined the effectiveness of the psychosocial evaluation by transplant professionals and the potential value of donor self-report measures in optimising the donor evaluation. Based on the stress-vulnerability model, the predictive value of predonation, intradonation and postdonation factors to impaired longer term health-related quality of life (HRQoL) of kidney donors was studied., Design: An observational prospective multicentre study., Setting: Seven Dutch transplantation centres., Participants: 588 potential donors participated, of whom 361 donated. Complete prospective data of 230 donors were available. Also, 1048 risk estimation questionnaires were completed by healthcare professionals., Methods: Transplant professionals (nephrologists, coordinating nurses, social workers and psychologists) filled in risk estimation questionnaires on kidney donor candidates. Furthermore, 230 kidney donors completed questionnaires (eg, on HRQoL) before and 6 and 12 months after donation., Primary and Secondary Outcome Measures: HRQoL, demographic and preoperative, intraoperative and postoperative health characteristics, perceived support, donor cognitions, recipient functioning and professionals risk estimation questionnaires., Results: On top of other predictors, such as the transplant professionals' risk assessments, donor self-report measures significantly predicted impaired longer term HRQoL after donation, particularly by poorer predonation physical (17%-28% explained variance) and psychological functioning (23%)., Conclusions: The current study endorses the effectiveness of the psychosocial donor evaluation by professionals and the additional value of donor self-report measures in optimising the psychosocial evaluation. Consequently, systematic screening of donors based on the most prominent risk factors provide ground for tailored interventions for donors at risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT., Methods: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection., Results: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events., Conclusion: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT., Trial Registration: The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy., (© 2022. The Author(s).)

Objectives: Cerebral palsy (CP) is the most common childhood motor disability, yet its link to single-gene disorders is under-characterized. To explore the genetic landscape of CP, we conducted whole exome sequencing (WES) in a cohort of patients with CP., Methods: We performed comprehensive phenotyping and WES on a prospective cohort of individuals with cryptogenic CP (who meet criteria for CP; have no risk factors), non-cryptogenic CP (who meet criteria for CP; have at least one risk factor), and CP masqueraders (who could be diagnosed with CP, but have regression/progressive symptoms). We characterized motor phenotypes, ascertained medical comorbidities, and classified brain MRIs. We analyzed WES data using an institutional pipeline., Results: We included 50 probands in this analysis (20 females, 30 males). Twenty-four had cryptogenic CP, 20 had non-cryptogenic CP, five had CP masquerader classification, and one had unknown classification. Hypotonic-ataxic subtype showed a difference in prevalence across the classification groups (p = 0.01). Twenty-six percent of participants (13/50) had a pathogenic/likely pathogenic variant in 13 unique genes (ECHS1, SATB2, ZMYM2, ADAT3, COL4A1, THOC2, SLC16A2, SPAST, POLR2A, GNAO1, PDHX, ACADM, ATL1), including one patient with two genetic disorders (ACADM, PDHX) and two patients with a SPAST-related disorder. The CP masquerader category had the highest diagnostic yield (n = 3/5, 60%), followed by the cryptogenic CP category (n = 7/24, 29%). Fifteen percent of patients with non-cryptogenic CP (n = 3/20) had a Mendelian disorder on WES., Interpretation: WES demonstrated a significant prevalence of Mendelian disorders in individuals clinically diagnosed with CP, including in individuals with known CP risk factors., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose of Review: Etiologic investigations for adults with intellectual disability (ID) pose a special challenge to many adult neurologists. The adaptability of pediatric guidelines for workup of ID to adult populations has not been clearly established. We review the current recommendations on etiologic workup of ID in children and adults and provide initial guidance for adult neurologists who care for individuals with ID of unknown etiology., Recent Findings: Etiologic workup, including genetic testing, is recommended in individuals with ID of unknown origin. Workup should be guided by a thoughtful history and physical examination, which can help identify certain causes of ID., Summary: Specific diagnoses may help guide management and surveillance of comorbid conditions in individuals with ID. Etiologic investigations of adults with ID include genetic and metabolic testing and brain imaging in the appropriate clinical setting., (© 2021 American Academy of Neurology.)

CD4 + T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4 + memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4 + memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4 + memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4 + memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation., Competing Interests: The authors of this manuscript have conflicts of interest to disclose. The UMC Utrecht has filed a patent application on the prediction of an alloimmune response against mismatched HLA. ES is listed as inventor on this patent. MN is employed by PIRCHE AG, which publishes the PIRCHE web-portal. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Peereboom, Matern, Tomosugi, Niemann, Drylewicz, Joosten, Allebes, van der Meer, Hilbrands, Baas, van Reekum, Verhaar, Kamburova, Seelen, Sanders, Hepkema, Lambeck, Bungener, Roozendaal, Tilanus, Voorter, Wieten, van Duijnhoven, Gelens, Christiaans, van Ittersum, Nurmohamed, Lardy, Swelsen, van der Pant, van der Weerd, ten Berge, Bemelman, de Vries, de Fijter, Betjes, Roelen, Claas, Otten, Heidt, van Zuilen, Kobayashi, Geneugelijk and Spierings.)

Nail pigmentation in children can cause significant anxiety in parents and clinicians. Different pigments of the nails, such as yellow, orange, and green, can all occur; however, this paper will focus on the dark pigments: brown, gray, and black pigmentation of the nails. Many causes of dark coloration of the nails exist; almost all causes in pediatric patients are benign and require no treatment. Melanoma is the one diagnosis that physicians do not want to miss. Fortunately, this is extremely rare in children., (© 2021 Wiley Periodicals LLC.)

Purpose of Review: The onset and progression of small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies has been linked to microbial infections. Here, we provide a brief overview of the association of nasal colonization of Staphylococcus aureus with ANCA-associated vasculitis (AAV) and discuss several recent studies mapping the nasal microbiome in AAV patients in particular., Recent Findings: Nasal microbiome studies revealed dysbiosis as a common trait in active AAV which tends to normalize upon immunosuppressive treatment and quiescent disease. However, due to differences in study design, patient selection, and methodology, the reported microbiome profiles differ considerably precluding conclusions on causal relationships. The microbiome is an emerging area of research in AAV warranting further investigation. Ideally, such studies should be combined with mechanistic studies to unravel key elements related to host-microbe interactions and their relevance for AAV pathogenesis.

Individuals with intellectual and developmental disabilities (IDDs) are among our most medically vulnerable neurologic patient population. As such, they are at particular risk of psychosocial and medical harm during the coronavirus disease 2019 (COVID-19) pandemic. Here, we highlight strategies to decrease potential infectious exposures and ensure continued optimal neurologic care for individuals with IDD during the COVID-19 pandemic. Finally, in a climate of potential medical resource restriction, we offer some suggestions for advocacy on behalf of individuals with IDD., (© 2020 American Academy of Neurology.)

Many pediatric nail findings are normal variants and are no cause for alarm. Others represent congenital abnormalities or genetic syndromes for which there is no cure. Still others are inflammatory or infectious entities that require treatment. Pediatric nail disorders are reviewed, along with management., Competing Interests: Disclosure The author has nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The halo of the Milky Way provides a laboratory to study the properties of the shocked hot gas that is predicted by models of galaxy formation. There is observational evidence of energy injection into the halo from past activity in the nucleus of the Milky Way 1-4 ; however, the origin of this energy (star formation or supermassive-black-hole activity) is uncertain, and the causal connection between nuclear structures and large-scale features has not been established unequivocally. Here we report soft-X-ray-emitting bubbles that extend approximately 14 kiloparsecs above and below the Galactic centre and include a structure in the southern sky analogous to the North Polar Spur. The sharp boundaries of these bubbles trace collisionless and non-radiative shocks, and corroborate the idea that the bubbles are not a remnant of a local supernova 5 but part of a vast Galaxy-scale structure closely related to features seen in γ-rays 6 . Large energy injections from the Galactic centre 7 are the most likely cause of both the γ-ray and X-ray bubbles. The latter have an estimated energy of around 10 56 erg, which is sufficient to perturb the structure, energy content and chemical enrichment of the circumgalactic medium of the Milky Way.

The PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal associations between plasma and urine PRO-C6 and proven histological changes after kidney transplantation. The current study is a post-hoc analysis of 94 participants of the MECANO trial, a 24-month prospective, multicenter, open-label, randomized, controlled trial aimed at comparing everolimus-based vs. cyclosporine-based immunosuppression. PRO-C6 was measured in plasma and urine samples collected 6 and 24 months post-transplantation. Fibrosis was evaluated in biopsies collected at the same time points by Banff interstitial fibrosis/tubular atrophy (IF/TA) scoring and collagen staining (Picro Sirius Red; PSR); inflammation was evaluated by the tubulo-interstitial inflammation score (ti-score). Linear regression analyses were performed. Six-month plasma PRO-C6 was cross-sectionally associated with IF/TA score (Std. β = 0.34), and prospectively with 24-month IF/TA score and ti-score (Std. β = 0.24 and 0.23, respectively) ( p < 0.05 for all). No significant associations were found between urine PRO-C6 and any of the biopsy findings. Fibrotic changes and urine PRO-C6 behaved differentially over time according to immunosuppressive therapy. These results are a first step towards non-invasive fibrosis detection after kidney transplantation by means of collagen VI synthesis measurement, and further research is required.

Background: Screw fixation is the most commonly employed fixation strategy for displaced medial epicondyle fractures, but in younger patients with minimal ossification, the fracture fragment may not accommodate a screw. In these situations, Kirschner-wires (K-wire) or suture anchors may be utilized as alternatives. The purposes of this study were to examine the biomechanical properties of medial epicondyle fractures fixed with a screw, K-wires, or suture anchors, to evaluate clinical outcomes and complications of patients 10 years of age or younger treated with these approaches, and to perform a cost-analysis., Methods: Biomechanical assessment: Immature pig forelimbs underwent an osteotomy through the medial epicondyle apophysis, simulating a fracture. These were then fixed with a screw, K-wires or suture anchors. Cyclic elongation (mm), displacement (mm), load to failure (N), and stiffness (N/mm) were assessed. Clinical assessment: a retrospective review was performed of patients 10 years of age or younger with a medial epicondyle fracture fixed with these strategies. Radiographic outcomes, postoperative data and complications were compared. These data were used to perform a cost-analysis of each treatment approach., Results: Biomechanically, screws were stronger (P=0.047) and stiffer (P=0.01) than the other constructs. Clinically, 51 patients met inclusion criteria (screw=27, wires=11, anchor=13). Patients treated with K-wires were younger (P<0.05) and patients treated with screw fixation had a shorter casting duration (P=0.008). Irrespective of treatment strategy, all fractures healed (100%) and only 1 patient in the screw group lost reduction. Clinical outcomes and complications were similar between groups, but the suture anchor group was less likely to require a second surgery for implant removal (P<0.05). This lower reoperation rate led to a cost-saving of 10%., Conclusions: Biomechanically, all 3 approaches provided initial fixation exceeding the forces observed across the elbow joint with routine motion. The screw construct was the strongest and stiffest. Clinically, all 3 strategies were acceptable, with screw fixation offering a shorter casting duration, but greater implant removal need with higher associated costs.

Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms underlying the potential differences in relapse rates., Competing Interests: The authors have declared that no competing interests exist.

The clinical significance of non-HLA antibodies on renal allograft survival is a matter of debate, due to differences in reported results and lack of large-scale studies incorporating analysis of multiple non-HLA antibodies simultaneously. We developed a multiplex non-HLA antibody assay against 14 proteins highly expressed in the kidney. In this study, the presence of pretransplant non-HLA antibodies was correlated to renal allograft survival in a nationwide cohort of 4770 recipients transplanted between 1995 and 2006. Autoantibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) were significantly associated with graft loss in recipients transplanted with a deceased-donor kidney (N = 3276) but not in recipients of a living-donor kidney (N = 1496). At 10 years after deceased-donor transplantation, recipients with anti-ARHGDIB antibodies (94/3276 = 2.9%) had a 13% lower death-censored covariate-adjusted graft survival compared to the anti-ARHGDIB-negative (3182/3276 = 97.1%) population (hazard ratio 1.82; 95% confidence interval, 1.32-2.53; P = .0003). These antibodies occur independently from donor-specific anti-HLA antibodies (DSA) or other non-HLA antibodies investigated. No significant relations with graft loss were found for the other 13 non-HLA antibodies. We suggest that pretransplant risk assessment can be improved by measuring anti-ARHGDIB antibodies in all patients awaiting deceased-donor transplantation., (© 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: To determine Bruton's tyrosine kinase (BTK) protein and phosphorylation levels in B cell subsets of granulomatosis with polyangiitis (GPA) patients and to investigate the effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production., Methods: BTK protein and phosphorylation levels were determined by flow cytometry in peripheral blood B cells of 29 untreated GPA patients [9 active and 20 remission GPA patients (10 ANCA- and 10 ANCA+)], 9 age- and sex-matched healthy controls (HCs) and 9 untreated active RA patients. The effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production was determined in the same donors in peripheral blood mononuclear cell cultures., Results: BTK protein levels were significantly increased in transitional and naïve B cells of active GPA and RA patients compared with remission GPA patients and HCs. Both B cell subsets of active patients were more sensitive to B cell receptor stimulation, as BTK and phospholipase Cγ2 phosphorylation were increased in these patients. In vitro BTK blockade had profound effects on B cell cytokine production, plasma cell formation and (auto)antibody production in both GPA patients and HCs. Interestingly, the effect of BTK blockade was less pronounced in active GPA patients, possibly due to increased activation of B cells., Conclusion: We show that BTK protein and phosphorylation levels are most profoundly increased in newly emerging B cells of active GPA patients compared with remission patients. BTK blockade greatly inhibits in vitro B cell effector functions in GPA patients and HCs. These promising data identify BTK as an interesting novel therapeutic target in the treatment of GPA., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)