Jeffrey Modell Foundation

Ever since the first description of an inherited immunodeficiency in 1952 in a boy with gammaglobulin deficiency, new insights have progressed rapidly in disorders that are now referred to as inborn errors of immunity. In a field where fundamental molecular biology, genetics, immune signaling, and clinical care are tightly intertwined, 2022-24 saw a multitude of advances. Here we report a selection of research updates with a main focus on (1) diagnosis and screening, (2) new genetic defects, (3) susceptibility to severe coronavirus disease 2019 infection and impact of vaccination, and (4) treatment. Importantly, new pathogenic insights more rapidly affect treatment outcomes, either through an earlier and more precise diagnosis or through implementation of novel, personalized treatment. The field is growing rapidly, so awareness, communication, and collaboration are key to improving treatment outcomes.

Objective: Postural orthostatic tachycardia syndrome (POTS) affects up to 3 million people in the United States. Although 78%–83% of POTS patients are female, gynecologic comorbidity has not been well-studied. We created an online questionnaire to assess outcomes in female patients with POTS formerly followed at a single-center pediatric POTS program.Design: Cross-sectional study.Setting: Single-center pediatric POTS program.Population or Sample: All female patients ≤ 18 years at diagnosis.Methods: We developed and distributed The Long-Term POTS Outcomes Survey with questions about diagnosis, therapy, education, employment, social impact, quality of life (QoL), and gynecologic symptoms and management.Main Outcome Measures: Gynecologic symptoms and QoL.Results: Regular menstrual cycles were seen in 81/167 participants (49.1%). POTS symptoms worsened prior to and during menses in 118/167 subjects (72.4%); hormonal contraceptive therapy helped to control symptoms in 52/110 subjects (50%). Menorrhagia, polycystic ovary syndrome, and endometriosis were not reported in higher numbers compared to the general population.Conclusions: Menstrual flow disorders are not more prevalent in younger females with POTS. Symptoms often worsen perimenstrually, and hormone therapy can help to reduce symptom severity. Further research is needed to better define optimal hormone therapy in suppressing perimenstrual symptoms.

BackgroundInborn errors of immunity (IEI) affecting B-cell receptor signaling cause predominantly antibody deficiency (PAD) with varying degrees of severity. Recently, four heterozygous variants in SYK were reported to cause hypogammaglobulinemia, multiorgan inflammatory disease and diffuse large B-cell lymphoma.ObjectiveWe aimed to unravel the genetic and functional cause of PAD in a 43-year-old female presenting with hypogammaglobulinemia, congenital heart disease and pulmonary hypertension requiring lung transplantation.MethodsPatient gDNA was subjected to whole-exome and Sanger sequencing. Blood B- and T-cell subsets, as well as tonic and antigen-receptor induced expression levels of phosphorylated-SYK, phosphorylated-ribosomal S6 and phosphorylated p38 were evaluated by flow cytometry.ResultsA novel heterozygous missense SYK variant was identified, mutating a residue in the protein kinase domain (c.1769G > A; p.R590Q), which is highly conserved across vertebrates. While total B- and T-cell numbers were within the normal range, the patient had reduced unswitched and class-switched memory B-cell numbers. Resting B cells from the patient demonstrated enhanced autophosphorylation of SYK, and tonic and ligand-induced phospho-S6 levels. Spontaneous SYK autophosphorylation, S6 and p38 phosphorylation were recapitulated in a pre-clinical cell model, i.e. expression of the SYK R590Q variant in HEK293T cells.ConclusionsWe identified a novel gain-of-function variant in SYK to underlie hypogammaglobulinemia and atypical autoinflammatory disease. Flowcytometric screening for phospho-S6 in lymphocytes of IEI patients can guide genetic diagnosis of B-cell signaling abnormalities.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10875-025-01950-7.

TRAF3, a versatile adaptor protein within the TRAF family, participates in various signaling pathways involving the tumor necrosis factor receptor, toll-like receptor, and retinoic acid-inducible gene I-like receptor families. In 2010, autosomal dominant TRAF3 deficiency was reported in a patient with herpes simplex virus-1 encephalitis, consistent with the role of TRAF3 in type I interferon production. Recently, a novel, completely different clinical phenotype was described in patients with TRAF3 haploinsufficiency (TRAF3Hl), characterized by recurrent bacterial infections, autoimmune features, systemic inflammation, and hypergammaglobulinemia. In this study, we conducted a TRAF3-targeted reanalysis of next-generation sequencing data from 800 patients with inborn errors of immunity. Through this reassessment and additional familial investigations, we identified three previously unidentified cases of TRAF3Hl within two different families. These individuals harbored stop-gain variants (p.Arg163* and p.Gln407*) and experienced recurrent bacterial infections with hypogammaglobulinemia. Previously, the patients had been diagnosed with common variable immunodeficiency (CVID) and were receiving immunoglobulin replacement therapy. In addition, a TRAF3 start-loss variant (c.3G > A) was identified in a fourth patient, but after familial and molecular studies, it was not considered disease-causing, excluding TRAF3Hl in this patient. This study illustrates the usefulness of targeted reanalysis of genes with reported novel phenotypes. We rescued three patients with TRAF3Hl, presenting similarities and differences with the previously reported patients. The most significant differences were hypogammaglobulinemia and a CVID-like presentation. These data expand the clinical phenotype of TRAF3Hl and pave the way for further investigation into loss-of-function variants in patients with CVID.

Visual biofeedback can be used to help people post-stroke reduce biomechanical gait impairments. Using visual biofeedback engages an explicit, cognitively demanding motor learning process. Participants with better overall cognitive function are better able to use visual biofeedback to promote locomotor learning; however, which specific cognitive domains are responsible for this effect are unknown. We aimed to understand which cognitive domains were associated with performance during acquisition and immediate retention when using visual biofeedback to increase paretic propulsion in individuals post-stroke. Participants post-stroke completed cognitive testing, which provided scores for different cognitive domains, including executive function, immediate memory, visuospatial/constructional skills, language, attention, and delayed memory. Next, participants completed a single session of paretic propulsion biofeedback training, where we collected treadmill-walking data for 20min with biofeedback and 2min without biofeedback. We fit separate regression models to determine if cognitive domain scores, motor impairment (measured with the lower-extremity Fugl-Meyer), and gait speed could explain propulsion error and variability during biofeedback use and recall error during immediate retention. Visuospatial/constructional skills and motor impairment best-explained propulsion error during biofeedback use (adjusted R 2 =0.56, P =0.0008), and attention best-explained performance variability (adjusted R 2 =0.17, P =0.048). Language skills best-explained recall error during immediate retention (adjusted R 2 =0.37, P =0.02). These results demonstrate that specific cognitive domain impairments explain variability in locomotor learning outcomes in individuals with chronic stroke. This suggests that with further investigation, specific cognitive impairment information may be useful to predict responsiveness to interventions and personalize training parameters to facilitate locomotor learning.

Convective cold pools routinely pass over the dense network of wind turbines in northern Germany, causing short-term changes in boundary-layer wind speeds (i.e., wind ramp events) and atmospheric stability. These large, rapid, and more-localized variations in the low-level kinematic and thermodynamic structure are difficult for numerical weather prediction models to forecast with sufficient spatial and temporal accuracy for utilization by wind turbine operators. As boundary-layer stability and winds strongly influence wind turbine structural loads, downstream turbulent wake behavior, and power generation, it is important to better understand how rapid changes in dynamic processes evolve within the vertical layer of wind turbine rotor blades (~50 - 150 meters altitude). Using in-situ observations and high-resolution modeling focused on the WiValdi research wind park in Krummendeich, Germany, we examine how convective cold pool passages during July 2023 impact the inflow and turbulent wakes for two installed turbines with a hub height of 92 meters. Meteorological mast, Doppler wind lidar, and microwave radiometer observations provide upstream and downstream measurements of stability, vertical shear, and turbulence variations at ~1-minute resolution. While this measurement coverage adequately captures the cold pool evolution relative to each turbine, we remain somewhat limited by the fixed instrument locations for measuring upstream conditions and the three-dimensional turbulent wake structure. Therefore, we also utilize the mesoscale model WRF in large-eddy-simulation mode, with inserted generalized actuator disks acting as proxy wind turbines, to analyze far-upstream inflow conditions and three-dimensional wake characteristics during cold pool passages. The proposed work will provide a foundation for future analysis which will more robustly verify WRF output using additional WiValdi instrumentation.

Introduction: In the early window, time to treatment with endovascular thrombectomy (EVT) is inversely associated with favorable clinical outcomes but this remains unclear in the extended window. We aimed to assess the impact of time to EVT on clinical outcomes in the DAWN trial. Methods: The association between every 1-hour treatment delay with 90-day functional independence (modified Rankin Scale [mRS] 0-2), symptomatic intracranial hemorrhage (SICH), and 90-day mortality was explored in the overall population and in three modes of onset subgroups (wake-up vs witnessed vs unwitnessed) considering both time from last seen well (TLSW) and time from symptoms first observed (TSFO). Results: Out of the 205 patients, 98 (47.8%) and 107 (52.2%) presented in the 6-12-hour and 12-24-hour time window, respectively. Considering all three modes of onset together, there was no statistically significant association between TLSW to randomization with either functional independence or mortality at 90 days in either the EVT (mRS0-2 OR 1-hour-delay:1.07;95%CI[0.93-1.24]; mRS6 OR:0.84;95%CI[0.65-1.03]) or medical management (mRS0-2 OR1-hour-delay:0.98;95%CI[0.80-1.14]; mRS6 OR 1-hour-delay:0.94;95%CI[0.79-1.09]) groups. Moreover, there was no significant interaction between treatment effect and time (p=0.439 and p=0.421 for mRS 0-2 and 6, respectively). However, within the thrombectomy group, the models that tested the association between TLSW to successful reperfusion (mTICI≥2b) and 90-day functional independence showed a significant interaction with mode of presentation (p=0.013). This appeared to be driven by a nominally positive slope for both witnessed and unwitnessed strokes versus a significantly (p=0.018) negative slope in wake-up patients. There was no association between treatment times and SICH. Comparable analysis using TSFO yielded similar results. Conclusion: In extended window patients, the association between time to treatment and clinical outcomes seems to be primarily driven by successfully perfused patients with wake-up rather than witnessed or unwitnessed strokes suggesting that wake-up strokes do not behave as “slow-progressors”.