Cortisol, Stress, and Disease-Bidirectional Associations; Role for Corticosteroid-Binding Globulin?

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.

The Windshield Wiper Sign Is an Instability-Related Osteochondral Defect of the Anterolateral Femoral Head.

PURPOSE: To investigate a radiographic sign believed to be indicative of hip instability and acetabular suction seal disruption in the native hip, coined the "windshield wiper" (WSW) sign. METHODS: A retrospective review was performed for patients who underwent periacetabular osteotomy (PAO) with the senior author between March 2021 and September 2023. A WSW sign was identified on plain films as a concave or flat osteochondral defect on the anterolateral femoral head extending medial to the head-neck junction with resultant loss of femoral head sphericity in the native hip. Every patient underwent a standardized series of radiographs, as well as computed tomography and magnetic resonance imaging. All patients underwent arthroscopy before PAO to address intra-articular pathology and other indicated procedures. The osteochondral defect and resultant suction seal disruption were verified during arthroscopy. These patients were then compared with a control group of arthroscopically treated hips without hip instability. RESULTS: Of 250 patients reviewed, a total of 19 hips in 17 patients (prevalence of 7.6%) demonstrated radiographic evidence of the WSW sign. All patients with a WSW sign presented with symptomatic clinical hip instability requiring a PAO. The mean patient age was 31.2 years, with a mean lateral center-edge angle (LCEA) of 14.3°. There were 13 hips (68.4%) with dysplasia, 4 (21.1%) with borderline dysplasia, and 2 (10.5%) with a normal LCEA. All patients with a WSW sign and LCEA ≥ 20° displayed significant femoral antetorsion abnormalities. All arthroscopic videos and images demonstrated a compromised suction seal. Of the 50 control group hips reviewed, the WSW sign was not identified. CONCLUSIONS: The WSW sign is an uncommon radiographic finding in patients with hip instability. When identified, it can be predictive of substantial instability, especially in cases which are otherwise considered borderline dysplasia or normal based on LCEA. LEVEL OF EVIDENCE: Level III, retrospective comparative case control study.

Arthroscopic Femoral Head Allograft With Proximal Femoral/Periacetabular Osteotomies for Sequelae of Perthes: A Case Report.

CASE: We describe the unique case of a 20-year-old man with a history of Legg-Calve-Perthes disease, hip dysplasia, and osteochondral fragmentation of the medial femoral head. We performed arthroscopic femoroplasty and femoral head allografting, followed by a valgus-producing derotational femoral osteotomy (DFO) and periacetabular osteotomy (PAO). At 1-year follow-up, the patient achieved osseous union and complete femoral head healing with return to his active hobbies. CONCLUSION: We describe the successful utilization of arthroscopic allografting for medial femoral head osteochondral fragmentation. To our knowledge, this is the first report on femoral head arthroscopic allografting before DFO and PAO.

The Everted Acetabular Labrum: Outcomes of Surgical Management.

BACKGROUND: An everted acetabular labrum (EL) is a pathologic variant in which the labrum is flipped to the capsular side of the acetabular rim. An iatrogenic EL is a known complication of a poorly executed labral repair, and a recent study described the native acetabular EL. PURPOSE: To analyze surgical outcomes after advancement or reconstruction of an EL in a native hip. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This was a multicenter retrospective review of prospectively collected data on primary hip arthroscopic surgeries performed between 2013 and 2023. An EL was identified arthroscopically as a labrum-femoral head gap while off traction in the native hip. All patients with EL who were analyzed in this study underwent arthroscopic labral repair and advancement or labral augmentation or reconstruction. Patients with hip dysplasia also underwent periacetabular osteotomy with or without a derotational femoral osteotomy. Patient-reported outcomes (PROs) were assessed using the 12-item International Hip Outcome Tool (iHOT-12) and the Nonarthritic Hip Score. PROs were obtained preoperatively and up to 24 months after surgery. PROs were compared with those of a case-matched control cohort in a 1:2 ratio. Only patients with PROs available at ≥1 year postoperatively were included in the outcome analysis. RESULTS: A total of 111 patients (129 hips) with EL during the study period were identified, with PROs available in 96 hips. The mean age of patients with EL was 30.5 years, and women made up 87% of the cohort. Of the 129 hips with an EL, an isolated diagnosis of an EL was present in 11.6% of hips. Deficient acetabular coverage (lateral center-edge angle <25°) was seen in 40.6% of EL hips. No difference was seen in iHOT-12 scores between EL and control groups at 12- or 24-month follow-up (P = .18 and .94, respectively). Patients with EL reported a significant improvement of PROs at latest follow-up (P < .001 for iHOT-12 and Nonarthritic Hip Score). CONCLUSION: Surgical management of a native EL with restoration of the labral seal on the femoral head and correction of concomitant pathologies resulted in significant clinical improvement, with postoperative outcome scores comparable to those of patients without an EL. These findings provide evidence supporting surgical intervention for a native EL.

During Postless Hip Arthroscopy, Male Patients, High Body Mass Index, Low Beighton Scores, and Limited Range of Motion Require High Traction Force.

PURPOSE: To determine the effects of demographic and anatomic factors on traction force required during postless hip arthroscopy. METHODS: A prospectively collected database was retrospectively analyzed on patients undergoing hip arthroscopy by the senior author, including patient sex, age, body mass index (BMI), Beighton Hypermobility Score, hip range of motion in clinic and under anesthesia, hip dysplasia, acetabular version, and femoral version. All patients underwent postless hip arthroscopy under general anesthesia. At the initiation of hip arthroscopy, the traction force required to distract the hip joint was measured before and following interportal capsulotomy. Multiple regression analysis was performed to determine the effects of demographic and anatomic factors on measured distraction force. RESULTS: In total, 352 hips (114 male, 238 female) were included with a mean age of 32.6 years and a mean BMI of 24.1 kg/m2. Mean initial traction force was 109 lbs and decreased to 94.3 lbs following capsulotomy (P < .0001). The starting traction force was significantly greater in male patients (P < .001), patients with a lack of hypermobility (Beighton Hypermobility Score of 0-2) (P = .026), and in patients with lower abduction (P < .001), lower internal rotation (P = .002), and lower external rotation (P = .012) on multiple regression analysis. When performing a subanalysis divided by sex, male patients with elevated BMI required significantly greater starting traction force (P = .014). Lateral center edge angle, sourcil angle, and the presence of hip dysplasia did not demonstrate a significant correlation with traction force. CONCLUSIONS: Male patients, patients with reduced preoperative hip range of motion, patients with a lack of joint hypermobility, and male patients with an elevated BMI require greater initial traction force during postless hip arthroscopy. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Corticosteroid-binding globulin (CBG): spatiotemporal distribution of cortisol in sepsis.

Corticosteroid-binding globulin (CBG) is a 50-60 kDa circulating glycoprotein with high affinity for cortisol. CBG is adapted for sepsis; its cortisol binding is reduced reversibly by pyrexia and acidaemia, and reduced irreversibly by neutrophil elastase (NE) cleavage, converting high cortisol-binding affinity CBG to a low affinity form. These characteristics allow for the targeted delivery of immunomodulatory cortisol to tissues at the time and body site where cortisol is required in sepsis and septic shock. In addition, high titer inflammatory cytokines in sepsis suppress CBG hepatic synthesis, increasing the serum free cortisol fraction. Recent clinical studies have highlighted the importance of CBG in septic shock, with CBG deficiency independently associated with mortality.

Adrenal insufficiency in pregnancy: Physiology, diagnosis, management and areas for future research.

Adrenal insufficiency requires prompt diagnosis in pregnancy, as untreated, it can lead to serious consequences such as adrenal crisis, intrauterine growth restriction and even foetal demise. Similarities between symptoms of adrenal insufficiency and those of normal pregnancy can complicate diagnosis. Previously diagnosed adrenal insufficiency needs monitoring and, often, adjustment of adrenal hormone replacement. Many physiological changes occur to the hypothalamic-pituitary-adrenal (HPA) axis during pregnancy, often making diagnosis and management of adrenal insufficiency challenging. Pregnancy is a state of sustained physiologic hypercortisolaemia; there are multiple contributing factors including high plasma concentrations of placental derived corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH) and increased adrenal responsiveness to ACTH. Despite increased circulating concentrations of CRH-binding protein (CRH-BP) and the major cortisol binding protein, corticosteroid binding globulin (CBG), free concentrations of both hormones are increased progressively in pregnancy. In addition, pregnancy leads to activation of the renin-angiotensin-aldosterone system. Most adrenocortical hormone diagnostic thresholds are not applicable or validated in pregnancy. The management of adrenal insufficiency also needs to reflect the physiologic changes of pregnancy, often requiring increased doses of glucocorticoid and at times mineralocorticoid replacement, especially in the last trimester. In this review, we describe pregnancy induced changes in adrenal function, the diagnosis and management of adrenal insufficiency in pregnancy and areas requiring further research.

A Technique for Optimizing Hip Labrum Suction Seal With a Double-Limb, Oblique Inverting Mattress Stitch: The "X" and the "M" Configurations.

Classic techniques in arthroscopic hip labral repair use circumferential or intrasubstance suture secured with anchors typically placed behind the labrum (capsular side). The primary goal of labral repair is to re-establish the hip suction seal and is often achieved via fixation techniques that invert viable labral tissue to restore or improve contact with the femoral head. Many repair techniques use only 1 suture limb either passed circumferentially around the labrum or passed in an intrasubstance manner, resulting in smaller purchase of labral tissue and lack of a strong inverting vector. In some cases, this may evert the labral tissue, compromising the suction seal. We describe a technique in which both suture limbs are passed in a mattress, figure-of-8 configuration, through the labral tissue, and tied on the capsular side to yield an inverting, double-limb repair. Therefore, each anchor results in a wider, more impactful repair footprint while reliably inverting the labral tissue.

Correlation of Delayed Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) Value With Hip Arthroscopy Intraoperative Findings and Midterm Periacetabular Osteotomy Outcomes.

Background: Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) is an advanced imaging technique that is purported to quantify cartilage damage in acute and chronic joint disease and predict periacetabular osteotomy (PAO) outcomes. There is a paucity of literature relating dGEMRIC values to arthroscopic findings before PAO and postoperative outcomes after PAO. Purpose: To assess the utility and validity of dGEMRIC as a preoperative and prognostic assessment tool of cartilage status and integrity as it relates to intraoperative findings and midterm postoperative outcomes after PAO. Study Design: Case series; Level of evidence, 4. Methods: We analyzed a cohort of 58 patients (70 hips) with a median age of 30.1 years (range, 15-50) with hip dysplasia who underwent hip arthroscopy, followed by a PAO with preoperative dGEMRIC. The primary outcome measures were intraoperative assessment and correlation with cartilage damage (presence of cartilage flap, Outerbridge grade of the acetabulum and femoral head). Secondary outcome measures were postoperative patient-reported outcome (PRO) scores, including the International Hip Outcome Tool and Non-arthritic Hip Score. Correlation analyses were performed to determine the relationship between dGEMRIC values and (1) PROs and (2) intraoperative assessment of cartilage damage. Results: There were significant negative linear relationships between dGEMRIC values and the primary outcome measures: presence of a cartilage flap (coronal, P = .004; sagittal, P < .001), Outerbridge grade of acetabular articular cartilage lesion (coronal, P = .002; sagittal, P = .003), and Outerbridge grade of femoral head articular cartilage lesion (coronal, P = .001; sagittal, P < .001). Despite significant overall improvement in all patients, there was no significant correlation between preoperative dGEMRIC values and improvement in PROs from presurgery to latest postoperative follow-up (median, 2.2 years; range, 1.0-5.0 years). Conclusion: Although dGEMRIC values (sagittal and coronal) were significant predictors of the intraoperative presence of cartilage flaps and overall cartilage integrity, they were not associated with midterm outcomes after PAO.

Structural Features of Antibody-Peptide Recognition.

Antibody recognition of antigens is a critical element of adaptive immunity. One key class of antibody-antigen complexes is comprised of antibodies targeting linear epitopes of proteins, which in some cases are conserved elements of viruses and pathogens of relevance for vaccine design and immunotherapy. Here we report a detailed analysis of the structural and interface features of this class of complexes, based on a set of nearly 200 nonredundant high resolution antibody-peptide complex structures that were assembled from the Protein Data Bank. We found that antibody-bound peptides adopt a broad range of conformations, often displaying limited secondary structure, and that the same peptide sequence bound by different antibodies can in many cases exhibit varying conformations. Propensities of contacts with antibody loops and extent of antibody binding conformational changes were found to be broadly similar to those for antibodies in complex with larger protein antigens. However, antibody-peptide interfaces showed lower buried surface areas and fewer hydrogen bonds than antibody-protein antigen complexes, while calculated binding energy per buried interface area was found to be higher on average for antibody-peptide interfaces, likely due in part to a greater proportion of buried hydrophobic residues and higher shape complementarity. This dataset and these observations can be of use for future studies focused on this class of interactions, including predictive computational modeling efforts and the design of antibodies or epitope-based vaccine immunogens.

Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19.

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.

Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) Antibody Responses in Children With Multisystem Inflammatory Syndrome in Children (MIS-C) and Mild and Severe Coronavirus Disease 2019 (COVID-19).

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) antibody responses in children remain poorly characterized. Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike immunoglobulin G (IgG) titers compared with those with severe coronavirus disease 2019, likely reflecting a longer time since the onset of infection in MIS-C patients.

Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations.

Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients. We enrolled 50 hospitalized pediatric patients with acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized children with SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.

Insulin use and new diabetes after acceptance for bariatric surgery: comparison of outcomes after completion of surgery or withdrawal from the program.

INTRODUCTION: In people accepted onto a bariatric surgery program we compared diabetes-related outcomes in those who completed surgery with those who withdrew before having surgery-examining rates of insulin use in people with type 2 diabetes (T2D), and rates of incident diabetes in people without pre-existing T2D. RESEARCH DESIGN AND METHODS: 771 people were accepted onto the program. 463 people (60%) had T2D at referral, of which 48% completed surgery and 52% withdrew. Of 308 people without T2D at referral, 49% completed surgery, and 51% withdrew. Rates of insulin use and incident diabetes were compared by Kaplan-Meier analyses. Among those with pre-existing T2D, we examined rates of remission and relapse after surgery. RESULTS: People without T2D who withdrew from the program had higher mean body mass index and glycated hemoglobin levels than those completing surgery (p<0.005). The rate of incident diabetes at 5 years was 19% in those who withdrew versus 0% in those completing surgery (p<0.001). 30% of people with T2D were taking insulin at referral and all stopped insulin after surgery. During follow-up, the rate of insulin (re)introduction was lower in those who completed surgery (8% vs 26% at 5 years, p<0.001). Of those with T2D who completed surgery, 80% had remission, but 34% had relapsed by 5 years. Diabetes relapse was associated with less weight loss after surgery, a longer duration of T2D and previous insulin use. CONCLUSIONS: Despite a high relapse rate, people with T2D who completed surgery had lower insulin use at 5 years than those withdrawing from the program. In people without T2D, bariatric surgery prevented incident diabetes. People without T2D who withdrew from the program were at greater risk of diabetes, suggesting those who could benefit the most in terms of T2D prevention are not completing bariatric surgery.

Deep Immune Profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19.

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8 T cells that correlated with use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct and implicate CD8 T cells in clinical presentation and trajectory of MIS-C.

Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome.

There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four pediatric patients with acute respiratory distress syndrome. We measured donor antibody levels and recipient antibody response prior to and following CP infusion. Infusion of CP was not associated with antibody-dependent enhancement (ADE) and did not suppress endogenous antibody response. We found CP was safe and possibly efficacious. Randomized pediatric trials are needed.

SARS-CoV-2 antibody responses in children with MIS-C and mild and severe COVID-19.

SARS-CoV-2 antibody responses in children remain poorly characterized. Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike IgG titers compared to those with severe coronavirus disease 2019 (COVID-19), likely reflecting a longer time since onset of infection in MIS-C patients.

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.