Objective
Identification of the incidence of juvenile idiopathic arthritis (JIA)–associated uveitis and its risk factors is essential to optimize early detection. Data from the Research in Arthritis ...in Canadian Children Emphasizing Outcomes inception cohort were used to estimate the annual incidence of new‐onset uveitis following JIA diagnosis and to identify associated risk factors.
Methods
Data were reported every 6 months for 2 years, then yearly to 5 years. Incidence was determined by Kaplan‐Meier estimators with time of JIA diagnosis as the reference point. Univariate log‐rank analysis identified risk factors and Cox regression determined independent predictors.
Results
In total, 1,183 patients who enrolled within 6 months of JIA diagnosis met inclusion criteria, median age at diagnosis of 9.0 years (interquartile range IQR 3.8–12.9), median follow‐up of 35.2 months (IQR 22.7–48.3). Of these patients, 87 developed uveitis after enrollment. The incidence of new‐onset uveitis was 2.8% per year (95% confidence interval 95% CI 2.0–3.5) in the first 5 years. The annual incidence decreased during follow‐up but remained at 2.1% (95% CI 0–4.5) in the fifth year, although confidence intervals overlapped. Uveitis was associated with young age (<7 years) at JIA diagnosis (hazard ratio HR 8.29, P < 0.001), positive antinuclear antibody (ANA) test (HR 3.20, P < 0.001), oligoarthritis (HR 2.45, P = 0.002), polyarthritis rheumatoid factor negative (HR 1.65, P = 0.002), and female sex (HR 1.80, P = 0.02). In multivariable analysis, only young age at JIA diagnosis and ANA positivity were independent predictors of uveitis.
Conclusion
Vigilant uveitis screening should continue for at least 5 years after JIA diagnosis, and priority for screening should be placed on young age (<7 years) at JIA diagnosis and a positive ANA test.
To assess the frequency of gastrostomy tube (GT) placement in extremely low birth weight (ELBW) infants, associated comorbidities, and long-term outcomes.
Analysis of ELBW infants from 25 centers ...enrolled in the National Institute of Child Health and Human Development Neonatal Research Network's Generic Database and Follow-up Registry from 2006 to 2012. Frequency of GT placement before 18-22 months, demographic and medical factors associated with GT placement, and associated long-term outcomes at 18-22 months of corrected age were described. Associations between GT placement and neonatal morbidities and long-term outcomes were assessed with logistic regression after adjustment for center and common co-variables.
Of the 4549 ELBW infants included in these analyses, 333 (7.3%) underwent GT placement; 76% had the GT placed postdischarge. Of infants with GTs, 11% had birth weights small for gestational age, 77% had bronchopulmonary dysplasia, and 29% severe intraventricular hemorrhage or periventricular leukomalacia. At follow-up, 56% of infants with a GT had weight <10th percentile, 61% had neurodevelopmental impairment (NDI), and 55% had chronic breathing problems. After adjustment, small for gestational age, bronchopulmonary dysplasia, intraventricular hemorrhage/periventricular leukomalacia, poor growth, and NDI were associated with GT placement. Thirty-two percent of infants with GTs placed were taking full oral feeds at follow-up.
GT placement is common in ELBW infants, particularly among those with severe neonatal morbidities. GT placement in this population was associated with poor growth, NDI, and chronic respiratory and feeding problems at follow-up. The frequency of GT placement postneonatal discharge indicates the need for close nutritional follow-up of ELBW infants.
ClinicalTrials.gov: NCT00063063
Introduction
Midwifery care is associated with positive birth outcomes, access to community birth options, and judicious use of interventions. The aim of this study was to characterize and compare ...maternity care preferences of university students across a range of maternity care systems and to explore whether preferences align with evidence‐based recommendations and options available.
Methods
A cross‐sectional, web‐based survey was completed in 2014 and 2015 by a convenience sample of university students in 8 high‐income countries across 4 continents (N = 4569). In addition to describing preferences for midwifery care and community birth options across countries, this study examined sociodemographic characteristics, psychological factors, knowledge about pregnancy and birth, and sources of information that shaped students’ attitudes toward birth in relation to preferences for midwifery care and community birth options.
Results
Approximately half of the student respondents (48.2%) preferred midwifery‐led care for a healthy pregnancy; 9.5% would choose to give birth in a birthing center, and 4.5% preferred a home birth. Preference for midwifery care varied from 10.3% among women in the United States to 78.6% among women in the United Kingdom. Preferences for home birth varied from 0.3% among US women to 18.3% among Canadian women. Women, health science students, those with low childbirth fear, those who learned about pregnancy and birth from friends (compared with other sources, eg, the media), and those who responded from Europe were significantly more likely to prefer midwifery care and community birth. High confidence in knowledge of pregnancy and birth was linked to significantly higher odds of community birth preferences and midwifery care preferences.
Discussion
It would be beneficial to integrate childbirth education into high school curricula to promote knowledge of midwifery care, pregnancy, and childbirth and to reduce fear among prospective parents. Community birth options need to be expanded to meet demand among the next generation of maternity service users.
Childhood autologous hematopoietic cell transplant (auto-HCT) survivors can be at risk for secondary malignant neoplasms (SMNs). We assembled a cohort of 1487 pediatric auto-HCT recipients to ...investigate the incidence and risk factors for SMNs. Primary diagnoses included neuroblastoma (39%), lymphoma (26%), sarcoma (18%), central nervous system tumors (14%) and Wilms tumor (2%). Median follow-up was 8 years (range, <1-21 years). SMNs were reported in 35 patients (AML/myelodysplastic syndrome (MDS)=13, solid cancers=20, subtype missing=2). The overall cumulative incidence of SMNs at 10 years from auto-HCT was 2.60% (AML/MDS=1.06%, solid tumors=1.30%). We found no association between SMNs risk and age, gender, diagnosis, disease status, time since diagnosis or use of TBI or etoposide as part of conditioning. OS at 5-years from diagnosis of SMNs was 33% (95% confidence interval (CI), 16-52%). When compared with age- and gender-matched general population, auto-HCT recipients had 24 times higher risks of developing SMNs (95% CI, 16.0-33.0). Notable SMN sites included bone (N=5 SMNs, observed (O)/expected (E)=81), thyroid (N=5, O/E=53), breast (N=2, O/E=93), soft tissue (N=2, O/E=34), AML (N=6, O/E=266) and MDS (N=7, O/E=6603). Risks of SMNs increased with longer follow-up from auto-HCT. Pediatric auto-HCT recipients are at considerably increased risk for SMNs and need life-long surveillance for SMNs.
A standardized human model to study early pathogenic events in patients with psoriasis is missing. Activation of Toll-like receptor 7/8 by means of topical application of imiquimod is the most ...commonly used mouse model of psoriasis.
We sought to investigate the potential of a human imiquimod patch test model to resemble human psoriasis.
Imiquimod (Aldara 5% cream; 3M Pharmaceuticals, St Paul, Minn) was applied twice a week to the backs of volunteers (n = 18), and development of skin lesions was monitored over a period of 4 weeks. Consecutive biopsy specimens were taken for whole-genome expression analysis, histology, and T-cell isolation. Plasmacytoid dendritic cells (pDCs) were isolated from whole blood, stimulated with Toll-like receptor 7 agonist, and analyzed by means of extracellular flux analysis and real-time PCR.
We demonstrate that imiquimod induces a monomorphic and self-limited inflammatory response in healthy subjects, as well as patients with psoriasis or eczema. The clinical and histologic phenotype, as well as the transcriptome, of imiquimod-induced inflammation in human skin resembles acute contact dermatitis rather than psoriasis. Nevertheless, the imiquimod model mimics the hallmarks of psoriasis. In contrast to classical contact dermatitis, in which myeloid dendritic cells sense haptens, pDCs are primary sensors of imiquimod. They respond with production of proinflammatory and T
17-skewing cytokines, resulting in a T
17 immune response with IL-23 as a key driver. In a proof-of-concept setting systemic treatment with ustekinumab diminished imiquimod-induced inflammation.
In human subjects imiquimod induces contact dermatitis with the distinctive feature that pDCs are the primary sensors, leading to an IL-23/T
17 deviation. Despite these shortcomings, the human imiquimod model might be useful to investigate early pathogenic events and prove molecular concepts in patients with psoriasis.
Estrogen receptor-positive (ER+) breast cancer is not considered immunogenic and, to date, has been proven resistant to immunotherapy. Endocrine therapy remains the cornerstone of treatment for ER+ ...breast cancers. However, constitutively activating mutations in the estrogen receptor alpha (ESR1) gene can emerge during treatment, rendering tumors resistant to endocrine therapy. Although these mutations represent a pathway of resistance, they also represent a potential source of neoepitopes that can be targeted by immunotherapy. In this study, we investigated ESR1 mutations as novel targets for breast cancer immunotherapy. Using machine learning algorithms, we identified ESR1-derived peptides predicted to form stable complexes with HLA-A*0201. We then validated the binding affinity and stability of the top predicted peptides through in vitro binding and dissociation assays and showed that these peptides bind HLA-A*0201 with high affinity and stability. Using tetramer assays, we confirmed the presence and expansion potential of antigen-specific CTLs from healthy female donors. Finally, using in vitro cytotoxicity assays, we showed the lysis of peptide-pulsed targets and breast cancer cells expressing common ESR1 mutations by expanded antigen-specific CTLs. Ultimately, we identified five peptides derived from the three most common ESR1 mutations (D538G, Y537S, and E380Q) and their associated wild-type peptides, which were the most immunogenic. Overall, these data confirm the immunogenicity of epitopes derived from ESR1 and highlight the potential of these peptides to be targeted by novel immunotherapy strategies.
Estrogen receptor (ESR1) mutations have emerged as a key factor in endocrine therapy resistance. We identified and validated five novel, immunogenic ESR1-derived peptides that could be targeted through vaccine-based immunotherapy.
Retinoic acid receptor-related orphan receptor-alpha (RORα) is a transcription factor from the nuclear receptor family expressed by immune cells and involved in the development of obesity, insulin ...resistance (IR) and non-alcoholic steatohepatitis (NASH). It was recently reported that mice deficient for RORα in macrophages develop more severe NASH upon high fat diet (HFD) feeding due to altered Kupffer cell function. To better understand the role of RORα in obesity and IR, we independently generated a macrophage RORα-deficient mouse line. We report that RORα deletion in macrophages does not impact on HFD-induced obesity and IR. Surprisingly, we did not confirm an effect on NASH development upon HFD feeding nor in the more severe and obesity-independent choline-deficient, L-amino acid-defined diet model. Our results therefore show that RORα deletion in macrophages does not alter the development of obesity and IR and question its role in NASH.
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