Objective
To characterize the early disease course in childhood‐onset antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and the 12‐month outcomes in children with AAV.
Methods
...Eligible subjects were children entered into the Pediatric Vasculitis Initiative study who were diagnosed before their eighteenth birthday as having granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg‐Strauss), or ANCA‐positive pauci‐immune glomerulonephritis. The primary outcome measure was achievement of disease remission (Pediatric Vasculitis Activity Score PVAS of 0) at 12 months with a corticosteroid dosage of <0.2 mg/kg/day. Secondary outcome measures included the rates of inactive disease (PVAS of 0, with any corticosteroid dosage) and rates of improvement at postinduction (4–6 months after diagnosis) and at 12 months, presence of damage at 12 months (measured by a modified Pediatric Vasculitis Damage Index PVDI; score 0 = no damage, score 1 = one damage item present), and relapse rates at 12 months.
Results
In total, 105 children with AAV were included in the study. The median age at diagnosis was 13.8 years (interquartile range 10.9–15.8 years). Among the study cohort, 42% of patients achieved remission at 12 months, 49% had inactive disease at postinduction (4–6 months), and 61% had inactive disease at 12 months. The majority of patients improved, even if they did not achieve inactive disease. An improvement in the PVAS score of at least 50% from time of diagnosis to postinduction was seen in 92% of patients. Minor relapses occurred in 12 (24%) of 51 patients after inactive disease had been achieved postinduction. The median PVDI damage score at 12 months was 1 (range 0–6), and 63% of patients had ≥1 PVDI damage item scored as present at 12 months.
Conclusion
This is the largest study to date to assess disease outcomes in pediatric AAV. Although the study showed that a significant proportion of patients did not achieve remission, the majority of patients responded to treatment. Unfortunately, more than one‐half of this patient cohort experienced damage to various organ systems early in their disease course.
IMPORTANCE: Animal experiments suggest that ingestion of pesticide mixtures at environmentally relevant concentrations decreases the number of live-born offspring. Whether the same is true in humans ...is unknown. OBJECTIVE: To examine the association of preconception intake of pesticide residues in fruits and vegetables (FVs) with outcomes of infertility treatment with assisted reproductive technologies (ART). DESIGN, SETTING, AND PARTICIPANTS: This analysis included 325 women who completed a diet assessment and subsequently underwent 541 ART cycles in the Environment and Reproductive Health (EARTH) prospective cohort study (2007-2016) at a fertility center at a teaching hospital. We categorized FVs as having high or low pesticide residues using a validated method based on surveillance data from the US Department of Agriculture. Cluster-weighted generalized estimating equations were used to analyze associations of high– and low–pesticide residue FV intake with ART outcomes. MAIN OUTCOMES AND MEASURES: Adjusted probabilities of clinical pregnancy and live birth per treatment cycle. RESULTS: In the 325 participants (mean SD age, 35.1 4.0 y; body mass index, 24.1 4.3), mean (SD) intakes of high– and low–pesticide residue FVs were 1.7 (1.0) and 2.8 (1.6) servings/d, respectively. Greater intake of high–pesticide residue FVs was associated with a lower probability of clinical pregnancy and live birth. Compared with women in the lowest quartile of high-pesticide FV intake (<1.0 servings/d), women in the highest quartile (≥2.3 servings/d) had 18% (95% CI, 5%-30%) lower probability of clinical pregnancy and 26% (95% CI, 13%-37%) lower probability of live birth. Intake of low–pesticide residue FVs was not significantly related to ART outcomes. CONCLUSIONS AND RELEVANCE: Higher consumption of high–pesticide residue FVs was associated with lower probabilities of pregnancy and live birth following infertility treatment with ART. These data suggest that dietary pesticide exposure within the range of typical human exposure may be associated with adverse reproductive consequences.
Objective To explore the relationship between urinary paraben concentrations and IVF outcomes among women attending an academic fertility center. Design Prospective cohort study. Setting Fertility ...clinic in a hospital setting. Patient(s) A total of 245 women contributing 356 IVF cycles. Intervention(s) None. Quantification of urinary concentrations of parabens by isotope-dilution tandem mass spectrometry, and assessment of clinical endpoints of IVF treatments abstracted from electronic medical records at the academic fertility center. Main Outcome Measure(s) Total and mature oocyte counts, proportion of high-quality embryos, fertilization rates, and rates of implantation, clinical pregnancy, and live births. Result(s) The geometric means of the urinary concentrations of methylparaben, propylparaben, and butylparaben in our study population were 133, 24, and 1.5 μg/L, respectively. In models adjusted for age, body mass index, race/ethnicity, smoking status, and primary infertility diagnosis, urinary methylparaben, propylparaben, and butylparaben concentrations were not associated with IVF outcomes, specifically total and mature oocyte counts, proportion of high embryo quality, and fertilization rates. Moreover, no significant associations were found between urinary paraben concentrations and rates of implantation, clinical pregnancy, and live births. Conclusion(s) Urinary paraben concentrations were not associated with IVF outcomes among women undergoing infertility treatments.
Objective. To examine racial differences in disease onset, extent, manifestations, and survival among women with scleroderma.
Methods. A retrospective cohort study of women with scleroderma, ...diagnosed in Michigan between 1980 and 1991, was conducted. Clinical, laboratory, and demographic data were ed from the patients' medical records.
Results. A total of 514 women with scleroderma were identified: 117 (23%) were black and 397 (77%) were white. Among black women, the mean age at diagnosis was lower (44.5 years versus 51.5 years; P < 0.001) and diffuse disease was more common (49.6% versus 24.9%; P < 0.001) than among white women. The overall incidence of scleroderma was 14.1 per million per year: 22.5 per million per year in black women versus 12.8 per million per year in white women (P < 0.001). Pericarditis (P = 0.009), pulmonary hypertension (P < 0.001), pleural effusions (P = 0.01), myositis (P = 0.02), and an erythrocyte sedimentation rate >40 mm/hour (P < 0.001) were more frequent among black women, while white women were more likely to have digital infarctions (P < 0.001). Survival at 7 years from diagnosis was 72.5% among black women and 77.6% among white women. Age‐adjusted survival was significantly reduced among black women (P = 0.033), most likely because of increased diffuse involvement. Survival among those with renal or pulmonary involvement was also significantly reduced.
Conclusion. Black women with scleroderma were significantly more likely than white women to develop diffuse disease, be diagnosed at a younger age, have a higher incidence of inflammatory features, and have a worse age‐adjusted survival rate.
Abstract The National Cholesterol Education Program Adult Treatment Panel guidelines have established low-density lipoprotein cholesterol (LDL-C) treatment goals, and secondary non-high-density ...lipoprotein (HDL)-C treatment goals for persons with hypertriglyceridemia. The use of lipid-lowering therapies, particularly statins, to achieve these goals has reduced cardiovascular disease (CVD) morbidity and mortality; however, significant residual risk for events remains. This, combined with the rising prevalence of obesity, which has shifted the risk profile of the population toward patients in whom LDL-C is less predictive of CVD events (metabolic syndrome, low HDL-C, elevated triglycerides), has increased interest in the clinical use of inflammatory and lipid biomarker assessments. Furthermore, the cost effectiveness of pharmacological intervention for both the initiation of therapy and the intensification of therapy has been enhanced by the availability of a variety of generic statins. This report describes the consensus view of an expert panel convened by the National Lipid Association to evaluate the use of selected biomarkers C-reactive protein, lipoprotein-associated phospholipase A2 , apolipoprotein B, LDL particle concentration, lipoprotein(a), and LDL and HDL subfractions to improve risk assessment, or to adjust therapy. These panel recommendations are intended to provide practical advice to clinicians who wrestle with the challenges of identifying the patients who are most likely to benefit from therapy, or intensification of therapy, to provide the optimum protection from CV risk.
Sensory inputs activate sparse neuronal ensembles in the dentate gyrus of the hippocampus, but how eligibility of individual neurons to recruitment is determined remains elusive. We identify ...thousands of largely bistable (CpG methylated or unmethylated) regions within neuronal gene bodies, established during mouse dentate gyrus development. Reducing DNA methylation and the proportion of the methylated epialleles at bistable regions compromises novel context-induced neuronal activation. Conversely, increasing methylation and the frequency of the methylated epialleles at bistable regions enhances intrinsic excitability. Single-nucleus profiling reveals enrichment of specific epialleles related to a subset of primarily exonic, bistable regions in activated neurons. Genes displaying both differential methylation and expression in activated neurons define a network of proteins regulating neuronal excitability and structural plasticity. We propose a model in which bistable regions create neuron heterogeneity and constellations of exonic methylation, which may contribute to cell-specific gene expression, excitability, and eligibility to a coding ensemble.
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•Numerous regions in DGCs show developmentally established methylation bistability•Increasing or reducing DNA methylation at regions alters neuron activation and excitability•Activated cells are enriched in one of the two states of bistable regions•Genes with bistable regions are associated with neuron excitability and plasticity
Odell et al. show regions within neuronal genes with bistable DNA methylation states that are associated with gene expression, excitability, and activation in the dentate gyrus of the hippocampus. These data suggest that the methylation state of bistable regions dictates, via modulating gene expression, neuron eligibility to a coding ensemble.
To characterize the whole spectrum of gene expression changes induced by diabetes in retinal Müller glial cells.
Müller cells were isolated from the retina of streptozotocin-diabetic and age-matched ...control rats by gradient centrifugation and immediately processed for RNA isolation. The gene expression profile of Müller cells was studied with the GeneChip Rat Genome oligonucleotide array (Affymetrix, Santa Clara, CA). The upregulation of acute-phase proteins in the retina of diabetic rats was confirmed by Northern and Western blot analyses. Real-time-RT-PCR was used to study the retinal expression of inflammatory cytokines.
Gene expression profiling identified 78 genes as differentially expressed in diabetic Müller cells. One third of these genes were associated with inflammation, including a large cluster (18% of the differentially expressed genes) of acute-phase response proteins: alpha2-macroglobulin, ceruloplasmin, complement components, lipocalin-2, metallothionein, serine protease inhibitor-2, transferrin, tissue inhibitor of metalloproteases-1, transthyretin, and the transcription factor C/EBPdelta. Northern and Western blot analyses confirmed the upregulation of alpha2-macroglobulin and ceruloplasmin in the diabetic retina, but not in the cerebral cortex and liver of the same animals. The acute-phase response of Müller cells in diabetes was associated with upregulation of interleukin (IL)-1beta in the retina.
Müller cells acquire a complex and specific reactive phenotype in diabetes characterized by the induction of acute-phase response proteins and other inflammation-related genes. The concomitant upregulation of IL-1beta in the retina of diabetic rats points to this cytokine as a possible mediator of the acute-phase response mounted by Müller cells in diabetes.
Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the cause of death in >50% of SSc cases, led by pulmonary fibrosis followed by pulmonary hypertension and then scleroderma ...renal crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal, nutritional and musculoskeletal complications can lead to disability and death.
Vascular injury with subsequent inflammation transforming to irreversible fibrosis and permanent damage characterizes SSc. Organ involvement is often present early in the disease course of SSc, but requires careful history-taking and vigilance in screening to detect. Inflammation is potentially reversible provided that treatment intensity quells inflammation and other immune mechanisms. In any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition.
A single SSc patient visit often requires much more physician and staff time, organization, vigilance, and direct management for multiple organ systems compared to other rheumatic or pulmonary diseases. Efficiency and efficacy of comprehensive SSc care enlists trending of symptoms and bio-data. Financial sustainability of SSc care benefits from understanding insurance reimbursement and health system allocation policies for complex patients. Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists.
As scleroderma specialists, we offer a practical framework with tools to facilitate an optimal, comprehensive and sustainable approach to SSc care. Improved health outcomes in SSc relies upon recogntion, management and, to the extent possible, prevention of SSc and treatment-related complications.
Abstract Purpose In children, persistent air leaks can result from pulmonary infection or barotrauma. Management strategies include surgery, prolonged pleural drainage, ventilator manipulation, and ...extracorporeal membrane oxygenation (ECMO). We report the use of endobronchial valve placement as an effective minimally invasive intervention for persistent air leaks in children. Methods Children with refractory prolonged air leaks were evaluated by a multidisciplinary team (pediatric surgery, interventional pulmonology, pediatric intensive care, and thoracic surgery) for endobronchial valve placement. Flexible bronchoscopy was performed, and air leak location was isolated with balloon occlusion. Retrievable one-way endobronchial valves were placed. Results Four children (16 months to 16 years) had prolonged air leaks following necrotizing pneumonia (2), lobectomy (1), and pneumatocele (1). Patients had 1–4 valves placed. Average time to air leak resolution was 12 days (range 0–39). Average duration to chest tube removal was 25 days (range 7–39). All four children had complete resolution of air leaks. All were discharged from the hospital. None required additional surgical interventions. Conclusion Endobronchial valve placement for prolonged air leaks owing to a variety of etiologies was effective in these children for treating air leaks, and their use may result in resolution of fistulae and avoidance of the morbidity of pulmonary surgery.
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