Validation of a clinical breast cancer risk assessment tool combining a polygenic score for all ancestries with traditional risk factors.

PURPOSE: We previously described a combined risk score (CRS) that integrates a multiple-ancestry polygenic risk score (MA-PRS) with the Tyrer-Cuzick (TC) model to assess breast cancer (BC) risk. Here, we present a longitudinal validation of CRS in a real-world cohort. METHODS: This study included 130,058 patients referred for hereditary cancer genetic testing and negative for germline pathogenic variants in BC-associated genes. Data were obtained by linking genetic test results to medical claims (median follow-up 12.1 months). CRS calibration was evaluated by the ratio of observed to expected BCs. RESULTS: Three hundred forty BCs were observed over 148,349 patient-years. CRS was well-calibrated and demonstrated superior calibration compared with TC in high-risk deciles. MA-PRS alone had greater discriminatory accuracy than TC, and CRS had approximately 2-fold greater discriminatory accuracy than MA-PRS or TC. Among those classified as high risk by TC, 32.6% were low risk by CRS, and of those classified as low risk by TC, 4.3% were high risk by CRS. In cases where CRS and TC classifications disagreed, CRS was more accurate in predicting incident BC. CONCLUSION: CRS was well-calibrated and significantly improved BC risk stratification. Short-term follow-up suggests that clinical implementation of CRS should improve outcomes for patients of all ancestries through personalized risk-based screening and prevention.

Racial/Ethnic Differences in Pediatric Emergency Department Wait Times.

OBJECTIVES: Wait time for emergency care is a quality measure that affects clinical outcomes and patient satisfaction. It is unknown if there is racial/ethnic variability in this quality measure in pediatric emergency departments (PEDs). We aim to determine whether racial/ethnic differences exist in wait times for children presenting to PEDs and examine between-site and within-site differences. METHODS: We conducted a retrospective cohort study for PED encounters in 2016 using the Pediatric Emergency Care Applied Research Network Registry, an aggregated deidentified electronic health registry comprising 7 PEDs. Patient encounters were included among all patients 18 years or younger at the time of the ED visit. We evaluated differences in emergency department wait time (time from arrival to first medical evaluation) considering patient race/ethnicity as the exposure. RESULTS: Of 448,563 visits, median wait time was 35 minutes (interquartile range, 17-71 minutes). Compared with non-Hispanic White (NHW) children, non-Hispanic Black (NHB), Hispanic, and other race children waited 27%, 33%, and 12% longer, respectively. These differences were attenuated after adjusting for triage acuity level, mode of arrival, sex, age, insurance, time of day, and month [adjusted median wait time ratios (95% confidence intervals): 1.11 (1.10-1.12) for NHB, 1.12 (1.11-1.13) for Hispanic, and 1.05 (1.03-1.06) for other race children compared with NHW children]. Differences in wait time for NHB and other race children were no longer significant after adjusting for clinical site. Fully adjusted median wait times among Hispanic children were longer compared with NHW children [1.04 (1.03-1.05)]. CONCLUSIONS: In unadjusted analyses, non-White children experienced longer PED wait times than NHW children. After adjusting for illness severity, patient demographics, and overcrowding measures, wait times for NHB and other race children were largely determined by site of care. Hispanic children experienced longer within-site and between-site wait times compared with NHW children. Additional research is needed to understand structures and processes of care contributing to wait time differences between sites that disproportionately impact non-White patients.

Performance of the IBIS/Tyrer-Cuzick model of breast cancer risk by race and ethnicity in the Women's Health Initiative.

BACKGROUND: The IBIS/Tyrer-Cuzick model is used clinically to guide breast cancer screening and prevention, but was developed primarily in non-Hispanic White women. Little is known about its long-term performance in a racially/ethnically diverse population. METHODS: The Women's Health Initiative study enrolled postmenopausal women from 1993-1998. Women were included who were aged <80 years at enrollment with no prior breast cancer or mastectomy and with data required for IBIS/Tyrer-Cuzick calculation (weight; height; ages at menarche, first birth, and menopause; menopausal hormone therapy use; and family history of breast or ovarian cancer). Calibration was assessed by the ratio of observed breast cancer cases to the number expected by the IBIS/Tyrer-Cuzick model (O/E; calculated as the sum of cumulative hazards). Differential discrimination was tested for by self-reported race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, Asian or Pacific Islander, and American Indian or Alaskan Native) using Cox regression. Exploratory analyses, including simulation of a protective single-nucleotide polymorphism (SNP), rs140068132 at 6q25, were performed. RESULTS: During follow-up (median 18.9 years, maximum 23.4 years), 6783 breast cancer cases occurred among 90,967 women. IBIS/Tyrer-Cuzick was well calibrated overall (O/E ratio = 0.95; 95% CI, 0.93-0.97) and in most racial/ethnic groups, but overestimated risk for Hispanic women (O/E ratio = 0.75; 95% CI, 0.62-0.90). Discrimination did not differ by race/ethnicity. Exploratory simulation of the protective SNP suggested improved IBIS/Tyrer-Cuzick calibration for Hispanic women (O/E ratio = 0.80; 95% CI, 0.66-0.96). CONCLUSIONS: The IBIS/Tyrer-Cuzick model is well calibrated for several racial/ethnic groups over 2 decades of follow-up. Studies that incorporate genetic and other risk factors, particularly among Hispanic women, are essential to improve breast cancer-risk prediction.

Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients With Active Ulcerative Colitis.

BACKGROUND & AIMS: New oral therapeutic agents are needed for patients with ulcerative colitis (UC) who are unresponsive or intolerant to conventional therapy. METHODS: We performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naïve to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies. The study was performed at 61 sites in 14 countries (screening from January 2015 through May 2017). Patients were randomly assigned to groups given apremilast 30 mg (n = 57), apremilast 40 mg (n = 55), or placebo (n = 58) twice daily for 12 weeks; patients were then randomly assigned to groups that received apremilast, 30 or 40 mg twice daily, for an additional 40 weeks. Endoscopies were performed and biopsies were collected during the screening phase, at week 12, and at week 52. Blood and fecal samples were also collected and analyzed throughout the study. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or less, with no individual subscore above 1. RESULTS: Clinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P = .01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P = .27 compared with placebo). Differences in clinical remission between the 30 mg and 40 mg apremilast groups were associated with differences in endoscopic improvement. Both apremilast groups had similar improvements from baseline in Mayo score components (stool frequency score, rectal bleeding score, physician's global assessment). The 30 mg and 40 mg apremilast groups had greater median percent reductions in C-reactive protein (measured by a high-sensitivity blood test) and fecal calprotectin through week 12 than the placebo group. At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group. The most frequent apremilast-associated adverse events were headache and nausea. CONCLUSIONS: Although the primary endpoint of clinical remission was not met in this phase 2 trial, a greater proportion of patients with active UC who received apremilast (30 mg or 40 mg) had improvements in clinical and endoscopic features, and markers of inflammation, at 12 weeks. Clinical remission was maintained to week 52 in up to 40% of patients who continued apremilast until that time point. ClinicalTrials.gov no: NCT02289417.

Exogenous polyunsaturated fatty acids (PUFAs) promote changes in growth, phospholipid composition, membrane permeability and virulence phenotypes in Escherichia coli.

BACKGROUND: The utilization of exogenous fatty acids by Gram-negative bacteria has been linked to many cellular processes, including fatty acid oxidation for metabolic gain, assimilation into membrane phospholipids, and control of phenotypes associated with virulence. The expanded fatty acid handling capabilities have been demonstrated in several bacteria of medical importance; however, a survey of the polyunsaturated fatty acid responses in the model organism Escherichia coli has not been performed. The current study examined the impacts of exogenous fatty acids on E. coli. RESULTS: All PUFAs elicited higher overall growth, with several fatty acids supporting growth as sole carbon sources. Most PUFAs were incorporated into membrane phospholipids as determined by Ultra performance liquid chromatography-mass spectrometry, whereas membrane permeability was variably affected as measured by two separate dye uptake assays. Biofilm formation, swimming motility and antimicrobial peptide resistance were altered in the presence of PUFAs, with arachidonic and docosahexaenoic acids eliciting strong alteration to these phenotypes. CONCLUSIONS: The findings herein add E. coli to the growing list of Gram-negative bacteria with broader capabilities for utilizing and responding to exogenous fatty acids. Understanding bacterial responses to PUFAs may lead to microbial behavioral control regimens for disease prevention.

Red blood cell transfusions during sickle cell anemia vaso-occlusive crises: a report from the magnesium in crisis (MAGiC) study.

BACKGROUND: Little is known about red blood cell (RBC) transfusion practices for children hospitalized for a sickle cell vaso-occlusive pain crisis (VOC). We hypothesized that transfusion would be associated with the development of acute chest syndrome (ACS), lower hemoglobin (Hb) concentration, and lack of hydroxyurea therapy. STUDY DESIGN AND METHODS: This is a secondary analysis of all children admitted for a sickle cell pain crisis enrolled in the Magnesium in Crisis (MAGiC) randomized trial; all had HbSS or S-ß0 thalassemia. ACS development and transfusion administration were prospectively collected during the parent trial. All Hb values during the hospitalization were recorded, as was parent report of child receiving hydroxyurea. Relative risks (RRs) of transfusion were compared between groups. RESULTS: Of 204 enrolled children, 40 (19.6%) received a transfusion. Of the 30 children who developed ACS, 22 (73.3%) received transfusions compared to 18 of 174 (10.3%) without ACS: the RR of transfusion in children with ACS was 7.1 (95% confidence interval [CI], 4.4-11.5). Among those without ACS, the lowest Hb was most strongly associated with transfusions: RR was 3.1 (95% CI 2.0 - 4.7) for each 1 g/dL decrease in lowest Hb. In a binary recursive partitioning model for those without ACS, a lowest recorded Hb level of less than 6.3 g/dL was significantly associated with transfusion during admission (p < 0.01). Hydroxyurea use was not associated with transfusions in any analysis. CONCLUSION: ACS increased the RR of transfusion in children hospitalized for VOC sevenfold. In children without ACS, transfusion was associated with lowest Hb concentration, particularly Hb concentration of less than 6.3 g/dL.

Impact of emergency department care on outcomes of acute pain events in children with sickle cell disease.

The impact of emergency department (ED) treatment on outcomes of sickle cell disease (SCD) acute pain hospitalizations is not well described. We investigated whether length of stay (LOS) and change in health-related quality of life (HRQL) are affected by initial opioid dose and time to administration. We conducted secondary analyses of data from the randomized-controlled Magnesium for children in Crisis (MAGiC) trial. The primary outcome was LOS. Secondary outcome was change in HRQL, assessed using PedsQL SCD Pain and Hurt and Pain Impact Domains measured in ED and at discharge. Independent variables were (1) time to first IV opioid, (2) total initial opioid dose (mg/kg/hr of morphine equivalents administered between ED and first study drug), and (3) Time to first oral opioid. Spearman correlations determined the associations with LOS. Using two-sample t-tests, we compared mean change in HRQL scores between IV opioid initiated within 60 and >60 min, opioid doses in the highest and lowest tertiles, and oral opioid initiated within 24 and >24 hr. Two hundred and four patients participated at 8 sites. Mean (SD) age was 13.6 (4.7) years. Earlier initiation of oral opioids was strongly correlated with shorter LOS (r = 0.61, P < 0.01). Higher initial opioid dose was weakly correlated with longer LOS (r = 0.34, P < 0.01). Higher initial opioid doses (6 vs -2.2; P = 0.01) and oral opioids initiated within 24 hr (5.7 vs -1.7, P = 0.04) were associated with larger mean change in HRQL at discharge. Prospective trials evaluating the impact of ED care on outcomes of pain hospitalizations could improve SCD pain treatment. Am. J. Hematol. 91:1175-1180, 2016. © 2016 Wiley Periodicals, Inc.

Cholesterol inhibits assembly and activation of the EphA2 receptor.

The receptor tyrosine kinase EphA2 drives cancer malignancy by facilitating metastasis. EphA2 can be found in different self-assembly states: as a monomer, dimer, and oligomer. However, our understanding remains limited regarding which EphA2 state is responsible for driving pro-metastatic signaling. To address this limitation, we have developed SiMPull-POP, a single-molecule method for accurate quantification of membrane protein self-assembly. Our experiments revealed that a reduction of plasma membrane cholesterol strongly promoted EphA2 self-assembly. Indeed, low cholesterol caused a similar effect to the EphA2 ligand ephrinA1-Fc. These results indicate that cholesterol inhibits EphA2 assembly. Phosphorylation studies in different cell lines revealed that low cholesterol increased phospho-serine levels, the signature of oncogenic signaling. Investigation of the mechanism that cholesterol uses to inhibit the assembly and activity of EphA2 indicate an in-trans effect, where EphA2 is phosphorylated by protein kinase A downstream of beta-adrenergic receptor activity, which cholesterol also inhibits. Our study not only provides new mechanistic insights on EphA2 oncogenic function, but also suggests that cholesterol acts as a molecular safeguard mechanism that prevents uncontrolled self-assembly and activation of EphA2.

Clinical Validation of EndoPredict in Pre-Menopausal Women with ER-Positive, HER2-Negative Primary Breast Cancer.

PURPOSE: The EndoPredict prognostic assay is validated to predict distant recurrence and response to chemotherapy primarily in post-menopausal women with estrogen receptor-positive (ER+), HER2- breast cancer. This study evaluated the performance of EndoPredict in pre-menopausal women. EXPERIMENTAL DESIGN: Tumor samples from 385 pre-menopausal women with ER+, HER2- primary breast cancer (pT1-3, pN0-1) who did not receive chemotherapy in addition to endocrine therapy were tested with EndoPredict to produce a 12-gene EP molecular score and an integrated EPclin score that includes pathologic tumor size and nodal status. Associations of molecular and EPclin scores with 10-year distant recurrence-free survival (DRFS) were evaluated by Cox proportional hazards models and Kaplan-Meier analysis. RESULTS: After a median follow-up of 9.7 years, both the EP molecular score and the molecular-clinicopathologic EPclin score were associated with increased risk of distant recurrence [HR, 1.33; 95% confidence interval (CI), 1.18-1.50; P = 7.2 × 10-6; HR, 3.58; 95% CI, 2.26-5.66; P = 9.8 × 10-8, respectively]. Both scores remained significant after adjusting for clinical factors in multivariate analysis. Patients with low-risk EPclin scores (64.7%) had significantly improved DRFS compared with high-risk patients (HR, 4.61; 95% CI, 1.40-15.17; P = 4.2 × 10-3). At 10 years, patients with low-risk and high-risk EPclin scores had a DRFS of 97% (95% CI, 93%-99%) and 76% (95% CI, 67%-82%), respectively. CONCLUSIONS: The EPclin score is strongly associated with DRFS in pre-menopausal women who received adjuvant endocrine therapy alone. On the basis of these data, pre-menopausal women with EPclin low-risk breast cancer may be treated with endocrine therapy only and safely forgo adjuvant chemotherapy.

Development and Validation of a Breast Cancer Polygenic Risk Score on the Basis of Genetic Ancestry Composition.

PURPOSE: Polygenic risk scores (PRSs) for breast cancer (BC) risk stratification have been developed primarily in women of European ancestry. Their application to women of non-European ancestry has lagged because of the lack of a formal approach to incorporate genetic ancestry and ancestry-dependent variant frequencies and effect sizes. Here, we propose a multiple-ancestry PRS (MA-PRS) that addresses these issues and may be useful in the development of equitable PRSs across other cancers and common diseases. MATERIALS AND METHODS: Women referred for hereditary cancer testing were divided into consecutive cohorts for development (n = 189,230) and for independent validation (n = 89,126). Individual genetic composition as fractions of three reference ancestries (African, East Asian, and European) was determined from ancestry-informative single-nucleotide polymorphisms. The MA-PRS is a combination of three ancestry-specific PRSs on the basis of genetic ancestral composition. Stratification of risk was evaluated by multivariable logistic regression models controlling for family cancer history. Goodness-of-fit analysis compared expected with observed relative risks by quantiles of the MA-PRS distribution. RESULTS: In independent validation, the MA-PRS was significantly associated with BC risk in the full cohort (odds ratio, 1.43; 95% CI, 1.40 to 1.46; P = 8.6 × 10-308) and within each major ancestry. The top decile of the MA-PRS consistently identified patients with two-fold increased risk of developing BC. Goodness-of-fit tests showed that the MA-PRS was well calibrated and predicted BC risk accurately in the tails of the distribution for both European and non-European women. CONCLUSION: The MA-PRS uses genetic ancestral composition to expand the utility of polygenic risk prediction to non-European women. Inclusion of genetic ancestry in polygenic risk prediction presents an opportunity for more personalized treatment decisions for women of varying and mixed ancestries.

Polyunsaturated fatty acids cause physiological and behavioral changes in Vibrio alginolyticus and Vibrio fischeri.

Vibrio alginolyticus and Vibrio (Aliivibrio) fischeri are Gram-negative bacteria found globally in marine environments. During the past decade, studies have shown that certain Gram-negative bacteria, including Vibrio species (cholerae, parahaemolyticus, and vulnificus) are capable of using exogenous polyunsaturated fatty acids (PUFAs) to modify the phospholipids of their membrane. Moreover, exposure to exogenous PUFAs has been shown to affect certain phenotypes that are important factors of virulence. The purpose of this study was to investigate whether V. alginolyticus and V. fischeri are capable of responding to exogenous PUFAs by remodeling their membrane phospholipids and/or altering behaviors associated with virulence. Thin-layer chromatography (TLC) analyses and ultra-performance liquid chromatography-electrospray ionization mass spectrometry (UPLC/ESI-MS) confirmed incorporation of all PUFAs into membrane phosphatidylglycerol and phosphatidylethanolamine. Several growth phenotypes were identified when individual fatty acids were supplied in minimal media and as sole carbon sources. Interestingly, several PUFAs acids inhibited growth of V. fischeri. Significant alterations to membrane permeability were observed depending on fatty acid supplemented. Strikingly, arachidonic acid (20:4) reduced membrane permeability by approximately 35% in both V. alginolyticus and V. fischeri. Biofilm assays indicated that fatty acid influence was dependent on media composition and temperature. All fatty acids caused decreased swimming motility in V. alginolyticus, while only linoleic acid (18:2) significantly increased swimming motility in V. fischeri. In summary, exogenous fatty acids cause a variety of changes in V. alginolyticus and V. fischeri, thus adding these bacteria to a growing list of Gram-negatives that exhibit versatility in fatty acid utilization and highlighting the potential for environmental PUFAs to influence phenotypes associated with planktonic, beneficial, and pathogenic associations.

Sequential chemotherapy followed by radical thoracic radiotherapy (50 Gy in 25 fractions) in limited stage small cell lung cancer.

INTRODUCTION: For limited stage small cell lung cancer (LS-SCLC) where concurrent chemoradiotherapy is inappropriate due to tumour bulk, co-morbidities or performance status, sequential treatment using chemotherapy followed by radiotherapy is the standard of care. The outcomes are not well established; we assessed in a single institution, the survival of these patients, prognostic factors and compared to the limited existing literature. MATERIALS AND METHOD: Retrospective data was collected on all 59 patients diagnosed with LS-SCLC from 2011 to 2016 who received chemotherapy consisting of Carboplatin or Cisplatin + Etoposide followed by thoracic radiotherapy (50 Gy in 25 fractions) +/- prophylactic cranial irradiation (PCI). RESULTS: Median age at diagnosis was 66 years (range 46-90). Patients received a median of four cycles of chemotherapy (range: 1-6) and all the patients completed a full course of radiotherapy with only one patient experiencing grade >2 radiation induced toxicity. With a median follow up of 20.6 months, 45 patients had died with a median survival of 20.6 months. 2-year overall survival (OS) rates were 42%. Age using a cut-off of 65 was prognostic (median OS 25.6 months ≤65 years versus 14.1 months >65 years, p = 0.013) but gender, stage and receipt of PCI were not. CONCLUSIONS: Most of the literature reporting outcome from sequential treatment in LS-SCLC is old and used a variety of radiotherapy regimens. Our data shows inferior outcomes to the gold standard concurrent chemoradiotherapy but support its usage in less fit patients with reasonable outcome observed.

Maternal and Perinatal Exposures Are Associated With Risk for Pediatric-Onset Multiple Sclerosis.

OBJECTIVE: To determine if prenatal, pregnancy, or postpartum-related environmental factors are associated with multiple sclerosis (MS) risk in children. METHODS: This is a case-control study of children with MS or clinically isolated syndrome and healthy controls enrolled at 16 clinics participating in the US Network of Pediatric MS Centers. Parents completed a comprehensive environmental questionnaire, including the capture of pregnancy and perinatal factors. Case status was confirmed by a panel of 3 pediatric MS specialists. Multivariable logistic regression analyses were used to determine association of these environmental factors with case status, adjusting for age, sex, race, ethnicity, US birth region, and socioeconomic status. RESULTS: Questionnaire responses were available for 265 eligible cases (median age 15.7 years, 62% girls) and 412 healthy controls (median age 14.6, 54% girls). In the primary multivariable analysis, maternal illness during pregnancy was associated with 2.3-fold increase in odds to have MS (95% confidence interval [CI] 1.20-4.21, P = .01) and cesarean delivery with 60% reduction (95% CI 0.20-0.82, P = .01). In a model adjusted for these variables, maternal age and BMI, tobacco smoke exposure, and breastfeeding were not associated with odds to have MS. In the secondary analyses, after adjustment for age, sex, race, ethnicity, and socioeconomic status, having a father who worked in a gardening-related occupation (odds ratio [OR] 2.18, 95% CI 1.14-4.16, P = .02) or any use in household of pesticide-related products (OR 1.73, 95% CI 1.06-2.81, P = .03) were both associated with increased odds to have pediatric MS. CONCLUSION: Cesarean delivery and maternal health during pregnancy may influence risk for pediatric-onset MS. We report a new possible association of pesticide-related environmental exposures with pediatric MS that warrants further investigation and replication.

Racial and Ethnic Differences in Antibiotic Use for Viral Illness in Emergency Departments.

BACKGROUND AND OBJECTIVES: In the primary care setting, there are racial and ethnic differences in antibiotic prescribing for acute respiratory tract infections (ARTIs). Viral ARTIs are commonly diagnosed in the pediatric emergency department (PED), in which racial and ethnic differences in antibiotic prescribing have not been previously reported. We sought to investigate whether patient race and ethnicity was associated with differences in antibiotic prescribing for viral ARTIs in the PED. METHODS: This is a retrospective cohort study of encounters at 7 PEDs in 2013, in which we used electronic health data from the Pediatric Emergency Care Applied Research Network Registry. Multivariable logistic regression was used to examine the association between patient race and ethnicity and antibiotics administered or prescribed among children discharged from the hospital with viral ARTI. Children with bacterial codiagnoses, chronic disease, or who were immunocompromised were excluded. Covariates included age, sex, insurance, triage level, provider type, emergency department type, and emergency department site. RESULTS: Of 39 445 PED encounters for viral ARTIs that met inclusion criteria, 2.6% (95% confidence interval [CI] 2.4%-2.8%) received antibiotics, including 4.3% of non-Hispanic (NH) white, 1.9% of NH black, 2.6% of Hispanic, and 2.9% of other NH children. In multivariable analyses, NH black (adjusted odds ratio [aOR] 0.44; CI 0.36-0.53), Hispanic (aOR 0.65; CI 0.53-0.81), and other NH (aOR 0.68; CI 0.52-0.87) children remained less likely to receive antibiotics for viral ARTIs. CONCLUSIONS: Compared with NH white children, NH black and Hispanic children were less likely to receive antibiotics for viral ARTIs in the PED. Future research should seek to understand why racial and ethnic differences in overprescribing exist, including parental expectations, provider perceptions of parental expectations, and implicit provider bias.

A case-control study of dietary salt intake in pediatric-onset multiple sclerosis.

BACKGROUND: High salt intake may be associated with pro-inflammatory changes in the immune response, and increased clinical and MRI activity in adults with relapsing-remitting multiple sclerosis. OBJECTIVE: We sought to determine if dietary salt intake is associated with pediatric-onset MS risk in a multicenter, case-control study. METHODS: Pediatric-onset CIS/MS cases within four years of onset and controls less than 22 years old recruited from 14 pediatric-MS centers were studied. Dietary sodium intake was assessed using the validated Block Kids Food Screener (NutritionQuest). Sodium intake, excess sodium, and sodium terciles were compared between cases and controls. Logistic regression models were adjusted for age, gender, ethnicity, body mass index, and socioeconomic status. RESULTS: Among 170 cases (mean age=15.2±3.5) and 331 controls (mean age=14.0±3.7), no significant difference in unadjusted mean sodium intake was found between cases (2044mg/d) and controls (2030mg/d, p=0.99). The proportion of subjects consuming excess sodium, based on the adequate intake for age and gender, was similar between cases and controls (65% versus 69%, p=0.34). There were no increased odds of higher sodium intake among cases as compared to controls (for each 100mg/d increase in sodium, OR=1.00, 95% CI 0.98, 1.02; p=0.93, for excess sodium intake, OR=1.05, 95% CI 0.67, 1.64; p=0.84). CONCLUSIONS: Our results show no strong association between dietary salt intake and pediatric-onset MS risk, suggesting that salt intake may not play a prominent role in susceptibility to MS in children.

Protective environmental factors for neuromyelitis optica.

OBJECTIVE: To determine whether early environmental factors, such as cesarean delivery, breastfeeding, and exposure to smoking or herpes viruses, are associated with neuromyelitis optica (NMO) risk in children. METHODS: This is a case-control study of pediatric NMO, multiple sclerosis (MS), and healthy subjects. Early-life exposures were obtained by standardized questionnaire. Epstein-Barr virus, cytomegalovirus, and herpes simplex virus 1 antibody responses were determined by ELISA. Multivariate logistic regression models were used to adjust for age at sampling, sex, race, and ethnicity. RESULTS: Early-life exposures were obtained from 36 pediatric subjects with NMO, 491 with MS, and 224 healthy controls. Daycare (odds ratio [OR] 0.33, 95% confidence interval [CI] 0.14, 0.78; p < 0.01) and breastfeeding (OR 0.42, 95% CI 0.18, 0.99; p = 0.05) were associated with lower odds of having NMO compared with healthy subjects. Cesarean delivery tended to be associated with 2-fold-higher odds of NMO compared with having MS/clinically isolated syndrome (OR 1.98, 95% CI 0.88, 4.59; p = 0.12) or with being healthy (OR 1.95, 95% CI 0.81, 4.71; p = 0.14). Sera and DNA were available for 31 subjects with NMO, 189 with MS, and 94 healthy controls. Epstein-Barr virus, herpes simplex virus 1, cytomegalovirus exposure, and being HLA-DRB1*15 positive were not associated with odds of having NMO compared with healthy subjects. CONCLUSIONS: Exposure to other young children may be an early protective factor against the development of NMO, as previously reported for MS, consistent with the hypothesis that infections contribute to disease risk modification. Unlike MS, pediatric NMO does not appear to be associated with exposures to common herpes viruses.

Mutation of pescadillo disrupts oligodendrocyte formation in zebrafish.

BACKGROUND: In vertebrates, the myelin sheath is essential for efficient propagation of action potentials along the axon shaft. Oligodendrocytes are the cells of the central nervous system that create myelin sheaths. During embryogenesis, ventral neural tube precursors give rise to oligodendrocyte progenitor cells, which divide and migrate throughout the central nervous system. This study aimed to investigate mechanisms that regulate oligodendrocyte progenitor cell formation. METHODOLOGY/PRINCIPAL FINDINGS: By conducting a mutagenesis screen in transgenic zebrafish, we identified a mutation, designated vu166, by an apparent reduction in the number of oligodendrocyte progenitor cells in the dorsal spinal cord. We subsequently determined that vu166 is an allele of pescadillo, a gene known to play a role in ribosome biogenesis and cell proliferation. We found that pescadillo function is required for both the proper number of oligodendrocyte progenitors to form, by regulating cell cycle progression, and for normal levels of myelin gene expression. CONCLUSIONS/SIGNIFICANCE: Our data provide evidence that neural precursors require pes function to progress through the cell cycle and produce oligodendrocyte progenitor cells and for oligodendrocyte differentiation.