IMPORTANCE: There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. OBJECTIVE: To compare the effects of ...different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity. DESIGN, SETTING, AND PARTICIPANTS: Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks’ gestation. EXPOSURES: Spo2 target range that was lower (85%-89%) vs higher (91%-95%). MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities. RESULTS: A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% 95% CI, −1.3% to 4.6%; relative risk RR, 1.04 95% CI, 0.98 to 1.09, P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% 95% CI, 0.6% to 5.0%; RR, 1.17 95% CI, 1.04 to 1.31, P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, −4.0% 95% CI, −6.1% to −2.0%; RR, 0.74 95% CI, 0.63 to 0.86, P < .001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower Spo2 target group and 170 of 2465 infants (6.9%) in the higher Spo2 target group (risk difference, 2.3% 95% CI, 0.8% to 3.8%; RR, 1.33 95% CI, 1.10 to 1.61, P = .003). CONCLUSIONS AND RELEVANCE: In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.
The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with ...immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
The mechanisms controlling CD4
T cell switching from an effector to an anti-inflammatory (IL-10
) phenotype play an important role in the persistence of chronic inflammatory diseases. Here, we ...identify the cholesterol biosynthesis pathway as a key regulator of this process. Pathway analysis of cultured cytokine-producing human T cells reveals a significant association between IL-10 and cholesterol metabolism gene expression. Inhibition of the cholesterol biosynthesis pathway with atorvastatin or 25-hydroxycholesterol during switching from IFNγ
to IL-10
shows a specific block in immune resolution, defined as a significant decrease in IL-10 expression. Mechanistically, the master transcriptional regulator of IL10 in T cells, c-Maf, is significantly decreased by physiological levels of 25-hydroxycholesterol. Strikingly, progression to rheumatoid arthritis is associated with altered expression of cholesterol biosynthesis genes in synovial biopsies of predisposed individuals. Our data reveal a link between sterol metabolism and the regulation of the anti-inflammatory response in human CD4
T cells.
Context: Vitamin D has direct influence on molecular pathways proposed to be important in the pathogenesis of preeclampsia, yet the vitamin D-preeclampsia relation has not been studied.
Objectives: ...We aimed to assess the effect of maternal 25-hydroxyvitamin D 25(OH)D concentration on the risk of preeclampsia and to assess the vitamin D status of newborns of preeclamptic mothers.
Design and Setting: We conducted a nested case-control study of pregnant women followed from less than 16 wk gestation to delivery (1997–2001) at prenatal clinics and private practices.
Patients: Patients included nulliparous pregnant women with singleton pregnancies who developed preeclampsia (n = 55) or did not develop preeclampsia (n = 219). Women’s banked sera were newly measured for 25(OH)D.
Main Outcome Measure: The main outcome measure was preeclampsia (new-onset gestational hypertension and proteinuria for the first time after 20 wk gestation). Our hypotheses were formulated before data collection.
Results: Adjusted serum 25(OH)D concentrations in early pregnancy were lower in women who subsequently developed preeclampsia compared with controls geometric mean, 45.4 nmol/liter, and 95% confidence interval (CI), 38.6–53.4 nmol/liter, vs. 53.1 and 47.1–59.9 nmol/liter; P < 0.01. There was a monotonic dose-response relation between serum 25(OH)D concentrations at less than 22 wk and risk of preeclampsia. After confounder adjustment, a 50-nmol/liter decline in 25(OH)D concentration doubled the risk of preeclampsia (adjusted odds ratio, 2.4; 95% CI, 1.1–5.4). Newborns of preeclamptic mothers were twice as likely as control newborns to have 25(OH)D less than 37.5 nmol/liter (adjusted odds ratio, 2.2; 95% CI, 1.2–4.1).
Conclusions: Maternal vitamin D deficiency may be an independent risk factor for preeclampsia. Vitamin D supplementation in early pregnancy should be explored for preventing preeclampsia and promoting neonatal well-being.
This study investigates the protective role of ethnic-racial identity (ERI) affirmation on the longitudinal association between racism and Aboriginal Australian children's social and emotional ...well-being (SEWB).
408 children from the K-Cohort of the Longitudinal Study of Indigenous Children were included in the analysis. Data were collected through questionnaire-guided interviews at 7-10 and 9-12 years of age. Children's racism experience, SEWB (Strengths and Difficulties Questionnaire), and confounding were reported by caregivers. ERI was reported by children and dichotomized into high versus low. Generalized linear models with log-Poisson links and robust errors were used to estimate adjusted Risk Ratios (RRa) for the effect of racism on SEWB domains. Effect-measure modification analysis was used to verify differences on effect sizes per strata of ERI affirmation. The presence of modification was indicated by the Relative Excess Risk due to Interaction (RERI).
Slightly above half (51.4%) of the children presented high ERI affirmation. Children exposed to racism and with low ERI affirmation were at increased risk of hyperactive behavior (RRa 2.53, 95% CI 1.17, 5.48), conduct problems (RRa 2.35, 95% CI 1.07, 5.15), and total difficulties (RRa 1.73, 95% CI 0.84, 3.55). Positive RERIs indicated the joint effects of racism and low ERI affirmation surpassed the sum of their separate effects in these domains. Children with high ERI affirmation were at increased risk of peer problems (RRa 1.66, 95% CI 0.78, 3.52).
These findings suggest that ERI may mitigate the risk of poor SEWB due to racism. Fostering affirmative ERI can be an important strategy in promoting resilience in Aboriginal Australian children.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain ...incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression and therefore may affect placental antibody transfer. Here, we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon-stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed after maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2–specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.
Background: We sought to determine the association between maternal vitamin D status at ≤26 weeks' gestation and the risk of preeclampsia by clinical subtype. Methods: We conducted a case–cohort ...study among women enrolled at 12 US sites from 1959 to 1966 in the Collaborative Perinatal Project. In serum collected at ≤26 weeks' gestation (median 20.9 weeks) from 717 women who later developed preeclampsia (560 mild and 157 severe cases) and from 2986 mothers without preeclampsia, we measured serum 25-hydroxyvitamin D, over 40 years later, using liquid chromatography–tandem mass spectrometry. Results: Half of women in the subcohort had 25-hydroxyvitamin D (25(OH)D) >50 nmol/L. Maternal 25(OH)D 50 to 74.9 nmol/L was associated with a reduction in the absolute and relative risk of preeclampsia and mild preeclampsia compared with 25(OH)D <30 nmol/L in the crude analysis but not after adjustment for confounders, including race, prepregnancy body mass index, and parity. For severe preeclampsia, 25(OH)D ≥50 nmol/L was associated with a reduction in three cases per 1000 pregnancies (adjusted risk difference = −0.003 95% confidence interval = −0.005 to 0.0002) and a 40% reduction in risk (0.65 0.43 to 0.98) compared with 25(OH) D <50 nmol/L. Conclusions were unchanged (1) after restricting to women with 25(OH)D measured before 22 weeks' gestation or (2) with formal sensitivity analyses for unmeasured confounding. Conclusions: Maternal vitamin D deficiency may be a risk factor for severe preeclampsia but not for its mild subtypes. Contemporary cohorts with large numbers of severe preeclampsia cases would be needed to confirm or refute these findings.
Positive attitudes towards ethnic-racial identity (ERI) is a key factor in Aboriginal Australian children's development. The present study aims to offer evidence of construct and criterion validity, ...reliability, and measurement invariance of a brief measure of Aboriginal children's ERI affirmation.
Data was from 424 children aged 10-12 years (mean 10.5 years; SD 0.56) participating in the 8th wave of the Longitudinal Study of Indigenous Children (LSIC). Information on ERI was obtained from 4 child-reported items. Sociodemographic characteristics and child social and emotional outcomes were caregiver-reported. A factorial structure was tested by Confirmatory Factor Analysis. The estimation method was weighted least squares with mean and variance adjusted test statistic (WLSMV). For reliability verification, the ordinal α and Ω hierarchical α were assessed. For construct validity, a generalized linear model with log-Poisson link estimated the association between ERI and children's social and emotional outcomes. We hypothesized that children with positive ERI would have lower behavioural and emotional difficulties.
We found evidence of excellent fit for a unidimensional model of ERI affirmation after adjusting for correlated uniqueness between items 1 and 3 (χ2(2) = 0.06, p = 0.80; RMSEA = 0.000 90% CI 0.000-0.080, p = 0.088; CFI = 1.000). Internal consistency reliability was considered adequate (ordinal α = 0.83; Ω hierarchical α = 0.72). The unidimensional model was shown to be invariant among boys and girls (Δχ2 (4) = 6.20, p = 0.18; ΔCFI = 0.000). Higher ERI was associated with lower risk of problematic scores (>17) on the SDQ (Risk Ratioa = 0.91, 95% CI 0.64, 1.29).
The four LSIC items perform as a brief measure of Aboriginal children ERI affirmation among boys and girls. Results contribute much needed evidence for LSIC's ongoing success and to future research on Aboriginal children's development and wellbeing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The tumor microenvironment (TME) consists of cells, soluble factors, signaling molecules, extracellular matrix, and mechanical cues that can promote neoplastic transformation, support tumor growth ...and invasion, protect the tumor from host immunity, foster therapeutic resistance, and provide niches for dormant metastases to thrive. An American Association for Cancer Research (AACR) special conference held on November 3-6, 2011, addressed five emerging concepts in our understanding of the TME: its dynamic evolution, how it is educated by tumor cells, pathways of communication between stromal and tumor cells, immunomodulatory roles of the lymphatic system, and contribution of the intestinal microbiota. These discussions raised critical questions on how to include the analysis of the TME in personalized cancer diagnosis and treatment.
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