Background The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in ...asthma inception. Objective We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. Methods We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study n = 30 and the Childhood Origins of Asthma Study n = 28) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell–derived IL-1β levels were measured by means of ELISA. Results Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3 , the most connected node within the network of asthma-associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator. Conclusions The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory.
Studies of the olfactory epithelium model system have demonstrated that production of neurons is regulated by negative feedback. Previously, we showed that a locally produced signal, the TGFβ ...superfamily ligand GDF11, regulates the genesis of olfactory receptor neurons by inhibiting proliferation of the immediate neuronal precursors (INPs) that give rise to them. GDF11 is antagonized by follistatin (FST), which is also produced locally. Here, we show that Fst(-/-) mice exhibit dramatically decreased neurogenesis, a phenotype that can only be partially explained by increased GDF11 activity. Instead, a second FST-binding factor, activin βB (ACTβB), inhibits neurogenesis by a distinct mechanism: whereas GDF11 inhibits expansion of INPs, ACTβB inhibits expansion of stem and early progenitor cells. We present data supporting the concept that these latter cells, previously considered two distinct types, constitute a dynamic stem/progenitor population in which individual cells alternate expression of Sox2 and/or Ascl1. In addition, we demonstrate that interplay between ACTβB and GDF11 determines whether stem/progenitor cells adopt a glial versus neuronal fate. Altogether, the data indicate that the transition between stem cells and committed progenitors is neither sharp nor irreversible and that GDF11, ACTβB and FST are crucial components of a circuit that controls both total cell number and the ratio of neuronal versus glial cells in this system. Thus, our findings demonstrate a close connection between the signals involved in the control of tissue size and those that regulate the proportions of different cell types.
Few studies have examined longitudinal asthma incidence rates (IRs) from a public health surveillance perspective.
Our aim was to calculate descriptive asthma IRs in children over time with ...consideration for demographics and parental asthma history.
Data from 9 US birth cohorts were pooled into 1 population covering the period from 1980 to 2017. The outcome was earliest parental report of a doctor diagnosis of asthma. IRs per 1,000 person-years were calculated.
The racial/ethnic backgrounds of the 6,283 children studied were as follows: 55% European American (EA), 25.5% African American (AA), 9.5% Mexican-Hispanic American (MA) and 8.5% Caribbean-Hispanic American (CA). The average follow-up was 10.4 years (SD = 8.5 years; median = 8.4 years), totaling 65,291 person-years, with 1789 asthma diagnoses yielding a crude IR of 27.5 per 1,000 person-years (95% CI = 26.3-28.8). Age-specific rates were highest among children aged 0 to 4 years, notably from 1995 to 1999, with a decline in EA and MA children in 2000 to 2004 followed by a decline in AA and CA children in 2010 to 2014. Parental asthma history was associated with statistically significantly increased rates. IRs were similar and higher in AA and CA children versus lower but similar in EA and MA children. The differential rates by sex from birth through adolescence principally resulted from a decline in rates among males but relatively stable rates among females.
US childhood asthma IRs varied dramatically by age, sex, parental asthma history, race/ethnicity, and calendar year. Higher rates in the 0- to 4-year-olds group, particularly among AA/CA males with a parental history of asthma, as well as changes in rates over time and by demographic factors, suggest that asthma is driven by complex interactions between genetic susceptibility and variation in time-dependent environmental and social factors.
Abstract
A substantial body of research now exists demonstrating sensitivities of marine organisms to ocean acidification (OA) in laboratory settings. However, corresponding in situ observations of ...marine species or ecosystem changes that can be unequivocally attributed to anthropogenic OA are limited. Challenges remain in detecting and attributing OA effects in nature, in part because multiple environmental changes are co-occurring with OA, all of which have the potential to influence marine ecosystem responses. Furthermore, the change in ocean pH since the industrial revolution is small relative to the natural variability within many systems, making it difficult to detect, and in some cases, has yet to cross physiological thresholds. The small number of studies that clearly document OA impacts in nature cannot be interpreted as a lack of larger-scale attributable impacts at the present time or in the future but highlights the need for innovative research approaches and analyses. We summarize the general findings in four relatively well-studied marine groups (seagrasses, pteropods, oysters, and coral reefs) and integrate overarching themes to highlight the challenges involved in detecting and attributing the effects of OA in natural environments. We then discuss four potential strategies to better evaluate and attribute OA impacts on species and ecosystems. First, we highlight the need for work quantifying the anthropogenic input of CO2 in coastal and open-ocean waters to understand how this increase in CO2 interacts with other physical and chemical factors to drive organismal conditions. Second, understanding OA-induced changes in population-level demography, potentially increased sensitivities in certain life stages, and how these effects scale to ecosystem-level processes (e.g. community metabolism) will improve our ability to attribute impacts to OA among co-varying parameters. Third, there is a great need to understand the potential modulation of OA impacts through the interplay of ecology and evolution (eco–evo dynamics). Lastly, further research efforts designed to detect, quantify, and project the effects of OA on marine organisms and ecosystems utilizing a comparative approach with long-term data sets will also provide critical information for informing the management of marine ecosystems.
•Overall, there are differences in the participants excluded from four different quality control approaches across three pediatric datasets.•In clinically enriched samples, the greatest ...correspondence of excluded participants was between automated and visual quality control procedures.•Implementing quality control led to the exclusion of younger participants and those with greater clinical impairments.•Specific QC approach implemented did not lead to measurable differences in clinical or brain metric characteristics.
Poor quality T1-weighted brain scans systematically affect the calculation of brain measures. Removing the influence of such scans requires identifying and excluding scans with noise and artefacts through a quality control (QC) procedure. While QC is critical for brain imaging analyses, it is not yet clear whether different QC approaches lead to the exclusion of the same participants. Further, the removal of poor-quality scans may unintentionally introduce a sampling bias by excluding the subset of participants who are younger and/or feature greater clinical impairment. This study had two aims: (1) examine whether different QC approaches applied to T1-weighted scans would exclude the same participants, and (2) examine how exclusion of poor-quality scans impacts specific demographic, clinical and brain measure characteristics between excluded and included participants in three large pediatric neuroimaging samples.
We used T1-weighted, resting-state fMRI, demographic and clinical data from the Province of Ontario Neurodevelopmental Disorders network (Aim 1: n = 553, Aim 2: n = 465), the Healthy Brain Network (Aim 1: n = 1051, Aim 2: n = 558), and the Philadelphia Neurodevelopmental Cohort (Aim 1: n = 1087; Aim 2: n = 619). Four different QC approaches were applied to T1-weighted MRI (visual QC, metric QC, automated QC, fMRI-derived QC). We used tetrachoric correlation and inter-rater reliability analyses to examine whether different QC approaches excluded the same participants. We examined differences in age, mental health symptoms, everyday/adaptive functioning, IQ and structural MRI-derived brain indices between participants that were included versus excluded following each QC approach.
Dataset-specific findings revealed mixed results with respect to overlap of QC exclusion. However, in POND and HBN, we found a moderate level of overlap between visual and automated QC approaches (rtet=0.52–0.59). Implementation of QC excluded younger participants, and tended to exclude those with lower IQ, and lower everyday/adaptive functioning scores across several approaches in a dataset-specific manner. Across nearly all datasets and QC approaches examined, excluded participants had lower estimates of cortical thickness and subcortical volume, but this effect did not differ by QC approach.
The results of this study provide insight into the influence of QC decisions on structural pediatric imaging analyses. While different QC approaches exclude different subsets of participants, the variation of influence of different QC approaches on clinical and brain metrics is minimal in large datasets. Overall, implementation of QC tends to exclude participants who are younger, and those who have more cognitive and functional impairment. Given that automated QC is standardized and can reduce between-study differences, the results of this study support the potential to use automated QC for large pediatric neuroimaging datasets.
Intimate partners and other informal caregivers provide unpaid tangible, emotional, and decision-making support for patients with cancer, but relatively little research has investigated the cancer ...experiences of sexual minority women (SMW) with cancer and their partners/caregivers.
This review addressed 4 central questions: 1) What social support do SMW with cancer receive from partners/caregivers? 2) What effect does cancer have on intimate partnerships or caregiving relationships of SMW with cancer? 3) What effects does cancer have on partners/caregivers of SMW with cancer? 4) What interventions exist to support partners/caregivers of SMW or to strengthen the patient-caregiver relationship?
This systematic review, conducted in 2018 and updated in 2020, was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two independent coders screened abstracts and articles.
In total, 550 unique records were screened; 42 articles were assessed for eligibility, and 18 were included in a qualitative synthesis. Most studies were U.S.-based, involved breast cancer, included intimate partners, had primarily white/Caucasian samples, and were cross-sectional. Sexual minority female participants reported that partners/caregivers often provide important social support, including emotional support, decision-making support, and tangible support. Effects of cancer on relationships with partners/caregivers were mixed, with some studies finding relationships remained stable and others finding cancer either increased closeness or disrupted relationships. Participants reported partners/caregivers often experience distress and may experience discrimination, discomfort disclosing sexual orientation, and a lack of sexual minority-friendly services. No studies involved an intervention targeting partners/caregivers or the dyadic relationship.
More work is needed to understand SMW with cancers other than breast cancer, and future work should include more racially, ethnically, and economically diverse samples. Longitudinal research will allow an examination of patterns of mutual influence and change in relationships. These steps will enable the development of interventions to support SMW with cancer and people close to them.
•This review synthesized 18 articles about sexual minority women and cancer.•Partners/caregivers often provide crucial social support to sexual minority women.•Effects of cancer on relationships with partners/caregivers were mixed.•Partners/caregivers may experience distress and discrimination.•More work is needed in diverse samples and in cancers other than breast cancer.
Routine use of vitamin D supplements has increased substantially in the United States. However, the safety and tolerability of long-term use of high-dose vitamin D are not known. We assessed the ...safety and tolerability of high-dose, daily vitamin D
in the vitamin D and type 2 diabetes (D2d) study.
In total, 2423 overweight/obese persons with prediabetes were randomized in a double-blind manner to either 4000 IU of vitamin D
(the tolerable upper intake level for adults by the National Academy of Medicine) taken daily or matching placebo. All participants were included in this analysis. Incident adverse events (AE) were ascertained 4 times a year at in-person visits (twice a year) and interim remote encounters (twice a year) and were defined as untoward or unfavorable medical occurrences. Serious adverse events (SAE) included death, life-threatening events, and hospitalizations.
A total of 8304 AEs occurred during 3 years of follow-up and were less frequent in the vitamin D group compared to placebo (Incidence Rate Ratio IRR = 0.94; 95% Confidence Interval (CI) 0.90, 0.98). The overall frequency of protocol-specified AEs of interest, which included nephrolithiasis, hypercalcemia, hypercalciuria, or low estimated glomerular filtration rate, was low and did not differ by group. There were no significant between-group differences in total SAEs (IRR = 0.96 (0.81, 1.14)).
Vitamin D
supplementation at 4000 IU per day was safe and well tolerated among overweight/obese participants at high risk for diabetes who were appropriately monitored for safety. In this population, this dose of vitamin D
did not increase risk of AEs or SAEs, including those previously associated with vitamin D such as hypercalcemia, hypercalciuria, or nephrolithiasis.
ClinicalTrials.gov NCT01942694, prospectively registered September 16, 2013.
Objective
To examine the relationship between objectively assessed moderate‐to‐vigorous intensity physical activity (MVPA) and 4‐year weight loss (WL) and WL maintenance among individuals with ...diabetes enrolled in the Look AHEAD trial.
Methods
MVPA was measured in a subgroup of lifestyle intervention participants with accelerometry data at baseline and at 1 and 4 years (n = 553; age: 59.7 ± 6.8 y; BMI: 35.5 ± 5.9 kg/m2). Minutes per week of bout‐related MVPA were calculated (≥ 3 metabolic equivalents, ≥ 10‐min bouts), and adherence to the national physical activity (PA) recommendation for WL maintenance (≥ 250 min/wk) was assessed.
Results
Independent of 1‐year WL, 4‐year MVPA (β = −0.003, SE = 0.002, P = 0.006), but not 1‐year MVPA (β = 0.0001, SE = 0.001, P = 0.50), was significantly associated with 4‐year WL. Compared with “nonmaintainers” (≥ 10% WL at year 1, but < 10% at year 4; n = 132), WL maintainers (≥ 10% WL at years 1 and 4; n = 103) had higher MVPA at year 1 (253.4 ± 251.8 vs. 163.9 ± 158.2 min/wk, P = 0.002) and year 4 (155.3 ± 180.6 vs. 111.4 ± 154.5 min/wk, P = 0.046). Although 38.8% and 22.3% of WL maintainers engaged in ≥ 250 min/wk at years 1 and 4, respectively, many engaged in < 150 min/wk (year 1: 41%, year 4: 61%).
Conclusions
Higher weekly MVPA is associated with greater long‐term WL and weight maintenance; however, many individuals are able to maintain ≥ 10% WL while engaging in little MVPA.
Our objective was to compare the diagnostic performance and diagnostic confidence of convolutional neural networks (CNN) to radiologists in characterizing small hypoattenuating hepatic nodules (SHHN) ...in colorectal carcinoma (CRC) on CT scans. Retrospective review of CRC CT scans over 6-years yielded 199 patients (550 SHHN) defined as < 1 cm in diameter. The reference standard was established through 1-year stability/MRI for benign or nodule evolution for malignant nodules. Five CNNs underwent supervised training on 150 patients (412 SHHN). The remaining 49 patients (138 SHHN) were used as testing-set to compare performance of 3 radiologists to CNN, measured through ROC AUC analysis of confidence rating assigned to each nodule by the radiologists. Multivariable modeling was used to compensate for radiologist bias from visible findings other than SHHN. In characterizing SHHN as benign or malignant, the radiologists' mean AUC ROC (0.96) was significantly higher than CNN (0.84, p = 0.0004) but equivalent to CNN adjusted through multivariable modeling for presence of synchronous ≥ 1 cm liver metastases (0.95, p = 0.9). The diagnostic confidence of radiologists and CNN were analyzed. There were significantly lower number of nodules rated with low confidence by CNN (19.6%) and CNN with liver metastatic status (18.1%) than two (38.4%, 44.2%, p < 0.0001) but not a third radiologist (11.1%, p = 0.09). We conclude that in CRC, CNN in combination with liver metastatic status equaled expert radiologists in characterizing SHHN but with better diagnostic confidence.
To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of health care within the Look AHEAD trial.
A total of 5,121 overweight or obese adults with type 2 ...diabetes were randomly assigned to an ILI that promoted weight loss or to a comparison condition of diabetes support and education (DSE). Use and costs of health-care services were recorded across an average of 10 years.
ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P < 0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P < 0.001). ILI produced a mean relative per-person 10-year cost savings of $5,280 (95% CI 3,385-7,175); however, these were not evident among individuals with a history of cardiovascular disease.
Compared with DSE over 10 years, ILI participants had fewer hospitalizations, fewer medications, and lower health-care costs.
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