The IRG1-itaconate axis protects from cholesterol-induced inflammation and atherosclerosis.

Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested the therapeutic potential of the IRG1-itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found that IRG1 is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic Irg1-deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1ß. Mechanistically, absence of Irg1 increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1ß release. Conversely, supplementation of the Irg1-itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1ß levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1-itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.

Neighborhood deprivation, racial segregation and associations with cancer risk and outcomes across the cancer-control continuum.

The racial/ethnic disparities in cancer incidence and outcome are partially due to the inequities in neighborhood advantage. Mounting evidences supported a link between neighborhood deprivation and cancer outcomes including higher mortality. In this review, we discuss some of the findings related to work on area-level neighborhood variables and cancer outcomes, and the potential biological and built/natural environmental mechanisms that might explain this link. Studies have also shown that residents of deprived neighborhoods or of racially or economically segregated neighborhoods have worse health outcomes than residents of more affluent neighborhoods and/or less racially or economically segregated neighborhoods, even after adjusting for the individual-level socioeconomic status. To date, little research has been conducted investigating the biological mediators that may play roles in the associations of neighborhood deprivation and segregation with cancer outcomes. The psychophysiological stress induced by neighborhood disadvantage among people living in these neighborhoods could be a potential underlying biological mechanism. We examined a number of chronic stress-related pathways that may potentially mediate the relationship between area-level neighborhood factors and cancer outcomes, including higher allostatic load, stress hormones, altered epigenome and telomere maintenance and biological aging. In conclusion, the extant evidence supports the notion that neighborhood deprivation and racial segregation have unfavorable impacts on cancer. Understanding how neighborhood factors influence the biological stress response has the potential to inform where and what types of resources are needed within the community to improve cancer outcomes and reduce disparities. More studies are warranted to directly assess the role of biological and social mechanisms in mediating the relationship between neighborhood factors and cancer outcomes.

Advertising Exposure From Online and Offline Sources and Youth Tobacco Use: Findings From the Adolescents, Place, and Behavior Study.

INTRODUCTION: Tobacco use among adolescents is an ongoing public health concern. Youth tobacco use has been associated with advertising, from both online sources and retail environments. AIMS AND METHODS: This study examined associations between exposure to tobacco advertisements from tobacco retail outlets (TROs), internet, and social media sources and ever tobacco use among adolescents. Data were obtained from youth, aged 11-17 years (N = 401) from Richmond, VA. Bayesian index and group index models were fitted to estimate indices of exposure to (1) social media use, (2) tobacco ads on social media, and (3) TRO store visits and their association with ever tobacco use. The most important components of the exposure indices were also determined based on the index component weights from the Bayesian index models. RESULTS: In Bayesian index models of single exposures, each exposure index was significantly associated with tobacco use. In the best-fitting model, social media tobacco ads (odds ratio [OR] = 2.2; 95% credible interval [CI]: 1.2, 4.5) and TRO store visits (OR = 1.6; 95% CI: 1.1, 2.3) were significantly associated with ever tobacco use, as was older age (OR = 1.4; 95% CI: 1.2, 1.8). Index component weights revealed Snapchat ad frequency as the most important platform in the social media index and convenience stores as the most important type of store in the TRO index. CONCLUSIONS: Exposure to pro-tobacco advertisements on social media and visits to TROs are associated with adolescent ever tobacco use. Results provide support for policies that would restrict the promotion of tobacco products at TROs and on social media. Tobacco regulations and interventions targeting convenience stores and Snapchat may be warranted to reduce youth tobacco use. IMPLICATIONS: Current evidence provide support for policies that would restrict the promotion of tobacco products at TROs and on social media. Findings suggest that regulations and interventions that specifically target advertisements in convenience stores and on Snapchat may be currently warranted to reduce youth tobacco use.

Tobacco exposures are associated with health care utilization (HCU) and health care costs in pregnant persons and their newborn babies.

INTRODUCTION: Identifying health care utilization and costs associated with active and passive smoking during pregnancy could help improve health management strategies. METHODS: Data are from the Newborn Epigenetics STudy (NEST), a birth cohort enrolled from 2005-2011 in Durham and adjacent counties in North Carolina, United States. Participants included those for whom prenatal serum samples were assayed and for whom administrative data were obtainable (N=1,045). Zero-inflated Poisson (ZIP) regression models were used to assess associations between cotinine, adjusted for covariates (e.g., race and ethnicity, age at delivery, cohabitation status, education), and health care utilization outcomes. Generalized linear regression models were used to estimate average total charges. Simulation models were conducted to determine the economic benefits of reducing SHS and smoking during pregnancy. RESULTS: Increasing levels of cotinine were positively associated with parent's number of ED visits (coefficient(b)=0.0012, standard error (SE)=0.0002; P<.001), the number of ICU hours (b=0.0079, SE=0.0025; P=.002)), time spent in the ICU (b=0.0238, SE=0.0020, P<.001), and the number of OP visits (b=0.0003, SE=0.0001; P<.001). For infants, higher cotinine levels were associated with higher number of ED (b=0.0012, SE=0.0004; P=.005), ICU (b=0.0050, SE=0.001; P<.001), and OP (b=0.0006, SE=0.0002; P<.001) visits and longer time spent in the ED (b=0.0025, SE=0.0003; P<.001), ICU (b=0.0005, SE=0.0001; P<.001), and IP (b=0.0020, SE=0.0002; P<.001). Simulation results showed that a 5% reduction in smoking would correspond to a potential median cost savings of $150,533 from ED visits of parents and infants. CONCLUSION: Our findings highlight the importance of smoke exposure cessation during pregnancy to reduce health care utilization and costs for both parents and infants. IMPLICATIONS: This study reinforces the importance of reducing smoking and secondhand smoke exposure during pregnancy. Focusing on expanding cessation services to this group could help reduce morbidities observed within this population. Furthermore, there is the potential for health care costs savings to health care systems, especially to those with high delivery numbers. These cost savings are represented by potential reductions in ED, OP, and ICU hours and visits.

Modeling the Effects of Policies that Restrict Tobacco Retail Outlets on Prenatal Smoke Exposure and Perinatal Health Care Utilization.

Tobacco retail outlet (TRO) density has been associated with increased cotinine levels in pregnant persons and their children. As such, the higher densities of TROs may represent higher levels of active smoking during pregnancy. The purpose of this study is to simulate the reduction in cotinine (a biomarker of smoke exposure) and health care utilization that could occur in pregnant persons under enactment of several candidate TRO reduction policy recommendations. Using existing retail outlet data from the state of North Carolina and from the Newborn Epigenetic Study (NEST), the present study created hypothetical policy-informed datasets of TROs that a) limited the number of TROs to the same density as the 2014 San Francisco (SF) policy (Policy 1), b) set the minimum distance to 500 feet between TROs from a school and from other TROs (Policy 2), c) restricted the types of TROs to exclude pharmacies (Policy 3), and d) a combination of Policies 1-3 (Policy 4). We estimated the effects of each policy individually and in a separate model with their combined effects in terms of the reduction on cotinine levels and health care utilization, as measured by number of visits to the emergency department (ED). We found that the hypothetical policies were likely to be effective in reducing maternal cotinine and ED visits, with the majority of the mothers in the dataset demonstrating reductions in these outcomes after implementation of the policies. We found that Policy 1 led to moderate reductions in TRO exposure for the majority of the sample as well as stratified by race/ethnicity. Additionally, Policy 4 had slightly larger estimated effects than Policy 1, but could be more onerous to implement in practice. Overall, we identified evidence supporting the efficacy of TRO reduction strategies that could impact smoke exposure during pregnancy in our diverse sample in North Carolina.

Potential imaging targets in primary head and neck squamous cell carcinoma and lymph node metastases.

PURPOSE: To investigate glycoprotein nonmetastatic melanoma protein B (GPNMB) and vascular endothelial growth factor (VEGF) as potential fluorescent imaging markers by comparing their protein expression to epidermal growth factor receptor (EGFR). MATERIALS AND METHODS: Thirty-eight paired samples of untreated head and neck squamous cell carcinoma (HNSCC) primary tumours (PT) and corresponding synchronous lymph node metastases (LNM) were selected. After immunohistochemical staining, expression was assessed and compared by the percentage of positive tumour cells. Data were analysed using the Mann-Whitney test, effect sizes (ESr) and Spearman's correlation coefficient (r). RESULTS: GPNMB expression was observed in 100 % of PT, and median 80 % (range 5-100 %) of tumour cells, VEGF in 92 % and 60 % (0-100 %), EGFR in 87 % and 60 % (0-100 %) respectively. In corresponding LNM, GPNMB expression was observed in 100 % of LNM and median 90 % (20-100 %) of tumour cells, VEGF in 87 % and 65 % (0-100 %), and EGFR in 84 % and 35 % (0-100 %). A positive correlation was found between expression in PT and LNM for GPNMB (r = 0.548) and EGFR (r = 0.618) (p < 0.001), but not for VEGF (r = -0.020; p = 0.905). GPNMB expression was present in a higher percentage of tumour cells compared to EGFR in PT (p = 0.015, ESr = -0.320) and in LNM (p < 0.001, ESr = -0.478), while VEGF was not (p = 1.00, ESr = -0.109 and - 0.152, respectively). CONCLUSION: GPNMB expression is higher than EGFR in untreated HNSCC PT and corresponding LNM, while VEGF expression is comparable to EGFR. GPNMB is a promising target for fluorescent imaging in HNSCC.

Narrow band imaging reveals field cancerisation undetected by conventional white light: Optical diagnosis versus histopathology.

OBJECTIVE: To assess whether narrow band imaging (NBI) detects fields of cancerisation around suspicious lesions in the upper aerodigestive tract, which were undetected by white light imaging (WLI). METHODS: In 96 patients with laryngeal and pharyngeal lesions suspicious for malignancy, 206 biopsies were taken during laryngoscopy: 96 biopsies of suspicious lesions detected by both WLI and NBI (WLI+/NBI+), 60 biopsies adjacent mucosa only suspicious with NBI (WLI-/NBI+), and 46 biopsies of NBI and WLI unsuspicious mucosa (WLI-/NBI-) as negative controls. Optical diagnosis according to the Ni-classification was compared with histopathology. RESULTS: Signs of (pre)malignancy were found in 88% of WLI+/NBI+ biopsies, 32% of WLI-/NBI+ biopsies and 0% in WLI-/NBI- (p < .001). In 58% of the WLI-/NBI+ mucosa any form of dysplasia or carcinoma was detected. CONCLUSION: The use of additional NBI led to the detection of (pre)malignancy in 32% of the cases, that would have otherwise remained undetected with WLI alone. This highlights the potential of NBI as a valuable adjunct to WLI in the identification of suspicious lesions in the upper aerodigestive tract.

Association between allostatic load and breast cancer risk: a cohort study.

BACKGROUND: Allostatic load (AL) reflects the collective load of chronic stress during lifetime. Previous studies have shown that higher AL is associated with poor clinical outcomes among breast cancer patients. However, the relationship between AL and breast cancer risk is still unclear. METHODS: To fill the gap, we analyzed the association between AL and the development of breast cancer in 181,455 women identified from the UK Biobank. RESULTS: During the follow-up from 2006 to 2020, 5,701 women were diagnosed with incident breast cancer. Significantly higher AL was observed among incident breast cancer cases than all study participants (mean: 2.77 vs. 2.63, P < 0.01). Univariate Cox regression analysis indicated the risk of breast cancer was increased by 5% per one AL unit increase (hazard ratio (HR) = 1.05, 95% confidence interval (CI) 1.04, 1.07). In multivariate analyses, after adjusting demographics, family history of breast cancer, reproductive factors, socioeconomic status, lifestyle factors, and breast cancer polygenic risk score (PRS), the significant association remained (HR = 1.05, 95%CI 1.03, 1.07). The significant relationship was further confirmed in the categorical analysis. Compared with women in the low AL group (AL: 0 ~ 2), those in the high AL group (AL: 3 ~ 11) had a 1.17-fold increased risk of breast cancer (HR = 1.17, 95%CI 1.11, 1.24). Finally, in the stratified analysis, joint effects on the risk of breast cancer were observed between the AL and selected known breast cancer risk factors, including age, family history of breast cancer, PRS, income, physical activity, and alcohol consumption. CONCLUSION: In summary, those findings have demonstrated that higher AL was associated with an increased breast cancer risk in women. This association is likely independent of known breast cancer risk factors. Thus, the AL could be a valuable biomarker to help breast cancer risk prediction and stratification.

Prenatal and Childhood Smoke Exposure Associations with Cognition, Language, and Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: To assess the relationships of prenatal and childhood smoke exposure with specific neurodevelopmental and behavioral problems during early childhood. STUDY DESIGN: A subsample (n = 386) of mother-child dyads from the Newborn Epigenetic Study (NEST) prebirth cohort participated in the study. Cotinine concentrations were used to objectively measure prenatal and childhood smoke exposure when youth were aged 3-13 years. Multivariable regression models were used to estimate associations of prenatal and childhood cotinine concentrations with performance on the National Institutes of Health (NIH) Toolbox and attention-deficit/hyperactivity disorder and behavioral symptoms, measured using the Behavior Assessment System for Children, 2nd edition (BASC-2). RESULTS: After adjusting for confounders, childhood cotinine concentrations were associated with poorer cognitive performance on tasks measuring cognitive flexibility (B = -1.29; P = .03), episodic memory (B = -0.97; P = .02), receptive language development (B = -0.58; P = .01), and inhibitory control and attention (B = -1.59; P = .006). Although childhood cotinine concentration was associated with higher levels of attention problems (B = 0.83; P = .004) on the BASC-2, after adjustment for confounders, the association is nonsignificant. Although associations for maternal cotinine concentrations were null, an interaction was detected between prenatal and childhood cotinine concentrations on the NIH Toolbox Picture Vocabulary Task (P = .02). CONCLUSIONS: Our findings suggest that childhood tobacco smoke exposure may lead to poorer attention regulation and language acquisition, complex visual processing ability, and attention problems.

Electronic Cigarette Nicotine Flux, Nicotine Yield, and Particulate Matter Emissions: Impact of Device and Liquid Heterogeneity.

INTRODUCTION: Electronic cigarettes (ECIGs) heat a nicotine-containing liquid to produce an inhalable aerosol. ECIG power (wattage) and liquid nicotine concentration are two factors that predict nicotine emission rate ("flux"). These factors can vary greatly across devices and users. AIMS AND METHODS: The purpose of this study was to examine ECIG device and liquid heterogeneity in "real world" settings and the association with predicted nicotine flux, nicotine yield, and total particulate matter (TPM) emissions. Past 30-day ECIG users (n = 84; mean age = 23.8 years [SD = 9.6]) reported device and liquid characteristics. Device power was measured via multimeter, device display screens, or obtained via labeling. Liquid nicotine concentration was obtained via labeling or through chemical analysis. Predicted nicotine flux, nicotine yield, and TPM associated with 10 4-second puffs were calculated for participants' primary devices. RESULTS: Participants' primary devices were box mods (42.9%), disposable vapes (20.2%), and pod mods (36.9%). Most participants (65.5%) reported not knowing their primary device wattage. Rebuildable/box mods had the greatest power range (11.1-120.0 W); pod mod power also varied considerably (4.1-21.7 W). Unlike device wattage, most participants (95.2%) reported knowing their liquid nicotine concentration, which ranged from 3.0 to 86.9 mg/ml (M = 36.0, SD = 29.3). Predicted nicotine flux varied greatly across products (range =12.0-160.1 µg/s, M = 85.6 µg/s, SD = 34.3). Box mods had the greatest variability in wattage and predicted nicotine flux, nicotine yield, and TPM yield. CONCLUSIONS: ECIG device and liquid heterogeneity influence nicotine and other toxicant emissions. Better measurement of ECIG device and liquid characteristics is needed to understand nicotine and toxicant emissions and to inform regulatory policy. IMPLICATIONS: ECIG device and liquid heterogeneity cause great variability in nicotine flux and toxicants emitted. These data demonstrate the need to examine device and liquid characteristics to develop empirically informed, health-promoting regulatory policies. Policies may include setting product standards such that ECIG products cannot (1) have nicotine fluxes much greater than that of a cigarette to decrease the risk of dependence, (2) have nicotine fluxes that are very low and thus would have minimal appeal to cigarette smokers and may serve as starter products for youth or nontobacco users, and (3) emit large amounts of particulate matter and other toxicants.

Reading, sharing, creating Pinterest recipes: Parental engagement and feeding behaviors.

Pediatric overweight and obesity are associated with serious health concerns both during childhood and in adulthood. Visual social media platform Pinterest is often used to curate recipe content, but little is known about how, if at all, parents use the platform as a resource for meal planning for their families. This study focused on (1) describing how Pinterest using parents use the platform related to recipe searches and meal planning and (2) examining the association between parental feeding behaviors and frequency of Pinterest use related to recipes. Survey research firm Qualtrics was used to collect a nationwide sample of 659 Pinterest-using parents with children between ages 3-11 years of age. Data collection was initiated and completed in February of 2019. Measures included both parent and child demographics, Pinterest recipe use and engagement, and parental feeding practices using the Child Feeding Questionnaire (CFQ). Results showed that 26.9% of the respondents reported using Pinterest daily to read recipes, 17.9% to share recipes; 14.9% to comment on recipes on Pinterest; 10.3% reported creating and posting new recipes; and 13.8% mentioned making a recipe they find on Pinterest daily. Pinterest engagement was significantly negatively associated with parental age and with income insecurity, while positively associated with level of education. Hispanic participants showed higher levels of engagement as compared to White non-Hispanic participants. Among the CFQ subscales, Pressure and Perceived responsibility were significantly positively associated with Pinterest engagement while Monitoring and Restriction were not.

An epigenome-wide association study of child appetitive traits and DNA methylation.

The etiology of childhood appetitive traits is poorly understood. Early-life epigenetic processes may be involved in the developmental programming of appetite regulation in childhood. One such process is DNA methylation (DNAm), whereby a methyl group is added to a specific part of DNA, where a cytosine base is next to a guanine base, a CpG site. We meta-analyzed epigenome-wide association studies (EWASs) of cord blood DNAm and early-childhood appetitive traits. Data were from two independent cohorts: the Generation R Study (n = 1,086, Rotterdam, the Netherlands) and the Healthy Start study (n = 236, Colorado, USA). DNAm at autosomal methylation sites in cord blood was measured using the Illumina Infinium HumanMethylation450 BeadChip. Parents reported on their child's food responsiveness, emotional undereating, satiety responsiveness and food fussiness using the Children's Eating Behaviour Questionnaire at age 4-5 years. Multiple regression models were used to examine the association of DNAm (predictor) at the individual site- and regional-level (using DMRff) with each appetitive trait (outcome), adjusting for covariates. Bonferroni-correction was applied to adjust for multiple testing. There were no associations of DNAm and any appetitive trait when examining individual CpG-sites. However, when examining multiple CpGs jointly in so-called differentially methylated regions, we identified 45 associations of DNAm with food responsiveness, 7 associations of DNAm with emotional undereating, 13 associations of DNAm with satiety responsiveness, and 9 associations of DNAm with food fussiness. This study shows that DNAm in the newborn may partially explain variation in appetitive traits expressed in early childhood and provides preliminary support for early programming of child appetitive traits through DNAm. Investigating differential DNAm associated with appetitive traits could be an important first step in identifying biological pathways underlying the development of these behaviors.

Imaging recommendations and algorithms for pediatric tuberculosis: part 1-thoracic tuberculosis.

Tuberculosis (TB) remains a global health problem and is the second leading cause of death from a single infectious agent, behind the novel coronavirus disease of 2019. Children are amongst the most vulnerable groups affected by TB, and imaging manifestations are different in children when compared to adults. TB primarily involves the lungs and mediastinal lymph nodes. Clinical history, physical examination, laboratory examinations and various medical imaging tools are combined to establish the diagnosis. Even though chest radiography is the accepted initial radiological imaging modality for the evaluation of children with TB, this paper, the first of two parts, aims to discuss the advantages and limitations of the various medical imaging modalities and to provide recommendations on which is most appropriate for the initial diagnosis and assessment of possible complications of pulmonary TB in children. Practical, evidence-based imaging algorithms are also presented.

Imaging recommendations and algorithms for pediatric tuberculosis: part 2-extrathoracic tuberculosis.

Despite advances in diagnosis and treatment in recent years, tuberculosis (TB) remains a global health concern. Children are amongst the most vulnerable groups affected by this disease. Although TB primarily involves the lungs and mediastinal lymph nodes, it can affect virtually any organ system of the body. Along with clinical history combined with physical examination and laboratory tests, various medical imaging tools help establish the diagnosis. Medical imaging tests are also helpful for follow-up during therapy, to assess complications and exclude other underlying pathologies. This article aims to discuss the utility, strengths and limitations of medical imaging tools in the evaluation of suspected extrathoracic TB in the pediatric population. Imaging recommendations for the diagnosis will be presented along with practical and evidence-based imaging algorithms to serve as a guide for both radiologists and clinicians.

The relation between hypoxia and proliferation biomarkers with radiosensitivity in locally advanced laryngeal cancer.

PURPOSE: Treatment decision-making in advanced-stage laryngeal squamous cell carcinoma (LSCC) is difficult due to the high recurrence rates and the desire to preserve laryngeal functions. New predictive markers for radiosensitivity are needed to facilitate treatment choices. In early stage glottic LSCC treated with primary radiotherapy, expression of hypoxia (HIF-1α and CA-IX) and proliferation (Ki-67) tumour markers showed prognostic value for local control. The objective of this study is to examine the prognostic value of tumour markers for hypoxia and proliferation on locoregional recurrent disease and disease-specific mortality in a well-defined cohort of patients with locally advanced LSCC treated with primary, curatively intended radiotherapy. METHODS: In pre-treatment biopsy tissues from a homogeneous cohort of 61 patients with advanced stage (T3-T4, M0) LSCC primarily treated with radiotherapy, expression of HIF-1α, CA-IX and Ki-67 was evaluated with immunohistochemistry. Demographic data (age and sex) and clinical data (T- and N-status) were retrospectively collected from the medical records. Cox regression analysis was performed to assess the relation between marker expression, demographic and clinical data, and locoregional recurrence and disease-specific mortality. RESULTS: Patients with high expression of HIF-1α developed significantly more often a locoregional recurrence (39%) compared to patients with a low expression (21%) (p = 0.002). The expression of CA-IX and Ki-67 showed no association with locoregional recurrent disease. HIF-1α, CA-IX and Ki-67 were not significantly related to disease-specific mortality. Clinical N-status was an independent predictor of recurrent disease (p < 0.001) and disease-specific mortality (p = 0.003). Age, sex and T-status were not related to locoregional recurrent disease or disease-specific mortality. CONCLUSION: HIF-1α overexpression and the presence of regional lymph node metastases at diagnosis were independent predictors of locoregional recurrent disease after primary treatment with curatively intended radiotherapy in patients with locally advanced LSCC.

All-polyethylene versus metal-backed tibial components in total knee arthroplasty: a meta-analysis of randomized controlled trials.

OBJECTIVES: The design of tibial trays for total knee arthroplasty (TKA) has been a topic of research for several decades. Although all-polyethylene trays were developed to address issues such as osteolysis and to enhance the longevity of the prosthesis, as well as knee range of motion, metal-backed designs have remained the most commonly used type of prosthesis. This meta-analysis aimed to compare the clinical, radiological, and survival outcomes of both designs. METHODS: Five databases were searched from inception until October 1, 2020, for randomized controlled trials (RCTs) that compared the outcomes of all-polyethylene and metal-backed tibial components in TKA. The outcomes of interest included range of motion, knee society score, stairs climbing scores, radiostereographic analysis, survivorship and complication. This review was conducted in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Risk of bias was assessed using the Newcastle-Ottawa tool. RESULTS: A total of 14 RCTs with 1367 TKA were included with a mean age of - years and - years for all-polyethylene and metal-backed tibial components groups, respectively. All-polyethylene group demonstrated statistically significant differences in five-year survivorship (OR 0.27; 95% CI 0.10-0.75; p value 0.01) and stairs climbing score (OR - 2.07; 95% CI - 3.27-0.87; p value 0.0007) when compared to the metal-backed group. The metal-backed design was significantly more radiographically stable in anterior-posterior, varus-valgus, and internal-external rotations at the 2-year follow-up compared to all-polyethylene tibias (OR - 0.09; 95% CI - 0.16 to - 0.02; p value 0.02) as per the pooled radiostereographic analysis. However, ten-year survivorship (OR 0.92; 95% CI 0.53-1.60; p value 0.78), range of motion (OR - 0.57; 95% CI - 2.00-0.85, p value 0.43), knee society scores (OR 1.38; 95% CI - 0.47-3.23, p value 0.14), and complications (OR 0.83; 95% CI 0.5-1.39, p value 0.48) were comparable between both groups. CONCLUSIONS: While this meta-analysis suggests that all-polyethylene tibial components in total knee arthroplasty may offer advantages over metal-backed components in terms of five-year survivorship, and stairs climbing score, this finding should be considered in the context of potential confounding factors. Nonetheless, based on the results, the all-polyethylene implant should be considered a viable choice for primary knee replacement. LEVEL OF EVIDENCE: I.

Sleep onset, duration, or regularity: which matters most for child adiposity outcomes?

BACKGROUND/OBJECTIVES: Sleep measures, such as duration and onset timing, are associated with adiposity outcomes among children. Recent research among adults has considered variability in sleep and wake onset times, with the Sleep Regularity Index (SRI) as a comprehensive metric to measure shifts in sleep and wake onset times between days. However, little research has examined regularity and adiposity outcomes among children. This study examined the associations of three sleep measures (i.e., sleep duration, sleep onset time, and SRI) with three measures of adiposity (i.e., body mass index [BMI], waist circumference, and waist-to-height ratio [WHtR]) in a pediatric sample. SUBJECTS/METHODS: Children (ages 4-13 years) who were part of the U.S. Newborn Epigenetic STudy (NEST) participated. Children (N = 144) wore an ActiGraph for 1 week. Sleep measures were estimated from actigraphy data. Weight, height, and waist circumference were measured by trained researchers. BMI and WHtR was calculated with the objectively measured waist and height values. Multiple linear regression models examined associations between child sleep and adiposity outcomes, controlling for race/ethnicity, child sex, age, mothers' BMI and sleep duration. RESULTS: When considering sleep onset timing and duration, along with demographic covariates, sleep onset timing was not significantly associated with any of the three adiposity measures, but a longer duration was significantly associated with a lower BMI Z-score (ß = -0.29, p < 0.001), waist circumference (ß = -0.31, p < 0.001), and WHtR (ß = -0.38, p < 0.001). When considering SRI and duration, duration remained significantly associated with the adiposity measures. The SRI and adiposity associations were in the expected direction, but were non-significant, except the SRI and WHtR association (ß = -0.16, p = 0.077) was marginally non-significant. CONCLUSIONS: Sleep duration was consistently associated with adiposity measures in children 4-13 years of age. Pediatric sleep interventions should focus first on elongating nighttime sleep duration, and examine if this improves child adiposity outcomes.

Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation.

Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2-4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.

Long-Term Risk of Clinical Progression Utilizing Magnetic Resonance Imaging Findings of Locally Recurrent Prostate Cancer in Patients with Biochemical Recurrence following Radical Prostatectomy.

PURPOSE: Our goal was to evaluate the long-term prognostic value of magnetic resonance imaging of the prostatectomy bed in patients with biochemical recurrence after radical prostatectomy for prostate cancer. MATERIALS AND METHODS: Men with biochemical recurrence after radical prostatectomy who were studied by prostatectomy bed magnetic resonance imaging for suspected local recurrence were retrospectively evaluated. Locally recurrent tumors were noted and measured from imaging reports. Patients with nodal/bone lesions at the time of imaging were excluded. Kaplan-Meier and Cox regression analyses were used to assess systemic progression-free and prostate cancer-specific survival. RESULTS: A total of 896 men were enrolled and the imaging positive and negative groups for local recurrent tumor consisted of 441 and 455 men, respectively. On univariate analysis, preoperative prostate specific antigen (p=0.02), clinical tumor stage (p=0.006), pathological Gleason score from prostatectomy (p=0.02), subsequent salvage radiotherapy (p <0.001), biochemical recurrence to magnetic resonance imaging time interval (p <0.001), age at magnetic resonance imaging (p=0.047) and prostate specific antigen at magnetic resonance imaging (p <0.001) were significantly different between magnetic resonance imaging positive and negative groups. Patients with negative magnetic resonance imaging results had worse systemic progression-free survival rates (p=0.025) and better prostate cancer-specific survival (p=0.016) than those with recurrence. Larger lesion size significantly increased risk of prostate cancer death (hazard ratio: 1.07; p <0.001). On multivariable analysis, pathological Gleason scores ≥7 were independent prognostic factors of systemic progression (p <0.05). CONCLUSIONS: Prostatectomy bed magnetic resonance imaging provides long-term prognostic information for the evaluation of patients with biochemical recurrence after prostatectomy. Post-prostatectomy patients with recurrent lesions on imaging had longer progression-free survival but shorter prostate cancer-specific survival compared to those without lesions. Additionally, those with larger lesions were associated with poorer cancer-specific survival.

Shuffle the Decks: Children Are Sensitive to Incidental Nonrandom Structure in a Sequential-Choice Task.

As children age, they can learn increasingly complex features of environmental structure-a key prerequisite for adaptive decision-making. Yet when we tested children (N = 304, 4-13 years old) in the Children's Gambling Task, an age-appropriate variant of the Iowa Gambling Task, we found that age was negatively associated with performance. However, this paradoxical effect of age was found only in children who exhibited a maladaptive deplete-replenish bias, a tendency to shift choices after positive outcomes and repeat choices after negative outcomes. We found that this bias results from sensitivity to incidental nonrandom structure in the canonical, deterministic forms of these tasks-and that it would actually lead to optimal outcomes if the tasks were not deterministic. Our results illustrate that changes in decision-making across early childhood reflect, in part, increasing sensitivity to environmental structure.