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In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53-loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53-loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53-loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53-loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial (N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53-loss phenocopy tumors compared to non-TP53-loss phenocopy tumors (64% vs. 28%). The TP53-loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts. [ABSTRACT FROM AUTHOR]

We aimed to determine the prevalence and outcomes for forced vital capacity percent predicted (FVCpp) decline among patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). We identified patients with RA-ILD in the Mass General Brigham Healthcare system. RA-ILD diagnosis was determined by review of high-resolution computed tomography (HRCT) imaging by up to three thoracic radiologists. We abstracted FVCpp measurements, covariates, lung transplant, and ILD-related death from the medical record. We employed a relative FVCpp decline cutoff of > 10% within 24 months. We also used a group-based trajectory model to obtain patterns of change from RA-ILD diagnosis. We then assessed for associations of each FVC decline definition with risk of lung transplant or ILD-related death using multivariable logistic regression. We analyzed 172 patients with RA-ILD with a median of 6 FVCpp measurements per patient over 6.5 years of follow-up (mean age 62.2 years, 36% male). There were seven (4%) lung transplants and 44 (26%) ILD-related deaths. Ninety-eight (57%) patients had relative decline of FVCpp by > 10% in 24 months. We identified three trajectory groups of FVCpp change: rapidly declining (n = 24/168 [14%]), slowly declining (n = 90/168 [54%]), and stable/improving (n = 54/168 [32%]). The rapidly declining group and FVCpp > 10% had adjusted odds ratios (aOR) for lung transplant/ILD-related death of 19.2 (95%CI 4.9 to 75.5) and 2.8 (95%CI 1.3 to 6.1) respectively. Over half of patients with RA-ILD had declining FVCpp. The different trajectory patterns demonstrate the importance of FVC monitoring for identifying patients at the highest risk of poor outcomes. Key Points • Over half of patients with RA-ILD had declining FVCpp over a median of 6.5 years of follow-up. • The rapidly declining FVCpp trajectory group had stronger associations with lung transplant and ILD-related death compared to those with FVCpp decline by > 10%. • Clinicians can employ FVC monitoring to proactively treat patients who are at risk of poor outcomes. [ABSTRACT FROM AUTHOR]

Histopathologic diagnosis and classification of cancer plays a critical role in guiding treatment. Advances in next-generation sequencing have ushered in new complementary molecular frameworks. However, existing approaches do not independently assess both site-of-origin (e.g. prostate) and lineage (e.g. adenocarcinoma) and have minimal validation in metastatic disease, where classification is more difficult. Utilizing gradient-boosted machine learning, we developed ATLAS, a pair of separate AI Tumor Lineage and Site-of-origin models from RNA expression data on 8249 tumor samples. We assessed performance independently in 10,376 total tumor samples, including 1490 metastatic samples, achieving an accuracy of 91.4% for cancer site-of-origin and 97.1% for cancer lineage. High confidence predictions (encompassing the majority of cases) were accurate 98–99% of the time in both localized and remarkably even in metastatic samples. We also identified emergent properties of our lineage scores for tumor types on which the model was never trained (zero-shot learning). Adenocarcinoma/sarcoma lineage scores differentiated epithelioid from biphasic/sarcomatoid mesothelioma. Also, predicted lineage de-differentiation identified neuroendocrine/small cell tumors and was associated with poor outcomes across tumor types. Our platform-independent single-sample approach can be easily translated to existing RNA-seq platforms. ATLAS can complement and guide traditional histopathologic assessment in challenging situations and tumors of unknown primary. ATLAS is a pair of AI Tumor Lineage and Site-of-origin machine learning models, that can accurately classify both primary and metastatic tumors using high-throughput RNA expression data and can identify de-differentiated anaplastic tumors. [ABSTRACT FROM AUTHOR]

We performed a deep proteogenomic analysis of bulk tumor and laser microdissection enriched tumor cell populations from high-grade serous ovarian cancer (HGSOC) tissue specimens spanning a broad spectrum of purity. We identified patients with longer progression-free survival had increased immune-related signatures and validated proteins correlating with tumor-infiltrating lymphocytes in 65 tumors from an independent cohort of HGSOC patients, as well as with overall survival in an additional 126 HGSOC patient cohort. We identified that homologous recombination deficient (HRD) tumors are enriched in pathways associated with metabolism and oxidative phosphorylation that we validated in independent patient cohorts. We further identified that polycomb complex protein BMI-1 is elevated in HR proficient (HRP) tumors, that elevated BMI-1 correlates with poor overall survival in HRP but not HRD HGSOC patients, and that HRP HGSOC cells are uniquely sensitive to BMI-1 inhibition. [ABSTRACT FROM AUTHOR]

For American Indians and Alaska Native (AIAN) and other communities of color, experiences with discrimination and historical trauma may contribute to healthcare system distrust and negatively affect health care decisions, including vaccination. A saturated path analysis was conducted to examine the direct and indirect associations of thoughts regarding historical losses (of culture, language, and traditional ways) and AIAN racial discrimination with historical loss associated distress, healthcare system distrust, and COVID-19 vaccine hesitancy among AIAN college students (N = 391). Historical loss thoughts and experiences with racial discrimination were strongly associated with each other, and both were uniquely associated with greater historical loss associated distress. In turn, historical loss associated distress was associated with greater healthcare system distrust, which in turn was associated with greater likelihood of being COVID-19 vaccine hesitant. While further research is needed, the findings suggest that to address health disparities for AIAN people it is necessary to consider how to best overcome healthcare system distrust and factors that contribute to it, including historical trauma and contemporary experiences with discrimination. [ABSTRACT FROM AUTHOR]

After decades of work, several interventions to prevent severe respiratory syncytial virus (RSV) disease in high-risk infant and older adult populations have finally been approved. There were many setbacks along the road to victory. In this review, I will discuss the impact of RSV on human health and how structure-based vaccine design set the stage for numerous RSV countermeasures to advance through late phase clinical evaluation. While there are still many RSV countermeasures in preclinical and early-stage clinical trials, this review will focus on products yielding long-awaited efficacy results. Finally, I will discuss some challenges and next steps needed to declare a global victory against RSV. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV), an arbovirus transmitted by mosquitoes, was identified as a cause of congenital disease during a major outbreak in the Americas in 2016. Vaccine design strategies relied on limited available isolate sequence information due to the rapid response necessary. The first-generation ZIKV mRNA vaccine, mRNA-1325, was initially generated and, as additional strain sequences became available, a second mRNA vaccine, mRNA-1893, was developed. Herein, we compared the immune responses following mRNA-1325 and mRNA-1893 vaccination and reported that mRNA-1893 generated comparable neutralizing antibody titers to mRNA-1325 at 1/20th of the dose and provided complete protection from ZIKV challenge in non-human primates. In-depth characterization of these vaccines indicated that the observed immunologic differences could be attributed to a single amino acid residue difference that compromised mRNA-1325 virus-like particle formation. [ABSTRACT FROM AUTHOR]

Substantial productivity increases have been reported when incentives are framed as losses rather than gains. Loss-framed contracts have also been reported to be preferred by workers. The results from our meta-analysis and real-effort experiment challenge these claims. The meta-analysis' summary effect size of loss framing is a 0.16 SD increase in productivity. Whereas the summary effect size in laboratory experiments is a 0.33 SD, the summary effect size from field experiments is 0.02 SD. We detect evidence of publication biases among laboratory experiments. In a new laboratory experiment that addresses prior design weaknesses, we estimate an effect size of 0.12 SD. This result, in combination with the meta-analysis, suggests that the difference between the effect size estimates in laboratory and field experiments does not stem from the limited external validity of laboratory experiments, but may instead stem from a mix of underpowered laboratory designs and publication biases. Moreover, in our experiment, most workers preferred the gain-framed contract and the increase in average productivity is only detectable in the subgroup of workers (~ 20%) who preferred the loss-framed contracts. Based on the results from our experiment and meta-analysis, we believe that behavioral scientists should better assess preferences for loss-framed contracts and the magnitude of their effects on productivity before advocating for greater use of such contracts among private and public sector actors. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus is a leading cause of morbidity and mortality in children, due in part to their distinct immune system, characterized by impaired induction of Th 1 immunity. Here we show application of cationic adjuvant formulation CAF08, a liposomal vaccine formulation tailored to induce Th 1 immunity in early life via synergistic engagement of Toll-like Receptor 7/8 and the C-type lectin receptor Mincle. We apply quantitative phosphoproteomics to human dendritic cells and reveal a role for Protein Kinase C-δ for enhanced Th1 cytokine production in neonatal dendritic cells and identify signaling events resulting in antigen cross-presentation. In a murine in vivo model a single immunization at birth with CAF08-adjuvanted RSV pre-fusion antigen protects newborn mice from RSV infection by induction of antigen-specific CD8+ T-cells and Th1 cells. Overall, we describe a pediatric adjuvant formulation and characterize its mechanism of action providing a promising avenue for development of early life vaccines against RSV and other respiratory viral pathogens. Respiratory syncytial virus is a major pathogen with burden observed and associated with childhood infection. Here the authors characterise a cationic adjuvant formulation and show single immunisation results in protection in a murine neonate model of respiratory syncytial virus infection. [ABSTRACT FROM AUTHOR]

Purpose of Review: To review emerging treatments for thyroid eye disease (TED) associated extraocular muscle myopathy and dysthyroid optic neuropathy (DON). Recent Findings: Emerging targeted biologic therapies may alter the disease course in TED. Teprotumumab, a type I insulin-like growth factor receptor inhibitor, is the most recent addition to the treatments available for TED-associated extraocular muscle myopathy causing diplopia. Small studies also suggest a potential therapeutic benefit for DON. Various recent studies have also expanded our knowledge on conventional TED therapies. Summary: The therapeutic landscape of TED and its sequelae has evolved in recent years. New targeted therapies have the potential to reduce the extraocular muscle and orbital volume expansion which can lead to diplopia and vision loss from optic nerve compression. Longer term efficacy and durability data is needed to determine the role biologics, such as teprotumumab, should play in the treatment of TED patients compared to the current standard of care. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix gene expression. Treatment of RA-ILD fibroblasts with the proteoglycan syndecan-2 (SDC2) yielded similar antifibrotic effects through regulation of PAD2 expression, phosphoinositide 3-kinase/Akt signaling, and Sp1 activation in a CD148-dependent manner. Furthermore, SDC2-transgenic mice exposed to bleomycin-induced lung injury in an inflammatory arthritis model expressed lower levels of PAD2 and were protected from the development of pulmonary fibrosis. Together, our results support a SDC2-sensitive profibrotic role for PAD2 in RA-ILD fibroblasts and identify PAD2 as a promising therapeutic target of RA-ILD. [ABSTRACT FROM AUTHOR]

Brain metastases comprise 40% of all metastatic tumours and breast tumours are among the tumours that most commonly metastasise to the brain, the role that epigenetic gene dysregulation plays in this process is not well understood. We carried out 450 K methylation array analysis to investigate epigenetically dysregulated genes in breast to brain metastases (BBM) compared to normal breast tissues (BN) and primary breast tumours (BP). For this, we referenced 450 K methylation data for BBM tumours prepared in our laboratory with BN and BP from The Cancer Genome Atlas. Experimental validation on our initially identified genes, in an independent cohort of BP and in BBM and their originating primary breast tumours using Combined Bisulphite and Restriction Analysis (CoBRA) and Methylation Specific PCR identified three genes (RP11-713P17.4, MIR124-2, NUS1P3) that are hypermethylated and three genes (MIR3193, CTD-2023M8.1 and MTND6P4) that are hypomethylated in breast to brain metastases. In addition, methylation differences in candidate genes between BBM tumours and originating primary tumours shows dysregulation of DNA methylation occurs either at an early stage of tumour evolution (in the primary tumour) or at a later evolutionary stage (where the epigenetic change is only observed in the brain metastasis). Epigentic changes identified could also be found when analysing tumour free circulating DNA (tfcDNA) in patient's serum taken during BBM biopsies. Epigenetic dysregulation of RP11-713P17.4, MIR3193, MTND6P4 are early events suggesting a potential use for these genes as prognostic markers. [ABSTRACT FROM AUTHOR]

Plant microbiomes have been extensively studied for their agricultural relevance on growth promotion and pathogenesis, but little is known about their role as part of the diet when fresh fruits and vegetables are consumed raw. Most studies describing these communities are based on 16S rRNA gene amplicon surveys, limiting our understanding of the taxonomic resolution at the species level and functional capabilities. In this study, we characterized microbes colonizing tomatoes, spinach, brined olives, and dried figs using shotgun metagenomics. We recovered metagenome-assembled genomes of novel lactic acid bacteria from green olives and identified high intra- and inter-specific diversity of Pseudomonas in tomatoes. All samples were colonized by Pseudomonas, consistent with other reports with distinct community structure. Functional characterization showed the presence of enzymes involved in vitamin and short chain fatty acid metabolism and degradation of diverse carbohydrate substrates including plant fibers. The dominant bacterial members were isolated, sequenced, and mapped to its metagenome confirming their identity and indicating the microbiota is culturable. Our results reveal high genetic diversity, previously uncultured genera, and specific functions reflecting a likely plant host association. This study highlights the potential that plant microbes can play when consumed as part of our diet and proposes these as transient contributors to the gut microbiome. [ABSTRACT FROM AUTHOR]

Background: Furniture and television tip-over injuries are an important source of injury to children, especially those younger than 6 years old. A current epidemiologic evaluation of tip-over injuries is needed, especially considering changes in the voluntary safety standard for clothing storage units (CSUs) and the shift in the consumer market from cathode ray tube to flat-screen televisions (TVs), and a decline in household TV ownership during recent years. The objective of this study is to update our understanding of the epidemiologic characteristics and trends of furniture (especially CSU) and TV tip-over injuries treated in United States emergency departments among children < 18 years old. Methods: This study retrospectively analyzed data from the National Electronic Injury Surveillance System from 1990 to 2019. Trends in population-based rates were evaluated with regression techniques. All numbers of cases are expressed as national estimates. Results: An estimated 560,203 children < 18 years old were treated in United States emergency departments for furniture or TV tip-over injuries during the 30-year study period, averaging 18,673 children annually. CSUs were involved in 17.2% (n = 96,321) of tip-overs, and TVs accounted for 41.1% (n = 230,325), which included 16,904 tip-overs (3.0%) that involved both a CSU and TV. The rate of furniture and TV tip-over injuries among children < 18 years old increased by 53.8% (p < 0.0001) from 1990 to 2010, and then decreased by 56.8% (p < 0.0001) from 2010 to 2019. Almost half (47.0%) of injuries occurred to the head/neck; 3.4% of children were admitted to the hospital. Children < 6 years old accounted for 69.9% of furniture and TV tip-over injuries overall; they accounted for 82.5% of CSU-related and 74.7% of TV-related tip-over injuries. Conclusions: Despite the decline in tip-over injuries since 2010, more should be done to prevent these injuries, especially among children < 6 years old, because the number of injuries remains high, outcomes can be life-threatening, and effective prevention strategies are known. Safety education, warning labels, and promotion and use of tip restraint devices, while important, are not a substitute for strengthening and enforcing the stability requirements for CSUs and TVs. [ABSTRACT FROM AUTHOR]

Joint engagement involves a child coordinating their attention between a person and a shared event. Children with autism present with impaired joint engagement. Playdates are a common way that children socially engage yet have been largely overlooked in the social skills literature. Requesting skills have been conceptualized as pivotal, producing collateral effects. In the current study, we conducted a secondary analysis of a single-case design that evaluated a parent-implemented playdate intervention focused on supporting children and peers to request and respond to one another during games. We examined the collateral effects of the playdate intervention on joint engagement. Two children demonstrated gains in joint engagement with a peer, and the third exhibited variable changes. Implications for future research are discussed. [ABSTRACT FROM AUTHOR]

Multiple studies show an increased prevalence of gambling disorder among African Americans compared to whites. However, few studies take an analytic approach to understanding differences in risk factors by race/ethnicity. Income is inversely associated with gambling disorder; we hypothesized that this association would vary by race/ethnicity. The main objective was to evaluate whether the association between income and gambling disorder varies by race/ethnicity. With data from the baseline visit of a prospective cohort study, Prevention and Etiology of Gambling Addiction Study in the United States, we used multivariable logistic regression analysis to determine whether the association between income and gambling disorder varies by race/ethnicity. 1164 participants were included in the final analyses. Measures included: demographics (age, sex, race/ethnicity, education, employment, annual household income), veteran status, marital status, homelessness, smoking, substance abuse, alcohol abuse, marijuana use, and lifetime gambling disorder diagnosis as derived from Alcohol Use Disorder and Associated Disabilities Interview Schedule. There was no evidence of effect modification by race/ethnicity in the association between income and gambling disorder (global p value = 0.17). Income was associated with increased odds of gambling disorder, but only for those with low income (< $15,000; OR 2.27, 95% CI 1.46, 3.53). There was no evidence that the effect of income on gambling disorder varies by race/ethnicity. For all race/ethnicities combined, low income was associated with significantly increased odds of gambling disorder (OR 2.27, 95% CI 1.46, 3.53). Further research is needed to better understand racial/ethnic differences in gambling disorder. [ABSTRACT FROM AUTHOR]

Background: As the cost of health care increases in the US, focus has been placed upon efficiency, cost reduction, and containment of spending. Operating room costs play a significant role in this spending. We investigated whether surgeon education and universal preference cards can have an impact on reducing the disposable supply costs for common laparoscopic general surgery procedures.Methods: General surgeons at two institutions participated in an educational session about the costs of the operative supplies used to perform laparoscopic appendectomies and cholecystectomies. All the surgeons at one institution agreed upon a universal preference card, with other supplies opened only by request. At the other, no universal preference cards were created, and surgeons were free to modify their own existing preference cards. Case cost data for these procedures were collected for each institution pre- (July 2014-December 2014) and post-intervention (February 2015-November 2017).Results: At the institution with an education only program, there was no statistically significant change in supply costs after the intervention. At the institution that intervened with the combined education and universal preference card program, there was a statistically significant supply cost decrease for these common laparoscopic procedures combined. This significant cost decrease persisted for each appendectomies and cholecystectomies when analyzed independently as well (p = 0.001 and p < 0.001 respectively).Conclusions: In this study, surgeon education alone was not effective in reducing operating room disposable supply costs. Surgeon education, combined with the implementation of universal preference cards, significantly maintains reductions in operating room supply costs. As health care costs continue to increase in the US and internationally, universal preference cards can be an effective tool to contain cost for common laparoscopic general surgery procedures. [ABSTRACT FROM AUTHOR]

Automated neuroimaging methods like FreeSurfer (https://surfer.nmr.mgh.harvard.edu/) have revolutionized quantitative neuroimaging analyses. Such analyses provide a variety of metrics used for image quantification, including magnetic resonance imaging (MRI) volumetrics. With the release of FreeSurfer version 6.0, it is important to assess its comparability to the widely-used previous version 5.3. The current study used data from the initial 249 participants in the ongoing Chronic Effects of Neurotrauma Consortium (CENC) multicenter observational study to compare the volumetric output of versions 5.3 and 6.0 across various regions of interest (ROI). In the current investigation, the following ROIs were examined: total intracranial volume, total white matter volume, total ventricular volume, total gray matter volume, and right and left volumes for the thalamus, pallidum, putamen, caudate, amygdala and hippocampus. Absolute ROI volumes derived from FreeSurfer 6.0 differed significantly from those obtained using version 5.3. We also employed a clinically-based evaluation strategy to compare both versions in their prediction of age-mediated volume reductions (or ventricular increase) in the aforementioned structures. Statistical comparison involved both general linear modeling (GLM) and random forest (RF) methods, where cross-validation error was significantly higher using segmentations from FreeSurfer version 5.3 versus version 6.0 (GLM: t = 4.97, df = 99, p value = 2.706e-06; RF: t = 4.85, df = 99, p value = 4.424e-06). Additionally, the relative importance of ROIs used to predict age using RFs differed between FreeSurfer versions, indicating substantial differences in the two versions. However, from the perspective of correlational analyses, fitted regression lines and their slopes were similar between the two versions, regardless of version used. While absolute volumes are not interchangeable between version 5.3 and 6.0, ROI correlational analyses appear to yield similar results, suggesting the interchangeability of ROI volume for correlational studies. [ABSTRACT FROM AUTHOR]

Purpose: Forward progress in cancer treatment has resulted in fewer adverse consequences of cancer during and after treatment, offering employed cancer patients the possibility of continuing to work during treatment, returning to work after treatment, or implementing a combination of strategies to manage the cancer-work interface. Yet, much of the research on cancer and employment examines return to work as the primary outcome, neglecting to consider the circumstances of survivors who maintain employment while engaged in active treatment. We introduce the Cancer-Work Management Framework (CWMF), a conceptual framework for understanding the cancer and job demands survivors who continue to work during active treatment experience and how cancer and job resources and strategies could promote cancer-work fit and ultimately optimize employment and health outcomes.Methods: We provide an overview of the research describing the cancer-work management experiences of survivors who maintain employment during active treatment and summarize the theories that informed the CWMF including ecological systems, boundary-spanning, and job demands and resources theories.Results: The paper presents a description of the components of the CWMF which include cancer demands, cancer care resources and strategies, work demands, and workplace resources. We also describe a process-cancer-work fit-that reflects the interplay between demands and resources influence employment and health outcomes.Conclusions: Future research directions for developing knowledge about the cancer-work management process are proposed with suggestions for study of how cancer and job demands influence cancer treatment and employment decisions. [ABSTRACT FROM AUTHOR]

Introduction: Limitations in inflammatory bowel disease (IBD) care necessitate greater patient activation and self-efficacy, measures associated with positive health outcomes.Methods: We assessed change in patient activation and general self-efficacy from baseline to 12 months through our TELEmedicine for IBD trial, a multicenter, randomized controlled trial consisting of a web-based monitoring system that interacts with participants via text messaging. A total of 222 adults with IBD who had experienced an IBD flare within 2 years prior to the trial were randomized into either a control arm that received standard care (SC) or an intervention arm that completed self-testing through the TELE-IBD system every other week (EOW) or weekly (W).Results: Changes in self-efficacy scores were not significantly different between control and experimental groups. Patient activation scores were significantly different between standard care and the TELE-IBD EOW group only (p = 0.03).Conclusions: Use of remote monitoring did not improve self-efficacy or patient activation compared to routine care. [ABSTRACT FROM AUTHOR]

Introduction: We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with abnormalities on pulmonary function tests (PFTs). Methods: We studied RA serostatus and PFT abnormalities within a RA registry. RA serostatus was assessed by research assays for cyclic citrullinated peptide (CCP) and rheumatoid factor (RF). Outcomes were abnormalities on clinically indicated PFTs, including restriction, obstruction, and diffusion abnormality. Logistic regression was used to obtain ORs and 95% CIs for the PFT abnormalities by RA serologic phenotypes independent of lifestyle and RA characteristics. Results: Among 1272 analyzed subjects, mean age was 56.3 years (SD 14.1), 82.2% were female, and 69.5% were seropositive. There were 100 subjects with abnormal PFTs. Compared with seronegativity, seropositivity was associated with increased odds of any PFT abnormality (multivariable OR 2.29, 95% CI 1.30–4.03). When analyzing type of PFT abnormality, seropositivity was also associated with restriction, obstruction, and diffusion abnormalities; multivariable ORs were 2.48 (95% CI 1.26–4.87), 3.12 (95% CI 1.28–7.61), and 2.30 (95% CI 1.09–4.83), respectively. When analyzing by CCP and RF status, the associations were stronger for RF+ than for CCP+ (any PFT abnormality OR 1.99, 95% CI 1.21–3.27 for RF+ vs. RF−; OR 1.67, 95% CI 1.03–2.69 for CCP+ vs. CCP−) with a dose effect of higher RF titer increasing odds for each PFT abnormality (p for trend < 0.05). Conclusions: Seropositive RA patients had two-fold increased risk for abnormalities on PFTs performed for clinical indications compared with seronegative RA. Patients with seropositive RA, particularly those with high-titer RF positivity, may be more likely to have obstructive and restrictive abnormalities, independent of smoking. Key points • Due to the known excess pulmonary morbidity/mortality in RA, we studied the relationship of rheumatoid arthritis (RA)-related autoantibodies with pulmonary function test (PFT) abnormalities using a large RA registry. • We evaluated whether presence and levels of cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) were associated with restriction, obstruction, and diffusion abnormalities on PFTs among 1272 subjects with RA. • Seropositivity was associated with two-fold increased risk for any PFT abnormality, independent of confounders including smoking. Higher titers of RF conferred greatest risk for all PFT outcomes: obstruction, restriction, and diffusion abnormality. • These results provide evidence that patients with RA should be closely monitored for pulmonary involvement, particularly those with high-titer RF seropositivity. [ABSTRACT FROM AUTHOR]

Children on the autism spectrum experience difficulties with social interactions, often resulting in lower quality of friendships. As such, children with autism often benefit from support with social skills, which are usually delivered in school settings. Social skills are not limited to school settings. Playdates are defined as prearranged gatherings between two children at one of their homes and are fundamental to social emotional development in childhood, providing opportunities for conversation, empathy, and friendship development. In the current scoping review, we analyzed the literature on playdates for children with autism. Twelve studies of varying methodologies qualified. Results indicate that playdates may have several positive effects for children with autism, including increased social engagement at school and reciprocal interactions with peers. Playdate interventions have involved components such as information exchange leading to shared activities, conflict avoidance and resolution, and gameplay. Continued research is needed in this emerging area. [ABSTRACT FROM AUTHOR]

Parent-implemented Naturalistic Developmental Behavioral Interventions (NDBIs), rooted from applied behavioral and developmental sciences, focus on empowering families by training and coaching natural change agents to embed evidence-based strategies during regular events or contexts (e.g., play time). No research, however, has relied on strength-based video feedback coaching within parent-implemented NDBIs while providing flexibility with self-recorded sessions. We conducted a single case multiple-baseline design across five parent-child dyads to evaluate the effects of a telepractice-based parent-training on five NDBI strategies (i.e., Follow and Imitate, Model Language, Arrange Environment, Wait Time, Reward and Expand), utilizing strength-based video feedback coaching with parents (i.e., two mothers and three fathers) of young autistic children (i.e., ages 2 to 5) on parent strategy use and child social communication. An additional coaching package (i.e., parent self-reflections, goal setting, and joint discussions) was introduced to parents who did not meet a predetermined criterion. Maintenance data were collected 2-, 4-, and 6-weeks after intervention concluded. Visual analyses, nonoverlap calculations, and standardized mean difference effect sizes indicate strong effects for parent strategy use and small, varied effects on child social communication. Maintenance of parent strategy use and child social communication varied, with most remaining at equivalent or higher levels. Parent-implemented interventions that are delivered via telepractice may continue to be successful when coaching is focused on the parents’ strengths, all coaching feedback is provided asynchronously, and families can flexibly record sessions based upon their week’s schedules rather than relying on regularly scheduled meeting times with a coach. [ABSTRACT FROM AUTHOR]

Children with autism spectrum disorder (ASD) display social-communication deficits and present with rigid and repetitive patterns of behavior and/or interests (RRBIs). Compared to interventions for social-communication skills, less attention has been given to RRBIs, especially with regard to interventions for young children. We surveyed 128 behavior analysts who implemented interventions for young children with ASD on their use of 16 practices and one assessment for the treatment of RRBIs. The majority of our sample perceived the practices to be effective in producing sustainable behavior change. Behavior analysts generally responded in the same way to items about reinforcement-based practices, punishment-based practices, and a group of commonly packaged antecedent and consequence-based package components. Implications and future directions are discussed. [ABSTRACT FROM AUTHOR]

Objective: Children with autism spectrum disorder (ASD) are at an increased risk to develop problem behavior, which can have deleterious effects on child and parental well-being. Because of this, parents are often provided with Behavioral Parent Training (BPT). However, attrition rates in BPT are high, and there is a relative dearth of research investigating factors that influence parental engagement in BPT.Methods: We ran seven semi-structured online focus groups with a total of 30 parents of children with ASD and related disabilities. Parents were interviewed in order to gain a greater understanding of variables that enable or pose barriers to parental engagement in BPT. An inductive qualitative analysis was conducted by two independent authors.Results: Our analyses revealed three themes indicating the need for (a) supportive, professional feedback; (b) accessible, flexible, and affordable training; and (c) social-emotional support and community connection in BPT for parents of children with ASD.Conclusions: Results from this study suggest that parental engagement in BPT for children with ASD may be enhanced if it is relevant to the needs of families, facilitated by responsive professionals, flexible, and readily accessible. Additionally, parents may benefit from BPT that includes social and emotional support, such as assistance connecting with other families and evidence-based strategies to manage the stress associated with parenting a child with ASD and challenging behavior. [ABSTRACT FROM AUTHOR]

To review the scientific literature examining gambling behavior in military veterans in order to summarize factors associated with gambling behavior in this population. Database searches were employed to identify articles specifically examining gambling behavior in military veterans. Cumulative search results identified 52 articles (1983-2017) examining gambling behavior in veteran populations. Articles generally fell into one or more of the following categories: prevalence, psychological profiles and psychiatric comorbidities, treatment evaluations, measurement, and genetic contributions to gambling disorder. Results from reviewed articles are presented and implications for future research discussed. Research to date has provided an excellent foundation to inform potential screening, intervention and research activities going forward. The authors suggest that a public health approach to future research endeavors would strengthen the evidence base regarding gambling in veteran populations and better inform strategies for screening, prevention and treatment. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to analyze secondary data from three mother-child dyads in order to evaluate how family photographs and training in naturalistic strategies affected the way mothers reminisce with their children with autism spectrum disorders.A secondary analysis (i.e., collateral effects) of a single-case dataset was conducted to assess the impact of family photographs and training in naturalistic strategies on the selected variables.The introduction of family photographs showed positive effects on the mother’s reminiscing style and the child’s memory responses across all dyads. Furthermore, additional improvements were observed in these areas after training and coaching in the target strategies.This study demonstrates the positive impact of using family photographs and naturalistic based strategies in joint-reminiscing conversations for mothers and children with autism spectrum disorder. The intervention improved the mothers reminiscing style and child’s memory responses, highlighting the potential value of parent-implemented interventions, especially those based on naturalistic strategies, in supporting individuals with autism spectrum disorder and their caregivers.Method: The purpose of this study was to analyze secondary data from three mother-child dyads in order to evaluate how family photographs and training in naturalistic strategies affected the way mothers reminisce with their children with autism spectrum disorders.A secondary analysis (i.e., collateral effects) of a single-case dataset was conducted to assess the impact of family photographs and training in naturalistic strategies on the selected variables.The introduction of family photographs showed positive effects on the mother’s reminiscing style and the child’s memory responses across all dyads. Furthermore, additional improvements were observed in these areas after training and coaching in the target strategies.This study demonstrates the positive impact of using family photographs and naturalistic based strategies in joint-reminiscing conversations for mothers and children with autism spectrum disorder. The intervention improved the mothers reminiscing style and child’s memory responses, highlighting the potential value of parent-implemented interventions, especially those based on naturalistic strategies, in supporting individuals with autism spectrum disorder and their caregivers.Results: The purpose of this study was to analyze secondary data from three mother-child dyads in order to evaluate how family photographs and training in naturalistic strategies affected the way mothers reminisce with their children with autism spectrum disorders.A secondary analysis (i.e., collateral effects) of a single-case dataset was conducted to assess the impact of family photographs and training in naturalistic strategies on the selected variables.The introduction of family photographs showed positive effects on the mother’s reminiscing style and the child’s memory responses across all dyads. Furthermore, additional improvements were observed in these areas after training and coaching in the target strategies.This study demonstrates the positive impact of using family photographs and naturalistic based strategies in joint-reminiscing conversations for mothers and children with autism spectrum disorder. The intervention improved the mothers reminiscing style and child’s memory responses, highlighting the potential value of parent-implemented interventions, especially those based on naturalistic strategies, in supporting individuals with autism spectrum disorder and their caregivers.Conclusion: The purpose of this study was to analyze secondary data from three mother-child dyads in order to evaluate how family photographs and training in naturalistic strategies affected the way mothers reminisce with their children with autism spectrum disorders.A secondary analysis (i.e., collateral effects) of a single-case dataset was conducted to assess the impact of family photographs and training in naturalistic strategies on the selected variables.The introduction of family photographs showed positive effects on the mother’s reminiscing style and the child’s memory responses across all dyads. Furthermore, additional improvements were observed in these areas after training and coaching in the target strategies.This study demonstrates the positive impact of using family photographs and naturalistic based strategies in joint-reminiscing conversations for mothers and children with autism spectrum disorder. The intervention improved the mothers reminiscing style and child’s memory responses, highlighting the potential value of parent-implemented interventions, especially those based on naturalistic strategies, in supporting individuals with autism spectrum disorder and their caregivers. [ABSTRACT FROM AUTHOR]

The most prevalent neurological disorders of myelin include perinatal brain injury leading to cerebral palsy in infants and multiple sclerosis in adults. Although these disorders have distinct etiologies, they share a common neuropathological feature of failed progenitor differentiation into myelin-producing oligodendrocytes and lack of myelin, for which there is an unmet clinical need. Here, we reveal that a molecular pathology common to both disorders is dysregulation of activin receptors and that activin receptor signaling is required for the majority of myelin generation in development and following injury. Using a constitutive conditional knockout of all activin receptor signaling in oligodendrocyte lineage cells, we discovered this signaling to be required for myelination via regulation of oligodendrocyte differentiation and myelin compaction. These processes were found to be dependent on the activin receptor subtype Acvr2a, which is expressed during oligodendrocyte differentiation and axonal ensheathment in development and following myelin injury. During efficient myelin regeneration, Acvr2a upregulation was seen to coincide with downregulation of Acvr2b, a receptor subtype with relatively higher ligand affinity; Acvr2b was shown to be dispensable for activin receptor-driven oligodendrocyte differentiation and its overexpression was sufficient to impair the abovementioned ligand-driven responses. In actively myelinating or remyelinating areas of human perinatal brain injury and multiple sclerosis tissue, respectively, oligodendrocyte lineage cells expressing Acvr2a outnumbered those expressing Acvr2b, whereas in non-repairing lesions Acvr2b+ cells were increased. Thus, we propose that following human white matter injury, this increase in Acvr2b expression would sequester ligand and consequently impair Acvr2a-driven oligodendrocyte differentiation and myelin formation. Our results demonstrate dysregulated activin receptor signaling in common myelin disorders and reveal Acvr2a as a novel therapeutic target for myelin generation following injury across the lifespan. [ABSTRACT FROM AUTHOR]

This paper presents a conceptual model to improve the early intervention of repetitive behavior in infants and young children with autism spectrum disorder (ASD). We include (a) a description of the trajectory of repetitive behavior in typical and atypical development and an explanation of its relation to screening and assessment and (b) a selective review of the intervention literature for rigid and repetitive patterns of behavior and interests (RRBIs) in infants and young children with ASD. These two sets of literature are used to build the rationale for a conceptual model to improve early developmentally appropriate intervention for RRBIs in ASD. The conceptual model posits that (a) increased sensitivity of measurement tools will allow for proper identification of when intervention is warranted and (b) increased research on focused interventions and dissemination of teaching protocols will improve the comprehensiveness of developmentally appropriate intervention. Finally, other areas for future research are highlighted. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the breast, cervical, ovarian, lung, and colorectal cancer literatures using a novel application of the cancer disparities grid to identify disparities along domains of the cancer continuum focusing on lesbians as a minority population.Methods: Computerized databases were searched for articles published from 1981 to present. Cumulative search results identified 51 articles related to lesbians and disparities, which were classified by domain.Results: The majority of articles identified were related to breast and cervical cancer screening. Barriers to adequate screening for both cancers include personal factors, poor patient-provider communication, and health care system factors. Tailored risk counseling has been successful in increasing lesbian's mammography and Pap screening. Ovarian, lung, and colorectal cancer have been virtually unexplored in this population. An "Adjustment to Illness/Quality of Life" domain was added to capture literature on psychosocial aspects of cancer.Conclusions: This review revealed a lack of research for specific cancers and for specific aspects of the cancer continuum. The limited number of studies identified focused on issues related to screening/prevention in cervical and breast cancers, with almost no attention to incidence, etiology, diagnosis, treatment, survival, morbidity, or mortality. We present implications for social and public health policy, research, and prevention. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to learn about the level of experience with, interest in, and desire for knowledge about integrative medicine (IM) among cancer survivors.Methods: Cancer survivors attending the 2014 National Cancer Survivors Day in Rochester, MN, were recruited to participate in a one-page survey about their ongoing health concerns and symptoms, as well as their experience with, interest in, and desire for knowledge about IM. Two-sided t test was used for univariate analyses of impact of sex, time since diagnosis, and age.Results: Among the 260 cancer survivors, 171 persons (female, 74 %; male, 26 %) completed the survey (mean age, 64.6 years). Symptoms most commonly somewhat or more bothersome were fear of recurrence (52 %), stress (43 %), fatigue (43 %), difficulty sleeping (33 %), and weight gain (31 %). The most used IM resources were exercise (75 %), improved nutrition and diet (66 %), stress management (42 %), dietary supplementation (33 %), meditation (25 %), and massage (22 %). Older patients (age, ≥65 years) were less experienced with, interested in, and desiring of knowledge about IM techniques. Sex and time since diagnosis were not strongly predictive of most survey response categories.Conclusions: Cancer survivors have adverse effects for years into survivorship. They use and express interest in various IM techniques to help manage symptoms. It is critical that oncology providers help survivors address ongoing health concerns. Education about and access to evidence-based IM techniques may have important roles in comprehensive cancer survivorship programs. [ABSTRACT FROM AUTHOR]

Damage in continuous fiber CMCs with weakly bonded fiber-matrix interfaces evolves in several stages that span multiple length scales. Comprehensive damage characterization necessitates identifying how damage initiates as well as how it accumulates (through final failure), which is not feasible with information gathered from a single length scale. Using digital image correlation to measure full-field surface deformations, damage evolutions in continuous fiber SiC/SiC laminates were analyzed at three distinct length scales: constituent, lamina, and laminate. Constituent scale analyses indicated that fine matrix cracks initiated in localized regions of transverse fiber coatings at low stresses. Investigations at the larger lamina scale revealed that some, but not all, of the coating cracks evolved into matrix cracks, the propagation of which was dependent on the state of stress near the crack tip and the local microstructure. Many of these matrix cracks morphed into cracks large enough to be detected at the (largest) laminate scale. The density of the large matrix cracks increased with load, reaching saturation prior to failure. While the constituent scale identifies when (with respect to stress state) and where (with respect to local microstructure) damage initiates, the lamina scale elucidates damage progression between neighboring constituents. Only laminate scale fields of view are large enough to capture the accumulation of the large matrix cracks that ultimately lead to final fracture. However, as spatial resolution is reduced at this scale, finer cracks (which may provide pathways for environmental ingress) go undetected. As each length scale provides a unique perspective of damage evolution in CMCs, multiscale analysis is essential for comprehensive damage characterization. [ABSTRACT FROM AUTHOR]

The complex nature of damage in ceramic matrix composites (CMCs) renders conventional methods of measuring quantitative fracture properties impractical. This paper is the first of two-part series that assesses the feasibility of using the J-integral with full-field deformation data from digital image correlation (DIC) to characterize toughness in continuous fiber SiC/SiC CMC laminates. It provides a resource for best practices when incorporating experimentally measured, full-field deformation data into J-integral evaluations of toughness. The techniques discussed are important for researchers attempting to measure fracture properties in advanced materials with damage mechanisms that have yet to be well characterized. Two methods for evaluating potential energy release rates J are presented: (1) numerical integration over a line contour and (2) Gaussian integration over an area contour. Accuracy and path independency for both methods were verified using analytically derived deformation fields for a center-cracked, infinite plate of isotropic material under equi-biaxial tension. Inherent noise in the deformation data and necessary contour truncation at the crack surfaces reduced accuracy and introduced path dependency. However, this was mitigated by careful noise filtering of the deformation data prior to the evaluation of J. Applying the line and area integrals to DIC data from tapered, double-cantilever beam, acrylic compact tension specimens resulted in the findings that (1) both integrals measured fracture toughness within a range of published values; (2) both integrals captured the constant stress intensity factor behavior that is characteristic of the tapered beam geometry; and (3) the area integral measurements were consistently larger than line integral measurements. The area integral is more accurate than the line integral as it samples more data points, reducing its sensitivity to experimental noise. Although variability in experimental data can be minimized, it cannot be eliminated. Measurement error is inevitable; thus, the line and area integrals must be used with caution when characterizing quantitative properties including fracture toughness. [ABSTRACT FROM AUTHOR]

This paper is the second of a two-part series assessing the feasibility of using the J-integral with full-field deformation data from digital image correlation (DIC) to characterize toughness in continuous fiber, SiC/SiC ceramic matrix composites (CMCs). In part I, line and area integral adaptations of the J-integral were validated with analytical and experimental deformation fields. It was found that variability in experimental data and contour truncation at the crack wake introduced error and path-dependency, but this could be mitigated through data filtering. In this paper, the line and area integral methods were evaluated for cross-ply and longitudinal CMC tensile specimens. It is demonstrated that these approaches cannot be used for quantitative characterization, but can be successfully used to examine qualitative trends. For both architectures, area integral measurements of the potential energy release rate, J, were larger (and arguably more accurate) than line integral measurements. Resistance curves were characteristic of tough materials, but the stress intensity magnitudes were larger in the longitudinal laminates than the cross-ply (for equivalent crack extension). Experimentally derived bridging laws showed that fiber bridging tractions were largest in the cross-ply laminates, which was attributed to a lower volume fraction of longitudinal fibers. Quantitative, single-value measurements of fracture toughness could not be established since (1) noise in the DIC data masked strain signals indicative of first matrix cracking, and (2) widespread matrix cracking rendered the J-integral invalid (regardless of size and position, the boundaries of the line and area contours inevitably intercepted microcracks). Rather, gross estimates of toughness and stress intensity factors were made under the assumption that the limitations in the spatial resolution of the DIC data essentially transforms regions with fine microcracking along the contour into continuous regions of elastic deformation. When evaluated with the J-integral, the smoothed deformation fields manifest as resistance curves indicative of a tough material. Thus, the J-integral was valuable for qualitative assessments of toughening mechanisms in the CMCs. [ABSTRACT FROM AUTHOR]

In colon cancer, mutation of the Wnt repressor APC (encoding adenomatous polyposis coli) leads to a state of aberrant and unrestricted high-activity signaling. However, the relevance of high Wnt tone in non-genetic human disease is unknown. Here we demonstrate that distinct functional states of Wnt activity determine oligodendrocyte precursor cell (OPC) differentiation and myelination. Mouse OPCs with genetic Wnt dysregulation (high tone) express multiple genes in common with colon cancer, including Lef1, Sp5, Ets2, Rnf43 and Dusp4. Surprisingly, we found that OPCs in lesions of hypoxic human neonatal white matter injury upregulated markers of high Wnt activity and lacked expression of APC. We also found that lack of Wnt repressor tone promoted permanent white matter injury after mild hypoxic insult. These findings suggest a state of pathological high-activity Wnt signaling in human disease tissues that lack predisposing genetic mutation. [ABSTRACT FROM AUTHOR]

The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia and macrophages, which can be polarized to distinct functional phenotypes: pro-inflammatory (M1) and anti-inflammatory or immunoregulatory (M2). We found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 cell conditioned media and impaired in vivo following intra-lesional M2 cell depletion. M2 cell densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger mouse and in multiple sclerosis lesions that normally show remyelination. Blocking M2 cell-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Thus, our results indicate that M2 cell polarization is essential for efficient remyelination and identify activin-A as a therapeutic target for CNS regeneration. [ABSTRACT FROM AUTHOR]

Colonies of the cyanobacterium Trichodesmium are abundant in the oligotrophic ocean, and through their ability to fix both CO2 and N2, have pivotal roles in the cycling of carbon and nitrogen in these highly nutrient-depleted environments. Trichodesmium colonies host complex consortia of epibiotic heterotrophic bacteria, and yet, the regulation of nutrient acquisition by these epibionts is poorly understood. We present evidence that epibiotic bacteria in Trichodesmium consortia use quorum sensing (QS) to regulate the activity of alkaline phosphatases (APases), enzymes used by epibionts in the acquisition of phosphate from dissolved-organic phosphorus molecules. A class of QS molecules, acylated homoserine lactones (AHLs), were produced by cultivated epibionts, and adding these AHLs to wild Trichodesmium colonies collected at sea led to a consistent doubling of APase activity. By contrast, amendments of (S)-4,5-dihydroxy-2,3-pentanedione (DPD)-the precursor to the autoinducer-2 (AI-2) family of universal interspecies signaling molecules-led to the attenuation of APase activity. In addition, colonies collected at sea were found by high performance liquid chromatography/mass spectrometry to contain both AHLs and AI-2. Both types of molecules turned over rapidly, an observation we ascribe to quorum quenching. Our results reveal a complex chemical interplay among epibionts using AHLs and AI-2 to control access to phosphate in dissolved-organic phosphorus. [ABSTRACT FROM AUTHOR]

Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting ?-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process. [ABSTRACT FROM AUTHOR]