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Telomere length (TL) and DNA methylation–based epigenetic clocks are markers of biological age, but the relationship between the two is not fully understood. Here, we used multivariable regression models to evaluate the relationships between leukocyte TL (LTL; measured by qPCR [ n  = 635] or flow FISH [ n  = 144]) and five epigenetic clocks (Hannum, DNAmAge pan-tissue, PhenoAge, SkinBlood, or GrimAge clocks), or their epigenetic age acceleration measures in healthy adults (age 19–61 years). LTL showed statistically significant negative correlations with all clocks (qPCR: r  =  − 0.26 to − 0.32; flow FISH: r  =  − 0.34 to − 0.49; p  < 0.001 for all). Yet, models adjusted for age, sex, and race revealed significant associations between three of five clocks (PhenoAge, GrimAge, and Hannum clocks) and LTL by flow FISH ( p  < 0.01 for all) or qPCR ( p  < 0.001 for all). Significant associations between age acceleration measures for the same three clocks and qPCR or flow FISH TL were also found ( p  < 0.01 for all). Additionally, LTL (by qPCR or flow FISH) showed significant associations with extrinsic epigenetic age acceleration (EEAA: p  < 0.0001 for both), but not intrinsic epigenetic age acceleration (IEAA; p  > 0.05 for both). In conclusion, the relationships between LTL and epigenetic clocks were limited to clocks reflecting phenotypic age. The observed association between LTL and EEAA reflects the ability of both measures to detect immunosenescence. The observed modest correlations between LTL and epigenetic clocks highlight a possible benefit from incorporating both measures in understanding disease etiology and prognosis.

Families with rare diseases, such as telomere biology disorders (TBDs), may have extensive unmet needs given the heterogeneity, chronicity, and potential severity of illness. TBDs are rare inherited syndromes associated with high risk of bone marrow failure, cancer, pulmonary fibrosis, and other severe, chronic complications. To identify gaps in clinical care, we aimed to ascertain the perceived unmet needs of adults and family caregivers, current or bereaved, of individuals with TBDs. Participants were aged ≥18 years with a self-reported TBD diagnosis and/or ever caregivers to one or more family members with a TBD. Participants completed an online survey (N = 35) and/or an audio-recorded telephone interview (N = 32). We calculated descriptive statistics in SPSS and thematically analyzed interview transcripts. Quantitative and qualitative data were analyzed concurrently. Most participants were aged ≥35 years, female, highly educated, and medically insured. Survey respondents reported numerous unmet needs in psychosocial, medical, financial, and daily activity domains. In interviews, participant descriptions validated and contextualized the salience of these unmet needs. Both qualitative and quantitative data identified critical shortfalls in addressing chronic family distress and specialty care coordination. Adults and caregivers of individuals with TBDs have a high risk of adverse psychosocial sequelae given extensive unmet needs. These findings provide a foundation for understanding the range and extent of gaps in care for families with rare diseases, especially TBDs but that are likely applicable to others. Tailored multi-disciplinary interventions involving patients, families, clinicians, researchers, and patient advocacy communities are required to appropriately address care needs for all rare diseases.

Background: Telomere biology disorders (TBDs) are rare, cancer-predisposing, genetic conditions with wide phenotypic spectrums and ages of onset creating a burden of medical uncertainty. No research addresses medical uncertainty in this context.Methods: Study 1 is a qualitative thematic analysis of telephone interviews to explore medical uncertainty sources, issues, and management strategies of patients with TBDs and their caregivers. Study 2 is a mixed methods content analysis of TBD-related social media posts to assess types of medical uncertainty discussed online in the TBD community. Study 3 used the same methods as Study 1 to explore motivations for and perceived benefits and barriers to the use of online support resources.Results: Individuals with TBDs and their caregivers experience chronic or recurrent uncertainty, with a range of interrelated, dynamic, sources, issues, and management strategies. Scientific uncertainty included diagnostic and prognostic ambiguity and limited clinician knowledge of TBDs. Practical uncertainty focused on logistics of maintaining care teams across medical disciplines. Personal uncertainty encompassed self-identity, life goals, and relationship expectations post-diagnosis. Scientific, practical, and personal issues of uncertainty were interrelated: limited scientific knowledge of TBDs gave rise to practical and personal issues, which created psychosocial burdens including anxiety and barriers to relationship formation and health decision-making. Individuals with TBDs and their caregivers reported multiple evolving management strategies which included information-seeking and sharing, organizing aspects of uncertainty, stress-relief techniques, and connecting with peer support. In study 2, TBD social media posts included information exchange regarding diagnostic and prognostic uncertainty. Overall, post creators were white, female, parents of patients with TBDs. Study 3 revealed that most participants engaged in online support but expressed contradictory feelings about online resources. Perceived barriers included distrust of online platforms and lack of targeted resources.Conclusions: Medical uncertainty is a burden for patients with TBDs and their caregivers, but uncertainty sources and issues may change over time, impacting the utility of different management strategies. The intractability, continuity, variety, and fluctuation of medical uncertainty throughout the illness experience creates barriers to management peculiar to TBDs and may limit the effectiveness of uncertainty-management approaches developed in other rare and high-risk disease contexts.

Through reduced 3-D printer cost, increased usability, and greater material selection, additive manufacturing has transitioned from business manufacturing to the average prosumer. This study serves as a representative model for the potential future of 3-D printing in the average American household by employing a printer operator who was relatively unfamiliar with 3-D printing and the 3-D design files of common items normally purchased by the average consumer. Twenty-six items were printed in thermoplastic and a cost analysis was performed through comparison to comparable, commercially available products at a low and high price range. When compared to the low-cost items, investment in a 3-D printer represented a return of investment of over 100% in five years. The simple payback time for the high-cost comparison was less than 6 months, and produced a 986% return. Thus, fully-assembled commercial open source 3-D printers can be highly profitable investments for American consumers. Finally, as a preliminary gauge of the effect that widespread prosumer use of 3-D printing might have on the economy, savings were calculated based on the items’ download rates from open repositories. Results indicate that printing these selected items have already saved prosumers over $4 million by substituting for purchases.

The 2020 toy and game market is projected to be US $135 billion. To determine if 3D printing could affect these markets if consumers offset purchases by 3D printing free designs, this study investigates the 100 most popular downloaded designs at MyMiniFactory in a month. Savings are quantified for using a Lulzbot Mini 3D printer and three filament types: commercial filament, pellet-extruded filament, and post-consumer waste converted to filament with a recyclebot. Case studies probed the quality of: (1) six common complex toys; (2) Lego blocks; and (3) the customizability of open source board games. All filaments analyzed saved the user over 75% of the cost of commercially available true alternative toys and over 90% for recyclebot filament. Overall, these results indicate a single 3D printing repository among dozens is saving consumers well over $ 60 million/year in offset purchases. The most common savings fell by 40%–90% in total savings, which came with the ability to make novel toys and games. The results of this study show consumers can generate higher value items for less money using the open source distributed manufacturing paradigm. It appears clear that consumer do-it-yourself (DIY) manufacturing is set to have a significant impact on the toy and game markets in the future.

Loneliness is a relatively common problem in young people (14–24 years) and predicts the onset of depression and anxiety. Interventions to reduce loneliness thus have significant potential as active ingredients in strategies to prevent or alleviate anxiety and depression among young people. Previous reviews have focused on quantitative evidence and have not examined potential mechanisms that could be targets for intervention strategies. To build on this work, in this review we aimed to combine qualitative and quantitative evidence with stakeholder views to identify interventions that appear worth testing for their potential effectiveness in reducing loneliness, anxiety and depression in young people aged 14–24 years, and provide insights into the potential mechanisms of action. We conducted a Critical Interpretative Synthesis, a systematic review method that iteratively synthesises qualitative and quantitative evidence and is explicitly focused on building theory through a critical approach to the evidence that questions underlying assumptions. Literature searches were performed using nine databases, and eight additional databases were searched for theses and grey literature. Charity and policy websites were searched for content relevant to interventions for youth loneliness. We incorporated elements of Rapid Realistic Review approaches by consulting with young people and academic experts to feed into search strategies and the resulting conceptual framework, in which we aimed to set out which interventions appear potentially promising in terms of theoretical and empirical underpinnings and which fit with stakeholder views. We reviewed effectiveness data and quality ratings for the included randomised controlled trials only. Through synthesising 27 studies (total participants n = 105,649; range 1–102,072 in different studies) and grey literature, and iteratively consulting with stakeholders, a conceptual framework was developed. A range of ‘Intrapersonal’ (e.g. therapy that changes thinking and behaviour), ‘Interpersonal’ (e.g. improving social skills), and ‘Social’ Strategies (e.g. enhancing social support, and providing opportunities for social contact) seem worth testing further for their potential to help young people address loneliness, thereby preventing or alleviating depression and/or anxiety. Such strategies should be co-designed with young people and personalised to fit individual needs. Plausible mechanisms of action are facilitating sustained social support, providing opportunities for young people to socialise with peers who share similar experiences, and changing thinking and behaviour, for instance through building positive attitudes to themselves and others. The most convincing evidence of effectiveness was found in support of Intrapersonal Strategies: two randomised controlled studies quality-rated as ‘good’ found decreases in loneliness associated with different forms of therapy (Cognitive Behavioural Therapy or peer network counselling), although power calculations were not reported, and effect sizes were small or missing. Strategies to address loneliness and prevent or alleviate anxiety and depression need to be co-designed and personalised. Promising elements to incorporate into these strategies are social support, including from peers with similar experiences, and psychological therapy.

Prenatal exposure to some per- and polyfluoroalkyl substances (PFASs) may disrupt maternal and neonatal thyroid function, which is critical for normal growth and neurodevelopment. We examined associations of PFAS exposure during early pregnancy with maternal and neonatal thyroid hormone levels. We studied 732 mothers and 480 neonates in Project Viva, a longitudinal prebirth cohort in Boston, Massachusetts. We quantified six PFASs, including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), and maternal thyroid hormones [thyroxine (T ), Free T Index (FT I), thyroid stimulating hormone (TSH)] in plasma samples collected at a median 9.6 wk gestation and neonatal T levels from postpartum heel sticks. We estimated associations of PFAS concentrations with thyroid hormone levels using covariate-adjusted linear regression models and explored effect measure modification by maternal thyroid peroxidase antibody (TPOAb) status and infant sex. PFAS concentrations were not associated with maternal T , but PFOA, perfluorohexane sulfonate (PFHxS), and 2-(N-methyl-perfluorooctane sulfonamido) acetate (MeFOSAA) were inversely associated with maternal FT I [e.g., -1.87% (95% confidence interval (CI): -3.40, -0.31) per interquartile (IQR) increase in PFOA]. PFAS concentrations [PFOA, PFOS, and perfluorononanoate (PFNA)] were inversely associated with TSH levels in TPOAb-positive women only. Prenatal PFOS, PFOA, and PFHxS concentrations were inversely associated with T levels in male [e.g., PFHxS, quartile 4 vs.1: -2.51μg/dL (95% CI: -3.99, -1.04 )], but not female neonates [0.40μg/dL (95% CI: -0.98, 1.79)]. In this study, prenatal exposure to some PFASs during early pregnancy was inversely associated with maternal FT I and neonatal T in male infants. These results support the hypothesis that prenatal exposure to PFASs influences thyroid function in both mothers and infants. https://doi.org/10.1289/EHP2534.

This study investigated the relationship between concussions and medication adherence among 247 adults experiencing homelessness in Oklahoma City, Oklahoma, who were prescribed medication for a psychiatric disorder. Participants were asked whether they had “ever experienced a blow to the head that caused a concussion,” and medication adherence was measured by asking participants whether they had taken their psychiatric medication yesterday. The data were analyzed using univariate and multivariable logistic regressions. Results showed that more than half of the sample had a concussion history (61.9%), and homeless adults with a concussion history had higher odds of non-adherence to psychiatric medications compared with those who reported no concussion history (OR = 2.13 [95% CI = 1.08, 4.18]). Findings suggest that concussions may be associated with medication non-adherence. Raising awareness among service providers of the relationship between traumatic brain injury and medication adherence may increase efforts to improve adherence in this underserved population.

Obesity affects over 40% of women in the US and increases the risk and progression of several cancers, including triple-negative breast cancer (TNBC), in part through chronic low-grade inflammation and impaired antitumor immunity. While weight loss can reverse obesity-driven cancer risk, cost and other factors limit the accessibility of effective weight loss interventions. This study investigated whether sulindac, a nonsteroidal anti-inflammatory drug (NSAID), could mitigate obesity-driven TNBC progression. Using multiple preclinical models, we demonstrate that sulindac treatment abrogates obesity-accelerated tumor growth and metastasis without affecting body weight or composition. Bulk transcriptomic profiling revealed obesity-driven suppression of immune-related gene signatures in the tumor microenvironment (TME)—including antigen presentation—while sulindac treatment restored these signatures. Single-cell RNA sequencing identified sulindac-mediated reprogramming of tumoral metabolism toward oxidative phosphorylation and restoration of antigen presentation machinery in tumor-associated macrophages. Sulindac also reversed obesity-driven reduction in T cell receptor diversity within the TME. We conclude that sulindac treatment remodels the TME and restores obesity-associated impairments of immunosurveillance, offering a potentially accessible intervention to limit obesity-driven TNBC progression. We demonstrate that NSAIDs, which are generally safe, cheap, and readily available, limit the burden of obesity-driven TNBC preclinically, warranting further evaluation as a targeted clinical intervention. Graphical abstract

Colorectal cancer (CRC) care costs the Australian healthcare system more than any other cancer. We estimated costs and days in hospital for CRC cases, stratified by site (colon/rectal cancer) and disease stage, to inform detailed analyses of CRC-related healthcare. Incident CRC patients were identified using the Australian 45 and Up Study cohort linked with cancer registry records. We analysed linked hospital admission records, emergency department records, and reimbursement records for government-subsidised medical services and prescription medicines. Cases' health system costs (2020 Australian dollars) and hospital days were compared with those for cancer-free controls (matched by age, sex, geography, smoking) to estimate excess resources by phase of care, analysed by sociodemographic, health, and disease characteristics. 1200 colon and 546 rectal cancer cases were diagnosed 2006-2013, and followed up to June 2016. Eighty-nine percent of cases had surgery, chemotherapy or radiotherapy, and excess costs were predominantly for hospitalisations. Initial phase (12 months post-diagnosis) mean excess health system costs were $50,434 for colon and $60,877 for rectal cancer cases, with means of 16 and 18.5 excess hospital days, respectively. The annual continuing mean excess costs were $6,779 (colon) and $8,336 (rectal), with a mean of 2 excess hospital days each. Resources utilised (costs and days) in these phases increased with more advanced disease, comorbidities, and younger age. Mean excess costs in the year before death were $74,952 (colon) and $67,733 (rectal), with means of 34 and 30 excess hospital days, respectively-resources utilised were similar across all characteristics, apart from lower costs for cases aged ≥75 at diagnosis. Health system costs and hospital utilisation for CRC care are greater for people with more advanced disease. These findings provide a benchmark, and will help inform future cost-effectiveness analyses of potential approaches to CRC screening and treatment.