FAM86A methylation of eEF2 links mRNA translation elongation to tumorigenesis.

eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation. FAM86A depletion in LUAD cells causes 80S monosome accumulation and mRNA translation inhibition. FAM86A is overexpressed in LUAD and eEF2K525me3 levels increase through advancing LUAD disease stages. FAM86A knockdown attenuates LUAD cell proliferation and suppression of the FAM86A-eEF2K525me3 axis inhibits cancer cell and patient-derived LUAD xenograft growth in vivo. Finally, FAM86A ablation strongly attenuates tumor growth and extends survival in KRASG12C-driven LUAD mouse models. Thus, our work uncovers an eEF2 methylation-mediated mRNA translation elongation regulatory node and nominates FAM86A as an etiologic agent in LUAD.

Capacity to Consent to Research Among Adolescent-Parent Dyads in Rakai, Uganda.

OBJECTIVES: To assess the cognitive capacity of early, middle, and late adolescents and their parents or guardians to provide informed consent to a population-based cohort study. STUDY DESIGN: Adolescent-parent/guardian dyads including 40 early (n = 80; 10-14 years), 20 middle (15-17 years), and 20 late (18-19 years) adolescents were recruited from the Rakai Community Cohort Study, an open demographic cohort in Uganda. Participants were administered the MacArthur Competence Assessment Tool for Clinical Research, a structured open-ended assessment; interviews were recorded and transcribed. Twenty transcripts were scored independently by two coders; the intraclass correlation coefficient was 0.89. The remaining interviews were scored individually. We compared mean scores for early and middle/late adolescents using a one-sided t test and score differences between parent/guardian and adolescent dyads using two-sided paired t tests. RESULTS: Early adolescents (mean score, 28.8; 95% CI, 27.1-30.5) scored significantly lower (P < .01) than middle/late adolescents (32.4; 31.6-33.1). In paired dyad comparisons, we observed no statistically significant difference in scores between parents/guardians and middle/late adolescents (difference, -0.2; 95% CI, -1.0-0.6). We found a statistically significant difference in scores between parents/guardians and early adolescents (difference, 3.0; 95% CI, 1.2-4.8). CONCLUSIONS: The capacity of adolescents-of different ages and in diverse settings-to comprehend risks, benefits, and other elements of informed consent is a critical but understudied area in research ethics. Our findings support the practice of having middle and late adolescents provide independent informed consent for sexual and reproductive health studies. Early adolescents may benefit from supported decision-making approaches.

The importance of early immunotherapy in patients with faciobrachial dystonic seizures.

Faciobrachial dystonic seizures and limbic encephalitis closely associate with antibodies to leucine-rich glioma-inactivated 1 (LGI1). Here, we describe 103 consecutive patients with faciobrachial dystonic seizures and LGI1 antibodies to understand clinical, therapeutic and serological differences between those with and without cognitive impairment, and to determine whether cessation of faciobrachial dystonic seizures can prevent cognitive impairment. The 22/103 patients without cognitive impairment typically had normal brain MRI, EEGs and serum sodium levels (P < 0.0001). Overall, cessation of faciobrachial dystonic seizures with antiepileptic drugs alone occurred in only 9/89 (10%) patients. By contrast, 51% showed cessation of faciobrachial dystonic seizures 30 days after addition of immunotherapy (P < 0.0001), with earlier cessation in cognitively normal patients (P = 0.038). Indeed, expedited immunotherapy (P = 0.031) and normal cognition (P = 0.0014) also predicted reduced disability at 24 months. Furthermore, of 80 patients with faciobrachial dystonic seizures as their initial feature, 56% developed cognitive impairment after 90 days of active faciobrachial dystonic seizures. Whereas only one patient developed cognitive impairment after cessation of faciobrachial dystonic seizures (P < 0.0001). All patients had IgG4-LGI1 antibodies, but those with cognitive impairment had higher proportions of complement-fixing IgG1 antibodies (P = 0.03). Both subclasses caused LGI1-ADAM22 complex internalization, a potential non-inflammatory epileptogenic mechanism. In summary, faciobrachial dystonic seizures show striking time-sensitive responses to immunotherapy, and their cessation can prevent the development of cognitive impairment.awx323media15681705685001.

Measuring Unfinished Nursing Care: What to Consider When Choosing and Scoring Surveys.

Unfinished nursing care is common in the inpatient setting and is associated with negative patient outcomes. This indicator is being assessed with increasing frequency to determine the quality of nursing services. Measurement bias was identified in this comparison of unfinished care surveys. Potential sources of bias should be considered when selecting and scoring unfinished nursing care surveys for quality assessment.

Do Parents and Overweight, Treatment-Seeking Youth Provide Similar Ratings of Youths' Psychosocial Functioning and Fatigue?

Patterns of agreement between parent and child ratings of psychosocial functioning and fatigue in children with obesity were examined. Analyses demonstrated moderate agreement for social anxiety in elementary children and small agreement for social anxiety in adolescents. Results of analyses of overall quality of life revealed small agreement in children under the age of 8, large agreement in children ages 8-12, and moderate agreement in adolescents ages 13-18. Overall ratings of fatigue demonstrated moderate agreement both in elementary children and in adolescents. A meaningful relationship was found between each factor measured by a parent and a child. Patterns which were unexpected given the existing literature were found; possible hypotheses explaining these patterns are presented; and the need for further research is highlighted.

Clinical characteristics and outcomes of patients requiring prolonged mechanical circulatory support after high-risk percutaneous coronary intervention.

BACKGROUND: There are limited data on the clinical characteristics and outcomes of patients who require prolonged mechanical circulatory support (MCS) after Impella-supported high-risk percutaneous coronary intervention (HR-PCI). AIMS: The aim of this study is to describe the contemporary clinical characteristics, outcomes, and predictors associated with prolonged MCS support after assisted HR-PCI. METHODS: Patients enrolled in the prospective, multicentre, clinical endpoint-adjudicated PROTECT III study who had undergone HR-PCI using Impella were evaluated. Patient and procedural characteristics and outcomes for those who received prolonged MCS beyond the duration of their index procedure were compared to those in whom MCS was successfully weaned and explanted at the conclusion of the index PCI. RESULTS: Among 1,155 patients who underwent HR-PCI with Impella between 2017 and 2020 and had sufficient data to confirm the duration of Impella support, 16.5% received prolonged MCS (mean duration 25.2±31.1 hours compared with 1.8±5.8 hours for those who only received intraprocedural MCS). Patients receiving prolonged support presented with more urgent indications (e.g., acute coronary syndromes [ACS], lower ejection fraction [EF], elevated baseline heart rate and lower systolic blood pressure). Use of the Impella CP, intraprocedural complications, periprocedural complications and in-hospital mortality were all more common amongst the prolonged MCS group. Prolonged MCS was associated with increased rates of major adverse cardiovascular and cerebrovascular events, cardiovascular death, and all-cause mortality at 90-day follow-up. CONCLUSIONS: Patients receiving prolonged MCS after Impella-supported HR-PCI presented with more ACS, reduced EF and less favourable haemodynamics. Additionally, they were more likely to experience intraprocedural and periprocedural complications as well as increased in-hospital and post-discharge mortality.

Antigenic and molecular evidence of Brucella sp.-associated epididymo-orchitis in frugivorous (Artibeus lituratus) and nectarivorous (Glossophaga soricina) bats in Brazil.

This study included 47 free-ranging bats from the State of Minas Gerais, Brazil. Six bats (12.8%) had genital inflammatory lesions, and two of them (one Artibeus lituratus and one Glossophaga soricina, a frugivorous and a nectarivorous, respectively) were diagnosed with Brucella sp. infection through PCR, and antigens in intralesional macrophages were detected using immunohistochemistry.

Psychosocial functioning in children and adolescents with extreme obesity.

The aim of this study was to investigate the psychosocial differences among obese pediatric patients, particularly those who are "extremely obese" as compared to "obese." Information was collected for 249 subjects at a multidisciplinary treatment clinic for obese youth. A battery of measures was administered and demographic data and height/weight was obtained. The results showed positive correlations between degree of obesity, psychosocial functioning, and quality of life. Specifically, the "extremely obese" were significantly more depressed, more socially anxious, and had poorer quality of life than the "obese" group. Girls and Caucasians were more socially anxious than boys and African Americans, respectively. There is mounting evidence that children and adolescents who are extremely obese are most at risk for psychiatric and medical disorders. Thus, targeting this group for assessment and/or designing treatment options specific for "extremely obese" youth is critical for the successful management of this population.

An 11-year longitudinal analysis of refracture rates and public hospital service utilisation in Australia's most populous state.

This detailed 11-year longitudinal analysis calculated the public health cost of managing refractures in people aged ≥ 50 years in Australia's most populous state. It provides current and projected statewide health system costs associated with managing osteoporosis and provides a foundation to evaluate a novel statewide model of fracture prevention. PURPOSE: The purpose of this longitudinal analysis was to calculate current and projected refracture rates and associated public hospital utilisation and costs in New South Wales (NSW), Australia. These results will be used to inform scaled implementation and evaluation of a statewide Osteoporotic Refracture Prevention (ORP) model of care. METHODS: Linked administrative data (inpatient admissions, outpatient attendances, Emergency Department presentations, deaths, cost) were used to calculate annual refracture rates and refracture-related service utilisation between 2007 and 2018 and healthcare costs between 2008 and 2019. Projections for the next decade were made using 'business-as-usual' modelling. RESULTS: Between 2007 and 2018, 388,743 people aged ≥ 50 years experienced an index fracture and 81,601 had a refracture. Refracture was more common in older people (rising from a cumulative refracture rate at 5 years of 14% in those aged 50-64 years, to 44% in those aged > 90 years), women with a major index fracture (5-year cumulative refracture rate of 26% in females, compared to 19% for males) or minimal trauma index fracture and those with an osteoporosis diagnosis (5-year cumulative refracture rate of 36% and 22%, respectively in those with and without an osteoporosis diagnosis). Refractures increased from 8774 in 2008 to 14,323 in 2018. The annual cost of refracture to NSW Health increased from AU$130 million in 2009 to AU$194 million in 2019. It is projected that, over the next decade, if nothing changes, 292,537 refracture-related hospital admissions and Emergency Department presentations and 570,000 outpatient attendances will occur, at an estimated total cost to NSW Health of AU$2.4 billion. CONCLUSION: This analysis provides a detailed picture of refractures and associated projected service utilisation and costs over the next decade in Australia's most populous state. Understanding the burden of refracture provides a foundation for evaluation of a novel statewide ORP model of care to prevent refractures in people aged ≥ 50 years.

Otologic Examination Findings In Afebrile Young Infants Clinically Diagnosed With Acute Otitis Media.

There are limited data on examination criteria for diagnosing acute otitis media in young infants. In this 33-site retrospective study of afebrile infants ≤90 days, clinicians typically documented tympanic membrane erythema with ≥1 other otologic abnormalities (64.1%) to diagnose acute otitis media. Notable differences in ear examination findings used for diagnosis existed across age subgroups.

Tumor Immune Microenvironment and Response to Neoadjuvant Chemotherapy in Hormone Receptor/HER2+ Early Stage Breast Cancer.

BACKGROUND: Pathologic response at the time of surgery after neoadjuvant therapy for HER2 positive early breast cancer impacts both prognosis and subsequent adjuvant therapy. Comprehensive descriptions of the tumor microenvironment (TME) in patients with HER2 positive early breast cancer is not well described. We utilized standard stromal pathologist-assessed tumor infiltrating lymphocyte (TIL) quantification, quantitative multiplex immunofluorescence, and RNA-based gene pathway signatures to assess pretreatment TME characteristics associated pathologic complete response in patients with hormone receptor positive, HER2 positive early breast cancer treated in the neoadjuvant setting. METHODS: We utilized standard stromal pathologist-assessed TIL quantification, quantitative multiplex immunofluorescence, and RNA-based gene pathway signatures to assess pretreatment TME characteristics associated pathologic complete response in 28 patients with hormone receptor positive, HER2 positive early breast cancer treated in the neoadjuvant setting. RESULTS: Pathologist-assessed stromal TILs were significantly associated with pathologic complete response (pCR). By quantitative multiplex immunofluorescence, univariate analysis revealed significant increases in CD3+, CD3+CD8-FOXP3-, CD8+ and FOXP3+ T-cell densities as well as increased immune cell aggregates in pCR patients. In subsets of paired pre/post-treatment samples, we observed significant changes in gene expression signatures in non-pCR patients and significant decreases in CD8+ densities after treatment in pCR patients. No RNA based pathway signature was associated with pCR. CONCLUSION: TME characterization HER2 positive breast cancer patients revealed several stromal T-cell densities and immune cell aggregates associated with pCR. These results demonstrate the feasibility of these novel methods in TME evaluation and contribute to ongoing investigations of the TME in HER2+ early breast cancer to identify robust biomarkers to best identify patients eligible for systemic de-escalation strategies.

Rapid counting and spectral sorting of live coral larvae using large-particle flow cytometry.

Research with coral embryos and larvae often requires laborious manual counting and sorting of individual specimens, usually via microscopy. Because many coral species spawn only once per year during a narrow temporal window, sample processing is a time-limiting step for research on the early life-history stages of corals. Flow cytometry, an automated technique for measuring and sorting particles, cells, and cell-clusters, is a potential solution to this bottleneck. Yet most flow cytometers do not accommodate live organisms of the size of most coral embryos (> 250 µm), and sample processing is often destructive. Here we tested the ability of a large-particle flow cytometer with a gentle pneumatic sorting mechanism to process and spectrally sort live and preserved Montipora capitata coral embryos and larvae. Average survival rates of mechanically-sorted larvae were over 90% and were comparable to those achieved by careful hand-sorting. Preserved eggs and embryos remained intact throughout the sorting process and were successfully sorted based on real-time size and fluorescence detection. In-line bright-field microscopy images were captured for each sample object as it passed through the flow-cell, enabling the identification of early-stage embryos (2-cell to morula stage). Samples were counted and sorted at an average rate of 4 s larva-1 and as high as 0.2 s larva-1 for high-density samples. Results presented here suggest that large-particle flow cytometry has the potential to significantly increase efficiency and accuracy of data collection and sample processing during time-limited coral spawning events, facilitating larger-scale and higher-replication studies with an expanded number of species.

Otx/otd homeobox genes specify distinct sensory neuron identities in C. elegans.

The mechanisms by which the diverse functional identities of neurons are generated are poorly understood. C. elegans responds to thermal and chemical stimuli using 12 types of sensory neurons. The Otx/otd homolog ttx-1 specifies the identities of the AFD thermosensory neurons. We show here that ceh-36 and ceh-37, the remaining two Otx-like genes in the C. elegans genome, specify the identities of AWC, ASE, and AWB chemosensory neurons, defining a role for this gene family in sensory neuron specification. All C. elegans Otx genes and rat Otx1 can substitute for ceh-37 and ceh-36, but only ceh-37 functionally substitutes for ttx-1. Functional substitution in the AWB neurons is mediated by activation of the same downstream target lim-4 by different Otx genes. Misexpression experiments indicate that although the specific identity adopted upon expression of an Otx gene may be constrained by the cellular context, individual Otx genes preferentially promote distinct neuronal identities.

How should health policy and practice respond to the increased genetic risk associated with close relative marriage? results of a UK Delphi consensus building exercise.

OBJECTIVES: (1) To explore professional and lay stakeholder views on the design and delivery of services in the area of consanguinity and genetic risk. (2) To identify principles on which there is sufficient consensus to warrant inclusion in a national guidance document. (3) To highlight differences of opinion that necessitate dialogue. (4) To identify areas where further research or development work is needed to inform practical service approaches. DESIGN: Delphi exercise. Three rounds and one consensus conference. SETTING: UK, national, web-based and face-to-face. PARTICIPANTS: Recruitment via email distribution lists and professional networks. 42 participants with varied professional and demographic backgrounds contributed to at least one round of the exercise. 29 people participated in statement ranking across both rounds 2 and 3. RESULTS: Over 700 individual statements were generated in round 1 and consolidated into 193 unique statements for ranking in round 2, with 60% achieving 80% or higher agreement. In round 3, 74% of statements achieved 80% or higher agreement. Consensus conference discussions resulted in a final set of 148 agreed statements, providing direction for both policy-makers and healthcare professionals. 13 general principles were agreed, with over 90% agreement on 12 of these. Remaining statements were organised into nine themes: national level leadership and coordination, local level leadership and coordination, training and competencies for healthcare and other professionals, genetic services, genetic literacy, primary care, referrals and coordination, monitoring and evaluation and research. Next steps and working groups were also identified. CONCLUSIONS: There is high agreement among UK stakeholders on the general principles that should shape policy and practice responses in this area: equity of access, cultural competence, coordinated inter-agency working, co-design and empowerment and embedded evaluation. The need for strong national leadership to ensure more efficient sharing of knowledge and promotion of more equitable and consistent responses across the country is emphasised.

Economic considerations in treating overweight youth.

Research suggests that children from low-income households are particularly at risk for pediatric obesity. In treating these youth, practitioners must understand the unique obstacles to making health-related behavioral changes. Both limited access and cost of many foods high in nutritive value are prohibitive for many families. Furthermore, the poor safety of neighborhoods preclude walking programs and the limited access or excessive cost of other physical activity options also present barriers. It is critical for practitioners to understand the potential economic barriers that may limit success in treating overweight patients, and this article presents some options that circumvent these barriers.

Impact of Degree of Obesity on Sleep, Quality of Life, and Depression in Youth.

OBJECTIVE: Obese youth are more likely to report difficulties with sleep, depression, and quality of life (QOL). This study aims to characterize sleep problems, QOL, and symptoms of depression by degree of obesity. METHOD: The cross-sectional study was conducted in a specialized obesity clinic. Obese youth and their caregivers (N = 150) were evaluated with the Child Sleep Habits Questionnaire and Pediatric Quality of Life. Youth completed the Children's Depression Inventory. Regression models and correlations were calculated. RESULTS: Degree of obesity was predictive of increased sleep difficulties and decreased QOL scores. Children's Depression Inventory scores showed that children with more symptoms of depression had more sleep problems, and these were not associated with the degree of obesity. Adolescents with more difficulties sleeping also reported more symptoms of depression and lower QOL. CONCLUSIONS: Degree of obesity negatively affected QOL and sleep variables. Patients with greater sleeping difficulties reported more symptoms of depression.

Why work in perioperative nursing? Baby boomers and Generation Xers tell all.

This quantitative and qualitative study explored factors that influence nurses of different age groups to choose to work in and remain in the specialty of OR nursing, including the effect of work environment perceptions. Baby boomer nurses (n = 130) and Generation X nurses (n = 117) were surveyed, and seven RNs from each group also participated in semistructured interviews. Results showed that nurses of both age groups were more alike than different in the factors that influence them to choose and remain in OR nursing and in their perceptions of their work environment. Baby Boomers indicated a higher level of commitment to their jobs than did Generation Xers.

The effect of health insurance disparities on the health care system.

Uninsured patients put a strain on the health care system that ultimately results in increased health care costs for everyone. The challenges faced by the Harris County Hospital District in Houston, TX, as a result of an increasing number of uninsured and underinsured patients include overcrowding in its health care facilities, decreased reimbursement from government programs, and patients who postpone seeking medical treatment until their situation is emergent and whose care is therefore more expensive. Strategies for addressing these problems may include instituting an "everybody pays" program, improving access to care for the uninsured, and reducing or eliminating unnecessary services.

Burning Out Faculty at Doctoral Research Universities.

The present study examined the importance of time allocation, pressure and support variables together as determinants of faculty burnout. Using a large sample of university faculty (N = 1439), we were able to show that time allocation variables and perceived pressure contribute to faculty burnout. As expected, decreased social support, family, sleep and leisure time were related to higher levels of burnout. Grantsmanship and service activities appeared as the most critical factors associated with faculty burnout. Faculty burnout is an important topic, and the insights provided here help offer some directions for future research as well as the development of effective institutional policies. Copyright © 2015 John Wiley & Sons, Ltd.