Coupling Conjugation and Deconjugation Activities to Achieve Cellular Ubiquitin Dynamics.

In eukaryotic cells, proteome remodeling is mediated by the ubiquitin-proteasome system, which regulates protein degradation, trafficking, and signaling events in the cell. Interplay between the cellular proteome and ubiquitin is complex and dynamic and many regulatory features that support this system have only recently come into focus. An unexpected recurring feature in this system is the physical interaction between E3 ubiquitin ligases and deubiquitylases (DUBs). Recent studies have reported on the regulatory significance of DUB-E3 interactions and it is becoming clear that they play important but complicated roles in the regulation of diverse cellular processes. Here, we summarize the current understanding of interactions between ubiquitin conjugation and deconjugation machineries and we examine the regulatory logic of these enigmatic complexes.

Breaking the Habit? Identifying Discrete Dimensions of Sitting Automaticity and Their Responsiveness to a Sitting-Reduction Intervention.

BACKGROUND: Growing evidence suggests that sitting is activated automatically on exposure to associated environments, yet no study has yet sought to identify in what ways sitting may be automatic. METHOD: This study used data from a 12-month sitting-reduction intervention trial to explore discrete dimensions of sitting automaticity, and how these dimensions may be affected by an intervention. One hundred ninety-four office workers reported sitting automaticity at baseline, and 3 months, 6 months, 9 months and 12 months after receiving one of two sitting-reduction intervention variants. RESULTS: Principal component analysis extracted two automaticity components, corresponding to a lack of awareness and a lack of control. Scores on both automaticity scales decreased over time post-intervention, indicating that sitting became more mindful, though lack of awareness scores were consistently higher than lack of control scores. CONCLUSION: Attempts to break office workers' sitting habits should seek to enhance conscious awareness of alternatives to sitting and afford office workers a greater sense of control over whether they sit or stand.

#PathX: #PathTwitter's Transformation and a Discussion on Different Social Media Platforms Used by Pathologists in 2024.

#PathTwitter is a well-known virtual community that has historically been positive for pathologists, trainees, and medical students worldwide to communicate, collaborate, and connect for free. However, in 2023, the popular social media platform Twitter (parent company: X Corp.) transitioned to "X" and, with this, #PathTwitter evolved into #PathX. Although the overall user experience of X and Twitter has not changed significantly, this transition brought much anecdotal hesitancy from the online virtual pathology community early on. Thus, the purpose of this review is to discuss the background of Twitter's importance in pathology, the implications of this transition to the online pathology community, current views from this community regarding Twitter versus X, and to provide an overview of pertinent changes in the platform, as well as of different popular social media platforms that may be used by pathologists in 2024.

Macrophages and Intervertebral Disc Degeneration.

The intervertebral disc (IVD) aids in motion and acts to absorb energy transmitted to the spine. With little inherent regenerative capacity, degeneration of the intervertebral disc results in intervertebral disc disease, which contributes to low back pain and significant disability in many individuals. Increasing evidence suggests that IVD degeneration is a disease of the whole joint that is associated with significant inflammation. Moreover, studies show elevated macrophage accumulation within the IVD with increasing levels of disease severity; however, we still need to understand the roles, be they causative or consequential, of macrophages during the degenerative process. In this narrative review, we discuss hallmarks of IVD degeneration, showcase evidence of macrophage involvement during disc degeneration, and explore burgeoning research aimed at understanding the molecular pathways regulating macrophage functions during intervertebral disc degeneration.

Rising to Meet the Moment: What Does the Public Health Workforce Need to Modernize?

OBJECTIVE: This study uses findings from the most recent iterations of the Public Health Workforce Interest and Needs Survey (PH WINS) to describe importance, skill level, and gaps of key public health competencies as well as characteristics associated with gaps. DESIGN: Repeated cross-sectional analysis of the 2017 and 2021 PH WINS data. SETTING: State and local health departments. PARTICIPANTS: Nationally representative population of state and local governmental public health workers. MAIN OUTCOME MEASURES: Gaps of key public health competencies related to data, evidence-based approaches, health equity and social justice, factors that affect public health, cross-sectoral partnerships, and community health assessments and improvement plans. Gaps reflect areas of high importance and low skill level. Differences in gaps among the traditional public health workforce and those hired specifically for COVID-19 response. RESULTS: For most competency areas, more than 20% of the public health workforce perceived a gap. Gaps related to environmental factors that affect public health, social determinants of health and cross-sector partnerships, and community health assessments and improvement plans were the largest. Tenure in public health practice, highest level of education, and having formal public health training were associated with lower odds of gaps in most areas. In a secondary analysis of traditional public health workforce compared with those hired specifically for COVID-19 response, those hired for COVID-19 response reported significantly fewer gaps for all but one competency considered. CONCLUSIONS: A substantial proportion of the public health workforce perceives gaps in competency areas that are of high importance to the evolving role of public health. As public health continues to adjust and modernize in response to the COVID-19 pandemic and other historic changes, understanding and addressing training needs of the workforce will be instrumental to public health's ability to respond to the needs of the public.

Innate Immune Responses and Gut Microbiomes Distinguish HIV-Exposed from HIV-Unexposed Children in a Population-Specific Manner.

In both high- and low-income countries, HIV-negative children born to HIV-positive mothers (HIV exposed, uninfected [HEU]) are more susceptible to severe infection than HIV-unexposed, uninfected (HUU) children, with altered innate immunity hypothesized to be a cause. Both the gut microbiome and systemic innate immunity differ across biogeographically distinct settings, and the two are known to influence each other. And although the gut microbiome is influenced by HIV infection and may contribute to altered immunity, the biogeography of immune-microbiome correlations among HEU children have not been investigated. To address this, we compared the innate response and the stool microbiome of 2-y-old HEU and HUU children from Belgium, Canada, and South Africa to test the hypothesis that region-specific immune alterations directly correlate to differences in their stool microbiomes. We did not detect a universal immune or microbiome signature underlying differences between HEU versus HUU that was applicable to all children. But as hypothesized, population-specific differences in stool microbiomes were readily detected and included reduced abundances of short-chain fatty acid-producing bacteria in Canadian HEU children. Furthermore, we did not identify innate immune-microbiome associations that distinguished HEU from HUU children in any population. These findings suggest that maternal HIV infection is independently associated with differences in both innate immunity and the stool microbiome in a biogeographical population-specific way.

Acceptance- and mindfulness-based techniques for physical activity promotion in breast cancer survivors: a qualitative study.

PURPOSE: The purpose of this study was to develop and characterize the relevance and potential utility of an electronically delivered acceptance- and mindfulness-based approaches to physical activity promotion for insufficiently active breast cancer survivors. METHODS: The acceptance- and mindfulness-based physical activity intervention was delivered to participants electronically over the course of 4-8 weeks. It consisted of didactic videos, experiential exercises, and workbook-type activities that targeted principles from acceptance and commitment therapy (ACT). We conducted semi-structured, in-depth interviews with participants after they completed the intervention. Three coders conducted qualitative data analysis on interview transcripts to identify overarching themes and subthemes. RESULTS: We recruited 30 participants. Of those, 16 engaged in an individual interview. The mean age of the sample was 58.4 years (SD = 13.8). The sample was relatively well educated (50.0% college graduates) and mostly overweight or obese (58.8%). We identified two overarching themes from interviews. They were centered on (1) internal and external barriers to physical activity adherence and (2) the utility of targeting core ACT processes (acceptance and defusion, mindfulness, and values clarification) for physical activity promotion. CONCLUSION: Intervention content was perceived to be acceptable, relevant, and to fulfill important needs related to healthy living. Findings suggest that this approach to physical activity promotion can be delivered effectively online. Electronically delivered acceptance- and mindfulness-based approaches hold promise for helping insufficiently active breast cancer survivors increase physical activity.

Screening for Obstructive Sleep Apnea in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Obstructive sleep apnea (OSA) is associated with adverse health outcomes. Objective: To review the evidence on screening for OSA in asymptomatic adults or those with unrecognized OSA symptoms to inform the US Preventive Services Task Force. Data Sources: PubMed/MEDLINE, Cochrane Library, Embase, and trial registries through August 23, 2021; surveillance through September 23, 2022. Study Selection: English-language studies of screening test accuracy, randomized clinical trials (RCTs) of screening or treatment of OSA reporting health outcomes or harms, and systematic reviews of treatment reporting changes in blood pressure and apnea-hypopnea index (AHI) scores. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality. Meta-analysis of intervention trials. Main Outcomes and Measures: Test accuracy, excessive daytime sleepiness, sleep-related and general health-related quality of life (QOL), and harms. Results: Eighty-six studies were included (N = 11 051). No study directly compared screening with no screening. Screening accuracy of the Multivariable Apnea Prediction score followed by unattended home sleep testing for detecting severe OSA syndrome (AHI ≥30 and Epworth Sleepiness Scale [ESS] score >10) measured as the area under the curve in 2 studies (n = 702) was 0.80 (95% CI, 0.78 to 0.82) and 0.83 (95% CI, 0.77 to 0.90). Five studies assessing the accuracy of other screening tools were heterogeneous and results were inconsistent. Compared with inactive control, positive airway pressure was associated with a significant improvement in ESS score from baseline (pooled mean difference, -2.33 [95% CI, -2.75 to -1.90]; 47 trials; n = 7024), sleep-related QOL (standardized mean difference, 0.30 [95% CI, 0.19 to 0.42]; 17 trials; n = 3083), and general health-related QOL measured by the 36-Item Short Form Health Survey (SF-36) mental health component summary score change (pooled mean difference, 2.20 [95% CI, 0.95 to 3.44]; 15 trials; n = 2345) and SF-36 physical health component summary score change (pooled mean difference, 1.53 [95% CI, 0.29 to 2.77]; 13 trials; n = 2031). Use of mandibular advancement devices was also associated with a significantly larger ESS score change compared with controls (pooled mean difference, -1.67 [95% CI, 2.09 to -1.25]; 10 trials; n = 1540). Reporting of other health outcomes was sparse; no included trial found significant benefit associated with treatment on mortality, cardiovascular events, or motor vehicle crashes. In 3 systematic reviews, positive airway pressure was significantly associated with reduced blood pressure; however, the difference was relatively small (2-3 mm Hg). Conclusions and Relevance: The accuracy and clinical utility of OSA screening tools that could be used in primary care settings were uncertain. Positive airway pressure and mandibular advancement devices reduced ESS score. Trials of positive airway pressure found modest improvement in sleep-related and general health-related QOL but have not established whether treatment reduces mortality or improves most other health outcomes.

Estimating Public Health Workforce Efforts Toward Foundational Public Health Services.

CONTEXT: The Foundational Public Health Services (FPHS) include a core set of activities that every health department should be able to provide in order to ensure that each resident has access to foundational services that protect and preserve health. Estimates of the public health workforce necessary to provide the FPHS are needed. OBJECTIVE: This study assessed the potential use of an FPHS calculator to assess health department workforce needs. DESIGN AND SETTING: Qualitative interviews were conducted via Zoom in December 2020-January 2021. PARTICIPANTS: Seventeen state and local public health leaders. MAIN OUTCOME MEASURES: Qualitative insights into the potential use of an FPHS calculator. RESULTS: Almost all participants expressed that a reliable estimate would help them justify requests for new staff and that a calculator based on the FPHS would help organizations to critically assess whether they are meeting the needs of their communities and the core expectations of public health. Although participants expected that a tool to calculate full-time equivalent needs by the FPHS would be helpful, some participants expressed concerns in regard to using the tool, given ongoing workforce issues such as recruitment challenges, hiring freezes, and funding restrictions. An anticipated positive consequence of using this tool was that it may lead to cross-training the workforce and result in more diverse expertise and skills among existing workers. The other unintended consequences were that an FPHS calculator would require a substantial amount of time assessing the current FPHS efforts of existing staff and the results of the FPHS gap estimate could become the bar rather than the minimum needed. CONCLUSIONS: The current public and political focus on public health infrastructure as a result of the COVID-19 pandemic has created a window of opportunity to create change. An FPHS-based staffing tool may help transform public health and initiate a new era.

Regarding Investment in a Healthier Future: Impact of the 2012 Institute of Medicine Finance Report.

CONTEXT: Governments at all levels work to ensure a healthy public, yet financing, organization, and delivery of public health services differ across the United States. A 2012 Institute of Medicine Finance report provided a series of recommendations to ensure a high-performing and adequately funded public health infrastructure. OBJECTIVES: This review examines the influence of the Finance report's 10 recommendations on public health policy and practice. DESIGN: This review utilized peer-reviewed and gray literature published since 2012. ELIGIBILITY CRITERIA: Documents that address at least one of the Finance report's 10 recommendations and contain information on either official actions taken in response to the Finance report or evidence of the report's influence on the practice community. RESULTS: Of 2394 unique documents found, a total of 56 documents met the eligibility criteria. Review of these 56 documents indicated that the most substantial activity related to the recommendations was focused on the "minimum package of public health services" concept and establishment of a uniform chart of accounts. DISCUSSION: Progress has been mixed on the Finance report recommendations. Improved tracking and auditing of public health activity appears to be advancing, yet financial benchmarks remain unmet. Challenges remain in determining actual investment in public health and equitable resource allocation approaches. State and local health department use of cost estimation methodology and a uniform chart of accounts tool has contributed to an increase in understanding and improvement in public health spending. CONCLUSIONS: The Finance report has served as a strong impetus for advocating for an increased investment in governmental public health. Efforts are bolstered by informed public health practitioners and stakeholders but often stymied by policy makers who must balance complex competing issues and priorities. Although many successes have occurred, further work is needed toward improving investment in the nation's public health.

Funding Public Health: Achievements and Challenges in Public Health Financing Since the Institute of Medicine's 2012 Report.

OBJECTIVE: The purpose of this study was to review changes in public health finance since the 2012 Institute of Medicine (IOM) report "For the Public's Health: Investing in a Healthier Future." DESIGN: Qualitative study involving key informant interviews. SETTING AND PARTICIPANTS: Purposive sample of US public health practitioners, leaders, and academics expected to be knowledgeable about the report recommendations, public health practice, and changes in public health finance since the report. MAIN OUTCOME MEASURES: Qualitative feedback about changes to public health finance since the report. RESULTS: Thirty-two interviews were conducted between April and May 2019. The greatest momentum toward the report recommendations has occurred predominantly at the state and local levels, with recommendations requiring federal action making less progress. In addition, much of the progress identified is consensus building and preparation for change rather than clear changes. Overall, progress toward the recommendations has been slow. CONCLUSIONS: Many of the achievements reported by respondents were characterized as increased dialogue and individual state or local progress rather than widespread, identifiable policy or practice changes. Participants suggested that public health as a field needs to achieve further consensus and a uniform voice in order to advocate for changes at a federal level. IMPLICATIONS FOR POLICY AND PRACTICE: Slow progress in achieving 2012 IOM Finance Report recommendations and lack of a cohesive voice pose threats to the public's health, as can be seen in the context of COVID-19 emergency response activities. The pandemic and the nation's inadequate response have highlighted deficiencies in our current system and emphasize the need for coordinated and sustained core public health infrastructure funding at the federal level.

Work-life balance among health administration faculty before and during the COVID-19 pandemic.

This current study examines measures of work-life balance among health administration faculty prior to and during the COVID-19 pandemic. A repeated cross-sectional design is used to analyze data collected from a national survey in 2018 and 2021. Changes in six different outcome measures of work-life balance were examined using multivariable logistic regression, controlling for health administration faculty characteristics. Compared to 2018 respondents, faculty respondents in 2021 were more likely to report that family and personal matters were interfering with their ability to do their job (OR = 1.93, p=0.001). Females more frequently reported that their career had suffered because of personal issues/obligations (OR = 1.82, p=0.003) but were less likely to report having enough time to get their teaching (OR = 0.68, p=0.026). Respondents with children 18 years or younger reported higher rates of regularly having to miss a meeting or event at home (OR = 1.88, p<0.001) and an event at work (OR = 3.74, p<0.001). These faculty also more frequently reported that family or personal matters were interfering with their ability to do their job (OR = 3.04, p<0.001) and that their career suffered because of personal issues/obligations (OR = 2.09, p=0.001). Given the implications of work-life conflicts to organizational outcomes, academic leaders and university decision-makers should consider adopting strategies to mitigate the effects of these disruptions to the work-life equilibrium of academics.

Faculty salaries in health administration: trends and correlates 2015-2021.

In this study, we provide updated information on salaries of academic health administration (HA) faculty members based on data collected in 2015, 2018, and 2021 and examine characteristics associated with earnings. We present mean inflation-adjusted salaries by demographic characteristics, education, experience, productivity, and job activities. We find that salaries of assistant, associate, and full professors have kept up with inflation and there have not been significant changes in salary by any characteristics over time. As in previous iterations of similar survey data, there remain differences in salary by both gender and race. Higher salaries were associated with having a 12-month contract, being tenured or tenure-track, having an administrative position, and being in a department whose focus is not primarily teaching. Findings from our study will be of interest to individuals on the HA job market, hiring committees, and doctoral students preparing for a position after graduation.

Ontogeny of plasma cytokine and chemokine concentrations across the first week of human life.

INTRODUCTION/BACKGROUND & AIMS: Early life is marked by distinct and rapidly evolving immunity and increased susceptibility to infection. The vulnerability of the newborn reflects development of a complex immune system in the face of rapidly changing demands during the transition to extra-uterine life. Cytokines and chemokines contribute to this dynamic immune signaling network and can be altered by many factors, such as infection. Newborns undergo dynamic changes important to health and disease, yet there is limited information regarding human neonatal plasma cytokine and chemokine concentrations over the first week of life. The few available studies are limited by small sample size, cross-sectional study design, or focus on perturbed host states like severe infection or prematurity. To characterize immune ontogeny among healthy full-term newborns, we assessed plasma cytokine and chemokine concentrations across the first week of life in a robust longitudinal cohort of healthy, full-term African newborns. METHODS: We analyzed a subgroup of a cohort of healthy newborns at the Medical Research Council Unit in The Gambia (West Africa; N = 608). Peripheral blood plasma was collected from all study participants at birth (day of life (DOL) 0) and at one follow-up time point at DOL 1, 3, or 7. Plasma cytokine and chemokine concentrations were measured by bead-based cytokine multiplex assay. Unsupervised clustering was used to identify patterns in plasma cytokine and chemokine ontogeny during early life. RESULTS: We observed an increase across the first week of life in plasma Th1 cytokines such as IFNγ and CXCL10 and a decrease in Th2 and anti-inflammatory cytokines such as IL-6 and IL-10, and chemokines such as CXCL8. In contrast, other cytokines and chemokines (e.g. IL-4 and CCL5, respectively) remained unchanged during the first week of life. This robust ontogenetic pattern did not appear to be affected by gestational age or sex. CONCLUSIONS: Ontogeny is a strong driver of newborn plasma-based levels of cytokines and chemokines throughout the first week of life with a rising IFNγ axis suggesting post-natal upregulation of host defense pathways. Our study will prove useful to the design and interpretation of future studies aimed at understanding the neonatal immune system during health and disease.

Epiphyseal cartilage canal architecture and extracellular matrix remodeling in mucopolysaccharidosis VII dogs at the onset of postnatal growth.

Purpose: Mucopolysaccharidosis (MPS) VII is a genetic, lysosomal storage disease characterized by abnormal accumulation of glycosaminoglycans in cells and tissues. MPS VII patients exhibit multiple failures of endochondral ossification during postnatal growth, including markedly delayed cartilage-to-bone conversion in the vertebrae and long bones. Cartilage canals provide the template for vascularization at the onset of secondary ossification. The objective of this study was to investigate whether abnormal cartilage canal architecture and enzyme-mediated extracellular matrix (ECM) remodeling contribute to delayed cartilage-to-bone conversion in MPS VII.Materials and Methods: The epiphyseal cartilage canal networks of 9-day-old healthy control and MPS VII-affected dog vertebrae were characterized using high-resolution, contrast-free quantitative susceptibility mapping magnetic resonance imaging. Relative expression levels of matrix metalloproteinases (MMPs) 9, 13 and 14 were examined using immunohistochemistry, while tartrate-resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP) were examined using in situ enzyme staining.Results: Interestingly, the density, number, connectivity and thickness of cartilage canals was not significantly different between MPS VII and control vertebrae. Immunohistochemistry revealed diminished MMP-9, but normal MMP-13 and 14 expression by epiphyseal cartilage chondrocytes, while ALP and TRAP enzyme expression by chondrocytes and chondroclasts, respectively, were both diminished in MPS VII.Conclusions: Our findings suggest that while the epiphyseal cartilage canal network in MPS VII is normal at the onset of secondary ossification, expression of enzymes required for cartilage resorption and replacement with mineralized ECM, and initiation of angiogenesis, is impaired.

Facility and resident characteristics associated with variation in nursing home transfers: evidence from the OPTIMISTIC demonstration project.

BACKGROUND: Centers for Medicare and Medicaid Services (CMS) funded demonstration project to evaluate financial incentives for nursing facilities providing care for 6 clinical conditions to reduce potentially avoidable hospitalizations (PAHs). The Optimizing Patient Transfers, Impacting Medical Quality, and Improving Symptoms: Transforming Institutional Care (OPTIMISTIC) site tested payment incentives alone and in combination with the successful nurse-led OPTIMISTIC clinical model. Our objective was to identify facility and resident characteristics associated with transfers, including financial incentives with or without the clinical model. METHODS: This was a longitudinal analysis from April 2017 to June 2018 of transfers among nursing home residents in 40 nursing facilities, 17 had the full clinical + payment model (1726 residents) and 23 had payment only model (2142 residents). Using CMS claims data, the Minimum Data Set, and Nursing Home Compare, multilevel logit models estimated the likelihood of all-cause transfers and PAHs (based on CMS claims data and ICD-codes) associated with facility and resident characteristics. RESULTS: The clinical + payment model was associated with 4.1 percentage points (pps) lower risk of all-cause transfers (95% confidence interval [CI] - 6.2 to - 2.1). Characteristics associated with lower PAH risk included residents aged 95+ years (- 2.4 pps; 95% CI - 3.8 to - 1.1), Medicare-Medicaid dual-eligibility (- 2.5 pps; 95% CI - 3.3 to - 1.7), advanced and moderate cognitive impairment (- 3.3 pps; 95% CI - 4.4 to - 2.1; - 1.2 pps; 95% CI - 2.2 to - 0.2). Changes in Health, End-stage disease and Symptoms and Signs (CHESS) score above most stable (CHESS score 4) increased the risk of PAH by 7.3 pps (95% CI 1.5 to 13.1). CONCLUSIONS: Multiple resident and facility characteristics are associated with transfers. Facilities with the clinical + payment model demonstrated lower risk of all-cause transfers compared to those with payment only, but not for PAHs.

Screening for Prediabetes and Type 2 Diabetes: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Type 2 diabetes is common and is a leading cause of morbidity and disability. Objective: To review the evidence on screening for prediabetes and diabetes to inform the US Preventive Services Task Force (USPSTF). Data Sources: PubMed/MEDLINE, Cochrane Library, and trial registries through September 2019; references; and experts; literature surveillance through May 21, 2021. Study Selection: English-language controlled studies evaluating screening or interventions for prediabetes or diabetes that was screen detected or recently diagnosed. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings; meta-analyses conducted when at least 3 similar studies were available. Main Outcomes and Measures: Mortality, cardiovascular morbidity, diabetes-related morbidity, development of diabetes, quality of life, and harms. Results: The review included 89 publications (N = 68 882). Two randomized clinical trials (RCTs) (25 120 participants) found no significant difference between screening and control groups for all-cause or cause-specific mortality at 10 years. For harms (eg, anxiety or worry), the trials reported no significant differences between screening and control groups. For recently diagnosed (not screen-detected) diabetes, 5 RCTs (5138 participants) were included. In the UK Prospective Diabetes Study, health outcomes were improved with intensive glucose control with sulfonylureas or insulin. For example, for all-cause mortality the relative risk (RR) was 0.87 (95% CI, 0.79 to 0.96) over 20 years (10-year posttrial assessment). For overweight persons, intensive glucose control with metformin improved health outcomes at the 10-year follow-up (eg, all-cause mortality: RR, 0.64 [95% CI, 0.45 to 0.91]), and benefits were maintained longer term. Lifestyle interventions (most involving >360 minutes) for obese or overweight persons with prediabetes were associated with reductions in the incidence of diabetes (23 RCTs; pooled RR, 0.78 [95% CI, 0.69 to 0.88]). Lifestyle interventions were also associated with improved intermediate outcomes, such as reduced weight, body mass index, systolic blood pressure, and diastolic blood pressure (pooled weighted mean difference, -1.7 mm Hg [95% CI, -2.6 to -0.8] and -1.2 mm Hg [95% CI, -2.0 to -0.4], respectively). Metformin was associated with a significant reduction in diabetes incidence (pooled RR, 0.73 [95% CI, 0.64 to 0.83]) and reduction in weight and body mass index. Conclusions and Relevance: Trials of screening for diabetes found no significant mortality benefit but had insufficient data to assess other health outcomes; evidence on harms of screening was limited. For persons with recently diagnosed (not screen-detected) diabetes, interventions improved health outcomes; for obese or overweight persons with prediabetes, interventions were associated with reduced incidence of diabetes and improvement in other intermediate outcomes.

DIABLO: an integrative approach for identifying key molecular drivers from multi-omics assays.

MOTIVATION: In the continuously expanding omics era, novel computational and statistical strategies are needed for data integration and identification of biomarkers and molecular signatures. We present Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO), a multi-omics integrative method that seeks for common information across different data types through the selection of a subset of molecular features, while discriminating between multiple phenotypic groups. RESULTS: Using simulations and benchmark multi-omics studies, we show that DIABLO identifies features with superior biological relevance compared with existing unsupervised integrative methods, while achieving predictive performance comparable to state-of-the-art supervised approaches. DIABLO is versatile, allowing for modular-based analyses and cross-over study designs. In two case studies, DIABLO identified both known and novel multi-omics biomarkers consisting of mRNAs, miRNAs, CpGs, proteins and metabolites. AVAILABILITY AND IMPLEMENTATION: DIABLO is implemented in the mixOmics R Bioconductor package with functions for parameters' choice and visualization to assist in the interpretation of the integrative analyses, along with tutorials on http://mixomics.org and in our Bioconductor vignette. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

7T bone perfusion imaging of the knee using arterial spin labeling MRI.

PURPOSE: To evaluate the feasibility of arterial spin labeling (ASL) imaging of epiphyseal bone marrow in the distal femoral condyle of the knee at 7T MRI. METHODS: The knees of 7 healthy volunteers were imaged with ASL using a 7T whole body MRI scanner and a 28-channel knee coil. ASL imaging used a flow-sensitive alternating inversion recovery method for labeling and a single-shot fast spin echo sequence for image readout. ASL imaging with a single oblique transverse slice was performed at 2 slice positions in the distal femoral condyle. Blood flow was measured in 2 regions of interest: the epiphyseal bone marrow and the overlying patellofemoral cartilage. To analyze perfusion SNR, 200 noise images were also acquired using the same ASL imaging protocol with RF pulses turned off. RESULTS: Knee bone marrow perfusion imaging was successfully performed with all volunteers. The overall mean of blood flow in the knee bone marrow was 32.90 ± 2.41 mL/100 g/min, and the blood flow was higher at the more distal slice position. We observed significant B0 and B1+ inhomogeneities, which need to be addressed in the future to improve the quality of ASL imaging and increase the reliability of knee bone marrow perfusion measurements. CONCLUSION: Bone marrow perfusion imaging of the distal femoral condyle is feasible using ASL at 7T. Further technical development is needed to improve the ASL method to overcome existing challenges.

Three-Dimensional GRE T1ρ mapping of the brain using tailored variable flip-angle scheduling.

PURPOSE: To introduce a new approach called tailored variable flip-angle (VFA) scheduling for SNR-efficient 3D T1ρ mapping of the brain using a magnetization-prepared gradient-echo sequence. METHODS: Simulations were used to assess the relative SNR efficiency, quantitative accuracy, and spatial blurring of tailored VFA scheduling for T1ρ mapping of brain tissue compared with magnetization-prepared angle-modulated partitioned k-space spoiled gradient-echo snapshots (MAPSS), a state-of-the-art technique for accurate 3D gradient-echo T1ρ mapping. Simulations were also used to calculate optimal imaging parameters for tailored VFA scheduling versus MAPSS, without and with nulling of CSF. Four participants were imaged at 3T MRI to demonstrate the feasibility of tailored VFA scheduling for T1ρ mapping of the brain. Using MAPSS as a reference standard, in vivo data were used to validate the relative SNR efficiency and quantitative accuracy of the new approach. RESULTS: Tailored VFA scheduling can provide a 2-fold to 4-fold gain in the SNR of the resulting T1ρ map as compared with MAPSS when using identical sequence parameters while limiting T1ρ quantification errors to 2% or less. In vivo whole-brain 3D T1ρ maps acquired with tailored VFA scheduling had superior SNR efficiency than is achievable with MAPSS, and the SNR efficiency improved with a greater number of views per segment. CONCLUSIONS: Tailored VFA scheduling is an SNR-efficient GRE technique for 3D T1ρ mapping of the brain that provides increased flexibility in choice of imaging parameters compared with MAPSS, which may benefit a variety of applications.