Game-Theoretic, Interposable Communication

Recent advances in distributed epistemologies and ubiquitous configurations have paved the way for superpages. Here, we show the explo- ration of thin clients. Here we disprove not only that superpages can be made “fuzzy”, “fuzzy”, and knowledge-based, but that the same is true for the UNIVAC computer

Wing Defects in Drosophila xenicid Mutant Clones Are Caused by C-Terminal Deletion of Additional Sex Combs (Asx)

Background: The coordinated action of genes that control patterning, cell fate determination, cell size, and cell adhesion is required for proper wing formation in Drosophila. Defects in any of these basic processes can lead to wing aberrations, including blisters. The xenicid mutation was originally identified in a screen designed to uncover regulators of adhesion between wing surfaces [1]. Principal Findings: Here, we demonstrate that expression of the bPS integrin or the patterning protein Engrailed are not affected in developing wing imaginal discs in xenicid mutants. Instead, expression of the homeotic protein Ultrabithorax (Ubx) is strongly increased in xenicid mutant cells. Conclusion: Our results suggest that upregulation of Ubx transforms cells from a wing blade fate to a haltere fate, and that the presence of haltere cells within the wing blade is the primary defect leading to the adult wing phenotypes observed

Lifetime Risk of Lower-Extremity Peripheral Artery Disease Defined by Ankle-Brachial Index in the United States.

Background There are no available lifetime risk estimates of lower-extremity peripheral artery disease (PAD). Methods and Results Using data from 6 US community-based cohorts and the vital statistics, we estimated the prevalence and incidence of PAD, defined as an ankle-brachial index < 0.90, at each year of age from birth to 80 years for white, black, and Hispanic men and women. Then, we used Markov Monte Carlo simulations in a simulated cohort of 100 000 individuals to estimate lifetime risk of PAD. On the basis of odds ratios of PAD for traditional atherosclerotic risk factors (eg, diabetes mellitus and smoking), we developed a calculator providing residual lifetime risk of PAD. In an 80-year horizon, lifetime risks of PAD were 30.0% in black men and 27.6% in black women, but ≈19% in white men and women and ≈22% in Hispanic men and women. From another perspective, 9% of blacks were estimated to develop PAD by 60 years of age, while the same proportion was seen at ≈70 years for whites and Hispanics. The residual lifetime risk within the same race/ethnicity varied by 3.5- to 5-fold according to risk factors (eg, residual lifetime risk in 45-year-old black men was 19.9% when current smoking, diabetes mellitus, and history of cardiovascular disease were absent versus 70.4% when all were present). Conclusions In the United States, ≈30% of blacks are estimated to develop PAD during their lifetime, whereas the corresponding estimate is ≈20% for whites and Hispanics. The residual lifetime risk within the same race/ethnicity substantially varies according to traditional risk factors

Precision medicine for suicidality: from universality to subtypes and personalization

Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a ‘liquid biopsy’ approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies. Such markers may reflect and/or be a proxy for the core biology of suicide. We were successful in this endeavor, using a comprehensive stepwise approach, leading to a wealth of findings. Steps 1, 2 and 3 were discovery, prioritization and validation for tracking suicidality, resulting in a Top Dozen list of candidate biomarkers comprising the top biomarkers from each step, as well as a larger list of 148 candidate biomarkers that survived Bonferroni correction in the validation step. Step 4 was testing the Top Dozen list and Bonferroni biomarker list for predictive ability for suicidal ideation (SI) and for future hospitalizations for suicidality in independent cohorts, leading to the identification of completely novel predictive biomarkers (such as CLN5 and AK2), as well as reinforcement of ours and others previous findings in the field (such as SLC4A4 and SKA2). Additionally, we examined whether subtypes of suicidality can be identified based on mental state at the time of high SI and identified four potential subtypes: high anxiety, low mood, combined and non-affective (psychotic). Such subtypes may delineate groups of individuals that are more homogenous in terms of suicidality biology and behavior. We also studied a more personalized approach, by psychiatric diagnosis and gender, with a focus on bipolar males, the highest risk group. Such a personalized approach may be more sensitive to gender differences and to the impact of psychiatric co-morbidities and medications. We compared testing the universal biomarkers in everybody versus testing by subtypes versus personalized by gender and diagnosis, and show that the subtype and personalized approaches permit enhanced precision of predictions for different universal biomarkers. In particular, LHFP appears to be a strong predictor for suicidality in males with depression. We also directly examined whether biomarkers discovered using male bipolars only are better predictors in a male bipolar independent cohort than universal biomarkers and show evidence for a possible advantage of personalization. We identified completely novel biomarkers (such as SPTBN1 and C7orf73), and reinforced previously known biomarkers (such as PTEN and SAT1). For diagnostic ability testing purposes, we also examined as predictors phenotypic measures as apps (for suicide risk (CFI-S, Convergent Functional Information for Suicidality) and for anxiety and mood (SASS, Simplified Affective State Scale)) by themselves, as well as in combination with the top biomarkers (the combination being our a priori primary endpoint), to provide context and enhance precision of predictions. We obtained area under the curves of 90% for SI and 77% for future hospitalizations in independent cohorts. Step 5 was to look for mechanistic understanding, starting with examining evidence for the Top Dozen and Bonferroni biomarkers for involvement in other psychiatric and non-psychiatric disorders, as a mechanism for biological predisposition and vulnerability. The biomarkers we identified also provide a window towards understanding the biology of suicide, implicating biological pathways related to neurogenesis, programmed cell death and insulin signaling from the universal biomarkers, as well as mTOR signaling from the male bipolar biomarkers. In particular, HTR2A increase coupled with ARRB1 and GSK3B decreases in expression in suicidality may provide a synergistic mechanistical corrective target, as do SLC4A4 increase coupled with AHCYL1 and AHCYL2 decrease. Step 6 was to move beyond diagnostics and mechanistical risk assessment, towards providing a foundation for personalized therapeutics. Items scored positive in the CFI-S and subtypes identified by SASS in different individuals provide targets for personalized (psycho)therapy. Some individual biomarkers are targets of existing drugs used to treat mood disorders and suicidality (lithium, clozapine and omega-3 fatty acids), providing a means toward pharmacogenomics stratification of patients and monitoring of response to treatment. Such biomarkers merit evaluation in clinical trials. Bioinformatics drug repurposing analyses with the gene expression biosignatures of the Top Dozen and Bonferroni-validated universal biomarkers identified novel potential therapeutics for suicidality, such as ebselen (a lithium mimetic), piracetam (a nootropic), chlorogenic acid (a polyphenol) and metformin (an antidiabetic and possible longevity promoting drug). Finally, based on the totality of our data and of the evidence in the field to date, a convergent functional evidence score prioritizing biomarkers that have all around evidence (track suicidality, predict it, are reflective of biological predisposition and are potential drug targets) brought to the fore APOE and IL6 from among the universal biomarkers, suggesting an inflammatory/accelerated aging component that may be a targetable common denominator

Toward the clinical application of time-domain fluorescence lifetime imaging

High-speed (video-rate) fluorescence lifetime imaging (FLIM) through a flexible endoscope is reported based on gated optical image intensifier technology. The optimization and potential application of FLIM to tissue autofluorescence for clinical applications are discussed. (c) 2005 Society of Photo-Optical Instrumentation Engineers

Partition Function Zeros and Finite Size Scaling of Helix-Coil Transitions in a Polypeptide

We report on multicanonical simulations of the helix-coil transition of a polypeptide. The nature of this transition was studied by calculating partition function zeros and the finite-size scaling of various quantities. Estimates for critical exponents are presented.Comment: RevTex, 4 eps-files; to appear in Phys. Rev. Le

Older adult preferences regarding benefits and harms of statin and aspirin therapy for cardiovascular primary prevention

OBJECTIVE Personalizing preventive therapies for atherosclerotic cardiovascular disease (ASCVD) is particularly important for older adults, as they tend to have multiple chronic conditions, increased risk for medication adverse effects, and may have heterogenous preferences when weighing health outcomes. However, little is known about outcome preferences related to ASCVD preventive therapies in older adults. METHODS In May 2021, using an established online panel, KnowledgePanel, we surveyed older US adults aged 65-84 years without history of ASCVD on outcome preferences related to statin therapy (benefit outcomes to be reduced by the therapy: heart attack, stroke; adverse effects: diabetes, abnormal liver test, muscle pain) or aspirin therapy (benefit outcomes: heart attack, stroke; adverse effects: brain bleed, bowel bleed, stomach ulcer). We used standardized best-worst scores (range of -1 for "least worrisome" to +1 for "most worrisome") and conditional logistic regression to examine the relative importance of the outcomes. RESULTS In this study, 607 ASCVD-free participants (median age 74, 46% male, 81% White) were included; 304 and 303 completed the statin and aspirin versions of the survey, respectively. For statin-related outcomes, stroke and heart attack were most worrisome (score 0.55; 95% CI 0.51, 0.60) and (0.53; 0.48, 0.58), followed by potential harms of diabetes (-0.07; -0.10, -0.03), abnormal liver test (-0.25; -0.29, -0.20), and muscle pain (-0.77; -0.82, -0.73). For aspirin-related outcomes, stroke and heart attack were similarly most worrisome (0.48; 0.43, 0.52) and (0.43; 0.38, 0.48), followed by brain bleed (0.30; 0.25, 0.34), bowel bleed (-0.31; -0.33, -0.28), and stomach ulcer (-0.90; -0.92, -0.87). Conditional logistic regression and subgroup analyses by age, sex, and race yielded similar results. CONCLUSIONS Older adults generally consider outcomes related to benefits of ASCVD primary preventive therapies-stroke and heart attack-more important than their adverse effects. Integrating patient preferences with risk assessment is an important next step for personalizing ASCVD preventive therapies for older adults

Defining Demographic-specific Coronary Artery Calcium Percentiles in the Population Aged ≥75: The ARIC Study and MESA

BackgroundCurrent clinical guidelines recommend a coronary artery calcium (CAC) score of 100 Agatston Units or demographic-specific 75th percentile as high-risk thresholds for guiding atherosclerotic cardiovascular disease preventive therapy. Meanwhile, low CAC can help derisk individuals who may safely defer statin therapy. However, limited data from the early 2000s, including just 208 older Black individuals, inform CAC percentiles for adults aged 75 to 85 years, and none have been established in adults aged ≥85 years. This study aims to characterize the distribution of CAC and establish demographic-specific CAC percentiles in the population aged ≥75 years.MethodsWe assessed 2886 participants aged ≥75 years without clinical coronary heart disease from the ARIC study (Atherosclerosis Risk in Communities) visit 7 (2018-2019; n=2217) and the MESA (Multi-Ethnic Study of Atherosclerosis) visit 5 (2010-2011; n=669). Prevalence of any CAC >0 and sex- and race-specific CAC percentiles across age were estimated nonparametrically with locally weighted regression models and pooled residual ranking.ResultsThe median age was 80 (interquartile interval, 77-83) years, and 60% were female. The prevalence of zero CAC was lowest in White males (4%), followed by Black males (13%), White females (14%), and highest in Black females (18%). Regardless of sex and race, most participants had CAC>100 (62.5%). CAC scores increased with age, with CAC identified in ≈95% of participants aged ≥90 years across sex-race subgroups. The 75th percentile corresponded to higher CAC scores for Black older adults (n=741), especially females, than currently used thresholds.ConclusionsIn community-dwelling adults aged ≥75 years free of clinical coronary heart disease, the prevalence of zero CAC was 11%, and CAC >100 as a threshold for high ASCVD risk would categorize most of this older population as high risk. Demographic-specific CAC percentiles from this study are a valuable tool for interpreting CAC in the population aged ≥75 years

The Utility of ctDNA in Lung Cancer Clinical Research and Practice: A Systematic Review and Meta-Analysis of Clinical Studies.

This systematic review with embedded meta-analysis aimed to evaluate the clinical utility of circulating tumor DNA (ctDNA) in lung cancer. After screening and review of the Embase database search, 111 studies from 2015 to 2020 demonstrated ctDNA's value in prognostication/monitoring disease progression, mainly in patients with advanced/metastatic disease and non-small cell lung cancer. ctDNA positivity/detection at any time point was associated with shorter progression-free survival and overall survival, whereas ctDNA clearance/decrease during treatment was associated with a lower risk of progression and death. Validating these findings and addressing challenges regarding ctDNA testing integration into clinical practice will require further research

Numerical comparison of two approaches for the study of phase transitions in small systems

We compare two recently proposed methods for the characterization of phase transitions in small systems. The validity and usefulness of these approaches are studied for the case of the q=4 and q=5 Potts model, i.e. systems where a thermodynamic limit and exact results exist. Guided by this analysis we discuss then the helix-coil transition in polyalanine, an example of structural transitions in biological molecules.Comment: 16 pages and 7 figure