Associations of Relative Intensity of Physical Activity with Incident Cardiovascular Events and All-Cause Mortality.

BACKGROUND: The relative intensity of a physical activity (PA) can be estimated as the percent of one's maximal effort required. METHODS: We compared associations of relative and absolute intensity PA with incident major cardiovascular disease (CVD) and all-cause mortality in 5,633 women from the Objective Physical Activity and Cardiovascular Health Study (mean age 78.5±6.7). Absolute intensity was measured by accelerometry. Relative intensity was estimated by dividing accelerometer-estimated metabolic equivalents (METs) by maximal MET capacity. Both were aggregated into mean daily hours of light intensity PA (LPA) and moderate-to-vigorous PA (MVPA). Cox proportional hazards models estimated hazard ratios (HRs) for one-hour higher amounts of PA on outcomes. RESULTS: During follow-up (median=7.4 years), there were 748 incident CVD events and 1,312 deaths. Greater LPA and MVPA, on either scale, was associated with reduced risk of both outcomes. HRs for a one-hour increment of absolute LPA were 0.88 (95% CI:0.83-0.93) and 0.88 (95% CI:0.84-0.92) for incident CVD and mortality, respectively. HRs for a one-hour increment of absolute MPVA were 0.73 (95% CI:0.61-0.87) and 0.55 (95% CI:0.48-0.64) for the same outcomes. HRs for a one-hour increment of relative LPA were 0.70 (95% CI:0.59-0.84) and 0.78 (95% CI:0.68-0.89) for incident CVD and mortality, respectively. HRs for a one-hour increment of relative MPVA were 0.89 (95% CI:0.83-0.96) and 0.82 (95% CI:0.77-0.87) for the same outcomes. On the relative scale, LPA was more strongly, inversely associated with both outcomes than relative MVPA. Absolute MVPA was more strongly inversely associated with the outcomes than relative MVPA. CONCLUSION: Findings support the continued shift in the PA intensity paradigm towards recommendation of more movement, regardless of intensity. Relative LPA--a modifiable, more easily achieved behavioral target, particularly among ambulatory older adults--was associated with reduced risk of incident major CVD and death.

Development, validation, and transportability of several machine-learned, non-exercise-based VO2max prediction models for older adults.

PURPOSE: There exist few maximal oxygen uptake (VO2max) non-exercise-based prediction equations, fewer using machine learning (ML), and none specifically for older adults. Since direct measurement of VO2max is infeasible in large epidemiologic cohort studies, we sought to develop, validate, compare, and assess the transportability of several ML VO2max prediction algorithms. METHODS: The Baltimore Longitudinal Study of Aging (BLSA) participants with valid VO2max tests were included (n = 1080). Least absolute shrinkage and selection operator, linear- and tree-boosted extreme gradient boosting, random forest, and support vector machine (SVM) algorithms were trained to predict VO2max values. We developed these algorithms for: (a) for the overall BLSA, (b) by sex, (c) using all BLSA variables, and (d) for variables common in aging cohorts. Finally, we quantified the associations between measured and predicted VO2max and mortality. RESULTS: The age was 69.0 ± 10.4 years (mean ± SD) and the measured VO2max was 21.6 ± 5.9 mL/kg/min. Least absolute shrinkage and selection operator, linear- and tree-boosted extreme gradient boosting, random forest, and support vector machine yielded root mean squared errors of 3.4 mL/kg/min, 3.6 mL/kg/min, 3.4 mL/kg/min, 3.6 mL/kg/min, and 3.5 mL/kg/min, respectively. Incremental quartiles of measured VO2max showed an inverse gradient in mortality risk. Predicted VO2max variables yielded similar effect estimates but were not robust to adjustment. CONCLUSION: Measured VO2max is a strong predictor of mortality. Using ML can improve the accuracy of prediction as compared to simpler approaches but estimates of association with mortality remain sensitive to adjustment. Future studies should seek to reproduce these results so that VO2max, an important vital sign, can be more broadly studied as a modifiable target for promoting functional resiliency and healthy aging.

The association between frailty and perceived physical and mental fatigability: The Long Life Family Study.

BACKGROUND: Higher levels of frailty, quantified by a frailty index (FI), may be linked to fatigue severity as tasks become more physically and mentally demanding. Fatigue, a component of frailty research, has been ambiguous and inconsistent in its operationalization. Fatigability-the quantification of vulnerability to fatigue in relation to specific intensity and duration of activities-offers a more sensitive and standardized approach, though the association between frailty and fatigability has not been assessed. METHODS: Using cross-sectional data from the Long Life Family Study at Visit 2 (2014-2017; N = 2524; mean age ± standard deviation (SD) 71.4 ± 11.2 years; 55% women; 99% White), we examined associations between an 83-item FI after excluding fatigue items (ratio of number of health problems reported (numerator) out of the total assessed (denominator); higher ratio = greater frailty) and perceived physical and mental fatigability using the Pittsburgh Fatigability Scale (PFS) (range 0-50; higher scores = greater fatigability). RESULTS: Participants had mean ± standard deviation FI (0.08 ± 0.06; observed range: 0.0-0.43), PFS Physical (13.7 ± 9.6; 39.5% more severe, ≥15), and PFS Mental (7.9 ± 8.9; 22.8% more severe, ≥13). The prevalence of more severe physical and mental fatigability was higher across FI quartiles. In mixed effects models accounting for family structure, a clinically meaningful 3%-higher FI was associated with 1.9 points higher PFS Physical score (95% confidence interval (CI) 1.7-2.1) and 1.7 points higher PFS Mental score (95% CI 1.5-1.9) after adjusting for covariates. CONCLUSIONS: Frailty was associated with perceived physical and mental fatigability severity. Understanding this association may support the development of interventions to mitigate the risks associated with greater frailty and perceived fatigability. Including measurements of perceived fatigability, in lieu of fatigue, in frailty indices has the potential to alleviate the inconsistencies and ambiguity surrounding the operationalization of fatigue and provide a more precise and sensitive measurement of frailty.

Lower Physical Activity Modifies the Association between Perceived Fatigability and Executive Function but not Memory: The Study of Muscle, Mobility and Aging (SOMMA).

OBJECTIVE: Emerging evidence shows that perceived fatigability-the quantification of vulnerability to fatigue in relation to specific intensity and duration of activities-may be associated with cognitive function. We sought to quantify associations with multiple domains of cognitive function and the role of physical activity (PA). METHODS: SOMMA participants completed the Pittsburgh Fatigability Scale (PFS) Physical and Mental subscales (each range 0-50; higher scores=greater fatigability) and three cognitive function assessments [Digit Symbol Substitution Test (DSST), executive function; Montreal Cognitive Assessment (MoCA), general function; and California Verbal Learning Test (CVLT), memory]. Linear regression quantified associations cross-sectionally between each PFS subscale and cognitive assessment scores adjusting for covariates. Effect modification by volume and intensity of accelerometer-measured PA was assessed. RESULTS: In 873 participants (59.2% women; age 76.3±5.0; 85% White), mean PFS Physical, Mental, and DSST scores were 15.8±8.7, 7.7±7.8, and 55.4±13.7. After adjustments, for each 4-point higher PFS Physical and 3-point higher PFS Mental, participants had nearly one fewer correct DSST items [ß coefficient and 95% confidence interval for PFS Physical: -0.69 (-1.09, - 0.29); PFS Mental: -0.64 (-0.97, -0.30)]. Volume and intensity of PA modified the association of PFS Mental and DSST ( P interactions <0.01). All associations were strongest in those with the lowest volume and intensity of PA. PFS was not associated with MoCA or CVLT. DISCUSSION: Greater perceived fatigability may be associated with poorer executive function, but not memory. Individuals with greater perceived fatigability, particularly those less active, might benefit from interventions that reduce fatigability and may beneficially influence cognitive function.

AZG1 is a cytokinin transporter that interacts with auxin transporter PIN1 and regulates the root stress response.

An environmentally responsive root system is crucial for plant growth and crop yield, especially in suboptimal soil conditions. This responsiveness enables the plant to exploit regions of high nutrient density while simultaneously minimizing abiotic stress. Despite the vital importance of root systems in regulating plant growth, significant gaps of knowledge exist in the mechanisms that regulate their architecture. Auxin defines both the frequency of lateral root (LR) initiation and the rate of LR outgrowth. Here, we describe a search for proteins that regulate root system architecture (RSA) by interacting directly with a key auxin transporter, PIN1. The native separation of Arabidopsis plasma membrane protein complexes identified several PIN1 co-purifying proteins. Among them, AZG1 was subsequently confirmed as a PIN1 interactor. Here, we show that, in Arabidopsis, AZG1 is a cytokinin (CK) import protein that co-localizes with and stabilizes PIN1, linking auxin and CK transport streams. AZG1 expression in LR primordia is sensitive to NaCl, and the frequency of LRs is AZG1-dependent under salt stress. This report therefore identifies a potential point for auxin:cytokinin crosstalk, which shapes RSA in response to NaCl.

Prenatal cannabis use disorder and infant hospitalization and death in the first year of life.

OBJECTIVE: To determine whether maternal cannabis use disorder is associated with infant hospitalization or death in the first year of life. METHODS: We queried an administrative birth cohort derived from the hospital discharge database maintained by the California Office of Statewide Health Planning and Development and linked with vital statistics files. We included singleton, live-birth deliveries between 2011 and 2018. Pregnancies with cannabis use disorder were classified from International Classification of Disease codes. Outcomes included infant emergency department visits and hospital admissions identified from health records, and infant deaths identified from death records. Models were adjusted for sociodemographic variables, psychiatric comorbidities and other substance use disorders. RESULTS: There were 34,544 births (1.0 %) with a cannabis use disorder diagnosis in pregnancy, with increasing prevalence over the study period. The incidence of infant death in the first year of life was greater among those with a maternal cannabis use disorder diagnosis than those without (1.0 % vs 0.4 %; adjusted risk ratio 1.4 95 % CI: 1.2-1.6). When examining specific causes of death, the increased risk estimates were attributable to perinatal conditions and sudden unexpected infant death. After adjustment, there was no increased risk of infant hospitalizations or emergency department visits. CONCLUSIONS: These findings warrant further investigation into the underlying mechanisms of maternal prenatal CUD on infant outcomes, and add to a rapidly expanding body of literature supporting the need for effective treatment options for pregnant individuals with cannabis use disorders.

Validation, Recalibration, and Predictive Accuracy of Published V̇O 2max Prediction Equations for Adults Ages 50-96 Yr.

PURPOSE: Maximal oxygen uptake ( ) is the criterion measure of cardiorespiratory fitness. Lower cardiorespiratory fitness is a strong predictor of poor health outcomes, including all-cause mortality. Because testing is resource intensive, several non-exercise-based V˙O 2max prediction equations have been published. We assess these equations' ability to predict measured V˙O 2max , recalibrate these equations, and quantify the association of measured and predicted V˙O 2max with all-cause mortality. METHODS: Baltimore Longitudinal Study of Aging participants with valid V˙O 2max tests were included ( n = 1080). Using published V˙O 2max prediction equations, we calculated predicted V˙O 2max and present performance metrics before and after recalibration (deriving new regression estimates by regressing measured V˙O 2max on Baltimore Longitudinal Study of Aging covariates). Cox proportional hazards models were fit to quantify associations of measured, predicted, and recalibration-predicted values of V˙O 2max with mortality. RESULTS: Mean age and V˙O 2max were 69.0 ± 10.4 yr and 21.6 ± 5.9 mL·kg -1 ·min -1 , respectively. The prediction equations yielded root mean square error values ranging from 4.2 to 20.4 mL·kg -1 ·min -1 . After recalibration, these values decreased to 3.9-4.2 mL·kg -1 ·min -1 . Adjusting for all covariates, all-cause mortality risk was 66% lower for the highest quartile of measured V˙O 2max relative to the lowest. Predicted V˙O 2max variables yielded similar estimates in unadjusted models but were not robust to adjustment. CONCLUSIONS: Measured V˙O 2max is an extremely strong predictor of all-cause mortality. Several published V˙O 2max prediction equations yielded the following: 1) reasonable performance metrics relative to measured V˙O 2max especially when recalibrated, and 2) all-cause mortality hazard ratios similar to those of measured V˙O 2max , especially when recalibrated, yet 3) were not robust to adjustment for basic demographic covariates likely because these were used in the equation for predicted V˙O 2max .

Interpretation of Quantum Theory: The Quantum "Grue-Bleen" Problem.

We present a critique of the many-world interpretation of quantum mechanics, based on different "pictures" that describe the time evolution of an isolated quantum system. Without an externally imposed frame to restrict these possible pictures, the theory cannot yield non-trivial interpretational statements. This is analogous to Goodman's famous "grue-bleen" problem of language and induction. Using a general framework applicable to many kinds of dynamical theories, we try to identify the kind of additional structure (if any) required for the meaningful interpretation of a theory. We find that the "grue-bleen" problem is not restricted to quantum mechanics, but also affects other theories including classical Hamiltonian mechanics. For all such theories, absent external frame information, an isolated system has no interpretation.

Relationship of Social Connectedness With Decreasing Physical Activity During the COVID-19 Pandemic Among Older Women Participating in the Women's Health Initiative Study.

BACKGROUND: Aging is generally accompanied by decreasing physical activity (PA), which is associated with a decline in many health parameters, leading to recommendations for older adults to increase or at least maintain PA. METHODS: We determined relationships between social connectedness and decreasing or increasing PA levels during the coronavirus disease 2019 pandemic among 41 443 participants of the Women's Health Initiative Extension Study. Outcomes of logistic regression models were decreasing PA activity (reference: maintaining or increasing) and increasing PA activity (reference: maintaining or decreasing). The main predictor was social connectedness as a combined variable: not living alone (reference: living alone) and communicating with others outside the home more than once/week (reference: once/week or less). We adjusted for age, race, ethnicity, body mass index, physical function level, and education. RESULTS: Compared with participants who were not socially connected, socially connected participants had lower odds of decreasing PA (adjusted odds ratio 0.91, 95% confidence interval 0.87-0.95). Odds of increasing PA (vs decreasing or maintaining PA) were not significantly different among socially connected and not socially connected participants. Associations between social connectedness and decreasing PA did not significantly differ by age (<85 vs ≥85 years), race/ethnicity (non-Hispanic White vs other races/ethnicity), education (college vs 75). CONCLUSION: Social connectedness was associated with lower odds of decreasing PA among older women during the pandemic. These findings could inform the development of future interventions to help older women avoid decreasing PA.

Associations of Daily Steps and Step Intensity With Incident Diabetes in a Prospective Cohort Study of Older Women: The OPACH Study.

OBJECTIVE: The primary aim was to assess associations between total steps per day and incident diabetes, whereas the secondary aim was to assess whether the intensity and/or cadence of steps is associated with incident diabetes. RESEARCH DESIGN AND METHODS: Women without physician-diagnosed diabetes (n = 4,838; mean [SD] age 78.9 [6.7] years) were followed up to 6.9 years; 395 developed diabetes. Hip-worn ActiGraph GT3X+ accelerometers worn for 1 week enabled measures of total, light-intensity, and moderate- to vigorous-intensity (MV-intensity) steps per day. Using Cox proportional hazards analysis we modeled adjusted change in the hazard rate for incident diabetes associated with total, light-intensity, and MV-intensity steps per day. We further estimated the proportion of the steps-diabetes association mediated by BMI. RESULTS: On average, participants took 3,729 (SD 2,114) steps/day, of which 1,875 (791) were light-intensity steps and 1,854 ± 1,762 were MV-intensity. More steps per day were associated with a lower hazard rate for incident diabetes. Confounder-adjusted models for a 2,000 steps/day increment yielded hazard ratio (HR) 0.88 (95% CI 0.78-1.00; P = 0.046). After further adjustment for BMI, HR was 0.90 (95% CI 0.80-1.02; P = 0.11). BMI did not significantly mediate the steps-diabetes association (proportion mediated = 17.7% [95% CI -55.0 to 142.0]; P = 0.09]). The relationship between MV-intensity steps per day (HR 0.86 [95% CI 0.74-1.00]; P = 0.04) and incident diabetes was stronger than for light-intensity steps per day (HR 0.97 [95% CI 0.73-1.29]; P = 0.84). CONCLUSIONS: These findings suggest that for older adults, more steps per day are associated with lower incident diabetes and MV-intensity steps are most strongly associated with a lower hazard of diabetes. This evidence supports that regular stepping is an important risk factor for type 2 diabetes prevention in older adults.

Accelerometer-Measured Daily Steps, Physical Function, and Subsequent Fall Risk in Older Women: The Objective Physical Activity and Cardiovascular Disease in Older Women Study.

Steps per day were measured by accelerometer for 7 days among 5,545 women aged 63-97 years between 2012 and 2014. Incident falls were ascertained from daily fall calendars for 13 months. Median steps per day were 3,216. There were 5,473 falls recorded over 61,564 fall calendar-months. The adjusted incidence rate ratio comparing women in the highest versus lowest step quartiles was 0.71 (95% confidence interval [0.54, 0.95]; ptrend across quartiles = .01). After further adjustment for physical function using the Short Physical Performance Battery, the incidence rate ratio was 0.86 ([0.64, 1.16]; ptrend = .27). Mediation analysis estimated that 63.7% of the association may be mediated by physical function (p = .03). In conclusion, higher steps per day were related to lower incident falls primarily through their beneficial association with physical functioning. Interventions that improve physical function, including those that involve stepping, could reduce falls in older adults.

Cohort profile: the Women's Health Accelerometry Collaboration.

PURPOSE: This paper describes the Women's Health Accelerometry Collaboration, a consortium of two prospective cohort studies of women age 62 years or older, harmonised to explore the association of accelerometer-assessed physical activity and sedentary behaviour with cancer incidence and mortality. PARTICIPANTS: A total of 23 443 women (age mean 73.4, SD 6.8) living in the USA and participating in an observational study were included; 17 061 from the Women's Health Study (WHS) and 6382 from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health (WHI/OPACH) Study. FINDINGS TO DATE: Accelerometry, cancer outcomes and covariate harmonisation was conducted to align the two cohort studies. Physical activity and sedentary behaviour were measured using similar procedures with an ActiGraph GT3X+ accelerometer, worn at the hip for 1 week, during 2011-2014 for WHS and 2012-2014 for WHI/OPACH. Cancer outcomes were ascertained via ongoing surveillance using physician adjudicated cancer diagnosis. Relevant covariates were measured using questionnaire or physical assessments. Among 23 443 women who wore the accelerometer for at least 10 hours on a single day, 22 868 women wore the accelerometer at least 10 hours/day on ≥4 of 7 days. The analytical sample (n=22 852) averaged 4976 (SD 2669) steps/day and engaged in an average of 80.8 (SD 46.5) min/day of moderate-to-vigorous, 105.5 (SD 33.3) min/day of light high and 182.1 (SD 46.1) min/day of light low physical activity. A mean of 8.7 (SD 1.7) hours/day were spent in sedentary behaviour. Overall, 11.8% of the cohort had a cancer diagnosis (other than non-melanoma skin cancer) at the time of accelerometry measurement. During an average of 5.9 (SD 1.6) years of follow-up, 1378 cancer events among which 414 were fatal have occurred. FUTURE PLANS: Using the harmonised cohort, we will access ongoing cancer surveillance to quantify the associations of physical activity and sedentary behaviour with cancer incidence and mortality.

Contribution of Concurrent Comorbidities to Sepsis-Related Mortality in Preterm Infants ≤32 Weeks of Gestation at an Academic Neonatal Intensive Care Network.

OBJECTIVE: This study sought to identify concurrent major comorbidities in preterm infants ≤32 weeks of gestation that may have contributed to sepsis-related mortality following a diagnosis of bacteremia or blood culture-negative sepsis within the neonatal period (≤28 days of life). STUDY DESIGN: This is a retrospective chart review of infants ≤32 weeks of gestation who were admitted to a single academic network of multiple neonatal intensive care units between January 1, 2012, and December 31, 2015, to determine the primary cause(s) and timing of death in those diagnosed with bacteremia or blood culture-negative sepsis. Direct comparisons between early-onset sepsis (EOS; ≤72 hours) and late-onset sepsis (LOS; >72 hours) were made. RESULTS: In our study cohort, of 939 total patients with ≤32 weeks of gestation, 182 infants were diagnosed with 198 episodes of sepsis and 7.7% (14/182) died. Mortality rates did not significantly differ between neonates with bacteremia or blood culture-negative sepsis (7/14 each group), and those diagnosed with EOS compared with LOS (6/14 vs. 8/14). Nearly 80% (11/14) of infants were transitioned to comfort care prior to their death secondary to a coinciding diagnosis of severe grade-3 or -4 intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, and/or intestinal perforation. CONCLUSION: Preexisting comorbidities commonly associated with extreme preterm birth contributed to sepsis-related mortality in our patient cohort. KEY POINTS: · Concurrent comorbidities contribute to, and may artificially inflate, sepsis-related mortality.. · Absence of a consensus definition for neonatal sepsis complicates the investigation of infection.. · Accurate assessment of the incidence of sepsis in very low birth weight infants is vital for future investigations.

Cannabis-related diagnosis in pregnancy and adverse maternal and infant outcomes.

BACKGROUND: Cannabis use and cannabis use disorders are increasing in prevalence, including among pregnant women. The objective was to evaluate the association of a cannabis-related diagnosis (CRD) in pregnancy and adverse maternal and infant outcomes. METHODS: We queried an administrative birth cohort of singleton deliveries in California between 2011-2017 linked to maternal and infant hospital discharge records. We classified pregnancies with CRD from International Classification of Disease codes. We identified nicotine and other substance-related diagnoses (SRD) in the same manner. Outcomes of interest included maternal (hypertensive disorders) and infant (prematurity, small for gestational age, NICU admission, major structural malformations) adverse outcomes. RESULTS: From 3,067,069 pregnancies resulting in live births, 29,112 (1.0 %) had a CRD. CRD was associated with an increased risk of all outcomes studied; the strongest risks observed were for very preterm birth (aRR 1.4, 95 % CI 1.3, 1.6) and small for gestational age (aRR 1.4, 95 % CI 1.3, 1.4). When analyzed with or without co-exposure diagnoses, CRD alone conferred increased risk for all outcomes compared to no use. The strongest effects were seen for CRD with other SRD (preterm birth aRR 2.3, 95 % CI 2.2, 2.5; very preterm birth aRR 2.6, 95 % CI 2.3, 3.0; gastrointestinal malformations aRR 2.0, 95 % CI 1.6, 2.6). The findings were generally robust to unmeasured confounding and misclassification analyses. CONCLUSIONS: CRD in pregnancy was associated with increased risk of adverse maternal and infant outcomes. Providing education and effective treatment for women with a CRD during prenatal care may improve maternal and infant health.

Arabidopsis AZG2 transports cytokinins in vivo and regulates lateral root emergence.

Cytokinin and auxin are key regulators of plant growth and development. During the last decade transport mechanisms have turned out to be the key for the control of local and long-distance hormone distributions. In contrast with auxin, cytokinin transport is poorly understood. Here, we show that Arabidopsis thaliana AZG2, a member of the AZG purine transporter family, acts as cytokinin transporter involved in root system architecture determination. Even though purines are substrates for both AZG1 and AZG2, we found distinct transport mechanisms. The expression of AZG2 is restricted to a small group of cells surrounding the lateral root (LR) primordia and induced by auxins. Compared to the wild-type (WT), mutants carrying loss-of-function alleles of AZG2 have higher LR density, suggesting that AZG2 is part of a regulatory pathway in LR emergence. Moreover, azg2 is partially insensitive to exogenous cytokinin, which is consistent with the observation that the cytokinin reporter TCSnpro :GFP showed lower fluorescence signal in the roots of azg2 compared to the WT. These results indicate a defective cytokinin signalling pathway in the region of LR primordia. The integration of AZG2 subcellular localization and cytokinin transport capacity data allowed us to propose a local cytokinin : auxin signalling model for the regulation of LR emergence.

Population-Based Registry Linkages to Improve Validity of Electronic Health Record-Based Cancer Research.

BACKGROUND: There is tremendous potential to leverage the value gained from integrating electronic health records (EHR) and population-based cancer registry data for research. Registries provide diagnosis details, tumor characteristics, and treatment summaries, while EHRs contain rich clinical detail. A carefully conducted cancer registry linkage may also be used to improve the internal and external validity of inferences made from EHR-based studies. METHODS: We linked the EHRs of a large, multispecialty, mixed-payer health care system with the statewide cancer registry and assessed the validity of our linked population. For internal validity, we identify patients that might be "missed" in a linkage, threatening the internal validity of an EHR study population. For generalizability, we compared linked cases with all other cancer patients in the 22-county EHR catchment region. RESULTS: From an EHR population of 4.5 million, we identified 306,554 patients with cancer, 26% of the catchment region patients with cancer; 22.7% of linked patients were diagnosed with cancer after they migrated away from our health care system highlighting an advantage of system-wide linkage. We observed demographic differences between EHR patients and non-EHR patients in the surrounding region and demonstrated use of selection probabilities with model-based standardization to improve generalizability. CONCLUSIONS: Our experiences set the foundation to encourage and inform researchers interested in working with EHRs for cancer research as well as provide context for leveraging linkages to assess and improve validity and generalizability. IMPACT: Researchers conducting linkages may benefit from considering one or more of these approaches to establish and evaluate the validity of their EHR-based populations.See all articles in this CEBP Focus section, "Modernizing Population Science."

Axiomatic Information Thermodynamics.

We present an axiomatic framework for thermodynamics that incorporates information as a fundamental concept. The axioms describe both ordinary thermodynamic processes and those in which information is acquired, used and erased, as in the operation of Maxwell's demon. This system, similar to previous axiomatic systems for thermodynamics, supports the construction of conserved quantities and an entropy function governing state changes. Here, however, the entropy exhibits both information and thermodynamic aspects. Although our axioms are not based upon probabilistic concepts, a natural and highly useful concept of probability emerges from the entropy function itself. Our abstract system has many models, including both classical and quantum examples.

Involvement of 14-3-3 in tubulin instability and impaired axon development is mediated by Tau.

14-3-3 proteins act as adapters that exert their function by interacting with their various protein partners. 14-3-3 proteins have been implicated in a variety of human diseases including neurodegenerative diseases. 14-3-3 proteins have recently been reported to be abundant in the neurofibrillary tangles (NFTs) observed inside the neurons of brains affected by Alzheimer's disease (AD). These NFTs are mainly constituted of phosphorylated Tau protein, a microtubule-associated protein known to bind 14-3-3. Despite this indication of 14-3-3 protein involvement in the AD pathogenesis, the role of 14-3-3 in the Tauopathy remains to be clarified. In the present study, we shed light on the role of 14-3-3 proteins in the molecular pathways leading to Tauopathies. Overexpression of the 14-3-3σ isoform resulted in a disruption of the tubulin cytoskeleton and prevented neuritic outgrowth in neurons. NMR studies validated the phosphorylated residues pSer214 and pSer324 in Tau as the 2 primary sites for 14-3-3 binding, with the crystal structure of 14-3-3σ in complex with Tau-pSer214 and Tau-pSer324 revealing the molecular details of the interaction. These data suggest a rationale for a possible pharmacologic intervention of the Tau/14-3-3 interaction.

A semisynthetic fusicoccane stabilizes a protein-protein interaction and enhances the expression of K+ channels at the cell surface.

Small-molecule stabilization of protein-protein interactions is an emerging field in chemical biology. We show how fusicoccanes, originally identified as fungal toxins acting on plants, promote the interaction of 14-3-3 proteins with the human potassium channel TASK-3 and present a semisynthetic fusicoccane derivative (FC-THF) that targets the 14-3-3 recognition motif (mode 3) in TASK-3. In the presence of FC-THF, the binding of 14-3-3 proteins to TASK-3 was increased 19-fold and protein crystallography provided the atomic details of the effects of FC-THF on this interaction. We also tested the functional effects of FC-THF on TASK channels heterologously expressed in Xenopus oocytes. Incubation with 10 µM FC-THF was found to promote the transport of TASK channels to the cell membrane, leading to a significantly higher density of channels at the surface membrane and increased potassium current.

Structure of a 14-3-3σ-YAP phosphopeptide complex at 1.15 A resolution.

The 14-3-3 proteins are a class of eukaryotic acidic adapter proteins, with seven isoforms in humans. 14-3-3 proteins mediate their biological function by binding to target proteins and influencing their activity. They are involved in pivotal pathways in the cell such as signal transduction, gene expression, enzyme activation, cell division and apoptosis. The Yes-associated protein (YAP) is a WW-domain protein that exists in two transcript variants of 48 and 54 kDa in humans. By transducing signals from the cytoplasm to the nucleus, YAP is important for transcriptional regulation. In both variants, interaction with 14-3-3 proteins after phosphorylation of Ser127 is important for nucleocytoplasmic trafficking, via which the localization of YAP is controlled. In this study, 14-3-3σ has been cloned, purified and crystallized in complex with a phosphopeptide from the YAP 14-3-3-binding domain, which led to a crystal that diffracted to 1.15 A resolution. The crystals belonged to space group C222(1), with unit-cell parameters a=82.3, b=112.1, c=62.9 A.