Temporal trends in symptom experience predict the accuracy of recall PROs

Objective - Patient-reported outcome measures with reporting periods of a week or more are often used to evaluate the change of symptoms over time, but the accuracy of recall in the context of change is not well understood. This study examined whether temporal trends in symptoms that occur during the reporting period impact the accuracy of 7-day recall reports. Methods - Women with premenstrual symptoms (n = 95) completed daily reports of anger, depression, fatigue, and pain intensity for 4 weeks, as well as 7-day recall reports at the end of each week. Latent class growth analysis was used to categorize recall periods based on the direction and rate of change in the daily reports. Agreement (level differences and correlations) between 7-day recall and aggregated daily scores was compared for recall periods with different temporal trends. Results - Recall periods with positive, negative, and flat temporal trends were identified and they varied in accordance with weeks of the menstrual cycle. Replicating previous research, 7-day recall scores were consistently higher than aggregated daily scores, but this level difference was more pronounced for recall periods involving positive and negative trends compared with flat trends. Moreover, correlations between 7-day recall and aggregated daily scores were lower in the presence of positive and negative trends compared with flat trends. These findings were largely consistent for anger, depression, fatigue, and pain intensity. Conclusion - Temporal trends in symptoms can influence the accuracy of recall reports and this should be considered in research designs involving change

Psychometric characteristics of daily diaries for the Patient-Reported Outcomes Measurement Information System (PROMIS®): a preliminary investigation

Purpose - The Patient-Reported Outcomes (PRO) Measurement Information System (PROMIS®) has developed assessment tools for numerous PROs, most using a 7-day recall format. We examined whether modifying the recall period for use in daily diary research would affect the psychometric characteristics of several PROMIS measures. Methods - Daily versions of short-forms for three PROMIS domains (pain interference, fatigue, depression) were administered to a general population sample (n = 100) for 28 days. Analyses used multilevel item response theory (IRT) models. We examined differential item functioning (DIF) across recall periods by comparing the IRT parameters from the daily data with the PROMIS 7-day recall IRT parameters. Additionally, we examined whether the IRT parameters for day-to-day within-person changes are invariant to those for between-person (cross-sectional) differences in PROs. Results - Dimensionality analyses of the daily data suggested a single dimension for each PRO domain, consistent with PROMIS instruments. One-third of the daily items showed uniform DIF when compared with PROMIS 7-day recall, but the impact of DIF on the scale level was minor. IRT parameters for within-person changes differed from between-person parameters for 3 depression items, which were more sensitive for measuring change than between-person differences, but not for pain interference and fatigue items. Notably, mean scores from daily diaries were significantly lower than the PROMIS 7-day recall norms. Conclusions - The results provide initial evidence supporting the adaptation of PROMIS measures for daily diary research. However, scores from daily diaries cannot be directly interpreted on PROMIS norms established for 7-day recall

Clinic Blood Pressure Underestimates Ambulatory Blood Pressure in an Untreated Employer-Based US Population: Results From the Masked Hypertension Study

Background: Ambulatory blood pressure (ABP) is consistently superior to clinic blood pressure (CBP) as a predictor of cardiovascular morbidity and mortality risk. A common perception is that ABP is usually lower than CBP. The relationship of the CBP minus ABP difference to age has not been examined in the United States. Methods: Between 2005 and 2012, 888 healthy, employed, middle-aged (mean±SD age, 45±10.4 years) individuals (59% female, 7.4% black, 12% Hispanic) with screening BP <160/105 mm Hg and not taking antihypertensive medication completed 3 separate clinic BP assessments and a 24-hour ABP recording for the Masked Hypertension Study. The distributions of CBP, mean awake ABP (aABP), and the CBP−aABP difference in the full sample and by demographic characteristics were compared. Locally weighted scatterplot smoothing was used to model the relationship of the BP measures to age and body mass index. The prevalence of discrepancies in ABP- versus CBP-defined hypertension status—white-coat hypertension and masked hypertension—were also examined. Results: Average systolic/diastolic aABP (123.0/77.4±10.3/7.4 mm Hg) was significantly higher than the average of 9 CBP readings over 3 visits (116.0/75.4±11.6/7.7 mm Hg). aABP exceeded CBP by >10 mm Hg much more frequently than CBP exceeded aABP. The difference (aABP>CBP) was most pronounced in young adults and those with normal body mass index. The systolic difference progressively diminished, but did not disappear, at older ages and higher body mass indexes. The diastolic difference vanished around age 65 and reversed (CBP>aABP) for body mass index >32.5 kg/m2. Whereas 5.3% of participants were hypertensive by CBP, 19.2% were hypertensive by aABP; 15.7% of those with nonelevated CBP had masked hypertension. Conclusions: Contrary to a widely held belief, based primarily on cohort studies of patients with elevated CBP, ABP is not usually lower than CBP, at least not among healthy, employed individuals. Furthermore, a substantial proportion of otherwise healthy individuals with nonelevated CBP have masked hypertension. Demonstrated CBP−aABP gradients, if confirmed in representative samples (eg, NHANES [National Health and Nutrition Examination Survey]), could provide guidance for primary care physicians as to when, for a given CBP, 24-hour ABP would be useful to identify or rule out masked hypertension

Tumor cell–organized fibronectin maintenance of a dormant breast cancer population

Tumors can undergo long periods of dormancy, with cancer cells entering a largely quiescent, nonproliferative state before reactivation and outgrowth. To understand the role of the extracellular matrix (ECM) in regulating tumor dormancy, we created an in vitro cell culture system with carefully controlled ECM substrates to observe entrance into and exit from dormancy with live imaging. We saw that cell populations capable of surviving entrance into long-term dormancy were heterogeneous, containing quiescent, cell cycle–arrested, and actively proliferating cells. Cell populations capable of entering dormancy formed an organized, fibrillar fibronectin matrix via αvβ3 and α5β1 integrin adhesion, ROCK-generated tension, and TGFβ2 stimulation, and cancer cell outgrowth after dormancy required MMP-2–mediated fibronectin degradation. We propose this approach as a useful, in vitro method to study factors important in regulating dormancy, and we used it here to elucidate a role for fibronectin deposition and MMP activation

CRISPR/Cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus

Chronic hepatitis B virus (HBV) infection is prevalent, deadly, and seldom cured due to the persistence of viral episomal DNA (cccDNA) in infected cells. Newly developed genome engineering tools may offer the ability to directly cleave viral DNA, thereby promoting viral clearance. Here, we show that the CRISPR/Cas9 system can specifically target and cleave conserved regions in the HBV genome, resulting in robust suppression of viral gene expression and replication. Upon sustained expression of Cas9 and appropriately chosen guide RNAs, we demonstrate cleavage of cccDNA by Cas9 and a dramatic reduction in both cccDNA and other parameters of viral gene expression and replication. Thus, we show that directly targeting viral episomal DNA is a novel therapeutic approach to control the virus and possibly cure patients.United States. National Institutes of Health (DK085713)National Cancer Institute (U.S.) (P30-CA14051)National Institute of Environmental Health Sciences (P30-ES002109)United States. National Institutes of Health (1K08DK101754

Tumor cell-organized fibronectin is required to maintain a dormant breast cancer population [preprint]

Tumors can undergo long periods of dormancy, with cancer cells entering a largely quiescent, non-proliferative state before reactivation and outgrowth. For a patient, these post-remission tumors are often drug resistant and highly aggressive, resulting in poor prognosis. To understand the role of the extracellular matrix (ECM) in regulating tumor dormancy, we created an in vitro cell culture system that combines carefully controlled ECM substrates with nutrient deprivation to observe entrance into and exit from dormancy with live imaging. We saw that cell populations capable of surviving entrance into long-term dormancy were heterogeneous, containing quiescent, cell cycle arrested, and actively proliferating cells. Cell populations that endured extended periods of serum-deprivation-induced dormancy formed an organized, fibrillar fibronectin matrix via αvβ3 and α5β1 integrin adhesion, ROCK-generated tension, and TGFβ2 stimulation. We surmised that the fibronectin matrix was primarily a mediator of cell survival, not proliferation, during the serum-deprivation stress, bacause cancer cell outgrowth after dormancy required MMP-2-mediated fibronectin degradation. Given the difficulty of animal models in observing entrance and exit from dormancy in real-time, we propose this approach as a new, in vitro method to study factors important in regulating dormancy, and we used it here to elucidate a role for fibronectin deposition and MMP activation

Trait anxiety and trait anger measured by ecological momentary assessment and their correspondence with traditional trait questionnaires

Ecological momentary assessments (EMA) of anxiety and anger/hostility were obtained every 25–30 min over two 24-h periods, separated by a median of 6 months, from 165 employees at a university in the Northeast. We used a multilevel trait-state-error structural equation model to estimate: (1) the proportion of variance in EMA anxiety and anger/hostility attributable to stable trait-like individual differences; (2) the correspondence between these trait-like components of EMA anxiety and anger/hostility and traditional questionnaire measures of each construct; and (3) the test–retest correlation between two 24-h averages obtained several months apart. After adjustment for measurement error, more than half the total variance in EMA reports of anxiety and anger/hostility is attributable to stable trait-like individual differences; however, the trait-like component of each construct is only modestly correlated with questionnaire measures of that construct. The 6-month “test–retest” correlations of latent variables representing the true 24-h EMA average anxiety and average anger are quite high (r ≥ 0.83). This study represents the longest follow-up period over which EMA-based estimates of traits have been examined. The results suggest that although the trait component (individual differences) of EMA momentary ratings of anxiety and anger is larger than the state component, traditional self-report questionnaires of trait anxiety and anger correspond only weakly with EMA-defined traits

Personal values and involvement in problem behaviors among Bahamian early adolescents: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Few studies, particularly in developing countries, have explored the relationship between adolescents and parental values with adolescent problem behaviors. The objectives of the study are to (1) describe adolescents' personal values, their problem behaviors, and the relationships thereof according to gender and (2) examine the relationship between parental values, adolescent values, and adolescents' problem behaviors among sixth-grade students and one of their parents.</p> <p>Methods</p> <p>The data used in these analyses were from the baseline assessment of a school-based HIV risk reduction intervention being conducted and evaluated among sixth grade students and one of their parents across 9 elementary schools in The Bahamas. Personal values were measured by the Portrait Values Questionnaire (PVQ). Seven reported problem behaviors were queried from the students, which included physical fight with a friend, drank alcohol, beer, or wine, smoked a cigarette, pushed or carried any drugs, carried a gun, knife, screwdriver or cutlass to use as a weapon, had sex and used marijuana or other illicit drugs over the past 6 months. Multilevel modeling for binary data was performed to estimate the associations between adolescent and parental values and adolescent problem behaviors.</p> <p>Results</p> <p>Among 785 students, 47% of the students reported at least one problem behavior. More boys (54%) reported having one or more problem behaviors than girls (41%, p < 0.01). Boys compared to girls expressed a higher level of self-enhancement (means score: 36.5 vs. 35.1; p = 0.03), while girls expressed a higher level of self-transcendence (42.3 vs. 40.7; p = 0.03). The results of multilevel modeling indicates that boys with a higher level of self-enhancement and girls with a higher level of openness to change and a lower level of conservation were more likely to report engagement in problem behaviors. Only two parental values (self-transcendence and conservation) were low or modestly correlated with youth' values (openness to change and self-enhancement). Parental-reported values documented limited association on adolescents' reported values and behaviors.</p> <p>Conclusion</p> <p>In designing interventions for reducing adolescents' problem behaviors, it may be important to understand the values associated with specific problem behaviors. Further exploration regarding lack of association between adolescent and parental values and problem behaviors is needed.</p

Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2.

AIMS Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. METHODS AND RESULTS Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM. CONCLUSION A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.

Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others can exhibit syndrome-specific DNA methylation changes across multiple loci (epi-signatures). Here, we investigate the clinical diagnostic utility of genome-wide DNA methylation analysis of peripheral blood in unresolved ND/CAs. We generate a computational model enabling concurrent detection of 14 syndromes using DNA methylation data with full accuracy. We demonstrate the ability of this model in resolving 67 individuals with uncertain clinical diagnoses, some of whom had variants of unknown clinical significance (VUS) in the related genes. We show that the provisional diagnoses can be ruled out in many of the case subjects, some of whom are shown by our model to have other diseases initially not considered. By applying this model to a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants in this cohort, we identify 15 case subjects with syndromic Mendelian disorders, 12 case subjects with imprinting and trinucleotide repeat expansion disorders, as well as 106 case subjects with rare epi-variants, a portion of which involved genes clinically or functionally linked to the subjects\u27 phenotypes. This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlights the potential value of epigenomic testing in the routine clinical assessment of ND/CAs