Association of second antibiotic dose delays on mortality in patients with septic shock.

OBJECTIVE: Determine whether a delay in the administration of the second dose of antibiotics is associated with an increased risk of mortality for patients admitted with septic shock. DESIGN: Retrospective, observational evaluation. SETTING: Regional multicenter evaluation including four institutions in western Pennsylvania. PATIENTS: A total of 905 patients were included in this study who met the criteria for septic shock. Patients that did not receive a second dose of antibiotics, were transferred from an outside facility, or expected death within six hours of hospital admission were excluded. INTERVENTIONS: The frequency of second antibiotic dose administration delay was determined. A delay was defined as a delay greater than or equal to 25% of the antibiotic dosing interval. MEASUREMENTS AND MAIN RESULTS: A delay in second antibiotic dose administration was found in 181 (20%) of patients. Patients with a delay in the administration of second dose antibiotics had a higher mortality rate (35%) than patients without a delay (26%) (p =0.018). Patients with and without a delay in the administration of second-dose antibiotics had similar median 28-day vasopressor free days (median = 26.0, IQR = 2.0). Differences in the distribution of the 28-day vasopressor free days between groups resulted in the achievement of statistical significance (Mann-Whitney U = 57,294.5, z = -2.690, p = 0.006). There was no difference in 28-day ventilator-free days between groups. A delay in the administration of second dose antibiotics led to a longer in-hospital length of stay (9 days vs. 7 days; p = 0.022) and a longer ICU length of stay than patients without a delay (5 days vs. 3 days; p = 0.007). CONCLUSIONS: Delays in second antibiotic dose administration in septic shock patients were present but lower than previous studies. These delays were associated with increased mortality, increased ICU and hospital length of stay.

Synthetic and practical reconstructions of SST and seawater pH using the novel multiproxy SMITE method.

Geochemical proxies of sea surface temperature (SST) and seawater pH (pHsw) in scleractinian coral skeletons are valuable tools for reconstructing tropical climate variability. However, most coral skeletal SST and pHsw proxies are univariate methods that are limited in their capacity to circumvent non-climate-related variability. Here we present a novel multivariate method for reconstructing SST and pHsw from the geochemistry of coral skeletons. Our Scleractinian Multivariate Isotope and Trace Element (SMITE) method optimizes reconstruction skill by leveraging the covariance across an array of coral elemental and isotopic data with SST and pHsw. First, using a synthetic proxy experiment, we find that SMITE SST reconstruction statistics (correlation, accuracy, and precision) are insensitive to noise and variable calibration period lengths relative to Sr/Ca. While SMITE pHsw reconstruction statistics remain relative to δ11B throughout the same synthetic experiment, the magnitude of the long-term trend in pHsw is progressively lost under conditions of moderate-to-high analytical uncertainty. Next, we apply the SMITE method to an array of seven coral-based geochemical variables (B/Ca, δ11B, Li/Ca, Mg/Ca, Sr/Ca, U/Ca & Li/Mg) measured from two Bermudan Porites astreoides corals. Despite a <3.5 year calibration period, SMITE SST and pHsw estimates exhibit significantly better accuracy, precision, and correlation with their respective climate targets than the best single- and dual-proxy estimators. Furthermore, SMITE model parameters are highly reproducible between the two coral cores, indicating great potential for fossil applications (when preservation is high). The results shown here indicate that the SMITE method can outperform the most common coral-based SST and pHsw reconstructions methods to date, particularly in datasets with a large variety of geochemical variables. We therefore provide a list of recommendations and procedures for users to begin implementing the SMITE method as well as an open-source software package to facilitate dissemination of the SMITE method.

The role of the ThyGeNEXT oncogene panel used in combination with the expanded miRNA panel ThyraMIRv2 in Indeterminate thyroid nodules: A large, blinded, real-world, observational study.

BACKGROUND: Molecular analysis of fine-needle aspiration biopsies (FNAB) improves the diagnostic accuracy of cytologically indeterminate thyroid nodules (ITNs). Recently, the use of MPTXv2 has been shown to further improve the accuracy of risk stratification of ITNs. METHODS: A total of 338 patient samples with atypia of undetermined significance (n = 260) or follicular neoplasm (n = 78) cytology diagnosis and corresponding surgical outcomes or clinical follow-up, collected between 2016 and 2020 were included. All samples underwent multiplatform testing (MPTXv1), which includes an oncogene panel (ThyGeNEXT®) plus a microRNA risk classifier (ThyraMIR®). A blinded, secondary analysis was performed to assess the added utility of MPTXv2 (ThyraMIR®v2). The average length of follow-up for the surveillance group (n = 248) was 30 months. RESULTS: Sensitivity at moderate threshold was 96% and specificity at positive threshold was 99% for MPTXv2. At 14% disease prevalence, the negative predictive value at the moderate threshold was 99% and the positive predictive value at the positive threshold was 89% for MPTXv2. MPTXv2 had fewer patients classified into the moderate-risk group than MPTXv1, which was statistically significant (p < .001). Using surgical resection, the gold standard for outcomes, MPTXv2 showed a statistically greater area under the curve (p = .028) than MPTXv1, demonstrating greater accuracy for MPTXv2. CONCLUSION: Both test versions demonstrated robust performance with low false-positive molecular results. Data suggest that incorporation of MPTXv1, and more recently MPTXv2, into clinical practice within our healthcare network resulted in improved accuracy of ITN risk stratification.

Isolation-by-distance and isolation-by-oceanography in Maroon Anemonefish (Amphiprion biaculeatus).

Obtaining dispersal estimates for a species is key to understanding local adaptation and population dynamics and to implementing conservation actions. Genetic isolation-by-distance (IBD) patterns can be used for estimating dispersal, and these patterns are especially useful for marine species in which few other methods are available. In this study, we genotyped coral reef fish (Amphiprion biaculeatus) at 16 microsatellite loci across eight sites across 210 km in the central Philippines to generate fine-scale estimates of dispersal. All sites except for one followed IBD patterns. Using IBD theory, we estimated a larval dispersal kernel spread of 8.9 km (95% confidence interval of 2.3-18.4 km). Genetic distance to the remaining site correlated strongly with the inverse probability of larval dispersal from an oceanographic model. Ocean currents were a better explanation for genetic distance at large spatial extents (sites greater than 150 km apart), while geographic distance remained the best explanation for spatial extents less than 150 km. Our study demonstrates the utility of combining IBD patterns with oceanographic simulations to understand connectivity in marine environments and to guide marine conservation strategies.

Giant clams as open-source, scalable reef environmental biomonitors.

Valvometry, the electronic measurement of bivalve shell opening and closing, has been demonstrated to be a valuable biomonitoring technique in previous ecological and environmental studies. Valvometric data has been shown to relate significantly to pollution, predation, animal stress and feeding activity. However, there is a need for valvometric techniques applicable to coral reef environments, which may provide critical insights into reef resilience to ocean warming and acidification. Giant clams are endemic to coral reefs and hold great promise as valvometric recorders of light availability, productivity and other environmental variables. Despite this promise, prior valvometric work on giant clams has been limited by specialized hardware less accessible to developing countries where many coral reefs are found. Here we report on an open-source approach that uses off-the-shelf components to monitor smooth giant clam (Tridacna derasa) valve opening behavior, and tests this approach in the simulated reef environment of the Biosphere 2 Ocean. Valvometric data corroborates the influence of light availability on diurnal behavior of giant clams. The clams basked during daylight hours to expose their photosymbionts to light, and adopted a partially-closed defensive posture at night. The animals showed variations in the frequency of complete closures, with most occurring during night-time hours when the animals prioritize filter-feeding activity, clapping their valves to expel pseudofeces from their gills. Closure frequency showed a significant relation to pH and a significant lagged relationship to chlorophyll-a productivity, which are both a function of algal productivity in the Biosphere 2 Ocean tank. These results suggest that the animals fed on phytoplankton following periodic bloom events in the Biosphere 2 Ocean during the experiment. We propose that giant clams exhibit behavioral plasticity between individuals and populations, and advocate for the more widespread use of valvometry to enable comparative studies of reef environment and animal health.

A Retrospective Evaluation of the Diagnostic Performance of an Interdependent Pairwise MicroRNA Expression Analysis with a Mutation Panel in Indeterminate Thyroid Nodules.

Background: The addition of genetic analysis to the evaluation of thyroid nodule fine-needle aspiration biopsy samples improves diagnostic accuracy of cytologically indeterminate thyroid nodules (ITNs) with Bethesda III or IV cytopathology. We previously reported the performance of a multiplatform molecular test, referred to in this study as MPTXv1, that includes a mutation panel (ThyGeNEXT®) plus an algorithmic microRNA (miRNA) risk classifier (ThyraMIR®). Complex interactions of growth-promoting and -suppressing miRNAs affect the phenotype. We previously demonstrated that accounting for these interactions with pairwise miRNA expression analysis improves the diagnosis of medullary thyroid carcinoma. In this study, we assess the impact of pairwise miRNA expression analysis on risk stratification of ITNs. Methods: Pairwise expression analysis of 11 miRNAs was performed on a training cohort of histopathology-proven benign nodules (n = 50) to define the mean and standard deviation of each pairwise analysis and create a Benign/Malignant Profiler (MPTXv2), deviations from which predicted the malignancy risk. Clinical validation of MPTXv2 was assessed using a cohort of 178 ITN (Bethesda III and IV) samples from a multicentered, blinded retrospective study, previously evaluated by MPTXv1. Results: Compared with MPTXv1, MPTXv2 significantly improved the test performance. The receiver operating characteristic (ROC) areas under the curve (AUC) increased from 0.85 to 0.97 (p < 0.001), and the diagnostic accuracy at the positive threshold increased significantly (p < 0.05) from 83% [95% confidence interval (CI) = 76-88] to 93% [CI = 89-96]. The significant improvement in the ROC AUC and the diagnostic accuracy was due to a strong statistical trend for improvement in specificity at the positive threshold. At the positive threshold, the specificity for MPTXv1 was 90% [CI = 84-95] and improved to 98% [CI = 94-99] for MPTXv2. Using the MPTXv2, the Moderate-Risk cohort decreased from 50 samples (28% of the cohort) to 24 samples (13% of the cohort). This 52% decrease is statistically significant (p < 0.001) and clinically meaningful. Conclusion: As compared with MPTXv1, pairwise miRNA expression analysis used in MPTXv2 significantly improved the diagnostic accuracy of ITN risk stratification and reduced the size of the Moderate-Risk group. Prospective trials are indicated to confirm these findings in a clinical practice setting.

Human-induced ecological cascades: Extinction, restoration, and rewilding in the Galápagos highlands.

Oceanic islands support unique biotas but often lack ecological redundancy, so that the removal of a species can have a large effect on the ecosystem. The larger islands of the Galápagos Archipelago once had one or two species of giant tortoise that were the dominant herbivore. Using paleoecological techniques, we investigate the ecological cascade on highland ecosystems that resulted from whalers removing many thousands of tortoises from the lowlands. We hypothesize that the seasonal migration of a now-extinct tortoise species to the highlands was curtailed by decreased intraspecific competition. We find the trajectory of plant community dynamics changed within a decade of the first whaling vessels visiting the islands. Novel communities established, with a previously uncommon shrub, Miconia, replacing other shrubs of the genera Alternanthera and Acalypha. It was, however, the introduction of cattle and horses that caused the local extirpation of plant species, with the most extreme impacts being evident after c. 1930. This modified ecology is considered the natural state of the islands and has shaped subsequent conservation policy and practice. Restoration of El Junco Crater should emphasize exclusion of livestock, rewilding with tortoises, and expanding the ongoing plantings of Miconia to also include Acalypha and Alternanthera.

Perspectives of Health Care Providers in an Integrated Health Care Delivery Network on Inpatient Electronic Consultation (e-Consult) Use During the COVID-19 Pandemic.

A large academic hospital system (Allegheny Health Network) introduced inpatient electronic consultations (e-Consults) during the COVID-19 crisis. Providers were invited to complete an anonymous survey on their perceptions of e-Consults. Descriptive statistics were used to analyze Likert-scale data. Cronbach's alpha was used to assess internal consistency. Ninety-five providers completed the survey. Requesting and consulting providers agreed that e-Consults were easy to use (100% and 96.2%, respectively). Both groups also concurred that e-Consults either decreased or did not significantly impact their workload (81% and 74%, respectively) and that training was appropriate (77.8% and 86.8%, respectively). The advantage and barrier selected most frequently by specialists was "timelier completion of the consult versus in-person" and "inadequate information to complete the consult," respectively. The disadvantage selected most frequently by requesting physicians was "lack of communication between providers." Open-ended comments were categorized into themes. Concerns were raised regarding whether provider-provider communication via this platform offered enough information to make recommendations compared to traditional encounters. The perceived benefits and barriers of e-Consults should be further explored with the goal of improving patient care delivery and provider satisfaction.

Updated Approach to Stroke Rehabilitation.

This article summarizes stroke rehabilitation, with a particular focus on rehabilitation from acute diagnosis to chronic impairments of stroke. The emphasis is on both pharmacologic and nonpharmacologic intervention and interdisciplinary collaboration.

Extreme temperature events will drive coral decline in the Coral Triangle.

In light of rapid environmental change, quantifying the contribution of regional- and local-scale drivers of coral persistence is necessary to characterize fully the resilience of coral reef systems. To assess multiscale responses to thermal perturbation of corals in the Coral Triangle (CT), we developed a spatially explicit metacommunity model with coral-algal competition, including seasonal larval dispersal and external spatiotemporal forcing. We tested coral sensitivity in 2,083 reefs across the CT region and surrounding areas under potential future temperature regimes, with and without interannual climate variability, exploring a range of 0.5-2.0°C overall increase in temperature in the system by 2054. We found that among future projections, reef survival probability and mean percent coral cover over time were largely determined by the presence or absence of interannual sea surface temperature (SST) extremes as well as absolute temperature increase. Overall, reefs that experienced SST time series that were filtered to remove interannual variability had approximately double the chance of survival than reefs subjected to unfiltered SST. By the end of the forecast period, the inclusion of thermal anomalies was equivalent to an increase of at least 0.5°C in SST projections without anomalies. Change in percent coral cover varied widely across the region within temperature scenarios, with some reefs experiencing local extinction while others remaining relatively unchanged. Sink strength and current thermal stress threshold were found to be significant drivers of these patterns, highlighting the importance of processes that underlie larval connectivity and bleaching sensitivity in coral networks.

Patterned frequency-modulated oral stimulation in preterm infants: A multicenter randomized controlled trial.

OBJECTIVE: To evaluate the effect of patterned, frequency-modulated oro-somatosensory stimulation on time to full oral feeds in preterm infants born 26-30 weeks gestation. STUDY DESIGN: This is a multicenter randomized controlled trial. The experimental group (n = 109) received patterned, frequency-modulated oral stimulation via the NTrainer system through a pulsatile pacifier and the control group (n = 101) received a non-pulsatile pacifier. Intent-to-treat analysis (n = 210) was performed to compare the experimental and control groups and the outcomes were analyzed using generalized estimating equations. Time-to-event analyses for time to reach full oral feeds and length of hospital stay were conducted using Cox proportional hazards models. RESULTS: The experimental group had reduction in time to full oral feeds compared to the control group (-4.1 days, HR 1.37 (1.03, 1.82) p = 0.03). In the 29-30 weeks subgroup, infants in the experimental group had a significant reduction in time to discharge (-10 days, HR 1.87 (1.23, 2.84) p < 0.01). This difference was not observed in the 26-28 weeks subgroup. There was no difference in growth, mortality or morbidities between the two groups. CONCLUSIONS: Patterned, frequency-modulated oro-somatosensory stimulation improves feeding development in premature infants and reduces their length of hospitalization. TRIAL REGISTRATION: ClinicalTrials.gov NCT01158391.

Can 3D RVEF be Prognostic for the Non-Ischemic Cardiomyopathy Patient but not the Ischemic Cardiomyopathy Patient? A Cardiovascular MRI Study.

BACKGROUND: While left ventricular ejection fraction (LVEF) has been shown to have prognostic value in ischemic cardiomyopathy (ICMX) patients, right ventricular ejection fraction (RVEF) has not been systematically evaluated in either ICMX or non-ischemic cardiomyopathy (NICMX) patients. Moreover, an accurate estimation of RVEF is problematic due to the geometry of the right ventricle (RV). Over the years, there have been improvements in the resolution, image acquisition and post-processing software for cardiac magnetic resonance imaging (CMR), such that CMR has become the "gold standard" for measuring RV volumetrics and RVEF. We hypothesize that CMR defines RVEF more so than LVEF and might have prognostic capabilities in ischemic and non-ischemic cardiomyopathy patients (ICMX and NICMX). METHODS: Patients that underwent CMR at our institution between January 2005 and October 2012 were retrospectively selected if three-dimensional (3D) LVEF < 35%. Patients were further divided into ICMX and NICMX groups. The electronic medical record (EMR) database inquiry determined all-cause mortality and major adverse cardiovascular events (MACE). Additionally, a Social Security Death Index (SSI) database inquiry was performed to determine all-cause mortality in patients who were lost to follow-up. Patients were further sub-grouped on the basis of 3D RVEF ≥ 20%. Separately, patients were sub-grouped by LVEF ≥ 20% in both ICMX and NICMX cases. A cut-off of ≥20% was chosen for the RVEF based on the results of prior studies showing significance based on Kaplan⁻Meier (KM) survival curves. Cumulative event rates were estimated for each subgroup using the KM analysis and were compared using the log-rank test. The 3D RV/LVEFs were compared to all-cause mortality and MACE. ICMX patients were defined using the World Health Organization (WHO) criteria. RESULTS: From a 7000-patient CMR database, 753 heart failure patients were selected. Eighty-seven patients met WHO definition of ICMX and NICMX (43 ICMX and 44 NICMX). The study patients were followed for a median of 3 years (Interquartile range or IQR 1.5⁻6.5 years). The mean age of patients was 58 ± 13 years; 79% were male. In ICMX, mean 3D LVEF was 21% ± 6% and mean 3D RVEF was 38% ± 14%, while for NICMX, mean 3D LVEF was 16% ± 6% and mean 3D RVEF was 30% ± 14% (p < 0.005 for intra- and inter-group comparison). It should be noted that LVEF < RVEF in both groups and the ejection fraction (EF) in NICMX was less than the corresponding EF in ICMX. Overall mortality was higher in ICMX than NICMX (12/40, 30% vs. 7/43, 16%; p < 0.05). Patients were stratified based on both RVEF and LVEF with a threshold of EF ≥ 20% separately. RVEF but not LVEF was a significant predictor of death for NICMX (χ² = 8; p < 0.005), while LVEF did not predict death in ICMX (χ² = 2, p = not significant). Similarly, time to MACE was predicted by RVEF for NICMX (χ² = 9; p < 0.005) but not by LVEF in ICMX (χ² = 1; p = NS). Importantly, RVEF, while predictive of NICMX MACE, did not emerge as a predictor of survival or MACE in ICMX. CONCLUSIONS: Via 3D CMR in non-ischemic CMX patients, RVEF has important value in predicting death and time to first MACE while 3D LVEF is far less predictive.

Can cardiovascular MRI be used to more definitively characterize cardiac masses initially identified using echocardiography?

In diagnosing cardiac and paracardiac masses, cardiac MRI (CMR) has gained acceptance as the gold standard. CMR has been observed to be superior to echocardiography in characterizing soft-tissue structures and, specifically, in classifying cardiac masses. The aim of our study was to evaluate the association between mortality and cardiac or paracardiac masses initially identified by echocardiography (ECHO) and confirmed by CMR. Between January 2002 and August 2007, a total of 158 patients underwent both ECHO and CMR for the evaluation of cardiac masses that were equivocal or undefined by ECHO. The primary study endpoints were 5-year all-cause mortality and 5-year cardiac mortality. Causes of death as of April 1, 2015 were obtained from medical records or the National Death Index. Patients were analyzed according to mass type determined by CMR using the Kruskal-Wallis test, Kaplan-Meier curves, and the log-rank test. Over a mean duration of follow-up of 10.4 ± 2.9 years (range: 0.01-12 years) post-CMR, the overall all-cause mortality rate was 25.9% (41/158). Median age at death was 76 years and there were 21 females (51.2%). Mortality rates in the different classifications of cardiac masses by CMR were as follows: 20% (1/5) in patients with a Nondiagnostic CMR; 20% (1/5) in Other Diagnoses; 17.9% (7/39) in No Masses (includes Normal Anatomical Variants); 16.7% (3/18) in Benign Masses; 23.8% (15/63) in Fat; 50% (5/10) in Thrombus; and 61.5% (8/13) in Malignant Mass. The mean survival time in patients with No Mass (n = 39) was not significantly longer than patients with any type of cardiac mass (n = 114) (P = .16). No significant difference was found in age at death between patients when grouped by CMR classification (P = .40). However, among CMR-confirmed masses, there were some significant differences by mass classification type (P = .006). During the follow-up period, 26% (41/158) of patients died and 22% (9/41) of the deaths were cardiovascular related; there was no significant difference in mean survival times with respect to cause of mortality (P = .23). In patients with cardiac masses, dually confirmed by ECHO and CMR, significant differences in survival time were observed based upon CMR classified type of mass while CMR was instrumental in obviating invasive biopsy.

Ten-Year Mortality in the WISE Study (Women's Ischemia Syndrome Evaluation).

BACKGROUND: The WISE study (Women's Ischemia Syndrome Evaluation) was a prospective cohort study of 936 clinically stable symptomatic women who underwent coronary angiography to evaluate symptoms and signs of ischemia. Long-term mortality data for such women are limited. METHODS AND RESULTS: Obstructive coronary artery disease (CAD) was defined as ≥50% stenosis on angiography by core laboratory. We conducted a National Death Index search to assess the mortality of women who were alive at their final WISE contact date. Death certificates were obtained. All deaths were adjudicated as cardiovascular or noncardiovascular by a panel of WISE cardiologists masked to angiographic data. Multivariate Cox proportional hazards regression was used to identify significant independent predictors of mortality. At baseline, mean age was 58±12 years; 176 (19%) were non-white, primarily black; 25% had a history of diabetes mellitus, 59% hypertension, 55% dyslipidemia, and 59% had a body mass index ≥30. During a median follow-up of 9.5 years (range, 0.2-11.5 years), a total of 184 (20%) died. Of these, 115 (62%) were cardiovascular deaths; 31% of all cardiovascular deaths occurred in women without obstructive CAD (<50% stenosis). Independent predictors of mortality were obstructive CAD, age, baseline systolic blood pressure, history of diabetes mellitus, history of smoking, elevated triglycerides, and estimated glomerular filtration rate. CONCLUSIONS: Among women referred for coronary angiography for signs and symptoms of ischemia, 1 in 5 died from predominantly cardiac pathogeneses within 9 years of angiographic evaluation. A majority of the factors contributing to the risk of death seem to be modifiable by existing therapies. Of note, 1 in 3 of the deaths in this cohort occurred in women without obstructive CAD, a condition often considered benign and without guideline-recommended treatments. Clinical trials are needed to provide treatment guidance for the group without obstructive CAD.

Sudden Cardiac Death in Women With Suspected Ischemic Heart Disease, Preserved Ejection Fraction, and No Obstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study.

BACKGROUND: Sudden cardiac death (SCD) is often the first presentation of ischemic heart disease; however, there is limited information on SCD among women with and without obstructive coronary artery disease (CAD). We evaluated SCD incidence in the WISE (Women's Ischemia Syndrome Evaluation) study. METHODS AND RESULTS: Overall, 904 women with suspected ischemic heart disease with preserved ejection fraction and core laboratory coronary angiography were followed for outcomes. In case of death, a death certificate and/or a physician or family narrative of the circumstances of death was obtained. A clinical events committee rated all deaths as cardiovascular or noncardiovascular and as SCD or non-SCD. In total, 96 women (11%) died over a median of 6 years (maximum: 8 years). Among 65 cardiovascular deaths, 42% were SCD. Mortality per 1000 person-hours increased linearly with CAD severity (no CAD: 5.8; minimal: 15.9; obstructive: 38.6; P<0.0001). However, the proportion of SCD was similar across CAD severity: 40%, 58%, and 38% for no, minimal, and obstructive CAD subgroups, respectively (P value not significant). In addition to traditional risk factors (age, diabetes mellitus, smoking), a history of depression (P=0.018) and longer corrected QT interval (P=0.023) were independent SCD predictors in the entire cohort. Corrected QT interval was an independent predictor of SCD in women without obstructive CAD (P=0.033). CONCLUSIONS: SCD contributes substantially to mortality in women with and without obstructive CAD. Corrected QT interval is the single independent SCD risk factor in women without obstructive CAD. In addition to management of traditional risk factors, these data indicate that further investigation should address mechanistic understanding and interventions targeting depression and corrected QT interval in women.

Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6.

The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics.

Aortic flow conditions predict ejection efficiency in the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: The Windkessel model of the cardiovascular system, both in its original wind-chamber and flow-pipe form, and in its electrical circuit analog has been used for over a century to modeled left ventricular ejection conditions. Using parameters obtained from aortic flow we formed a Flow Index that is proportional to the impedance of such a "circuit". We show that the impedance varies with ejection fraction (EF) in a manner characteristic of a resonant circuit with multiple resonance points, with each resonance point centrally located in a small range of EF values, i.e., corresponding to multiple contiguous EF bands. METHODS: Two target populations were used: (I) a development group comprising male and female subjects (n=112) undergoing cardiovascular magnetic resonance (CMR) imaging for a variety of cardiac conditions. The Flow Index was developed using aortic flow data and its relationship to left ventricular EF was shown. (II) An illustration group comprised of female subjects from the Women's Ischemia Syndrome Evaluation (WISE) (n=201) followed for 5 years for occurrence of major adverse cardiovascular events (MACE). Flow data was not available in this group but since the Flow Index was related to the EF we noted the MACE rate with respect to EF. RESULTS: The EFs of the development population covered a wide range (9%-76%) traversing six Flow Index resonance bands. Within each Flow Index resonance band the impedance varied from highly capacitive at the lower range of EF through minimal impedance at resonance, to highly inductive at the higher range of EF, which is characteristic of a resonant circuit. When transitioning from one EF band to a higher band, the Flow Index made a sudden transition from highly inductive to capacitive impedance modes. MACE occurred in 26 (13%) of the WISE (illustration) population. Distance in EF units (Deltacenter) from the central location between peaks of MACE activity was derived from EF data and was predictive of MACE rate with an area under the receiver operator curve of 0.73. Of special interest, Deltacenter was highly predictive of MACE in the sub-set of women with EF >60% (AUC 0.79) while EF was no more predictive than random chance (AUC 0.48). CONCLUSIONS: A Flow Index that describes impedance conditions of left ventricular ejection can be calculated using data obtained completely from the ascending aorta. The Flow Index exhibits a periodic variation with EF, and in a separate illustration population the occurrence of MACE was observed to exhibit a similar periodic variation with EF, even in cases of normal EF.

Migraine Headache and Long-Term Cardiovascular Outcomes: An Extended Follow-Up of the Women's Ischemia Syndrome Evaluation.

BACKGROUND: The association between migraine headache and cardiovascular events has been inconsistent. This study determines the long-term risk of cardiovascular events among women with and without a history of migraine headache who were under evaluation for suspected myocardial ischemia in the Women's Ischemia Syndrome Evaluation (WISE). METHODS: The WISE is a National Heart, Lung and Blood Institute-sponsored prospective, multicenter study that aims to improve myocardial ischemia evaluation in women. A total of 936 women presenting with symptoms of myocardial ischemia underwent structured data collection and coronary angiography. Information pertaining to migraine headache was available in 917 women. All-cause mortality data were available on all women for a median of 9.5 years, and nonfatal cardiovascular event data were available on 888 women for a median of 6.5 years. RESULTS: A total of 224 (24.4%) women reported a history of migraine headache. Compared with women who did not report a history of migraine headache, women with a history of migraine headache had an increased adjusted risk of cardiovascular event (cardiovascular death, nonfatal myocardial infarction, heart failure, or stroke) (hazard ratio 1.83; 95% confidence interval, 1.22-2.75) at a median follow-up of 6.5 years. This result was driven mainly by a twofold increase in the risk of stroke (hazard ratio 2.33; 95% confidence interval, 1.16-4.68). CONCLUSION: Among women being evaluated for ischemic heart disease, those reporting a history of migraine headache had increased risk of future cardiovascular events on long-term follow-up. This risk was primarily driven by a more-than twofold increase in the risk of stroke.

Does Late Gadolinium Enhancement still have Value? Right Ventricular Internal Mechanical Work, Ea/Emax and Late Gadolinium Enhancement as Prognostic Markers in Patients with Advanced Pulmonary Hypertension via Cardiac MRI.

OBJECTIVES: Investigate the impact of Right Ventricular (RV) Internal Work (IW), ratio of arterial to ventricular end-systolic elastance (Ea/Emax), and RV Insertion Point (IP) Late Gadolinium Enhancement (LGE) on outcome in Pulmonary Hypertension (PH) patients. BACKGROUND: LGE is well known to be present within the RVIPs and Inter Ventricular Septum (IVS) in PH patients, but its prognostic role remains complex and potentially overestimated via 2D qualitative relative to the 3D quantitative measures now available. However, Ea/Emax, a measure of ventricular-arterial coupling and IW, when added to external cardiac work i.e. the P-V loop area as correlates to the heart's energy demands, might fundamentally improve measures of prognosis as they interrogate physiology beyond just the RV. METHODS: Cardiac Magnetic Resonance Imaging (CMR) of 124 PH patients (age = 60±13, 85F) referred to a large tertiary PH center, was retrospectively examined for RV volumetric and functional indices and RVIP LGE%. Right Heart Catheterizations (RHC) performed within 1±2 months of the CMR were reviewed. Ea/Emax was derived as RV End-Systolic Volume (ESV/RVSV). IW was estimated as RVESV ×(RV end-systolic pressure-RV diastolic pressure). Patients were followed from date of CMR for up to 5 years for MACE (death, hospitalized RV failure, initiation of parenteral prostacyclin, sustained ventricular arrhythmia or referral for lung transplantation). RESULTS: MACE was high; 48/124 (39%) patients had MACE by 1.6±1.3 years. Neither RVIP nor IVS LGE using visual assessment or even 3D quantization predicted MACE. The strongest predictor of MACE was RVIW (OR=1.00013, p<0.002), vs. mPAP, RV mass, RV EF and IP LGE. CONCLUSIONS: Surprisingly, neither a single time-point RVIP nor whole IVS LGE% can predict outcome in the largest cohort of PH patients studied to date when compared with conventional or contemporary metrics of disease progression. CMR-LGE appears to lose its' prognostic value in PH patients in stark contradistinction to all other left and right-sided human myocardial pathologies.

Spatiotemporal variability in the δ18O-salinity relationship of seawater across the tropical Pacific Ocean.

The relationship between salinity and the stable oxygen isotope ratio of seawater (δ18Osw) is of utmost importance to the quantitative reconstruction of past changes in salinity from δ18O values of marine carbonates. This relationship is often considered to be uniform across water masses, but the constancy of the δ18Osw-salinity relationship across space and time remains uncertain, as δ18Osw responds to varying atmospheric vapor sources and pathways, while salinity does not. Here we present new δ18Osw-salinity data from sites spanning the tropical Pacific Ocean. New data from Palau, Papua New Guinea, Kiritimati, and Galápagos show slopes ranging from 0.09 ‰/psu in the Galápagos to 0.32‰/psu in Palau. The slope of the δ18Osw-salinity relationship is higher in the western tropical Pacific versus the eastern tropical Pacific in observations and in two isotope-enabled climate models. A comparison of δ18Osw-salinity relationships derived from short-term spatial surveys and multi-year time series at Papua New Guinea and Galápagos suggests spatial relationships can be substituted for temporal relationships at these sites, at least within the time period of the investigation. However, the δ18Osw-salinity relationship varied temporally at Palau, likely in response to water mass changes associated with interannual El Niño-Southern Oscillation (ENSO) variability, suggesting nonstationarity in this local δ18Osw-salinity relationship. Applying local δ18Osw-salinity relationships in a coral δ18O forward model shows that using a constant, basin-wide δ18Osw-salinity slope can both overestimate and underestimate the contribution of δ18Osw to carbonate δ18O variance at individual sites in the western tropical Pacific.