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We describe 14 yr of public data from the Parkes Pulsar Timing Array (PPTA), an ongoing project that is producing precise measurements of pulse times of arrival from 26 millisecond pulsars using the 64-m Parkes radio telescope with a cadence of approximately 3 weeks in three observing bands. A comprehensive description of the pulsar observing systems employed at the telescope since 2004 is provided, including the calibration methodology and an analysis of the stability of system components. We attempt to provide full accounting of the reduction from the raw measured Stokes parameters to pulse times of arrival to aid third parties in reproducing our results. This conversion is encapsulated in a processing pipeline designed to track provenance. Our data products include pulse times of arrival for each of the pulsars along with an initial set of pulsar parameters and noise models. The calibrated pulse profiles and timing template profiles are also available. These data represent almost 21 000 h of recorded data spanning over 14 yr. After accounting for processes that induce time-correlated noise, 22 of the pulsars have weighted root-mean-square timing residuals of
in at least one radio band. The data should allow end users to quickly undertake their own gravitational wave analyses, for example, without having to understand the intricacies of pulsar polarisation calibration or attain a mastery of radio frequency interference mitigation as is required when analysing raw data files.
Lumateperone (lumateperone tosylate, ITI-007) is an investigational drug for the treatment of schizophrenia, bipolar depression, and other disorders. Lumateperone has a unique mechanism of action that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. This may provide advantages in the treatment of the broad symptoms associated with schizophrenia, including negative and depression symptoms. In 2 previous placebo-controlled trials in patients with acute schizophrenia, lumateperone 42mg (ITI-007 60mg) demonstrated statistically significant improvement in the Positive and Negative Syndrome Scale (PANSS) Total score compared with placebo. In these studies, lumateperone was well tolerated with a safety profile similar to placebo. This open-label long-term study evaluated the safety and effectiveness of lumateperone 42mg in patients with schizophrenia and stable symptoms.
Patients with stable schizophrenia were treated for up to 1 year with lumateperone 42mg. Safety assessments included adverse events (AEs), body weight, laboratory parameters, and extrapyramidal symptoms (EPS)/motor symptom assessments. Efficacy analyses included evaluation of changes in PANSS Total score and in depression symptoms, as measured by the Calgary Depression Scale for Schizophrenia (CDSS).
In the 1-year open-label study, 602 patients received at least 1 dose of lumateperone 42mg; at the time of this interim analysis, 107 patients had completed 1 year of treatment. Only 4 TEAEs occurred in ≥5% of patients (weight decrease, dry mouth, headache and diarrhea); the majority of AEs were mild or moderate in intensity. Most metabolic parameters and mean prolactin levels decreased from SOC baseline, as did mean body weight and BMI. Based on AE reporting and EPS/motor symptom scales, lumateperone treatment was associated with minimal EPS risk. Lumateperone 42mg treatment was associated with significant reductions in PANSS Total score from baseline, with continuing PANSS improvement throughout the study. In patients with moderate-to-severe depression symptoms at baseline (CDSS>5), mean CDSS scores decreased from 7.4 (baseline) to 3.1 (Day 300); 60% of patients met CDSS response criteria (50% improvement from baseline) by Day 75 and this response rate was maintained through day 300. Similar magnitude of CDSS improvement was seen regardless of concurrent antidepressant therapy.
In long-term treatment, lumateperone was associated with minimal metabolic, EPS, and cardiovascular safety issues relative to current SOC antipsychotic therapy. Lumateperone improved schizophrenia symptoms with continued long-term treatment. In patients with moderate-to-severe depression symptoms at baseline, lumateperone treatment was associated with marked improvement in CDSS scores. These data are consistent with and extend data previously reported in placebo-controlled studies in patients with acute schizophrenia treated with lumateperone.
Supported by funding from Intra-Cellular Therapies, Inc.
Lumateperone (ITI-007) is in late-phase clinical development for schizophrenia. Lumateperone has a unique mechanism of action that modulates serotonin, dopamine, and glutamate neurotransmission. This pooled analysis of lumateperone in 3 randomized, double-blind, placebo-controlled studies was conducted to evaluate the safety and tolerability of lumateperone 42mg (ITI-007 60mg).
Data were pooled from the 3 controlled late-phase studies of lumateperone 42mg in patients with acute exacerbation of schizophrenia. Safety assessments of all patients who received at least one dose of any treatment included treatment-emergent adverse events (TEAEs), changes in laboratory parameters, extrapyramidal symptoms (EPS), and vital signs.
The safety population comprised 1,073 patients (placebo [n=412], lumateperone 42mg [n=406], risperidone [n=255]). TEAEs that occurred in the lumateperone 42mg group at a rate of ≥5% and twice placebo were somnolence/sedation (24.1% vs 10.0%) and dry mouth (5.9% vs 2.2%). Rates of discontinuation due to TEAEs with lumateperone 42mg (0.5%) were similar to placebo (0.5%) and lower than risperidone (4.7%). Mean change in weight and rates of EPS-related TEAEs were less for lumateperone 42mg and placebo patients than risperidone patients. Mean change from baseline in metabolic parameters were similar or smaller for lumateperone 42mg vs placebo. Mean changes were notably higher in risperidone patients vs lumateperone 42mg and placebo for glucose, cholesterol, triglycerides, and prolactin.
In this pooled analysis, lumateperone 42mg showed good tolerability with potential benefits over risperidone for metabolic, prolactin, and EPS risks. The only TEAE that occurred in >10% of lumateperone patients was somnolence/sedation, which was impacted by morning administration; in subsequent studies that administered lumateperone in the evening, somnolence/sedation rates were markedly reduced. These results suggest that lumateperone 42mg may be a promising new treatment for schizophrenia.
Supported by funding from Intra-Cellular Therapies, Inc.
Older adults often have atypical presentation of illness and are particularly vulnerable to influenza and its sequelae, making the validity of influenza case definitions particularly relevant. We sought to assess the performance of influenza-like illness (ILI) and severe acute respiratory illness (SARI) criteria in hospitalized older adults.
Prospective cohort study.
The Serious Outcomes Surveillance Network of the Canadian Immunization Research Network undertakes active surveillance for influenza among hospitalized adults.
Data were pooled from 3 influenza seasons: 2011/12, 2012/13, and 2013/14. The ILI and SARI criteria were defined clinically, and influenza was laboratory confirmed. Frailty was measured using a validated frailty index.
Of 11,379 adult inpatients (7,254 aged ≥65 years), 4,942 (2,948 aged ≥65 years) had laboratory-confirmed influenza. Their median age was 72 years (interquartile range [IQR], 58–82) and 52.6% were women. The sensitivity of ILI criteria was 51.1% (95% confidence interval [CI], 49.6–52.6) for younger adults versus 44.6% (95% CI, 43.6–45.8) for older adults. SARI criteria were met by 64.1% (95% CI, 62.7–65.6) of younger adults versus 57.1% (95% CI, 55.9–58.2) of older adults with laboratory-confirmed influenza. Patients with influenza who were prefrail or frail were less likely to meet ILI and SARI case definitions.
A substantial proportion of older adults, particularly those who are frail, are missed by standard ILI and SARI case definitions. Surveillance using these case definitions is biased toward identifying younger cases, and does not capture the true burden of influenza. Because of the substantial fraction of cases missed, surveillance definitions should not be used to guide diagnosis and clinical management of influenza.
The climate crisis requires nations to achieve human well-being with low national levels of carbon emissions. Countries vary from one another dramatically in how effectively they convert resources into well-being, and some nations with low levels of emissions have relatively high objective and subjective well-being. We identify urgent research and policy agendas for four groups of countries with either low or high emissions and well-being indicators. Least studied are those with low well-being and high emissions. Understanding social and political barriers to switching from high-carbon to lower-carbon modes of production and consumption, and ways to overcome them, will be fundamental.
To identify potential participants for clinical trials, electronic health records (EHRs) are searched at potential sites. As an alternative, we investigated using medical devices used for real-time diagnostic decisions for trial enrollment.
To project cohorts for a trial in acute coronary syndromes (ACS), we used electrocardiograph-based algorithms that identify ACS or ST elevation myocardial infarction (STEMI) that prompt clinicians to offer patients trial enrollment. We searched six hospitals’ electrocardiograph systems for electrocardiograms (ECGs) meeting the planned trial’s enrollment criterion: ECGs with STEMI or > 75% probability of ACS by the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI). We revised the ACI-TIPI regression to require only data directly from the electrocardiograph, the e-ACI-TIPI using the same data used for the original ACI-TIPI (development set n = 3,453; test set n = 2,315). We also tested both on data from emergency department electrocardiographs from across the US (n = 8,556). We then used ACI-TIPI and e-ACI-TIPI to identify potential cohorts for the ACS trial and compared performance to cohorts from EHR data at the hospitals.
Receiver-operating characteristic (ROC) curve areas on the test set were excellent, 0.89 for ACI-TIPI and 0.84 for the e-ACI-TIPI, as was calibration. On the national electrocardiographic database, ROC areas were 0.78 and 0.69, respectively, and with very good calibration. When tested for detection of patients with > 75% ACS probability, both electrocardiograph-based methods identified eligible patients well, and better than did EHRs.
Using data from medical devices such as electrocardiographs may provide accurate projections of available cohorts for clinical trials.
Point-prevalence surveys for infection or colonization with methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CREs), and for Clostridium difficile infection (CDI) were conducted in Canadian hospitals in 2010 and 2012 to better understanding changes in the epidemiology of antimicrobial-resistant organisms (AROs), which is crucial for public health and care management.
A third survey of the same AROs in adult inpatients in Canadian hospitals with ≥50 beds was performed in February 2016. Data on participating hospitals and patient cases were obtained using standard criteria and case definitions. Associations between ARO prevalence and institutional characteristics were assessed using logistic regression models.
In total, 160 hospitals from 9 of the 10 provinces with 35,018 adult inpatients participated in the survey. Median prevalence per 100 inpatients was 4.1 for MRSA, 0.8 for VRE, 1.1 for CDI, 0.8 for ESBLs, and 0 for CREs. No significant change occurred compared to 2012. CREs were reported from 24 hospitals (15%) in 2016 compared to 10 hospitals (7%) in 2012. Routine universal or targeted admission screening for VRE decreased from 94% in 2010 to 74% in 2016. Targeted screening for MRSA on admission was associated with a lower prevalence of MRSA infection. Large hospitals (>500 beds) had higher prevalences of CDI.
This survey provides national prevalence rates for AROs in Canadian hospitals. Changes in infection control and prevention policies might lead to changes in the epidemiology of AROs and our capacity to detect them.
Seven half-day regional listening sessions were held between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide-resistance management. The objective of the listening sessions was to connect with stakeholders and hear their challenges and recommendations for addressing herbicide resistance. The coordinating team hired Strategic Conservation Solutions, LLC, to facilitate all the sessions. They and the coordinating team used in-person meetings, teleconferences, and email to communicate and coordinate the activities leading up to each regional listening session. The agenda was the same across all sessions and included small-group discussions followed by reporting to the full group for discussion. The planning process was the same across all the sessions, although the selection of venue, time of day, and stakeholder participants differed to accommodate the differences among regions. The listening-session format required a great deal of work and flexibility on the part of the coordinating team and regional coordinators. Overall, the participant evaluations from the sessions were positive, with participants expressing appreciation that they were asked for their thoughts on the subject of herbicide resistance. This paper details the methods and processes used to conduct these regional listening sessions and provides an assessment of the strengths and limitations of those processes.
Herbicide resistance is ‘wicked’ in nature; therefore, results of the many educational efforts to encourage diversification of weed control practices in the United States have been mixed. It is clear that we do not sufficiently understand the totality of the grassroots obstacles, concerns, challenges, and specific solutions needed for varied crop production systems. Weed management issues and solutions vary with such variables as management styles, regions, cropping systems, and available or affordable technologies. Therefore, to help the weed science community better understand the needs and ideas of those directly dealing with herbicide resistance, seven half-day regional listening sessions were held across the United States between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide resistance management. The major goals of the sessions were to gain an understanding of stakeholders and their goals and concerns related to herbicide resistance management, to become familiar with regional differences, and to identify decision maker needs to address herbicide resistance. The messages shared by listening-session participants could be summarized by six themes: we need new herbicides; there is no need for more regulation; there is a need for more education, especially for others who were not present; diversity is hard; the agricultural economy makes it difficult to make changes; and we are aware of herbicide resistance but are managing it. The authors concluded that more work is needed to bring a community-wide, interdisciplinary approach to understanding the complexity of managing weeds within the context of the whole farm operation and for communicating the need to address herbicide resistance.
Objectives: As the number of adolescents and young adults (AYAs) surviving congenital heart disease (CHD) grows, studies of long-term outcomes are needed. CHD research documents poor executive function (EF) and cerebellum (CB) abnormalities in children. We examined whether AYAs with CHD exhibit reduced EF and CB volumes. We hypothesized a double dissociation such that the posterior CB is related to EF while the anterior CB is related to motor function. We also investigated whether the CB contributes to EF above and beyond processing speed. Methods: Twenty-two AYAs with CHD and 22 matched healthy controls underwent magnetic resonance imaging and assessment of EF, processing speed, and motor function. Volumetric data were calculated using a cerebellar atlas (SUIT) developed for SPM. Group differences were compared with t tests, relationships were tested with Pearson’s correlations and Fisher’s r to z transformation, and hierarchical regression was used to test the CB’s unique contributions to EF. Results: CHD patients had reduced CB total, lobular, and white matter volume (d=.52–.99) and poorer EF (d=.79–1.01) compared to controls. Significant correlations between the posterior CB and EF (r=.29–.48) were identified but there were no relationships between the anterior CB and motor function nor EF. The posterior CB predicted EF above and beyond processing speed (ps<.001). Conclusions: This study identified a relationship between the posterior CB and EF, which appears to be particularly important for inhibitory processes and abstract reasoning. The unique CB contribution to EF above and beyond processing speed alone warrants further study. (JINS, 2018, 24, 939–948)
The solar magnesium II core-to-wing ratio has been a well-studied proxy for chromospheric activity since 1978. Daily measurements at high spectral (0.1 nm) resolution began with the launch of the Solar Radiation and Climate Experiment (SORCE) in 2003. The next generation of measurements from the Extreme Ultraviolet Sensor (EUVS) on the Geostationary Operational Environmental Satellite 16 (GOES-16) will add high time cadence (every 30 seconds) to the observational Mg II irradiance record. We present a comparison of the two measurements during the period of overlap.
Ultraviolet (UV) Solar spectral Irradiance (SSI) has been measured from orbit on a regular basis since the beginning of the space age. These observations span four Solar Cycles, and they are crucial for our understanding of the Sun-Earth connection and space weather. SSI at these wavelengths are the main drivers for the upper atmosphere including the production and destruction of ozone in the stratosphere. The instruments that measure UV SSI not only require good preflight calibration, but also need a robust method to maintain that calibration on orbit. We will give an overview of the catalog of current and former UV SSI measurements along with the calibration philosophy of each instrument and an estimation of the uncertainties in the published irradiances.
The Yellow Chat Epthianura crocea is comprised of three disjunct subspecies. Subspecies E. c. macgregori (Capricorn Yellow Chat) is listed as Critically Endangered under the EPBC Act and has a distribution that also appears to be disjunct, with a limited geographic area of less than 7,000 ha. Some populations are threatened by rapid industrial development, and it is important for conservation of the subspecies to determine the extent to which the putative populations are connected. We used 14 microsatellite markers to measure genetic diversity and to determine the extent of gene flow between two disjunct populations at the northern and southern extremes of the subspecies’ range. No significant differences in genetic diversity (number of alleles and heterozygosity) were observed, but clear population structuring was apparent, with obvious differentiation between the northern and southern populations. The most likely explanation for reduced gene flow between the two populations is either the development of a geographic barrier as a consequence of shrinkage of the marine plains associated with the rise in sea levels following the last glacial maxima, or reduced connectivity across the largely unsuitable pasture and forest habitat that now separates the two populations, exacerbated by declining population size and fewer potential emigrants. Regardless of the mechanism, restricted gene flow between these two populations has important consequences for their ongoing conservation. The relative isolation of the smaller southern groups (the Fitzroy River delta and Curtis Island) from the much larger northern group (both sides of the Broad Sound) makes the southern population more vulnerable to local extinction. Conservation efforts should focus on nature refuge agreements with land owners agreeing to maintain favourable grazing management practices in perpetuity, particularly in the northern area where most chats occur. Supplemental exchanges of individuals from northern and southern populations should be explored as a way of increasing genetic diversity and reducing inbreeding.
Background: The use of maladaptive behaviors by individuals with generalized anxiety disorder (GAD) is theoretically important and clinically meaningful. However, little is known about the specificity of avoidant behaviors to GAD and how these behaviors can be reliably assessed. Aims: This study replicated and extended the psychometric evaluation of the Worry Behaviors Inventory (WBI), a brief self-report measure of avoidant behaviors associated with GAD. Method: The WBI was administered to a hospital-based sample of adults seeking treatment for symptoms of anxiety and/or depression (n = 639) and to a community sample (n = 55). Participants completed measures of symptom severity (GAD, depression, panic disorder, health anxiety, and personality disorder), and measures of checking, reassurance-seeking and behavioral inhibition. Analyses evaluated the factor structure, convergent, divergent, incremental, and discriminant validity, as well the temporal stability and treatment sensitivity of the WBI. Results: The two-factor structure found in the preliminary psychometric evaluation of the WBI was replicated. The WBI was sensitive to changes across treatment and correlated well with measures of GAD symptom severity and maladaptive behaviors. The WBI was more strongly related to GAD symptom severity than other disorders. The WBI discriminated between clinical and community samples. Conclusions: The WBI provides clinicians and researchers with a brief, clinically meaningful index of problematic behaviors that may guide treatment decisions and contribute to our understanding of maintaining factors in GAD.
Saline lagoons are priority habitats in the United Kingdom supporting several protected specialist species. One specialist, the amphipod Gammarus insensibilis, is infected with behaviour-altering microphallid trematodes such as Microphallus papillorobustus. In saline lagoons around the coast of England (Gilkicker and Lymington–Keyhaven on the Hampshire coast and Moulton Marsh in Lincolnshire) there is variation in the prevalence of this parasite in the gammarid populations (0 at Salterns in the Lymington–Keyhaven lagoon system to 98% at Gilkicker). Infection intensity ranged from 0 to 20 metacercariae in individual amphipods. Higher infection intensity can alter the shape of the amphipod's head. Under experimental conditions respiration rate is significantly reduced in infected animals and reproductive output (expressed as early stage embryos mg g dry weight−1) is significantly lower in infected females. It is important to consider the role of host–parasite interactions in order to understand the ecology of specialist lagoon species such as G. insensibilis and their lagoon habitats.
Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.