We present the final sample of 98 detached double white dwarf (WD) binaries found in the Extremely Low Mass (ELM) Survey, a spectroscopic survey targeting <0.3 M He-core WDs completed in the Sloan ...Digital Sky Survey footprint. Over the course of the survey we observed ancillary low-mass WD candidates like GD 278, which we show is a P = 0.19 day double WD binary, as well as candidates that turn out to be field blue straggler/subdwarf A-type stars with luminosities too high to be WDs given their Gaia parallaxes. Here, we define a clean sample of ELM WDs that is complete within our target selection and magnitude range 15 < g0 < 20 mag. The measurements are consistent with 100% of ELM WDs being 0.0089 < P < 1.5 day double WD binaries, 35% of which belong to the Galactic halo. We infer that these are mostly He+CO WD binaries given the measurement constraints. The merger rate of the observed He+CO WD binaries exceeds the formation rate of stable mass-transfer AM CVn binaries by a factor of 25, and so the majority of He+CO WD binaries must experience unstable mass transfer and merge. The systems with the shortest periods, such as J0651+2844, are signature LISA verification binaries that can be studied with gravitational waves and light.
To identify, in caregivers of patients with Alzheimer's disease (AD) dementia, factors associated with subjective (personal, physical, emotional, and social) and objective (informal caregiver time ...and costs) caregiver burden.
Prospective longitudinal European observational study: post-hoc analysis.
Clinic.
Community-dwelling patients in France and Germany aged ≥ 55 years (n = 969) with probable AD and their informal caregivers.
Mini-Mental State Examination (MMSE), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), 12-item Neuropsychiatric Inventory (NPI-12), Zarit Burden Interview (ZBI), informal caregiver basic and instrumental ADL hours (Resource Utilization in Dementia instrument), and informal caregiver costs. Mixed-effect models of repeated measures (MMRM) were run, including baseline and time-dependent covariates (change from baseline CFB to 18 months in MMSE, ADCS-ADL, and NPI-12 scores) associated with CFB in ZBI score/informal caregiver time over 36 months (analyzed using linear regression models) and informal caregiver costs over 36 months (analyzed using generalized linear models).
Greater decline in patient function (ADCS-ADL) over 18 months was associated with increased subjective caregiver burden (ZBI), hours, and costs over 36 months. Increased behavioral problems (NPI-12) over 18 months also negatively impacted ZBI. Cognitive decline (MMSE) over 18 months did not affect change in caregiver burden.
Long-term informal caregiver burden was driven by worsening functional abilities and behavioral symptoms but not cognitive decline, over 18 months in community-dwelling patients with AD dementia. Identifying the drivers of caregiver burden could highlight areas in which interventions may benefit both caregivers and patients.
This study estimated the minimal clinically important difference (MCID) for Mini Mental State Examination, Clinical Dementia Rating Scale sum of boxes, and Functional Activities Questionnaire across ...the Alzheimer's disease (AD) spectrum.
Retrospective analysis of the National Alzheimer's Coordinating Center Uniform Data Set (9/2005-9/2016) and MCID for clinical outcomes were estimated using anchor-based (clinician's assessment of meaningful decline) and distribution-based (1/2 baseline standard deviation) approaches, stratified by severity of cognitive impairment.
On average, a 1-3 point decrease in Mini Mental State Examination, 1-2 point increase in Clinical Dementia Scale sum of boxes, and 3-5 point increase in Functional Activities Questionnaire were indicative of a meaningful decline. The MCID values generally increased by disease severity; the effect size and standardized response mean for those with meaningful decline were consistently in the acceptable ranges for MCID.
These findings can inform design and interpretation of future clinical trials.
Genetic interactions influencing a phenotype of interest can be identified systematically using libraries of genetic tools that perturb biological systems in a defined manner. Systematic screens ...conducted in the yeast Saccharomyces cerevisiae have identified thousands of genetic interactions and provided insight into the global structure of biological networks. Techniques enabling systematic genetic interaction mapping have been extended to other single-celled organisms, the bacteria Escherichia coli and the yeast Schizosaccharomyces pombe, opening the way to comparative investigations of interaction networks. Genetic interaction screens in Caenorhabditis elegans, Drosophila melanogaster, and mammalian models are helping to improve our understanding of metazoan-specific signaling pathways. Together, our emerging knowledge of the genetic wiring diagrams of eukaryotic and prokaryotic cells is providing a new understanding of the relationship between genotype and phenotype.
We report national scale estimates of CO2 emissions from fossil-fuel combustion and cement production in the United States based directly on atmospheric observations, using a dual-tracer inverse ...modeling framework and CO2 and Δ14CO2 measurements obtained primarily from the North American portion of the National Oceanic and Atmospheric Administration's Global Greenhouse Gas Reference Network. The derived US national total for 2010 is 1,653 ± 30 TgC yr−1 with an uncertainty (1σ) that takes into account random errors associated with atmospheric transport, atmospheric measurements, and specified prior CO2 and 14C fluxes. The atmosphere-derived estimate is significantly larger (>3σ) than US national emissions for 2010 from three global inventories widely used for CO2 accounting, even after adjustments for emissions that might be sensed by the atmospheric network, but which are not included in inventory totals. It is also larger (>2σ) than a similarly adjusted total from the US Environmental Protection Agency (EPA), but overlaps EPA's reported upper 95% confidence limit. In contrast, the atmosphere-derived estimate is within 1σ of the adjusted 2010 annual total and nine of 12 adjusted monthly totals aggregated from the latest version of the high-resolution, US-specific "Vulcan" emission data product. Derived emissions appear to be robust to a range of assumed prior emissions and other parameters of the inversion framework. While we cannot rule out a possible bias from assumed prior Net Ecosystem Exchange over North America, we show that this can be overcome with additional Δ14CO2 measurements. These results indicate the strong potential for quantification of US emissions and their multiyear trends from atmospheric observations.
Recent cross-sectional studies have shown psychotic experiences (PEs) are associated with suicidal ideation and behaviours. We aimed to examine associations between psychotic experiences (including ...persistent PE), and contemporaneous and incident non-suicidal self-injury (NSSI) and suicide attempts.
Participants were from an Australian longitudinal cohort of 1896 adolescents (12-17 years). NSSI and suicide attempts were measured using the Self-Harm Behaviour Questionnaire. Items from the Diagnostic Interview Schedule for Children were used to assess psychotic experiences, and the General Health Questionnaire-12 measured psychological distress.
Adolescents both psychologically distressed and endorsing psychotic experiences had increased odds of contemporaneous and incident NSSI and attempted suicide. Psychotic experiences alone did not predict future risk. Persistent psychotic experiences were associated with increased risk of NSSI and suicide attempts.
Psychological distress with accompanying psychotic experiences and persistent psychotic experiences are important predictors of NSSI and suicide attempts. Screening these phenotypes in adolescents will assist in discerning those adolescents most at risk, providing opportunities for targeted suicide prevention strategies.
Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies associated with seizure and nonseizure symptoms. A comprehensive understanding of how many ...individuals are affected globally, the diagnostic journey they face, and the extent of mortality associated with these conditions is lacking. Here, we summarize and evaluate published data on the epidemiology of DS and LGS in terms of prevalence, incidence, diagnosis, genetic mutations, and mortality and sudden unexpected death in epilepsy (SUDEP) rates. The full study protocol is registered on PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided data on DS only, 17 provided data on LGS only, and seven provided data on both. Case definitions varied considerably across studies, particularly for LGS. Incidence and prevalence estimates per 100 000 individuals were generally higher for LGS than for DS (LGS: incidence proportion = 14.5–28, prevalence = 5.8–60.8; DS: incidence proportion = 2.2–6.5, prevalence = 1.2–6.5). Diagnostic delay was frequently reported for LGS, with a wider age range at diagnosis reported than for DS (DS, 1.6–9.2 years; LGS, 2–15 years). Genetic screening data were reported by 63 studies; all screened for SCN1A variants, and only one study specifically focused on individuals with LGS. Individuals with DS had a higher mortality estimate per 1000 person‐years than individuals with LGS (DS, 15.84; LGS, 6.12) and a lower median age at death. SUDEP was the most frequently reported cause of death for individuals with DS. Only four studies reported mortality information for LGS, none of which included SUDEP. This systematic review highlights the paucity of epidemiological data available for DS and especially LGS, demonstrating the need for further research and adoption of standardized diagnostic criteria.
Fully elucidating the burden that Lennox–Gastaut syndrome (LGS) places on individuals with the disease and their caregivers is critical to improving outcomes and quality of life (QoL). This ...systematic literature review evaluated the global burden of illness of LGS, including clinical symptom burden, care requirements, QoL, comorbidities, caregiver burden, economic burden, and treatment burden (PROSPERO ID: CRD42022317413). MEDLINE, Embase, and the Cochrane Library were searched for articles that met predetermined criteria. After screening 1442 deduplicated articles and supplementary manual searches, 113 articles were included for review. A high clinical symptom burden of LGS was identified, with high seizure frequency and nonseizure symptoms (including developmental delay and intellectual disability) leading to low QoL and substantial care requirements for individuals with LGS, with the latter including daily function assistance for mobility, eating, and toileting. Multiple comorbidities were identified, with intellectual disorders having the highest prevalence. Although based on few studies, a high caregiver burden was also identified, which was associated with physical problems (including fatigue and sleep disturbances), social isolation, poor mental health, and financial difficulties. Most economic analyses focused on the high direct costs of LGS, which arose predominantly from medically treated seizure events, inpatient costs, and medication requirements. Pharmacoresistance was common, and many individuals required polytherapy and treatment changes over time. Few studies focused on the humanistic burden. Quality concerns were noted for sample representativeness, disease and outcome measures, and reporting clarity. In summary, a high burden of LGS on individuals, caregivers, and health care systems was identified, which may be alleviated by reducing the clinical symptom burden. These findings highlight the need for a greater understanding of and better definitions for the broad spectrum of LGS symptoms and development of treatments to alleviate nonseizure symptoms.
Background
Focus on the frequency of migraine pain may undervalue the total burden of migraine as pain duration and severity may present unique, additive burden. A composite measure of total pain ...burden (TPB; frequency, severity, and duration) may provide a more comprehensive characterization of pain burden and treatment response in patients with episodic migraine (EM) or chronic migraine (CM). The impact of galcanezumab versus placebo on TPB among patients with EM or CM was analyzed.
Methods
Patients from randomized, double-blind, placebo-controlled episodic (two 6-month studies pooled) and chronic migraine (3-month) studies received once-monthly subcutaneous injection of galcanezumab 120 mg or placebo. A post hoc analysis of TPB for a given month was calculated as severity-weighted duration by multiplying duration (hours) and maximum pain severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) of migraine for each day and summing these over the days in a month. Least square mean change from baseline in monthly TPB across Months 1–6 (EM,
N
= 444 galcanezumab,
N
= 894 placebo) and Months 1–3 (CM,
N
= 278 galcanezumab,
N
= 558 placebo) were compared using a mixed-model repeated measures model. Correlation of the Migraine Specific Quality of Life Questionnaire (MSQ) and Migraine Disability Assessment Scale (MIDAS) to TPB at baseline was assessed.
Results
At baseline, the duration of migraine on a given migraine headache day accounted for the greatest unique proportion of variability (EM, 57.4% and CM, 61.1%) to TPB after adjusting for frequency of migraine headache days and maximum pain severity. The decrease from baseline in monthly TPB was greater with galcanezumab than placebo for patients with EM (68.6 versus 36.2) and CM (102.6 versus 44.4). The average percent reduction of TPB from baseline was significantly greater with galcanezumab compared with placebo in patients with EM (50.8% versus 17.2%) and CM (29.7% versus 11.0%). In patients with EM and CM, TPB correlated with MSQ total score (
r
= − 0.35 and
r
= − 0.37) and MIDAS (
r
= 0.34 and
r
= 0.32).
Conclusions
Greater reduction in TPB was seen in patients with EM and CM treated with galcanezumab 120 mg once-monthly injection relative to placebo. Discussing TPB supports patient-centric conversations regarding treatment expectations when clinicians are evaluating options for migraine prevention.
Trial registration
ClinicalTrials.gov
: #
NCT02614183
(I5Q-MC-CGAG; EVOLVE-1), #
NCT02614196
(I5Q-MC-CGAH; EVOLVE-2), and #
NCT02614261
(I5Q-MC-CGAI; REGAIN) – all 3 trials were registered on 23 November 2015.
Alzheimer's disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically ...meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18‐month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimer's Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified.
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