Incidence of and predictors for antiseizure medication gaps in Medicare beneficiaries with epilepsy: a retrospective cohort study.

BACKGROUND For the two-thirds of patients with epilepsy who achieve seizure remission on antiseizure medications (ASMs), patients and clinicians must weigh the pros and cons of long-term ASM treatment. However, little work has evaluated how often ASM discontinuation occurs in practice. We describe the incidence of and predictors for sustained ASM fill gaps to measure discontinuation in individuals potentially eligible for ASM withdrawal. METHODS This was a retrospective cohort of Medicare beneficiaries. We included patients with epilepsy by requiring International Classification of Diseases codes for epilepsy/convulsions plus at least one ASM prescription each year 2014-2016, and no acute visit for epilepsy 2014-2015 (i.e., potentially eligible for ASM discontinuation). The main outcome was the first day of a gap in ASM supply (30, 90, 180, or 360 days with no pills) in 2016-2018. We displayed cumulative incidence functions and identified predictors using Cox regressions. RESULTS Among 21,819 beneficiaries, 5191 (24%) had a 30-day gap, 1753 (8%) had a 90-day gap, 803 (4%) had a 180-day gap, and 381 (2%) had a 360-day gap. Predictors increasing the chance of a 180-day gap included number of unique medications in 2015 (hazard ratio [HR] 1.03 per medication, 95% confidence interval [CI] 1.01-1.05) and epileptologist prescribing physician (≥25% of that physician's visits for epilepsy; HR 2.37, 95% CI 1.39-4.03). Predictors decreasing the chance of a 180-day gap included Medicaid dual eligibility (HR 0.75, 95% CI 0.60-0.95), number of unique ASMs in 2015 (e.g., 2 versus 1: HR 0.37, 95% CI 0.30-0.45), and greater baseline adherence (> 80% versus ≤80% of days in 2015 with ASM pill supply: HR 0.38, 95% CI 0.32-0.44). CONCLUSIONS Sustained ASM gaps were rarer than current guidelines may suggest. Future work should further explore barriers and enablers of ASM discontinuation to understand the optimal discontinuation rate

Long-term effects of a protein-enriched diet on blood pressure in older women

Short-term randomised, controlled trials have found that dietary protein relative to carbohydrate can reduce blood pressure. Our objective was to investigate the effects on blood pressure of an increase in protein intake from whey over 2 years in women aged over 70 years. From the general population, 219 women aged between 70 and 80 years were recruited to a 2-year randomised, double-blind, placebo-controlled parallel-design trial: 181 women completed the trial to the end of year 2. Participants were randomly assigned to consume a daily whey protein-based beverage (protein) or an energy-matched low-protein high-carbohydrate beverage (control). Blood pressure measurements were performed at baseline, year 1 and year 2. For protein relative to control, the estimated mean net differences in protein and carbohydrate intakes were 18 (95 % CI 13, 23) and − 22 (95 % CI − 9, − 35) g/d at year 1, and 22 (95 % CI 17, 28) and − 18 (95 % CI − 6, − 31) g/d at year 2. Intention-to-treat analysis found no overall differences between groups in blood pressure (P>0.5). Net differences in systolic and diastolic blood pressure were – 2.3 (95 % CI – 5.3, 0.7) and – 1.5 (95 % CI – 3.6, 0.6) mmHg at year 1, and 1.6 (95 % CI – 1.5, 4.7) and 0.3 (95 % CI – 1.9, 2.4) mmHg at year 2. Similar differences in systolic and diastolic blood pressure at years 1 and 2 were observed with per-protocol analysis. Therefore, the present study did not provide evidence that a higher whey protein intake in older women can have prolonged effects on blood pressure

Expert opinion on NSCLC small specimen biomarker testing - Part 2: Analysis, reporting, and quality assessment

The diagnostic work-up for non-small cell lung cancer (NSCLC) requires biomarker testing to guide therapy choices. This article is the second of a two-part series. In Part 1, we summarised evidence-based recommendations for obtaining and processing small specimen samples (i.e. pre-analytical steps) from patients with advanced NSCLC. Here, in Part 2, we summarise evidence-based recommendations relating to analytical steps of biomarker testing (and associated reporting and quality assessment) of small specimen samples in NSCLC. As the number of biomarkers for actionable (genetic) targets and approved targeted therapies continues to increase, simultaneous testing of multiple actionable oncogenic drivers using next-generation sequencing (NGS) becomes imperative, as set forth in European Society for Medical Oncology guidelines. This is particularly relevant in advanced NSCLC, where tissue specimens are typically limited and NGS may help avoid tissue exhaustion compared with sequential biomarker testing. Despite guideline recommendations, significant discrepancies in access to NGS persist across Europe, primarily due to reimbursement constraints. The use of increasingly complex testing methods also has implications for the reporting of results. Molecular testing reports should include clinical interpretation with additional commentary on sample adequacy as appropriate. Molecular tumour boards are recommended to facilitate the interpretation of complex genetic information arising from NGS, and to collaboratively determine the optimal treatment for patients with NSCLC. Finally, whichever testing modality is employed, it is essential that adequate internal and external validation and quality control measures are implemented

Expert opinion on NSCLC small specimen biomarker testing - Part 1: Tissue collection and management

Biomarker testing is crucial for treatment selection in advanced non-small cell lung cancer (NSCLC). However, the quantity of available tissue often presents a key constraint for patients with advanced disease, where minimally invasive tissue biopsy typically returns small samples. In Part 1 of this two-part series, we summarise evidence-based recommendations relating to small sample processing for patients with NSCLC. Generally, tissue biopsy techniques that deliver the greatest quantity and quality of tissue with the least risk to the patient should be selected. Rapid on-site evaluation can help to ensure sufficient sample quality and quantity. Sample processing should be managed according to biomarker testing requirements, because tissue fixation methodology influences downstream nucleic acid, protein and morphological analyses. Accordingly, 10% neutral buffered formalin is recommended as an appropriate fixative, and the duration of fixation is recommended not to exceed 24-48 h. Tissue sparing techniques, including the 'one biopsy per block' approach and small sample cutting protocols, can help preserve tissue. Cytological material (formalin-fixed paraffin-embedded [FFPE] cytology blocks and non-FFPE samples such as smears and touch preparations) can be an excellent source of nucleic acid, providing either primary or supplementary patient material to complete morphological and molecular diagnoses. Considerations on biomarker testing, reporting and quality assessment are discussed in Part 2

Dietary inflammatory index and the aging kidney in older women: a 10‑year prospective cohort study

Purpose: Chronic inflammation plays a role in the pathogenesis of age-related renal disease and the diet can moderate systemic inflammation. The primary objective of this study was to examine the associations between a dietary inflammatory index ( DII®) score and renal function, the trajectory of renal function decline, and renal disease-related hospitalizations and/or mortality over 10 years. Methods: The study was conducted in 1422 Western Australian women without prevalent chronic kidney disease and aged ≥ 70 years. Baseline dietary data, obtained from a validated food frequency questionnaire, were used to calculate a DII score for each individual. Results: In this cohort, the mean [range] DII score was 0.19 [− 6.14 to 6.39]. A higher DII score was associated with poorer renal function at baseline and a greater renal function decline over 10 years; after multivariable adjustments, a one unit higher DII score was associated with a 0.55 mL/min/1.73 m2 lower eGFR at baseline (p = 0.01) and a 0.06 mL/min/1.73 m2 greater annual decline in eGFR over 10 years (p = 0.05). Restricted cubic splines provide evidence of a non-linear association between baseline DII score and risk of a renal disease-related event. Compared to participants in the lowest quintile, those in the highest quintile of DII score were at a higher risk of experiencing a renal disease-related event (adjusted HR 2.06, 95% CI 0.97, 4.37). Conclusion: Recommending an increased consumption of foods with a higher anti-inflammatory potential could form part of a multifaceted approach to reduce the risk of renal disease through diet and lifestyle changes

A population of gamma-ray emitting globular clusters seen with the Fermi Large Area Telescope

Globular clusters with their large populations of millisecond pulsars (MSPs) are believed to be potential emitters of high-energy gamma-ray emission. Our goal is to constrain the millisecond pulsar populations in globular clusters from analysis of gamma-ray observations. We use 546 days of continuous sky-survey observations obtained with the Large Area Telescope aboard the Fermi Gamma-ray Space Telescope to study the gamma-ray emission towards 13 globular clusters. Steady point-like high-energy gamma-ray emission has been significantly detected towards 8 globular clusters. Five of them (47 Tucanae, Omega Cen, NGC 6388, Terzan 5, and M 28) show hard spectral power indices $(0.7 < \Gamma <1.4)$ and clear evidence for an exponential cut-off in the range 1.0-2.6 GeV, which is the characteristic signature of magnetospheric emission from MSPs. Three of them (M 62, NGC 6440 and NGC 6652) also show hard spectral indices $(1.0 < \Gamma < 1.7)$, however the presence of an exponential cut-off can not be unambiguously established. Three of them (Omega Cen, NGC 6388, NGC 6652) have no known radio or X-ray MSPs yet still exhibit MSP spectral properties. From the observed gamma-ray luminosities, we estimate the total number of MSPs that is expected to be present in these globular clusters. We show that our estimates of the MSP population correlate with the stellar encounter rate and we estimate 2600-4700 MSPs in Galactic globular clusters, commensurate with previous estimates. The observation of high-energy gamma-ray emission from a globular cluster thus provides a reliable independent method to assess their millisecond pulsar populations that can be used to make constraints on the original neutron star X-ray binary population, essential for understanding the importance of binary systems in slowing the inevitable core collapse of globular clusters.Comment: Accepted for publication in A&A. Corresponding authors: J. Kn\"odlseder, N. Webb, B. Pancraz

Dynamic Changes in the Spatiotemporal Localization of Rab21 in Live RAW264 Cells during Macropinocytosis

Rab21, a member of the Rab GTPase family, is known to be involved in membrane trafficking, but its implication in macropinocytosis is unclear. We analyzed the spatiotemporal localization of Rab21 in M-CSF-stimulated RAW264 macrophages by the live-cell imaging of fluorescent protein-fused Rab21. It was demonstrated that wild-type Rab21 was transiently associated with macropinosomes. Rab21 was recruited to the macropinosomes after a decrease in PI(4,5)P2 and PI(3,4,5)P3 levels. Although Rab21 was largely colocalized with Rab5, the recruitment of Rab21 to the macropinosomes lagged a minute behind that of Rab5, and preceded that of Rab7. Then, Rab21 was dissociated from the macropinosomes prior to the accumulation of Lamp1, a late endosomal/lysosomal marker. Our analysis of Rab21 mutants revealed that the GTP-bound mutant, Rab21-Q78L, was recruited to the macropinosomes, similarly to wild-type Rab21. However, the GDP-bound mutant, Rab21-T33N, did not localize on the formed macropinosomes, suggesting that the binding of GTP to Rab21 is required for the proper recruitment of Rab21 onto the macropinosomes. However, neither mutation of Rab21 significantly affected the rate of macropinosome formation. These data indicate that Rab21 is a transient component of early and intermediate stages of macropinocytosis, and probably functions in macropinosome maturation before fusing with lysosomal compartments

Global and local concerns: What attitudes and beliefs motivate farmers to mitigate and adapt to climate change?

In response to agriculture\u27s vulnerability and contribution to climate change, many governments are developing initiatives that promote the adoption of mitigation and adaptation practices among farmers. Since most climate policies affecting agriculture rely on voluntary efforts by individual farmers, success requires a sound understanding of the factors that motivate farmers to change practices. Recent evidence suggests that past experience with the effects of climate change and the psychological distance associated with people\u27s concern for global and local impacts can influence environmental behavior. Here we surveyed farmers in a representative rural county in California\u27s Central Valley to examine how their intention to adopt mitigation and adaptation practices is influenced by previous climate experiences and their global and local concerns about climate change. Perceived changes in water availability had significant effects on farmers\u27 intention to adopt mitigation and adaptation strategies, which were mediated through global and local concerns respectively. This suggests that mitigation is largely motivated by psychologically distant concerns and beliefs about climate change, while adaptation is driven by psychologically proximate concerns for local impacts. This match between attitudes and behaviors according to the psychological distance at which they are cognitively construed indicates that policy and outreach initiatives may benefit by framing climate impacts and behavioral goals concordantly; either in a global context for mitigation or a local context for adaptation

TESS Hunt for Young and Maturing Exoplanets (THYME) VII : Membership, rotation, and lithium in the young cluster Group-X and a new young exoplanet

The public, all-sky surveys Gaia and TESS provide the ability to identify new young associations and determine their ages. These associations enable study of planetary evolution by providing new opportunities to discover young exoplanets. A young association was recently identified by Tang et al. and F{\"u}rnkranz et al. using astrometry from Gaia (called "Group-X" by the former). In this work, we investigate the age and membership of this association; and we validate the exoplanet TOI 2048 b, which was identified to transit a young, late G dwarf in Group-X using photometry from TESS. We first identified new candidate members of Group-X using Gaia EDR3 data. To infer the age of the association, we measured rotation periods for candidate members using TESS data. The clear color--period sequence indicates that the association is the same age as the $300\pm50$ Myr-old NGC 3532. We obtained optical spectra for candidate members that show lithium absorption consistent with this young age. Further, we serendipitously identify a new, small association nearby Group-X, which we call MELANGE-2. Lastly, we statistically validate TOI 2048 b, which is $2.6\pm0.2$ \rearth\ radius planet on a 13.8-day orbit around its 300 Myr-old host star.Comment: Revised to correct error in reported planet radius (original: 2.1 Earth radii, corrected: 2.6 Earth radii) and units for planetary radius ratio entries in Table 8. All data tables available open-access with the AJ articl