Phase 3 randomized COMMODORE 1 trial: Crovalimab versus eculizumab in complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria.

Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease.

Comparative Persistence of Non-tumor Necrosis Factor (TNF) vs. TNF Antagonists for Post-operative Prophylaxis in Crohn's Disease (CD).

BACKGROUND: The comparative safety and effectiveness of available biologics for post-operative prophylaxis in Crohn's disease (CD) is uncertain. Drug persistence may serve as a real-world proxy for tolerability and effectiveness. We evaluated the comparative persistence of non-TNF and TNF antagonists for post-operative prophylaxis and their comparative effectiveness for preventing early endoscopic post-operative recurrence (POR). METHODS: We conducted a single-center, retrospective study of surgically naïve CD subjects undergoing ileocecal or small bowel resection between 1/1/2000 and 12/31/2021 and prescribed a biologic for post-operative prophylaxis. We compared the risk of prophylaxis failure (requiring recurrent surgery or discontinuation of therapy due to persistent POR despite optimized drug level or dose escalation, immunogenicity, and/or adverse event) and early endoscopic POR (Rutgeert's score ≥ i2 within 15 months postoperatively) between non-TNF and TNF antagonist prophylaxis using Cox proportional hazard and logistic regression, respectively, adjusting for demographic and disease characteristics. RESULTS: The study included 291 subjects (81% TNF antagonists). After multivariable adjustment, non-TNF antagonist prophylaxis was associated with a significantly lower risk of prophylaxis failure than TNF antagonists (hazard ratio 0.26; 95% confidence interval (CI) [0.13-0.53]). Prophylaxis with non-TNF and TNF antagonists had similar risk of early endoscopic POR (odds ratio 0.66; 95% CI [0.32-1.36]). Stratifying the non-TNF antagonists by anti-integrin and anti-IL12/23 yielded similar results. CONCLUSION: In a cohort of surgically naïve CD subjects prescribed a biologic for post-operative prophylaxis, non-TNF antagonists had greater persistence than TNF antagonists with similar risk for early endoscopic POR. If confirmed by large, prospective studies, these findings can inform post-operative management strategies in CD.

Spatial transcriptomics: Technologies, applications and experimental considerations.

The diverse cell types of an organ have a highly structured organization to enable their efficient and correct function. To fully appreciate gene functions in a given cell type, one needs to understand how much, when and where the gene is expressed. Classic bulk RNA sequencing and popular single cell sequencing destroy cell structural organization and fail to provide spatial information. However, the spatial location of gene expression or of the cell in a complex tissue provides key clues to comprehend how the neighboring genes or cells cross talk, transduce signals and work together as a team to complete the job. The functional requirement for the spatial content has been a driving force for rapid development of the spatial transcriptomics technologies in the past few years. Here, we present an overview of current spatial technologies with a special focus on the commercially available or currently being commercialized technologies, highlight their applications by category and discuss experimental considerations for a first spatial experiment.

Novel Single-Particle Analytical Technique for Inhalable Airborne Microplastic Particles by the Combined Use of Fluorescence Microscopy, Raman Microspectrometry, and SEM/EDX.

This study presents a novel and efficient method for analyzing inhalable airborne microplastics (AMPs) in ambient PM10 aerosols. Although many studies have been conducted on MPs in a variety of environments, the physicochemical characteristics of AMPs of inhalable size (<10 µm) in ambient PM10 are poorly understood because of the lack of suitable analytical methods. The method employed in this study combines fluorescence microscopy, Raman microspectrometry (RMS), and scanning electron microscopy/energy-dispersive X-ray spectrometry (SEM/EDX) for an efficient and reliable investigation of inhalable AMPs, which constitute a small portion of ambient PM10 aerosol particles. Fluorescence microscopy and staining are used to select particles with high MP potential from ambient urban PM10 aerosols. The combination of RMS and SEM/EDX then allows for a detailed characterization of these particles on a single-particle basis. The results of the study show that ∼0.008% of the particles collected using a PM10 sampler had high MP potential, corresponding to ∼800 particles/m3. Among the stained particles of <10 µm, 27% were determined to be plastic, while the remaining 73% were found to be from tire/road wear. The number of inhalable AMPs was estimated to be 192 (±127) particles/m3. This study provides an important insight into the characteristics of inhalable AMPs in ambient PM10 aerosols that are particularly critical in respect of human health and climate change. The authors highlight that the use of a single fluorescence staining method can overestimate the number of inhalable AMPs in ambient air by including tire/road wear particles. To the best of their knowledge, this is the first study to demonstrate the morphological and spectroscopic characteristics of the same individual inhalable AMPs.

Inhalable Nitric Oxide Delivery Systems for Pulmonary Arterial Hypertension Treatment.

Pulmonary arterial hypertension (PAH) is a severe medical condition characterized by elevated blood pressure in the pulmonary arteries. Nitric oxide (NO) is a gaseous signaling molecule with potent vasodilator effects; however, inhaled NO is limited in clinical practice because of the need for tracheal intubation and the toxicity of high NO concentrations. In this study, inhalable NO-releasing microspheres (NO inhalers) are fabricated to deliver nanomolar NO through a nebulizer. Two NO inhalers with distinct porous structures are prepared depending on the molecular weights of NO donors. It is confirmed that pore formation can be controlled by regulating the migration of water molecules from the external aqueous phase to the internal aqueous phase. Notably, open porous NO inhalers (OPNIs) can deliver NO deep into the lungs through a nebulizer. Furthermore, OPNIs exhibit vasodilatory and anti-inflammatory effects via sustained NO release. In conclusion, the findings suggest that OPNIs with highly porous structures have the potential to serve as tools for PAH treatment.

Multidrug resistance-associated protein 4 (Mrp4) is a novel genetic factor in the pathogenesis of obesity and diabetes.

Multidrug resistance protein 4 (Mrp4) is an efflux transporter known to transport several xenobiotics and endogenous molecules. We recently identified that the lack of Mrp4 increases adipose tissue and body weights in mice. However, the role of Mrp4 in adipose tissue physiology are unknown. The current study aimed at characterizing these specific roles of Mrp4 using wild-type (WT) and knockout (Mrp4-/- ) mice. Our studies determined that Mrp4 is expressed in mouse adipose tissue and that the lack of Mrp4 expression is associated with adipocyte hypertrophy. Furthermore, the lack of Mrp4 increased blood glucose and leptin levels, and impaired glucose tolerance. Additionally, in 3T3-L1 cells and human pre-adipocytes, pharmacological inhibition of Mrp4 increased adipogenesis and altered expression of adipogenic genes. Lack of Mrp4 activity in both of our in vivo and in vitro models leads to increased activation of adipose tissue cAMP response element-binding protein (Creb) and decreased plasma prostaglandin E (PGE) metabolite levels. These changes in Creb activation, coupled with decreased PGE levels, together promoted the observed metabolic phenotype in Mrp4-/- mice. In conclusion, our results indicate that Mrp4 as a novel genetic factor involved in the pathogenesis of metabolic diseases, such as obesity and diabetes.

Effectiveness of a Second COVID-19 Vaccine Booster Dose Against Infection, Hospitalization, or Death Among Nursing Home Residents - 19 States, March 29-July 25, 2022.

Nursing home residents continue to experience significant COVID-19 morbidity and mortality (1). On March 29, 2022, the Advisory Committee on Immunization Practices (ACIP) recommended a second mRNA COVID-19 vaccine booster dose for adults aged ≥50 years and all immunocompromised persons who had received a first booster ≥4 months earlier.* On September 1, 2022, ACIP voted to recommend bivalent mRNA COVID-19 vaccine boosters for all persons aged ≥12 years who had completed the primary series using monovalent vaccines ≥2 months earlier (2). Data on COVID-19 booster dose vaccine effectiveness (VE) in the nursing home population are limited (3). For this analysis, academic, federal, and private partners evaluated routine care data collected from 196 U.S. community nursing homes to estimate VE of a second mRNA COVID-19 vaccine booster dose among nursing home residents who had received 3 previous COVID-19 vaccine doses (2 primary series doses and 1 booster dose). Residents who received second mRNA COVID-19 vaccine booster doses during March 29-June 15, 2022, with follow-up through July 25, 2022, were found to have 60-day VE of 25.8% against SARS-CoV-2 (the virus that causes COVID-19 infection), 73.9% against severe COVID-19 outcomes (a combined endpoint of COVID-19-associated hospitalizations or deaths), and 89.6% against COVID-19-associated deaths alone. During this period, subvariants BA.2 and BA.2.12.1 (March-June 2022), and BA.4 and BA.5 (July 2022) of the B.1.1.529 and BA.2 (Omicron) variant were predominant. These findings suggest that among nursing home residents, second mRNA COVID-19 vaccine booster doses provided additional protection over first booster doses against severe COVID-19 outcomes during a time of emerging Omicron variants. Facilities should continue to ensure that nursing home residents remain up to date with COVID-19 vaccination, including bivalent vaccine booster doses, to prevent severe COVID-19 outcomes.

Clinical-Diffusion Mismatch Is Associated with Early Neurological Improvement after Late-Window Endovascular Treatment.

BACKGROUND: Clinical-diffusion mismatch (CDM) and perfusion-diffusion mismatch (PDM) are used to select patients for endovascular thrombectomy (EVT) in the late-window period. As CDM well reflects true penumbra, we hypothesized that patients with CDM and PDM would respond better to EVT than those with PDM only at the late-window period. METHODS: Acute ischemic stroke patients who received EVT 6-24 h after stroke onset were included. PDM (perfusion-/diffusion-weighted image (DWI) lesion volume >1.8) was used to select candidates for EVT in this time-period in our center. CDM was defined according to the DAWN trial criteria. Response to EVT was compared between patients with and without CDM. Early neurological improvement (ENI) was defined as improvement >4 points on National Institutes of Health Stroke Scale (NIHSS) score 1 day after EVT. Multivariable analysis was performed to investigate independent factors associated with ENI. The correlation between DWI lesion volume and NIHSS score was investigated in those with and without CDM. RESULTS: Among 94 patients enrolled, all patients had PDM and 44 (46.3%) had CDM. Forty-eight patients (51.1%) showed ENI. The prevalence of hypertension, initial NIHSS score, improvement in NIHSS score after EVT, and prevalence of ENI were greater in patients with CDM than those without. ENI was independently associated with onset-to-door time (odds ratio [95% confidence interval]: 0.998 [0.997-1.000]; p = 0.042), complete recanalization (23.912 [2.238-255.489]; p = 0.009), initial NIHSS score (1.180 [1.012-1.377]; p = 0.034), and the presence of CDM (5.160 [1.448-18.386]; p = 0.011). The correlation between DWI lesion volume and initial NIHSS score was strong in patients without CDM (r = 0.731) but only moderate in patients with CDM (r = 0.355). CONCLUSION: Patients with both CDM and PDM had a better response to late-window EVT than those with PDM only.

The loss of histone deacetylase 4 in macrophages exacerbates hepatic and adipose tissue inflammation in male but not in female mice with diet-induced non-alcoholic steatohepatitis.

Epigenetic regulation in macrophages plays a crucial role in the inflammatory response of cells. We investigated the role of macrophage histone deacetylase 4 (HDAC4) in diet-induced obesity and non-alcoholic steatohepatitis using macrophage-specific Hdac4 knockout mice (Hdac4MKO ). Hdac4 floxed control (Hdac4fl/fl ) and Hdac4MKO mice were fed a regular chow diet or an obesogenic high-fat/high-sucrose/high-cholesterol (HF/HS/HC) diet for 12 weeks. The loss of macrophage Hdac4, compared with Hdac4fl/fl control, aggravated the diet-induced inflammation in the liver and white adipose tissue only in male mice. Splenic monocytes isolated from male mice fed the HF/HS/HC diet showed increased lipopolysaccharide (LPS) sensitivity and decreased Ly6C-/Ly6C+ ratios in male Hdac4MKO mice, but not in females. Bone marrow-derived macrophages (BMMs) from male Hdac4MKO mice had a lesser efferocytotic capacity but higher proinflammatory gene expression upon LPS stimulation than male Hdac4fl/fl mice. However, female Hdac4MKO BMMs exhibited the opposite responses. The induction of estrogen receptor α (ERα, Esr1) expression by LPS was less in male but more in female Hdac4MKO BMMs than Hdac4fl/fl BMMs. Moreover, overexpression of human HDAC4 decreased basal expression of Esr1 and abolished its induction by LPS. Inhibition of ERα increased Hdac4 with induction of inflammatory genes, whereas activation of ERα decreased Hdac4 with reduction of inflammatory genes in male and female Hdac4fl/fl BMMs treated with LPS. However, regardless of the inhibition or activation of ERα, proinflammatory genes were induced by LPS more in male Hdac4MKO BMMs than Hdac4fl/fl cells, whereas cells in females showed opposite responses. In conclusion, this study suggests that the lack of macrophage Hdac4 aggravates hepatic and white adipose inflammation in male mice with diet-induced obesity and non-alcoholic steatohepatitis, and not in female mice. HDAC4 and ERα appear to counteract each other, but ERα may not be a major player in sex-dependent inflammatory responses in macrophages deficient in HDAC4. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Medicaid Expansion and Incidence of Kidney Failure among Nonelderly Adults.

BACKGROUND: Low-income individuals without health insurance have limited access to health care. Medicaid expansions may reduce kidney failure incidence by improving access to chronic disease care. METHODS: Using a difference-in-differences analysis, we examined the association between Medicaid expansion status under the Affordable Care Act (ACA) and the kidney failure incidence rate among all nonelderly adults, aged 19-64 years, in the United States, from 2012 through 2018. We compared changes in kidney failure incidence in states that implemented Medicaid expansions with concurrent changes in nonexpansion states during pre-expansion, early postexpansion (years 2 and 3 postexpansion), and later postexpansion (years 4 and 5 postexpansion). RESULTS: The unadjusted kidney failure incidence rate increased in the early years of the study period in both expansion and nonexpansion states before stabilizing. After adjustment for population sociodemographic characteristics, Medicaid expansion status was associated with 2.20 fewer incident cases of kidney failure per million adults per quarter in the early postexpansion period (95% CI, -3.89 to -0.51) compared with nonexpansion status, a 3.07% relative reduction (95% CI, -5.43% to -0.72%). In the later postexpansion period, Medicaid expansion status was not associated with a statistically significant change in kidney failure incidence (-0.56 cases per million per quarter; 95% CI, -2.71 to 1.58) compared with nonexpansion status and the pre-expansion time period. CONCLUSIONS: The ACA Medicaid expansion was associated with an initial reduction in kidney failure incidence among the entire, nonelderly, adult population in the United States; but the changes did not persist in the later postexpansion period. Further study is needed to determine the long-term association between Medicaid expansion and changes in kidney failure incidence.

Elimination of Cost Sharing for Screening Mammography in Medicare Advantage Plans.

BACKGROUND: The Affordable Care Act (ACA) required most insurers and the Medicare program to eliminate cost sharing for screening mammography. METHODS: We conducted a difference-in-differences study of biennial screening mammography among 15,085 women 65 to 74 years of age in 24 Medicare Advantage plans that eliminated cost sharing to provide full coverage for screening mammography, as compared with 52,035 women in 48 matched control plans that had and maintained full coverage. RESULTS: In plans that eliminated cost sharing, adjusted rates of biennial screening mammography increased from 59.9% (95% confidence interval [CI], 54.9 to 65.0) in the 2-year period before cost-sharing elimination to 65.4% (95% CI, 61.8 to 69.0) in the 2-year period thereafter. In control plans, the rates of biennial mammography were 73.1% (95% CI, 69.2 to 77.0) and 72.8% (95% CI, 69.7 to 76.0) during the same periods, yielding a difference in differences of 5.7 percentage points (95% CI, 3.0 to 8.4). The difference in differences was 9.8 percentage points (95% CI, 4.5 to 15.2) among women living in the areas with the highest quartile of educational attainment versus 4.3 percentage points (95% CI, 0.2 to 8.4) among women in the lowest quartile. As indicated by the difference-in-differences estimates, after the elimination of cost sharing, the rate of biennial mammography increased by 6.5 percentage points (95% CI, 3.7 to 9.4) for white women and 8.4 percentage points (95% CI, 2.5 to 14.4) for black women but was almost unchanged for Hispanic women (0.4 percentage points; 95% CI, -7.3 to 8.1). CONCLUSIONS: The elimination of cost sharing for screening mammography under the ACA was associated with an increase in rates of use of this service among older women for whom screening is recommended. The effect was attenuated among women living in areas with lower educational attainment and was negligible among Hispanic women. (Funded by the National Institute on Aging.).

On the signal-to-noise ratio benefit of spiral acquisition in diffusion MRI.

PURPOSE: Spiral readouts combine several favorable properties that promise superior net sensitivity for diffusion imaging. The purpose of this study is to verify the signal-to-noise ratio (SNR) benefit of spiral acquisition in comparison with current echo-planar imaging (EPI) schemes. METHODS: Diffusion-weighted in vivo brain data from three subjects were acquired with a single-shot spiral sequence and several variants of single-shot EPI, including full-Fourier and partial-Fourier readouts as well as different diffusion-encoding schemes. Image reconstruction was based on an expanded signal model including field dynamics obtained by concurrent field monitoring. The effective resolution of each sequence was matched to that of full-Fourier EPI with 1 mm nominal resolution. SNR maps were generated by determining the noise statistics of the raw data and analyzing the propagation of equivalent synthetic noise through image reconstruction. Using the same approach, maps of noise amplification due to parallel imaging (g-factor) were calculated for different acceleration factors. RESULTS: Relative to full-Fourier EPI at b = 0 s/mm2 , spiral acquisition yielded SNR gains of 42-88% and 40-89% in white and gray matter, respectively, depending on the diffusion-encoding scheme. Relative to partial-Fourier EPI, the gains were 36-44% and 34-42%. Spiral g-factor maps exhibited less spatial variation and lower maxima than their EPI counterparts. CONCLUSION: Spiral readouts achieve significant SNR gains in the order of 40-80% over EPI in diffusion imaging at 3T. Combining systematic effects of shorter echo time, readout efficiency, and favorable g-factor behavior, similar benefits are expected across clinical and neurosciences uses of diffusion imaging.

Understanding the Relationship Between Nursing Home Experience With Human Immunodeficiency Virus and Patient Outcomes.

BACKGROUND: As the population with human immunodeficiency virus (HIV) continues to age, the need for nursing home (NH) care is increasing. OBJECTIVES: To assess whether NH's experience in treating HIV is related to outcomes. RESEARCH DESIGN: We used claims and assessment data to identify individuals with and without HIV who were admitted to NHs in 9 high HIV prevalent states. We classified NHs into HIV experience categories and estimate the effects of NH HIV experience on patient's outcomes. We applied an instrumental variable using distances between each individual's residence and NHs with different HIV experience. SUBJECTS: In all, 5,929,376 admissions for those without HIV and 53,476 admissions for residents with HIV. MEASURES: Our primary outcomes were 30-day hospital readmissions, likelihood of becoming a long stay resident, and 180-day mortality posthospital discharge. RESULTS: Residents with HIV tended to have poorer outcomes than residents without HIV, regardless of the NH they were admitted to. Residents with HIV admitted to high HIV experience NHs were more likely to be readmitted to the hospital than those admitted to NHs with lower HIV experience (19.6% in 0% HIV NHs, 18.7% in 05% HIV NHs and 22.9% in 5%-50% HIV NHs). CONCLUSIONS: Residents with HIV experience worse outcomes in NHs than residents without HIV. Increased HIV experience was not related to improved outcomes.

Identification and characterization of GAL4 drivers that mark distinct cell types and regions in the Drosophila adult gut.

The gastrointestinal tract in the adult Drosophila serves as a model system for exploring the mechanisms underlying digestion, absorption and excretion, stem cell plasticity, and inter-organ communication, particularly through the gut-brain axis. It is also useful for studying the cellular and adaptive responses to dietary changes, alterations in microbiota and immunity, and systematic and endocrine signals. Despite the various cell types and distinct regions in the gastrointestinal tract, few tools are available to target and manipulate the activity of each cell type and region, and their gene expression. Here, we report 353 GAL4 lines and several split-GAL4 lines that are expressed in enteric neurons (ENs), progenitors (ISCs and EBs), enterocytes (ECs), enteroendocrine cells (EEs), or/and other cell types that are yet to be identified in distinct regions of the gut. We had initially collected approximately 600 GAL4 lines that may be expressed in the gut based on RNA sequencing data, and then crossed them to UAS-GFP to perform immunohistochemistry to identify those that are expressed selectively in the gut. The cell types and regional expression patterns that are associated with the entire set of GAL4 drivers and split-GAL4 combinations are annotated online at http://kdrc.kr/index.php (K-Gut Project). This GAL4 resource can be used to target specific populations of distinct cell types in the fly gut, and therefore, should permit a more precise investigation of gut cells that regulate important biological processes.

Effects of Body Weight on the Safety of High-Dose Donepezil in Alzheimer's Disease: Post hoc Analysis of a Multicenter, Randomized, Open-Label, Parallel Design, Three-Arm Clinical Trial.

BACKGROUND: Donepezil 23 mg is considered for Alzheimer's disease (AD) to optimize cognitive benefits; however, increased adverse events (AEs) can negatively influence drug adherence. We investigated whether body weight (BW) differs based on the presence of AEs, and which baseline factors were relevant to the safety of high-dose donepezil. METHODS: This study was a post hoc analysis of a multicenter randomized trial between 2014 and 2016. We included patients with moderate to severe AD treated with 10 mg/day of donepezil, and the daily dose was escalated to 23 mg with/without dose titration. Dose titration indicates 15 mg/day of donepezil before escalation or 10 mg and 23 mg/day on alternate days before escalation during the first 4 weeks. The patients were divided into 2 groups based on occurrence of AEs of special interest (AESIs) to compare baseline characteristics. We also assessed relationships between BW and AESIs. RESULTS: Among the 160 participants in the safety population, the baseline BWs differed between the AESI (+) (n = 67) and AESI (-) (n = 93) groups. Baseline BW was inversely correlated with the occurrence of AESIs (p = 0.020), and this relationship was prominent in the no-dose titration group (p = 0.009) but absent in the dose-titration groups (p > 0.05). CONCLUSIONS: BW is the most important factor that correlated with cholinergic AEs. Hence, stepwise dose titration should be considered, particularly in patients with low BW, to minimize the inverse relationship between BW and the occurrence of AEs ("Clinicaltrials.gov" No. NCT02550665 registered on September 15, 2015).

The effect of cranberry consumption on lipid metabolism and inflammation in human apo A-I transgenic mice fed a high-fat and high-cholesterol diet.

Lipid metabolism and inflammation contribute to CVD development. This study investigated whether the consumption of cranberries (CR; Vaccinium macrocarpon) can alter HDL metabolism and prevent inflammation in mice expressing human apo A-I transgene (hApoAITg), which have similar HDL profiles to those of humans. Male hApoAITg mice were fed a modified American Institute of Nutrition-93M high-fat/high-cholesterol diet (16 % fat, 0·25 % cholesterol, w/w; n 15) or the high-fat/high-cholesterol diet containing CR (5 % dried CR powder, w/w, n 16) for 8 weeks. There were no significant differences in body weight between the groups. Serum total cholesterol, non-HDL-cholesterol and TAG concentrations were significantly lower in the control than CR group with no significant differences in serum HDL-cholesterol and apoA-I. Mice fed CR showed significantly lower serum lecithin-cholesterol acyltransferase activity than the control. Liver weight and steatosis were not significantly different between the groups, but hepatic expression of genes involved in cholesterol metabolism was significantly lower in the CR group. In the epididymal white adipose tissue (eWAT), the CR group showed higher weights with decreased expression of genes for lipogenesis and fatty acid oxidation. The mRNA abundance of F4/80, a macrophage marker and the numbers of crown-like structures were less in the CR group. In the soleus muscle, the CR group also demonstrated higher expression of genes for fatty acid ß-oxidation and mitochondrial biogenesis than those of the control. In conclusion, although CR consumption elicited minor effects on HDL metabolism, it prevented obesity-induced inflammation in eWAT with concomitant alterations in soleus muscle energy metabolism.

Use of Antiretroviral Therapy for a US Medicaid Enrolled Pediatric Cohort with HIV.

Appropriate antiretroviral therapy use in children with Human Immunodeficiency Virus (HIV) is essential for optimizing clinical outcomes and preventing HIV transmission. To describe and determine correlates of HIV antiretroviral therapy (ART) persistence and implementation for children and adolescents in the United States. We studied Medicaid enrollees (ages 2-19 years) with HIV in 14 states in 2011 and 2012. We defined non-persistence as a discontinuation of an ART regimen for at least 90 days, and calculated implementation as the proportion of days on ART while persistent. We used Cox proportional regression and logistic regression to determine characteristics associated with ART non-persistence and poor (< 90%) implementation, respectively. Among those with ≥ 1 year of observation (n = 8679), 55.7% never received ART. For ART recipients (n = 3849), 34.9% discontinued ART. Correlates of ART non-persistence included older age (e.g., 15-19 vs. 2-5 years [adjusted hazard ratio (aHR) 2.9, 95% CI 2.1-4.0]; females vs. males (aHR 1.2; 1.1-1.3); mental health conditions (aHR 1.3; 1.1-1.5), drug/alcohol abuse (aHR 1.2; 1.0-1.5) and HIV-related conditions (aHR 1.2; 1.0-1.4). Those with an outpatient visit were less likely to discontinue an ART (aHR 0.32; 0.28-0.36). During persistent episodes, 42.3% had poor ART implementation. Correlates of poor implementation included females vs. males (aOR 1.2; 95% CI 1.0-1.3), Black vs. White race (aOR 1.3; 95% CI 1.1-1.7) and Hispanic/Latino vs. White (aOR 1.3; 1.0-1.8). Among Medicaid youth with HIV, there were low rates of ART exposure, and ART discontinuation was common. Correlates of persistence and implementation differed, suggesting a need for varying clinical interventions to improve connection to care and ensuring ongoing engagement with ART use.

Multiple b-values improve discrimination of cortical gray matter regions using diffusion MRI: an experimental validation with a data-driven approach.

OBJECTIVE: To investigate whether varied or repeated b-values provide better diffusion MRI data for discriminating cortical areas with a data-driven approach. METHODS: Data were acquired from three volunteers at 1.5T with b-values of 800, 1400, 2000 s/mm2 along 64 diffusion-encoding directions. The diffusion signal was sampled from gray matter in seven regions of interest (ROIs). Rotational invariants of the local diffusion profile were extracted as features that characterize local tissue properties. Random forest classification experiments assessed whether classification accuracy improved when data with multiple b-values were used over repeated acquisition of the same (1400 s/mm2) b-value to compare all possible pairs of the seven ROIs. Three data sets from the Human Connectome Project were subjected to similar processing and analysis pipelines in eight ROIs. RESULTS: Three different b-values showed an average improvement in correct classification rates of 5.6% and 4.6%, respectively, in the local and HCP data over repeated measurements of the same b-value. The improvement in correct classification rate reached as high as 16% for individual binary classification experiments between two ROIs. Often using only two of the available three b-values were adequate to make such an improvement in classification rates. CONCLUSION: Acquisitions with varying b-values are more suitable for discriminating cortical areas.

Convergent validity and stability of secure base script knowledge from young adulthood to midlife.

Attachment theory posits that early experiences with caregivers are made portable across development in the form of mental representations of attachment experiences. These representations, the secure base script included, are thought to be stable across time. Here, we present data from two studies. Study 1 (N = 141) examined the degree of empirical convergence between the two major measures of secure base script knowledge in Study 2, we examined stability of secure base script knowledge from late adolescence to midlife combining data from both a high- and normative-risk cohort (N = 113). Study 1 revealed evidence for convergent validity (r = .50) and Study 2 revealed moderate rank-order stability (r = .43), which was not moderated by cohort risk status. Results support the validity of secure base script knowledge assessments and prediction that attachment representations show moderate stability across early adulthood and into midlife.

Potentially burdensome end-of-life transitions among nursing home residents with poor-prognosis cancer.

BACKGROUND: This study examined factors associated with potentially burdensome end-of-life (EOL) transitions between care settings among older adults with advanced cancer in nursing homes (NHs). METHODS: A retrospective analysis of deceased older NH residents with poor-prognosis solid tumors was conducted with Medicare claims and the Minimum Data Set. A potentially burdensome transition was defined as 2 or more hospitalizations or an intensive care unit admission in the last 90 days of life. RESULTS: Among 34,670 subjects, many had moderate to severe cognitive impairment (53.8%), full dependence in activities of daily living (ADLs; 66.5%), and comorbidities such as congestive heart failure (CHF; 29.3%) and chronic obstructive pulmonary disease (34.1%). Only 56.3% of the patients used hospice at any time in the 90 days before death; 36.0% of the patients experienced a potentially burdensome EOL transition, and this was higher among patients who did not receive hospice (45.4% vs 28.7%; P < .01). In multivariable analyses, full dependence in ADLs (odds ratio [OR], 1.70; P < .01), CHF (OR, 1.48; P < .01), and chronic obstructive pulmonary disease (OR, 1.28; P < .01) were associated with a higher risk of burdensome EOL transitions. Those with do-not-resuscitate directives (OR, 0.60; P < .01) and impaired cognition (OR, 0.89; P < .01) had lower odds of burdensome EOL transitions. CONCLUSIONS: NH residents with advanced cancer have substantial comorbidities and functional impairment, yet more than a third experience potentially burdensome EOL transitions. These findings help to identify a population at risk for poor EOL outcomes in order to target interventions, and they point to the importance of advanced care planning in this population.