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Co x Ni 1-x alloys (0 ≤ x ≤ 1) are successfully synthesized and immobilized on a reduced graphene oxide (RGO) surface using the dry plasma reduction method. HRSEM and XPS measurements are used to analyze the morphology and chemical composition of the developed materials. Then, the developed materials are applied as Pt-free counter electrodes (CEs) in liquid junction photovoltaic devices. In order to obtain efficient CEs, the chemical composition of the Co x Ni 1-x /RGO is controlled through optimizing the volume ratio of the Co and Ni precursors during the synthesizing process. It is found that the highest efficiency was 6.75% for the device using Co 0.3 Ni 0.7 /RGO CE, which is also higher than those of the devices using Pt CE (6.63%), Co/RGO (6.33%), and Ni/RGO (5.52%). The obtained results can be explained through the optimization of the charge-transfer resistance and diffusion impedance values of the developed materials. The strategy is simple and efficient; thus, it is promising for fabricating cost-effective CE materials for dye-sensitized solar cells.

Background The initial days of a Medicare-covered skilled nursing facility (SNF) stay may have no cost-sharing or daily copayments depending on beneficiaries’ enrollment in traditional Medicare or Medicare Advantage. Some policymakers have advocated imposing first-dollar cost-sharing to reduce post-acute expenditures. We examined the relationship between first-dollar cost-sharing for a SNF stay and use of inpatient and SNF services. Methods We identified seven Medicare Advantage plans that introduced daily SNF copayments of $25-$150 in 2009 or 2010. Copays began on the first day of a SNF admission. We matched these plans to seven matched control plans that did not introduce first-dollar cost-sharing. In a difference-in-differences analysis, we compared changes in SNF and inpatient utilization for the 172,958 members of intervention and control plans. Results In intervention plans the mean annual number of SNF days per 100 continuously enrolled inpatients decreased from 768.3 to 750.6 days when cost-sharing changes took effect. Control plans experienced a concurrent increase: 721.7 to 808.1 SNF days per 100 inpatients (adjusted difference-in-differences: −87.0 days [95% CI (−112.1,-61.9)]). In intervention plans, we observed no significant changes in the probability of any SNF service use or the number of inpatient days per hospitalized member relative to concurrent trends among control plans. Conclusions Among several strategies Medicare Advantage plans can employ to moderate SNF use, first-dollar SNF cost-sharing may be one influential factor. Trial registration Not applicable. Electronic supplementary material The online version of this article (10.1186/s12913-017-2558-8) contains supplementary material, which is available to authorized users.

Purpose To quantitatively assess the hypertension-induced cerebrovascular alterations by measuring the dynamics of arterial spin labeling (ASL) signals. Materials and methods The multiband Look-Locker ASL (MB LL-ASL) technique was evaluated in comparison to a single-band LL-ASL for three healthy subjects. Also, seven healthy subjects were scanned to determine the strength of the vascular crushing gradients applied to separate arterial from tissue ASL signal. With the optimized MB LL-ASL technique, multiple parameters, cerebral blood flow (CBF), transit times to artery (tA ), and capillary (tC ), delivery duration of labeled blood (τ), and arterial blood volume (CBVa ), were simultaneously quantified for age-matched eight control and eight hypertensive subjects with 259 msec of temporal resolution and 20 slices covering the whole-brain region at 3T. Results While CBF of hypertensives were comparable with those of normotensives (CBF of normotensives vs. hypertensives = 62.2 ± 6.87 vs. 61.9 ± 8.94 ml/100g/min, P = 0.960 for the whole gray matter), tC and τ were prolonged in hypertensives in most brain regions (tC = 1.30 ± 0.09 vs. 1.76 ± 0.16 sec, P = 0.034; τ = 1.46 ± 0.10 vs. 2.30 ± 0.22 sec, P = 0.006 for the whole gray matter). Two regions showed the increased CBVa in hypertensives compared to normotensives (hippocampus and thalamus with P = 0.009 and 0.035, respectively). Conclusion Hypertension slows the perfusion dynamics, while the remaining CBF is unchanged. A detailed characterization of regional cerebrovascular impairments by MB-LL-ASL technique provides better understanding of hypertension-induced cerebrovascular modifications. Level of evidence 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:663-672.

Medicare claims are commonly used to identify hip fractures, but there is no universally accepted definition. We found that a definition using inpatient claims identified fewer fractures than a definition including outpatient and provider claims. Few additional fractures were identified by including inconsistent diagnostic and procedural codes at contiguous sites. INTRODUCTION Medicare claims data is commonly used in research studies to identify hip fractures, but there is no universally accepted definition of fracture. Our purpose was to describe potential misclassification when hip fractures are defined using Medicare Part A (inpatient) claims without considering Part B (outpatient and provider) claims and when inconsistent diagnostic and procedural codes occur at contiguous fracture sites (e.g., femoral shaft or pelvic). METHODS Participants included all long-stay nursing home residents enrolled in Medicare Parts A and B fee-for-service between 1/1/2008 and 12/31/2009 with follow-up through 12/31/2011. We compared the number of hip fractures identified using only Part A claims to (1) Part A plus Part B claims and (2) Part A and Part B claims plus discordant codes at contiguous fracture sites. RESULTS Among 1,257,279 long-stay residents, 40,932 (3.2%) met the definition of hip fracture using Part A claims, and 41,687 residents (3.3%) met the definition using Part B claims. 4566 hip fractures identified using Part B claims would not have been captured using Part A claims. An additional 227 hip fractures were identified after considering contiguous fracture sites. CONCLUSIONS When ascertaining hip fractures, a definition using outpatient and provider claims identified 11% more fractures than a definition with only inpatient claims. Future studies should publish their definition of fracture and specify if diagnostic codes from contiguous fracture sites were used.

Activation of hepatic stellate cells (HSCs) is critical for liver fibrosis development. Previously, we showed that astaxanthin (ASTX), a xanthophyll carotenoid, has antifibrogenic effects in LX-2 cells, a human HSC cell line. We sought to determine the effect of ASTX on HSC activation, and to identify molecular mediators that are critically involved in the processes. ASTX prevented the activation of mouse primary HSCs, as evidenced by attenuated induction of procollagen type I α1. In human primary HSCs, ASTX also inhibited transforming growth factor β1 (TGFβ1)-induced fibrogenic gene expression. Among 11 classical histone deacetylases (HDACs), difference in HDAC9 mRNA levels between quiescent and activated HSCs was most evident while ASTX significantly decreased the expression of HDAC9 and its transcriptional regulator myocyte enhancer factor 2 (MEF2). ASTX decreased HDAC9 protein as well. In the activated HSCs, ASTX significantly reduced mRNA of HDAC9 and MEF2. Human primary biliary cirrhosis livers showed significantly higher HDAC9 mRNA and protein levels than normal livers, and other liver pathologies also exhibited induced HDAC9 expression. HDAC9 knockdown in LX-2 cells decreased TGFβ1-induced fibrogenic gene expression. In conclusion, ASTX inhibits HSC activation and facilitates HSC inactivation, which is attributable to its inhibitory action on HDAC9 expression.

Purpose To quantitatively assess the effects of high degree and order (1st–4th+) relative to 1st–2nd degree B0 shimming at 7 Tesla (T) on gradient-echo echo planar imaging (GE-EPI) and blood-oxygen-level dependent (BOLD) activation. Methods Simulations and GE-EPI were performed at (2mm)3 and (3mm)3 resolution, evaluating the temporal signal-to-noise ratio (tSNR), transverse relaxivity ( R2*), BOLD % signal change and activated pixel counts in a breath-hold task. Results Comparing the 1st–4th+ degree with 1st–2nd degree shimmed B0 maps generated spatially varying regions of Δ|B0|=|B01−2|−|B01−4+|. As binned in 10-Hz intervals, the two center Δ|B0| (±10 Hz) bins maintained the B0 offset of 48.6% of gray-matter pixels. In the positive Δ|B0| bins greater than 10 Hz, the 1st–4th+degree shimming improved the B0 offset in 41.1%; in negative Δ|B0| bins less than −10 Hz, the offset worsened in 10.2% of the pixels. In the positive Δ|B0| bins, we found variable but significant increases in BOLD sensitivity; the negative Δ|B0| bins showed significant decreases. In the breath-hold studies, positive bins showed significantly increased activated pixel numbers (+5–29%), whereas negative bins showed −18 to 0% decline. Conclusion 1st–4th+ degree shimming maintained B0 homogeneity over central brain regions while improving most of the other regions, including the inferior frontal lobe. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

Objectives To evaluate how often beta-blockers were started after acute myocardial infarction (AMI) in nursing home (NH) residents who previously did not use these drugs and to evaluate which factors were associated with post-AMI use of beta-blockers. Design Retrospective cohort using linked national Minimum Data Set assessments; Online Survey, Certification and Reporting records; and Medicare claims. Setting U.S. NHs. Participants National cohort of 15,720 residents aged 65 and older who were hospitalized for AMI between May 2007 and March 2010, had not taken beta-blockers for at least 4 months before their AMI, and survived 14 days or longer after NH readmission. Measurements The outcome was beta-blocker initiation within 30 days of NH readmission. Results Fifty-seven percent (n = 8,953) of residents initiated a beta-blocker after AMI. After covariate adjustment, use of beta-blockers was less in older residents (ranging from odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.79–1.00 for aged 75–84 to OR = 0.65, 95% CI = 0.54–0.79 for ≥95 vs 65–74) and less in residents with higher levels of functional impairment (dependent or totally dependent vs independent to limited assistance: OR = 0.84, 95% CI = 0.75–0.94) and medication use (≥15 vs ≤10 medications: OR = 0.89, 95% CI = 0.80–0.99). A wide variety of resident and NH characteristics were not associated with beta-blocker use, including sex, cognitive function, comorbidity burden, and NH ownership. Conclusion Almost half of older NH residents in the United States do not initiate a beta-blocker after AMI. The absence of observed factors that strongly predict beta-blocker use may indicate a lack of consensus on how to manage older NH residents, suggesting the need to develop and disseminate thoughtful practice standards.

Hispanics with incidence of end-stage renal disease (ESRD) have shown lower mortality despites their high incidence rates; However, prior research has excluded Puerto Rico (PR). This study compared mortality rates and predialysis nephrology care among Hispanics in the US, Hispanics in PR, and Whites in the US with ESRD from 2006-2015. We identified 791,443 patients using the Renal Management Information System. The primary outcome was age-adjusted 1-year mortality beginning with the 91st day following dialysis initiation. Secondary outcomes were the presence of arteriovenous fistula or graft at dialysis initiation, and receipt of predialysis nephrology care. Despite higher rates of insurance coverage, we identified substantial disparities in access to recommended nephrology care between PR and the US. In addition, the adjusted absolute difference in mortality rates was higher for PR Hispanics. This finding indicates shortcomings in quality of care for Puerto Rico with serious chronic illness and complex care needs.

Objectives To examine the association between use of opioids versus other analgesics with death and functioning after hip fracture in older nursing home (NH) residents. Design Retrospective cohort using national Medicare fee-for-service claims linked to the Minimum Data Set. Setting US NHs. Participants NH residents aged ≥65 years who became a long-stay resident (>100 days in the NH) between January 2008 and December 2009, had a hospitalized hip fracture, and returned to the NH. Exposure New use of opioid versus nonopioid analgesics (acetaminophen or nonsteroidal anti-inflammatory drugs) within 14 days post hip fracture. Measurements Follow-up began on the index date and continued until the first occurrence of death, significant functional decline (3-point increase on MDS Activities of Daily Living scale), or 120 days of follow-up. Odds ratios (ORs) with 95% confidence intervals (CIs) for outcomes were estimated using inverse probability of treatment–weighted multinomial logistic regression models. Results Among the 2755 NH residents with a hip fracture included in our study, 1155 (41.9%) were opioid users, and 1600 (58.1%) were nonopioid analgesic users. The mean age was 86.3 years, 73.8% were female, and 86.0% were white. Opioid use was associated with a significantly lower likelihood of death (OR = 0.47, 95% CI 0.39-0.56) and a nonsignificant decrease in functional decline (OR = 0.77, 95% CI 0.58-1.03). Conclusion A rigorous study that addresses the limitations of this study is critical to validate our preliminary findings and provide evidence about the effect of using opioid versus nonopioid analgesics to optimize acute pain in NH residents with a hip fracture.

OBJECTIVE: While Anti-Retroviral Therapy (ART) is essential to patients with HIV, there is substantial variation in adherence nationally. We assess how provider and practice factors contribute to successful HIV ART adherence. DESIGN: We used Medicaid Analytic Extract claims from 2008–2012. We attributed patients with HIV to the provider that provided the plurality of HIV-related services or primary care in a given year and assigned these providers to a medical practice based on the National Provider Identifier registry file. We fit successive linear hierarchical models with patient, provider, and practice characteristics to partition the variation in adherence driven by each factor. Our unit of analysis was the patient-year. SETTING: 14 US states with the highest HIV prevalence PARTICIPANTS: 111,013 patient-years representing 60,496 Medicaid enrollees living with HIV attributed to 4,930 providers and 1,960 practices MAIN OUTCOME MEASURE: Percent of year individual patients were adherent to an ART regimen RESULTS: Provider and practice random effects jointly explained 6.8% of variation in adherence with patient differences accounted for 45.2% of the variation. Patients seen by generalists and other specialists had a 1.6 (95%CI: 0.6–2.5) and 5.1 (95%CI: 4.1–6.1) percentage point greater adherence than those seen by infectious disease specialists (p

A recent study suggested a decline in the incidence of hip fracture among US women between 2002 and 2012, followed by a leveling in the incidence rate from 2013 to 2015. Newly admitted nursing home residents are particularly vulnerable to hip fracture, and it is unclear whether that trend is observed in this high risk group. The purpose of our study was to describe trends in hip fracture rates and postfracture mortality among 2.6 million newly admitted US nursing home residents from 2007 to 2015, and to examine whether these trends could be explained by differences in resident characteristics. Medicare claims data were linked with the Minimum Data Set (MDS), a clinical assessment performed quarterly on all nursing home residents. In each year (2007-2015), we identified newly admitted long-stay (ie, 100 days in the same facility) nursing home residents. Hip fracture was defined using Medicare Part A diagnostic codes. Follow-up time was calculated from the index date until the first event of hospitalized hip fracture, Medicare disenrollment, death, or until 1 year. Poisson regression was used to adjust rates of hip fracture for age and sex. The number of newly admitted nursing home residents ranged from 324,508 in 2007 to 257,350 in 2015. Although mean age remained similar (83 years), residents were more functionally dependent over time. There was a small absolute decrease in the incidence rate of hip fracture between 2007 (3.32/100 person-years) and 2013 (2.82/100 person-years), with an increase again in 2015 (3.03/100 person-years). Adjusting for patient characteristics somewhat attenuated these trends. One-year mortality was high following fracture in all years (42.6% in 2007, 42.1% in 2014). In summary, we observed a recent slight rise in the incidence rates of hip fracture among nursing home residents that was at least partially explained by differences in resident characteristics over time. © 2020 American Society for Bone and Mineral Research.

Objectives Clostridioides difficile infection is a major source of morbidity and mortality among frail older adults, especially those in nursing homes (NHs). Safety reports have signaled that bisphosphonate use may be a contributing cause. We therefore evaluated the risk of C difficile hospitalization associated with oral bisphosphonate use in the NH. Design Observational, retrospective new-user cohort study. Setting The cohort included US NH residents aged ≥65 years who became a long-stay resident (>100 days in the NH) between January 1, 2008 and December 31, 2009. Methods We conducted a study of NH residents using linked Medicare claims and Minimum Data Set records. Residents were new users of an oral bisphosphonate 1:1 matched to new calcitonin users (“active” comparator) on propensity scores controlling for more than 100 covariates. The outcome was risk of hospitalization for C difficile infection in a Cox proportional hazards model adjusted for previous antibiotic and proton pump inhibitor use. Results Our final analytical cohort included 17,753 bisphosphonate and 5348 calcitonin users. In the matched cohort, 84/5209 (1.6%) vs 71/5209 (1.4%) C difficile–related hospitalizations occurred in bisphosphonate and calcitonin users, respectively. We observed no significant difference in the risk of hospitalization among bisphosphonate users (hazard ratio: 1.11, 95% confidence interval: 0.80-1.51). Antibiotic and proton pump inhibitor exposure before and after osteoporosis treatment was also similar between bisphosphonate and calcitonin users. Conclusions and Implications C difficile infection should not be a consideration when prescribing bisphosphonates to frail older adults given the lack of a significant association.

Approximately 15-40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolysed, enhancing the CNS levels of the antibody by approximately tenfold with respect to the administration of naked rituximab. When the nanocapsules were functionalized with CXCL13-the ligand for the chemokine receptor CXCR5, which is frequently found on B-cell lymphoma-a single dose led to improved control of CXCR5-expressing metastases in a murine xenograft model of non-Hodgkin lymphoma, and eliminated lymphoma in a xenografted humanized bone marrow-liver-thymus mouse model. Encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of cancers with CNS metastases.

Introduction Adherence to antiretroviral therapy (ART) is essential to reduce HIV‐related morbidity and mortality as well as the risk of virological failure and HIV transmission. We determined the trends in ART adherence during the periods of therapeutic advances, wider use of ART and greater attention to ART adherence. To understand the general trends in medication adherence, we compared ART adherence with medications for other common chronic conditions. Methods A retrospective cohort study using Medicaid claims between 2001 and 2012 from 14 US states with the highest HIV prevalence. Medicaid is the largest source of care for HIV patients in the US. We identified Medicaid beneficiaries with HIV who initiated ART between 2001 and 2010 (n=23,343). Comparison groups included (1) HIV‐ persons who initiated a statin, angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB), or metformin and (2) HIV+ persons who initiated these control medications while on and not on ART. We estimated adjusted odds of >90% medication implementation during the two years following initiation. Results The proportion of HIV+ persons with >90% ART implementation increased from 33.5% in those who initiated in 2001 to 46.4% in 2005 and 52.4% in 2010. ART initiators in 2007 to 2010 had 53% increased odds of >90% implementation compared to those in 2001 to 2003 (adjusted OR 1.53, 99% CI: 1.34 to 1.75). Older age, male, White race, newer ART regimens and absence of substance use indicators were also associated with increased odds of >90% ART implementation. No or minimal improvements were found in the implementation of control medications in HIV‐ persons. For HIV‐ persons, the adjusted ORs comparing 2007–2010 to 2001–2003 were 1.06, 1.01 and 1.19 for statins, ACEI/ARB, metformin respectively. HIV+ persons who were on ART had, on average, 15.0 (SD: 4.2) and 16.1 (SD: 3.4) percentage points higher >90% implementation rates of concurrent statins, ACEI/ARB or metformin compared to HIV‐ persons and HIV+ persons who were not on ART respectively. Conclusions Adherence to ART substantially improved between 2001 and 2012. Nevertheless, the absolute rates of >90% implementation were low for all groups examined. Substantial disparities by age, sex and race were present, drawing attention to the need to continue to enhance medication adherence. Further studies are required to examine whether these trends and disparities persist in the most recent period.

OBJECTIVES: We investigated whether consumption of sugar kelp, an edible brown seaweed, can attenuate metabolic disturbances and nonalcoholic steatohepatitis (NASH) in a mouse model of NASH with evident liver fibrosis. METHODS: Male C57BL/6 J mice were fed a low-fat control (LF; 6% fat by wt), a high-fat/high-sucrose/high-cholesterol control (HF; 34% fat, 34% sucrose, 2.0% cholesterol by wt), or a HF containing sugar kelp (HF-Kelp; 6.0% dried sugar kelp powder by wt) for 14 weeks. Blood chemistry as well as biochemical, molecular, and histological analyses were conducted in the liver and epididymal white adipose tissue (eWAT). Metabolic rates, energy expenditure, and physical activity of mice were determined using indirect calorimetry RESULTS: Body weight of mice fed HF-Kelp was significantly lower than that of HF group. Compared to LF, HF significantly increased serum total cholesterol and glucose, which were decreased by kelp. In the liver, HF-Kelp group showed decreases in weight, triglycerides, total cholesterol, and steatosis compared with HF-fed mice. Also, kelp decreased hepatic expression of a macrophage marker F4/80 and an M1 macrophage marker CD11c. Mice fed HF-Kelp also exhibited decreased liver fibrosis as evidenced by less expression of fibrogenic genes and collagen accumulation than those of HF group. In eWAT, HF-Kelp diet reduced weight and adipocyte size compared with HF control. While HF-Kelp diet increased mRNA abundance of peroxisome proliferator activated receptor γ, it decreased the expression of collagen type VI alpha 1 chain, F4/80, CD11c, and tumor necrosis factor α, in eWAT. Oxygen consumption, carbon dioxide production, energy expenditure, and physical activity were significantly higher in HF-Kelp group than HF. CONCLUSIONS: Kelp consumption markedly prevented weight gain, fat accumulation, inflammation, and fibrosis in the liver and eWAT of mice with NASH. The health benefits of kelp were accompanied by increased metabolic rates, energy expenditure, and physical activity. Therefore, kelp may be consumed to prevent obesity-associated metabolic disturbances and NASH. FUNDING SOURCES: This study was supported by USDA Hatch.

OBJECTIVES: There is limited pharmacological treatment for liver fibrosis, which can result from chronic liver injury. In this study, we investigated the effect of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD) precursor, on the development of liver fibrosis in a diet-induced mouse model of liver fibrosis in vivo and in hepatic stellate cells (HSCs) in vitro. METHODS: Male C57BL/6 J mice were randomly assigned to three groups: a low-fat control (LF; 6% fat by wt), a high-fat/high-sucrose/high-cholesterol control (HF; 35%/34%/2.0% by wt, n = 13) or a HF diet supplemented with NR at 400 mg/kg/day (HF-NR, n = 14) for 20 weeks. Features of liver fibrosis were assessed by molecular, histological, and biochemical analyses to determine the effect of NR. Metabolic rates, energy expenditure and physical activity were measured using indirect calorimetry. Primary mouse and human HSCs, the primary extracellular matrix-producing cell-type in the liver, were used to determine the anti-fibrogenic effects of NR in vitro. RESULTS: HF-NR group had reduced body weight gain, which was attributable to increased energy expenditure. NR supplementation did not affect serum alanine aminotransferase levels and markers of steatosis and inflammation in the liver. However, liver trichrome and picrosirius red staining and total collagen quantification showed significant reductions of collagen by NR. Consistently, hepatic collagen 1a1 mRNA and protein were significantly reduced in the HF-NR group. Liver NAD levels were significantly reduced by HF, but was increased by NR supplementation. RNA-Seq analysis of NAD metabolism genes in quiescent and activated HSCs indicated that NAD levels might be reduced in activated HSCs due to repression of NAD salvage pathway, which regenerates NAD from nicotinamide. Indeed, treatment of primary human and mouse HSCs with NR significantly reduced their activation in vitro. CONCLUSIONS: NR supplementation prevented the development of liver fibrosis in a diet-induced mouse model of liver fibrosis independent of hepatic steatosis and inflammation. The data suggest that NR may directly reduce HSC activation to exert its anti-fibrotic effect. NR may be developed as a potential preventative for human liver fibrosis. FUNDING SOURCES: The NIH, USDA Multistate Hatch, and USDA Hatch.

OBJECTIVES: Macrophages play crucial roles in the development of alcohol-induced inflammation. We previously demonstrated the inhibitory effects of astaxanthin (ASTX), a xanthophyll carotenoid, on the expression of pro-inflammatory and antioxidant genes as well as cellular accumulation of reactive oxygen species (ROS) in macrophages stimulated with lipopolysaccharides. The objective of this study was to determine whether ASTX can prevent alcohol-induced inflammation and oxidative stress in macrophages with the elucidation of the underlying mechanisms. METHODS: RAW 264.7 macrophages, a murine macrophage cell line, and mouse bone marrow-derived macrophages (BMDM) were treated with 80 mM ethanol in the absence or presence of 25 mM of ASTX for 72 h with daily media change. The expression levels of pro-inflammatory and antioxidant genes and proteins were measured by quantitative real-time PCR and Western blot, respectively. Cellular ROS accumulation was also determined in both macrophage cell types. RESULTS: ASTX significantly decreased ethanol-induced mRNA expression of interleukin (IL)-6, IL-1β, and tumor necrosis factor α (TNFα) as well as TNFα secretion in RAW 264.7 macrophages. Elevated levels of cellular ROS levels by ethanol were also attenuated by ASTX with a concomitant decrease in the expression of NADPH oxidase 2, a ROS-producing enzyme, in RAW 264.7 macrophages. The similar inhibitory effects of ASTX on inflammatory gene expression and cellular ROS accumulation were observed with BMDM. Furthermore, ethanol significantly decreased in sirtuin1 (SIRT1) mRNA and protein levels, which were markedly attenuated by ASTX in RAW 264.7 macrophages. CONCLUSIONS: ASTX inhibited the expression and production of pro-inflammatory mediators and ROS accumulation in both RAW 264.7 macrophages and BMDM when the cells were exposed to ethanol. The anti-inflammatory effect of ASTX in ethanol-treated macrophages may be mediated, at least in part, by the activation of the SIRT1 pathway. Thus, ASTX may be used for the prevention of inflammatory and oxidative conditions triggered by excessive alcohol consumption. FUNDING SOURCES: This study was supported by USDA Multistate Hatch.

Limited-stage (Ann Arbor stage I or II) mantle cell lymphoma (MCL) is an extremely rare disease. Thus, there is little data on the clinical features and treatment outcomes of patients with early-stage MCL. We examined consecutive stage I or II MCL 41 cases diagnosed between 2000 and 2016 in 16 institutions of the Consortium for Improving Survival of Lymphoma group. All cases were pathologically confirmed and systemic evaluation was performed for staging. The clinical features were reviewed, and the treatment outcomes were analyzed. The median age of patients was 66 years (range 19-85 years); there were more men (n = 31, 75.6%) than women. Most patients (n = 28, 68.3%) had stage 2 disease, and 29 (70.7%) were symptomatic. The elevation of lactate dehydrogenase (n = 2, 4.9%) was not common; thus, 39 patients (95.1%) had a low-risk score (0 or 1) for the International Prognostic Index, and 28 (68.3%) had a low-risk score (1-3) for the MCL International Prognostic Index. Most patients (n = 37, 90.1%) received chemotherapy as the first therapeutic strategy, while some received radiotherapy (n = 2), surgical resection (n = 1), or no treatment (n = 1). Of the patients who received chemotherapy, 23 (56.9%) received a rituximab-containing regimen, and R-CHOP (n = 17) and R-bendamustine (n = 5) were commonly used. The best response was noted in 97.4% (n = 38) of patients, including 32 who showed a complete response (78%). With a median follow-up duration of 40.6 months, the 42 months relapse-free survival was 59.1%, and the 5-year overall survival rate was 80.4%. Limited-state MCL showed indolent clinical and low-risk prognostic features. Chemotherapy could be effective for controlling localized MCL lesions, with high complete response rates.

Macrophages are polarized into different phenotypes depending on tissue microenvironment where they reside. In obesity-associated inflammation, M1-type macrophages are predominant in the inflamed tissue, exerting pro-inflammatory responses. Our previous studies demonstrate that blackcurrant consumption attenuates hepatic inflammation and lipopolysaccharide-stimulated inflammatory responses of splenocytes in obese mice. In this study, we determined whether blackcurrant modulates macrophage phenotypes to exert its anti-inflammatory action. Mouse bone marrow-derived macrophages (BMDM) and human THP-1 macrophages were polarized into M1 macrophages in the presence or absence of blackcurrant extract (BCE). BCE repressed M1 polarization of both murine and human macrophages. Also, to gain insight into the role of blackcurrant metabolites produced in vivo in the regulation of macrophage phenotypes, BMDM were treated with serum obtained from lean or obese mice fed blackcurrant. While serum from lean mice fed blackcurrant did not exert either anti-inflammatory actions or suppressive effects on M1 polarization, serum from obese mice fed blackcurrant reduced the expression of pro-inflammatory genes in BMDM. Our data demonstrate that BCE suppresses M1 polarization, with reduced pro-inflammatory responses. Moreover, this study suggests that blackcurrant metabolites may not exert their anti-inflammatory effect directly by altering macrophage phenotypes, but possibly by inhibiting the production of obesity-associated inflammatory factors.

Objective Tools were unavailable to assess fracture risk in nursing homes (NH); therefore, we developed the Fracture Risk Assessment in Long term care (FRAiL) model. The objective of this validation study was to assess the performance of the FRAiL model to predict 2-year risk of non-vertebral and hip fractures in a separate large cohort of NH residents. Methods This retrospective cohort study included most long-stay NH residents in the United States (N = 896,840). Hip and non-vertebral fractures were identified using Medicare claims. The Minimum Data Set (MDS) was used to identify characteristics from the original FRAiL model. Multivariable competing risk regression was used to model risk of fracture. Results Mean age was 83.8 years (±8.2 years) and 70.7% were women. Over a mean follow-up of 1.52 years (SD 0.65), 41,531 residents (4.6%) were hospitalized with non-vertebral fracture (n = 30,356 hip fractures). In the fully adjusted model, 14/15 model characteristics remained significant predictors of non-vertebral fracture. Female sex (HR = 1.55, 95% CI 1.52, 1.59), wandering (HR = 1.30, 95% CI 1.26, 1.34), and falls (HR = 1.28, 95% CI 1.26, 1.31) were strongly associated with non-vertebral fracture rate. Total dependence in ADLs (versus independence) was associated with a decrease in non-vertebral fracture rate (HR = 0.57, 95% CI 0.52, 0.64). Discrimination was moderate in men (C-index = 0.68 for hip, 0.66 for non-vertebral) and women (C-index = 0.68 for hip, 0.65 for non-vertebral), and calibration was excellent. Conclusions Our model comprised entirely from routinely collected data was able to identify NH residents at greatest risk for non-vertebral fracture.

Although lenalidomide plus dexamethasone (RD) is a therapeutic option for relapsed/refractory multiple myeloma (RRMM), limited real-world clinical data exist. The purpose of this study was to estimate efficacy and safety of RD in RRMM patients of the clinical practice. Data from patients at 25 university hospitals in South Korea between October 2009 and December 2016 were collected retrospectively. We report the effectiveness and safety of RD in 546 RRMM patients in routine clinical practice in South Korea. Patients (median age, 65 years) typically received median 7 cycles of RD, and 184 (33.7%) patients were treated with 10 or more cycles of RD. Patients with renal impairment (CLCr 40 mL/min; 10.4%), comorbid conditions (≥ 2; 12.0%), and poor performance status (≥ 2; 25.1%) were included. The overall response rate was 64.2%: complete response (13.1%), very good partial response (VGPR 19.9%). With median follow-up duration of 18.6 months, median PFS and OS were 11.2 months and 25.2 months, respectively. In multivariate analysis, less than 2 comorbid conditions, normal LDH, failed one chemotherapy prior to RD, and ≥ 10 cycles of RD therapy had significantly prolonged PFS (P = 0.007, P = 0.011, P = 0.007, and P 0.001, respectively). Adverse events were acceptable. RD is effective and safe in real-life clinical practice, including patients with comorbidities. RD is an effective and safe treatment in a real clinical setting which includes patients with comorbidities. Early and continual use of RD treatment may improve RRMM survival outcomes.

Macrophages are polarized into different phenotypes depending on tissue microenvironment where they reside. In obesity-associated inflammation, M1-type macrophages are predominant in the inflamed tissue, exerting pro-inflammatory responses. Our previous studies demonstrate that blackcurrant consumption attenuates hepatic inflammation and lipopolysaccharide-stimulated inflammatory responses of splenocytes in obese mice. In this study, we determined whether blackcurrant modulates macrophage phenotypes to exert its anti-inflammatory action. Mouse bone marrow-derived macrophages (BMDM) and human THP-1 macrophages were polarized into M1 macrophages in the presence or absence of blackcurrant extract (BCE). BCE repressed M1 polarization of both murine and human macrophages. Also, to gain insight into the role of blackcurrant metabolites produced in vivo in the regulation of macrophage phenotypes, BMDM were treated with serum obtained from lean or obese mice fed blackcurrant. While serum from lean mice fed blackcurrant did not exert either anti-inflammatory actions or suppressive effects on M1 polarization, serum from obese mice fed blackcurrant reduced the expression of pro-inflammatory genes in BMDM. Our data demonstrate that BCE suppresses M1 polarization, with reduced pro-inflammatory responses. Moreover, this study suggests that blackcurrant metabolites may not exert their anti-inflammatory effect directly by altering macrophage phenotypes, but possibly by inhibiting the production of obesity-associated inflammatory factors.

Affective neuroscience research suggests that maturational changes in reward circuitry during adolescence present opportunities for new learning, but likely also contribute to increases in vulnerability for psychiatric disorders such as depression and substance abuse. Basic research in animal models and human neuroimaging has made progress in understanding the normal development of reward circuitry in adolescence, yet, few functional neuroimaging studies have examined puberty-related influences on the functioning of this circuitry. The goal of this study was to address this gap by examining the extent to which striatal activation and cortico-striatal functional connectivity to cues predicting upcoming rewards would be positively associated with pubertal status and levels of pubertal hormones (dehydroepiandrosterone, testosterone, estradiol). Participants included 79 adolescents (10–13 year olds; 47 girls) varying in pubertal status who performed a novel reward cue processing task during fMRI. Pubertal maturation was assessed using sex-specific standardized composite measures based on Tanner staging (self-report and clinical assessment) and scores from the Pubertal Development Scale. These composite measures were computed to index overall pubertal maturation as well as maturation of the adrenal and gonadal axes separately for boys and girls. Basal levels of circulating pubertal hormones were measured using immunoassays from three samples collected weekly upon awakening across a three-week period. Results indicated greater striatal activation and functional connectivity between nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) to reward cue (vs. no reward cue) on this task. Also, girls with higher levels of estradiol showed reduced activation in left and right caudate and greater NAcc-putamen connectivity. Girls with higher levels of testosterone showed greater NAcc connectivity with the anterior cingulate cortex and the insula. There were no significant associations in boys. Findings suggest that patterns of activation and connectivity in cortico-striatal regions are associated with reward cue processing, particularly in girls. Longitudinal follow-up neuroimaging studies are needed to fully characterize puberty-specific effects on the development of these neural regions and how such changes may contribute to pathways of risk or resilience in adolescence.

Treatment of liver fibrosis is very limited as there is currently no effective anti-fibrotic therapy. Spirulina platensis (SP) is a blue-green alga that is widely supplemented in healthy foods. The objective of this study was to determine whether SP supplementation can prevent obesity-induced liver fibrosis in vivo. Male C57BL/6J mice were randomly assigned to a low-fat or a high-fat (HF)/high-sucrose/high-cholesterol diet or an HF diet supplemented with 2·5 % SP (w/w) (HF/SP) for 16 or 20 weeks. There were no significant differences in body weight, activity, energy expenditure, serum lipids or glucose tolerance between mice on HF and HF/SP diets. However, plasma alanine aminotransferase level was significantly reduced by SP at 16 weeks. Expression of fibrotic markers and trichrome stains showed no differences between HF and HF/SP. Splenocytes isolated from HF/SP fed mice had lower inflammatory gene expression and cytokine secretion compared with splenocytes from HF-fed mice. SP supplementation did not attenuate HF-induced liver fibrosis. However, the expression and secretion of inflammatory genes in splenocytes were significantly reduced by SP supplementation, demonstrating the anti-inflammatory effects of SP in vivo. Although SP did not show appreciable effect on the prevention of liver fibrosis in this mouse model, it may be beneficial for other inflammatory conditions.

BACKGROUND/OBJECTIVES: Limited studies suggest lower extremity (LE) fractures are morbid events for nursing home (NH) residents. Our objective was to conduct a nationwide study comparing the incidence and resident characteristics associated with hip (proximal femur) versus non-hip LE (femoral shaft and tibia-fibula) fractures in the NH. DESIGN: Retrospective cohort study. SETTING: U.S. NHs. PARTICIPANTS: We included all long-stay residents aged ≥65 years enrolled in Medicare 1/1/2008-12/31/2009 (N=1,257,279). Residents were followed from long-stay qualification until the first event of LE fracture, death, or end of follow-up (2-years). MEASUREMENTS: Fractures were classified using Medicare diagnostic and procedural codes. Function, cognition, and medical status were obtained from the Minimum Data Set prior to long-stay qualification. Incidence rates (IR) were calculated as the total number of fractures divided by person-years. RESULTS: During 42,800 person-years follow-up, 52,177 residents had a LE fracture (43,695 hip, 6,001 femoral shaft, 2,481 tibia-fibula). The unadjusted IR of LE fractures were 1.32/1,000 person-years (95% CI, 1.27-1.38) for tibia-fibula, 3.20/1,000 person-years (95% CI, 3.12-3.29) for femoral shaft, and 23.32/1,000 person-years (95% CI, 23.11-23.54) for hip. As compared with hip fracture residents, non-hip LE fracture residents were more likely to be immobile (58.1% vs 18.4%), dependent in all ADLs (31.6% vs 10.8%), transferred mechanically (20.5% vs 4.4%), overweight (mean BMI 26.6 kg/m(2)vs. 24.0), and have diabetes (34.8% vs 25.7%). CONCLUSIONS: Our findings that non-hip LE fractures often occur in severely functionally impaired residents suggests these fractures may have a different mechanism of injury than hip fractures. The resident differences in our study highlight the need for distinct prevention strategies for hip and non-hip LE fractures.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases with a prevalence of ~25% worldwide. NAFLD includes simple hepatic steatosis, non-alcoholic steatohepatitis, fibrosis, and cirrhosis, which can further progress to hepatocellular carcinoma. Therefore, effective strategies for the prevention of NAFLD are needed. The pathogenesis of NAFLD is complicated due to diverse injury insults, such as fat accumulation, oxidative stress, inflammation, lipotoxicity, and apoptosis, which may act synergistically. Studies have shown that carotenoids, a natural group of isoprenoid pigments, prevent the development of NAFLD by exerting antioxidant, lipid-lowering, anti-inflammatory, anti-fibrotic, and insulin-sensitizing properties. This review summarizes the protective action of carotenoids, with primary focuses on astaxanthin, lycopene, β-carotene, β-cryptoxanthin, lutein, fucoxanthin, and crocetin, against the development and progression of NAFLD.

Existing studies find that tax avoidance affects the cost of debt and equity in different ways but does not examine the consequences of these associations. This study examines a direct and important implication of the effect of tax avoidance on the cost of debt and equity: capital structure choices. Using logit regressions, we find that tax avoidance is positively associated with the probability of issuing equity rather than debt. We use mediation (i.e., path) analyses to provide evidence that the effects of overall tax avoidance and risky tax avoidance on pre-corporate tax cost of equity and debt partially explain our main effects. For stronger identification, we exploit a plausibly exogenous Ninth Circuit decision to implement a difference-in-differences design. Finally, we find indirect evidence that managerial focus on GAAP effective tax rate to estimate the after-tax cost of debt (Graham, Hanlon, Shevlin, and Shroff 2017), partially explaining our main results.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its prevalence has been increasing globally. The development of NAFLD can be caused by multiple insults, such as steatosis, oxidative stress, inflammation, hepatocyte apoptosis, and fibrosis in the liver. NAFLD is closely associated with various metabolic diseases. However, there is no FDA-approved drug currently available for the treatment of NAFLD. Polyphenols have been suggested as beneficial bioactive compounds for the prevention and the treatment of NAFLD. Notably, studies have shown that polyphenols, including quercetin, epigallocatechin gallate, anthocyanins, and resveratrol, can prevent the development of NAFLD by exerting lipid-lowering, antioxidant, antiinflammatory, and antifibrotic effects. As primary sources of polyphenols in foods, the consumption of fruits and vegetables are recommended to prevent the development of NAFLD. Furthermore, understanding the pathogenesis of NAFLD and the role of polyphenols in the pathological process is critical to devising effective dietary strategies for NAFLD prevention.

Limited studies suggest lower extremity (LE) fractures are morbid events for nursing home (NH) residents. Our objective was to conduct a nationwide study comparing the incidence and potential risk factors associated with hip versus non-hip LE (femoral shaft and tibia-fibula) fractures in the NH. We included all U.S. long-stay residents aged ≥65 years enrolled in Medicare 1/1/2008–12/31/2009 (N=1,257,279). Residents were followed from long-stay qualification until the first event of LE fracture, death, or end of follow-up (2-years). Fractures were classified using Medicare diagnostic and procedural codes. Function, cognition, and medical status were obtained from the Minimum Data Set prior to long-stay qualification. Incidence rates (IR) were calculated as the total number of fractures divided by person-years. During 42,800 person-years follow-up, 52,177 residents had a LE fracture (43,695 hip, 6,001 femoral shaft, 2,481 tibia-fibula). The unadjusted IR of LE fractures were 1.32/1,000 person-years (95% CI, 1.27–1.38) for tibia-fibula, 3.20/1,000 person-years (95% CI, 3.12–3.29) for femoral shaft, and 23.32/1,000 person years (95% CI, 23.11–23.54) for hip. As compared with hip fracture residents, non-hip LE fracture residents were more likely to be immobile (58.1% vs 18.4%), dependent in all ADLs (31.6% vs 10.8%), transferred mechanically (20.5% vs 4.4%), overweight (mean BMI 26.6 kg/m2 vs. 24.0), and have diabetes (34.8% vs 25.7%). Our findings that non-hip LE fractures often occur in severely functionally impaired residents suggests these fractures may occur during lifting and transferring. The resident differences in our study highlight the need for distinct prevention strategies for hip and non-hip LE fractures.

Importance The Affordable Care Act Medicaid expansion may be associated with reduced mortality, but evidence to date is limited. Patients with end-stage renal disease (ESRD) are a high-risk group that may be particularly affected by Medicaid expansion. Objective To examine the association of Medicaid expansion with 1-year mortality among nonelderly patients with ESRD initiating dialysis. Design, Setting, and Participants Difference-in-differences analysis of nonelderly patients initiating dialysis in Medicaid expansion and nonexpansion states from January 2011 to March 2017. Exposure Living in a Medicaid expansion state. Main Outcomes and Measures The primary outcome was 1-year mortality. Secondary outcomes were insurance, predialysis nephrology care, and type of vascular access for hemodialysis. Results A total of 142 724 patients in expansion states (mean age, 50.2 years; 40.2% women) and 93 522 patients in nonexpansion states (mean age, 49.7; 42.4% women) were included. In Medicaid expansion states, 1-year mortality following dialysis initiation declined from 6.9% in the preexpansion period to 6.1% after expansion (change, −0.8 percentage points; 95% CI, −1.1 to −0.5). In nonexpansion states, mortality rates were 7.0% before expansion and 6.8% after expansion (change, −0.2 percentage points; 95% CI, −0.5 to 0.2), yielding an adjusted absolute reduction in mortality in expansion states of −0.6 percentage points (95% CI, −1.0 to −0.2). Mortality reductions were largest for black patients (−1.4 percentage points; 95% CI, −2.2, −0.7;P=.04 for interaction) and patients aged 19 to 44 years (−1.1 percentage points; 95% CI, −2.1 to −0.3;P=.01 for interaction). Expansion was associated with a 10.5-percentage-point (95% CI, 7.7-13.2) increase in Medicaid coverage at dialysis initiation, a −4.2-percentage-point (95% CI, −6.0 to −2.3) decrease in being uninsured, and a 2.3-percentage-point (95% CI, 0.6-4.1) increase in the presence of an arteriovenous fistula or graft. Changes in predialysis nephrology care were not significant. Conclusions and Relevance Among patients with ESRD initiating dialysis, living in a state that expanded Medicaid under the Affordable Care Act was associated with lower 1-year mortality. If this association is causal, further research is needed to understand what factors may have contributed to this finding.

The incidence of hip fractures in community-dwelling older adult populations declined substantially between 2002 and 2012; however, little is known about longitudinal changes in hip fracture rates and post-fracture mortality among nursing home(NH) residents. This study investigated trends in fracture rates and mortality among 1.9 million NH residents from 2007 to 2013. We found that the crude incidence rate of hip fractures decreased from 3.55/100 person-years in 2007 to 3.17/100 person-years in 2013. The age-adjusted hip fracture and one-year mortality rates were 14% [incidence rate ratio,1.14, 95% confidence interval (CI), 1.10–1.17] and 7% [hazard ratio,1.07, 95% CI, 1.02–1.12] greater in 2007 than in 2013, respectively. To our knowledge, this is the first national study describing declining trends in hip fractures and mortality among NH residents. These results are encouraging, but additional research is needed to identify the most effective strategies to reduce hip fractures and improve long-term outcomes.

Importance Enrollment in Medicaid managed care plans has increased rapidly, particularly in national commercial insurance plans. Whether the type of managed care plan is associated with the use of health services for Medicaid beneficiaries is unknown. Objective To compare the use of outpatient and acute care between Medicaid enrollees randomly assigned to a national commercial managed care plan or a local Medicaid-focused managed care plan. Design, setting, and participants This natural experiment of a cohort of Medicaid enrollees randomly assigned to 2 managed care plans in a Northeastern US state was conducted from June 30, 2009, to June 30, 2013. Statistical analysis was performed from September 1, 2019, to August 30, 2020. Interventions Assignment to a Medicaid-focused insurance plan or a commercial managed care plan. Main outcomes and measures Outpatient visits, emergency department visits, and total inpatient and ambulatory care-sensitive hospitalizations. Results A total of 8010 patients were included in the analysis: 4737 were assigned to a Medicaid-focused plan (2795 female [59.0%]; mean [SD] age, 17.8 [3.2] years) and 3273 to a commercial managed care plan (1915 female [58.5%]; mean [SD] age, 17.9 [3.3] years). Those randomly assigned to the Medicaid-focused plan had a mean (SD) of 6.67 (9.18) annual outpatient visits per person, and those assigned to the commercial plan had a mean (SD) of 8.36 (11.77) annual outpatient visits per person (adjusted absolute difference, 1.72 [95% CI, 1.31-2.13]; 22% relative difference). The increased use of outpatient visits in the commercial plan was associated with an increase in specialty care visits (mean [SD], 2.34 [6.31] visits in Medicaid-focused plan vs 3.75 [9.32] visits in commerical plan; adjusted absolute difference, 1.43 visits [95% CI, 1.25-1.56 visits]; 61% relative difference). Mean (SD) annual emergency department visits were 0.49 (1.39) per person in the Medicaid-focused plan and 0.51 (1.40) in the commercial plan (adjusted absolute difference, 0.02 [95% CI, -0.02 to 0.05]). Mean (SD) annual inpatient admissions were 0.067 (0.45) per person in the Medicaid-focused plan and 0.069 (0.53) in the commercial plan (adjusted absolute difference, 0.003 [95% CI, -0.01 to 0.02]). Plan assignment was not significantly associated with ambulatory care-sensitive admissions. Results were consistent in instrumental variables analyses that accounted for disenrollment and switching. Conclusions and relevance Compared with Medicaid managed care enrollees assigned to a Medicaid-focused plan, those assigned to a commercial plan had more outpatient visits, particularly for specialty care, but had similar rates of emergency department visits and hospitalizations. These findings suggest that the type of managed care plan may be associated with health services use and spending among Medicaid beneficiaries and that random assignment may help states understand how well different plans perform for enrollees.

Objectives Alcohol induces inflammation and oxidative stress, causing cell damages. We previously demonstrated that astaxanthin (ASTX), a xanthophyll carotenoid, exerts anti-inflammatory and antioxidant properties in macrophages exposed to inflammatory insults. In this study, we investigated whether ASTX can inhibit alcohol-induced inflammation and oxidative stress in macrophages with the elucidation of mechanisms. Methods RAW 264.7 macrophages and mouse bone marrow-derived macrophages were treated with 80 mM ethanol in the presence or absence of 25 μM of ASTX for 72 h. Subsequently, the expression of genes related to inflammation and oxidative stress, cellular reactive oxygen species accumulation, cellular NAD+ level and sirtuin 1 (SIRT1) activity were measured. In addition, RAW 264.7 macrophages were treated with sirtinol or resveratrol, which are known inhibitors or activators of SIRT1 activity, respectively, to determine the contribution of SIRT1 to the inhibitory effect of ASTX on inflammation and oxidative stress in macrophages exposed to ethanol. Results Ethanol increased mRNA expression of interleukin (Il)-6, Il-1b and tumor necrosis factor α with a concomitant increase in nuclear translocation of nuclear factor κB, which was abolished by ASTX. Importantly, ethanol significantly decreased SIRT1 activity and cellular NAD+ level, but ASTX markedly attenuated the decreases in RAW 264.7 macrophages. Sirtinol increased the expression of proinflammatory genes in ethanol-induced RAW 264.7 macrophages. In contrast, resveratrol decreased proinflammatory gene expression. Conclusions ASTX showed anti-inflammatory and antioxidant properties by inhibiting decreases in SIRT1 expression and cellular NAD+ level in ethanol-treated macrophages. Therefore, ASTX may be used for the prevention of alcohol-induced cell damages.

Purpose The objective of this study was to determine the fraction of variance in patient-level medication adherence accounted for by prescribers and pharmacies. Methods We used prescription drug claims paid between January 2010 and July 2011 to a national pharmacy benefits manager to define implementation during persistent episodes. Patients in Massachusetts or Rhode Island covered by Blue Cross Blue Shield of Rhode Island and their prescribers were included. Five drug classes were analyzed: angiotensin converting enzyme (ACE) inhibitors, antihyperglycemics (ANHGs), drugs for prostatic hyperplasia (PH), statins, and levothyroxine (THYR). We performed mixed models with random intercepts (drug, patient, prescriber, and pharmacy) and examined the fraction of variance explained at each level using intraclass correlations. Results Overall implementation ranged from 87 to 91%. The fraction of the explained variance in implementation to ACEs, ANHG, PH, statins, and THYR accounted for by prescribers was 16.4%, 12.6%, 14.6%, 15.6%, and 15% respectively; and for pharmacies 20.4%, 20%, 15.2%, 10.6%, and 9.4%, respectively. Conclusions Prescriber and pharmacy effects accounted for a substantial amount of the explained variance in implementation across all five drug classes. Adherence interventions for chronic conditions that target prescribers and pharmacies, in addition to patients, could be effective and efficient. Copyright © 2016 John Wiley & Sons, Ltd.

Background: The purpose of this study was to examine the incidence of adverse events in elderly patients who required inpatient admission after sustaining an ankle fracture and to consider these data in relation to geriatric hip fracture and other geriatric patient admissions. Methods: A retrospective cohort study of patients admitted with an ankle fracture, a hip fracture, or any other diagnosis was performed with the Medicare Part A database for 2008. The primary outcome measure was the one-year mortality rate, examined with multivariate analysis factoring for both patient age and preexisting comorbidity. Secondary outcome measures analyzed additional morbidity as reflected by length of stay, discharge disposition, readmissions, and medical complications. Results: There were 19,648 patients with ankle fractures, 193,980 patients with hip fractures, and 5,801,831 patients with other admitting diagnoses. Significant differences (p < 0.001) were noted in both age and comorbidity status between the group with ankle fractures and the group with hip fractures. The one-year mortality after admission was 11.9% for patients with ankle fracture, 28.2% for patients with hip fracture, and 21.5% for patients with any other admission. Upon using multivariate analysis to account for both age and comorbidity, the hazard ratio for one-year mortality associated with fracture was 1.088 for patients with hip fracture and 0.557 for patients with ankle fracture. Conclusions: Even after selecting for admitted patients and accounting for both age and comorbidity, geriatric patients with ankle fractures were found to have a lower one-year morbidity compared with geriatric patients who had sustained a hip fracture or alternative admitting diagnoses. Geriatric patients with ankle fractures are likely healthier and more active in ways that are not captured by simply accounting for age and comorbidity. These findings may support more aggressive definitive management of such injuries in this population. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Aims Hepatic stellate cells (HSCs) play an essential role in the development of liver fibrosis by producing extracellular matrix proteins, growth factors, and pro-inflammatory and pro-fibrogenic cytokines once activated. We previously demonstrated that astaxanthin (ASTX), a xanthophyll carotenoid, attenuates HSC activation. The objective of this study was to investigate whether there is a difference in glycolysis between quiescent and activated HSCs and the effect of ASTX on glycolysis during HSC activation. Materials and methods Mouse primary HSCs were activated for 7 days in the presence or absence of 25 μM of ASTX. Quiescent HSCs (qHSCs), 1 day after isolation, and activated HSCs (aHSCs) treated with/without ASTX were plated in a Seahorse XF24 cell culture microplate for Glycolysis Stress tests. Key findings aHSCs had significantly lower glycolysis, but higher glycolytic capacity, maximum capacity of glycolysis, and non-glycolytic acidification than qHSCs. Importantly, ASTX markedly increased glycolysis during HSC activation with a concomitant increase in lactate formation and secretion. Compared with qHSCs, aHSCs had significantly lower expression of glucose transporter 1, the major glucose transporter in HSCs, and its transcription factor hypoxia-inducible factor 1α, which was markedly increased by ASTX in aHSCs. Significance Our data suggest that ASTX may prevent the activation of HSCs by altering glycolysis and the expression of genes involved in the pathways.

BACKGROUND: Bisphosphonates are seldom used in frail, older adults, in part due to lack of direct evidence of efficacy in this population and increasing concerns about safety. OBJECTIVE: We estimated the effects of bisphosphonates on hip fractures, non-vertebral fractures, and severe esophagitis among frail, older adults. DESIGN: Population-based retrospective cohort using 2008-2013 linked national Minimum Data Set assessments; Online Survey, Certification and Reporting records; and Medicare claims. SETTING: U.S. nursing homes (NH). PARTICIPANTS: Long-stay NH residents ≥ 65 years without recent osteoporosis medication use (N=24,571). Bisphosphonate initiators were 1:1 propensity score matched to calcitonin initiators (active comparator). MEASUREMENTS: Hospitalized hip fracture, non-vertebral fracture, and esophagitis outcomes were measured using Part A claims. Hazard ratios and 95% confidence intervals (CI) were estimated controlling for over 100 baseline characteristics. RESULTS: The matched cohort included 5,209 new bisphosphonate users and an equal number of calcitonin users (mean age [SD], 85 [8] years; 87% female; 52% moderate-severe cognitive impairment). Over a mean follow-up of 2.5 years (SD 1.7), 568 residents (5.5%) had a hip fracture, 874 (8.4%) a non-vertebral fracture, and 199 (1.9%) a hospitalized esophagitis event. Users of bisphosphonates were less likely than calcitonin users to experience hip fracture (HR, 0.83; 95% CI, 0.71 to 0.98), with an average gain in time without fracture of 28.4 days (95% CI, 6.0 to 50.8). Bisphosphonate and calcitonin users had similar rates of non-vertebral fracture (HR, 0.91; 95% CI, 0.80 to 1.03) and esophagitis events (HR, 1.11; 95% CI, 0.84 to 1.47). The effects of bisphosphonates on fractures and esophagitis were generally homogenous across subgroups, including those defined by age, sex, history of prior fracture, and baseline fracture risk. CONCLUSIONS: Use of bisphosphonates is associated with a meaningful reduction in hip fracture among frail, older adults, but little difference in non-vertebral fracture or severe esophagitis.

AIMS: Some beta-blockers may worsen glycemic control, which could be important for frail older nursing home (NH) residents with type 2 diabetes mellitus (T2D). There is little evidence that prescribers consider the glycometabolic properties of beta-blockers or that such properties affect clinical outcomes. We assessed whether NH residents with T2D preferentially received “T2D-friendly” (versus “T2D-unfriendly”) beta-blockers after acute myocardial infarction (AMI), and evaluated their comparative effects. MATERIALS AND METHODS: This new-user retrospective cohort study of NH residents with AMI from May 2007 to March 2010 used national data from the Minimum Data Set and Medicare. T2D-friendly beta-blockers were those hypothesized to increase peripheral glucose uptake through vasodilation: carvedilol, nebivolol, and labetalol. Primary outcomes were hypoglycemia and hyperglycemia hospitalizations in the 90 days after AMI. Secondary outcomes were functional decline, death, all-cause rehospitalization and fracture hospitalization. We compared outcomes using binomial and multinomial logistic regression models after propensity score matching. RESULTS: Twenty-nine percent of 2,855 NH residents with T2D initiated a T2D-friendly beta-blocker versus 24% of 6,098 without T2D (p-value

Objective With increasing prevalence of nonalcoholic steatohepatitis (NASH), effective strategies to prevent NASH are needed. This study investigated whether the consumption of blackcurrant (Ribes nigrum) can prevent the development of obesity-induced NASH in vivo. Methods Male C57BL/6J mice were fed a low-fat control diet, a low-fat diet with 6% whole blackcurrant powder, an obesogenic high-fat/high-sucrose control diet (HF), or a high-fat/high-sucrose diet containing 6% whole blackcurrant powder (HF-B) for 24 weeks. Results HF significantly increased, whereas HF-B markedly decreased, liver weights and triglyceride. Furthermore, blackcurrant attenuated obesity-induced infiltration of macrophages in the liver, in particular, the M1 type, and also suppressed the hepatic expression of fibrogenic genes and fibrosis. Flow cytometric analysis showed that HF significantly increased the percentages of monocytes of total splenocytes, which was markedly attenuated by blackcurrant. HF-B decreased lipopolysaccharide-stimulated mRNA expression of interleukin 1β and tumor necrosis factor α in splenocytes, compared with those from HF controls. Moreover, the levels of circulating and hepatic miR-122-5p and miR-192-5p, known markers for nonalcoholic fatty liver disease, were significantly increased by HF but decreased by HF-B. Conclusions The study's findings indicate that blackcurrant consumption prevents obesity-induced steatosis, inflammation, and fibrosis in the liver.

Importance The decision whether to surgically repair a hip fracture in nursing home (NH) residents with advanced dementia can be challenging. Objective To compare outcomes, including survival, among NH residents with advanced dementia and hip fracture according to whether they underwent surgical hip fracture repair. Design, Setting, and Participants We conducted a retrospective cohort study of 3083 NH residents with advanced dementia and hip fracture, but not enrolled in hospice care, using nationwide Medicare claims data linked with Minimum Data Set (MDS) assessments from January 1, 2008, through December 31, 2013. Methods Residents with advanced dementia were identified using the MDS. Medicare claims were used to identify hip fracture and to determine whether the fracture was managed surgically. Survival between surgical and nonsurgical residents was compared using multivariable Cox proportional hazards with inverse probability of treatment weighting (IPTW). All analyses took place between November 2015 and January 2018. Among 6-month survivors, documented pain, antipsychotic drug use, physical restraint use, pressure ulcers, and ambulatory status were compared between surgical and nonsurgical groups. Results Among 3083 residents with advanced dementia and hip fracture (mean age, 84.2 years; 79.2% female [n = 2441], 28.5% ambulatory [n = 879]), 2615 (84.8%) underwent surgical repair. By 6-month follow-up, 31.5% (n = 824) and 53.8% (n = 252) of surgically and nonsurgically managed residents died, respectively. After IPTW modeling, surgically managed residents were less likely to die than residents without surgery (adjusted hazard ratio [aHR], 0.88; 95% CI, 0.79-0.98). Among 2007 residents who survived 6 months, residents with surgical vs nonsurgical management had less docmented pain (29.0% [n = 465] vs 30.9% [n = 59]) and fewer pressure ulcers (11.2% [n = 200] vs 19.0% [n = 41]). In IPTW models, surgically managed residents reported less pain (aHR, 0.78; 95% CI, 0.61-0.99) and pressure ulcers (aHR, 0.64; 95% CI, 0.47-0.86). There was no difference between antipsychotic drug use and physical restraint use between the groups. Few survivors remained ambulatory (10.7% [n = 55] of surgically managed vs 4.8% [n = 1] without surgery). Conclusions and Relevance Surgical repair of a hip fracture was associated with lower mortality among NH residents with advanced dementia and should be considered together with the residents’ goals of care in management decisions. Pain and other adverse outcomes were common regardless of surgical management, suggesting the need for broad improvements in the quality of care provided to NH residents with advanced dementia and hip fracture.

Since the development of CLARITY, a bioelectrochemical clearing technique that allows for three-dimensional phenotype mapping within transparent tissues, a multitude of novel clearing methodologies including CUBIC (clear, unobstructed brain imaging cocktails and computational analysis), SWITCH (system-wide control of interaction time and kinetics of chemicals), MAP (magnified analysis of the proteome), and PACT (passive clarity technique), have been established to further expand the existing toolkit for the microscopic analysis of biological tissues. The present study aims to improve upon and optimize the original PACT procedure for an array of intact rodent tissues, including the whole central nervous system (CNS), kidneys, spleen, and whole mouse embryos. Termed psPACT (process-separate PACT) and mPACT (modified PACT), these novel techniques provide highly efficacious means of mapping cell circuitry and visualizing subcellular structures in intact normal and pathological tissues. In the following protocol, we provide a detailed, step-by-step outline on how to achieve maximal tissue clearance with minimal invasion of their structural integrity via psPACT and mPACT.