Association of Antipsychotic Use With Hospital Events and Mortality Among Medicare Beneficiaries Residing in Long-Term Care Facilities

Objective—Antipsychotic (AP) utilization has grown significantly in long-term care (LTC) settings. Although a growing literature associates AP use with higher mortality in elderly with dementia, the association of APs with hospital events is unclear. The authors examine prevalence and trends in AP use by Medicare beneficiaries residing in LTC and the association of APs and other drug use variables with hospital events and mortality. Design—Retrospective analysis using sequential multivariate Cox proportional hazards models. Setting—Medicare Current Beneficiary Survey linked to Institutional Drug Administration and Minimum Data Set files. Participants—A total of 2,363 LTC Medicare beneficiaries, 1999–2002. Measurements—Trends in LTC AP use overall and by type and duplicative use; association of AP utilization and two outcomes: hospital events and all-cause mortality. Results—AP use rose markedly from 1999 to 2002 (26.4%–35.9%), predominantly due to increased use of atypical agents. After controlling for sociodemographic and clinical factors, AP use is not related to hospital events (hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.82–1.63 p = 0.7951). AP use is associated with reduced mortality in unadjusted and intermediate models, but loss of significance in the final model (HR = 0.83, 95% CI = 0.69–1.00, p = 0.0537) suggests that disease and drug burden factors may confound the AP-mortality relationship. Conclusion—This study provides no evidence of increased hospital events or mortality in LTC residents who use AP medications. Findings contribute to a growing body of evidence that APs, particularly atypical agents, may be associated with reduced mortality in LTC residents

The Micro-Randomized Trial for Developing Digital Interventions: Data Analysis Methods

Although there is much excitement surrounding the use of mobile and wearable technology for the purposes of delivering interventions as people go through their day-to-day lives, data analysis methods for constructing and optimizing digital interventions lag behind. Here, we elucidate data analysis methods for primary and secondary analyses of micro-randomized trials (MRTs), an experimental design to optimize digital just-in-time adaptive interventions. We provide a definition of causal "excursion" effects suitable for use in digital intervention development. We introduce the weighted and centered least-squares (WCLS) estimator which provides consistent causal excursion effect estimators for digital interventions from MRT data. We describe how the WCLS estimator along with associated test statistics can be obtained using standard statistical software such as SAS or R. Throughout we use HeartSteps, an MRT designed to increase physical activity among sedentary individuals, to illustrate potential primary and secondary analyses

Cyanidin-3-Glucoside, A Natural Product Derived From Blackberry, Exhibits Chemopreventive And Chemotherapeutic Activity

Epidemiological data suggest that consumption of fruits and vegetables has been associated with a lower incidence of cancer. Cyanidin-3-glucoside (C3G), a compound found in blackberry and other food products, was shown to possess chemopreventive and chemotherapeutic activity in the present study. In cultured JB6 cells, C3G was able to scavenge ultraviolet B-induced *OH and O2-* radicals. In vivo studies indicated that C3G treatment decreased the number of non-malignant and malignant skin tumors per mouse induced by 12-O-tetradecanolyphorbol-13-acetate (TPA) in 7,12-dimethylbenz[a]anthracene-initiated mouse skin. Pretreatment of JB6 cells with C3G inhibited UVB- and TPA-induced transactivation of NF-kappaB and AP-1 and expression of cyclooxygenase-2 and tumor necrosis factor-alpha. These inhibitory effects appear to be mediated through the inhibition of MAPK activity. C3G also blocked TPA-induced neoplastic transformation in JB6 cells. In addition, C3G inhibited proliferation of a human lung carcinoma cell line, A549. Animal studies showed that C3G reduced the size of A549 tumor xenograft growth and significantly inhibited metastasis in nude mice. Mechanistic studies indicated that C3G inhibited migration and invasion of A549 tumor cells. These finding demonstrate for the first time that a purified compound of anthocyanin inhibits tumor promoter-induced carcinogenesis and tumor metastasis in vivo

CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis

Macrophages abundantly found in the tumor microenvironment enhance malignancy(1). At metastatic sites a distinct population of metastasis associated macrophages (MAMs) promote tumor cell extravasation, seeding and persistent growth(2). Our study has defined the origin of these macrophages by showing Gr1+ inflammatory monocytes (IMs) are preferentially recruited to pulmonary metastases but not primary mammary tumors, a process also found for human IMs in pulmonary metastases of human breast cancer cells. The recruitment of these CCR2 (receptor for chemokine CCL2) expressing IMs and subsequently MAMs and their interaction with metastasizing tumor cells is dependent on tumor and stromal synthesized CCL2 (FigS1). Inhibition of CCL2/CCR2 signaling using anti-CCL2 antibodies blocks IM recruitment and inhibits metastasis in vivo and prolongs the survival of tumor-bearing mice. Depletion of tumor cell-derived CCL2 also inhibits metastatic seeding. IMs promote tumor cell extravasation in a process that requires monocyte-derived VEGF. CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer (Fig S2)(3-6). Our data provides the mechanistic link between these two clinical associations and indicates new therapeutic targets for treating metastatic breast disease

A Regional Climate Change Assessment Program for North America

There are two main uncertainties in determining future climate: the trajectories of future emissions of greenhouse gases and aerosols, and the response of the global climate system to any given set of future emissions [Meehl et al., 2007]. These uncertainties normally are elucidated via application of global climate models, which provide information at relatively coarse spatial resolutions. Greater interest in, and concern about, the details of climate change at regional scales has provided the motivation for the application of regional climate models, which introduces additional uncertainty [Christensen et al., 2007a]. These uncertainties in fine-scale regional climate responses, in contrast to uncertainties of coarser spatial resolution global models in which regional models are nested, now have been documented in numerous contexts [Christensen et al., 2007a] and have been found to extend to uncertainties in climate impacts [Wood et al., 2004; Oleson et al., 2007]. While European research in future climate projections has moved forward systematically to examine combined uncertainties from global and regional models [Christensen et al., 2007b], North American climate programs have lagged behind

Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes

OBJECTIVE: Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin. RESEARCH DESIGN AND METHODS: C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2) C-peptide positive, with low stimulated values ≥0.017 but <0.2 nmol/L; and 3) C-peptide <0.017 nmol/L. Longitudinal samples were analyzed from C-peptide-positive subjects with diabetes after 1, 2, and 4 years. RESULTS: Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (<0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (<0.017 nmol/L) residual C-peptide. CONCLUSIONS: In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide

Selenium Deficiency Is Associated with Mortality Risk from COVID-19

SARS-CoV-2 infections underlie the current coronavirus disease (COVID-19) pandemic and are causative for a high death toll particularly among elderly subjects and those with comorbidities. Selenium (Se) is an essential trace element of high importance for human health and particularly for a well-balanced immune response. The mortality risk from a severe disease like sepsis or polytrauma is inversely related to Se status. We hypothesized that this relation also applies to COVID-19. Serum samples (n = 166) from COVID-19 patients (n = 33) were collected consecutively and analyzed for total Se by X-ray fluorescence and selenoprotein P (SELENOP) by a validated ELISA. Both biomarkers showed the expected strong correlation (r = 0.7758, p < 0.001), pointing to an insufficient Se availability for optimal selenoprotein expression. In comparison with reference data from a European cross-sectional analysis (EPIC, n = 1915), the patients showed a pronounced deficit in total serum Se (mean ± SD, 50.8 ± 15.7 vs. 84.4 ± 23.4 µg/L) and SELENOP (3.0 ± 1.4 vs. 4.3 ± 1.0 mg/L) concentrations. A Se status below the 2.5th percentile of the reference population, i.e., [Se] < 45.7 µg/L and [SELENOP] < 2.56 mg/L, was present in 43.4% and 39.2% of COVID samples, respectively. The Se status was significantly higher in samples from surviving COVID patients as compared with non-survivors (Se; 53.3 ± 16.2 vs. 40.8 ± 8.1 µg/L, SELENOP; 3.3 ± 1.3 vs. 2.1 ± 0.9 mg/L), recovering with time in survivors while remaining low or even declining in non-survivors. We conclude that Se status analysis in COVID patients provides diagnostic information. However, causality remains unknown due to the observational nature of this study. Nevertheless, the findings strengthen the notion of a relevant role of Se for COVID convalescence and support the discussion on adjuvant Se supplementation in severely diseased and Se-deficient patients

Measurement of H₂O₂ within living drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix

Hydrogen peroxide (H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;) is central to mitochondrial oxidative damage and redox signaling, but its roles are poorly understood due to the difficulty of measuring mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; in vivo. Here we report a ratiometric mass spectrometry probe approach to assess mitochondrial matrix H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; levels in vivo. The probe, MitoB, comprises a triphenylphosphonium (TPP) cation driving its accumulation within mitochondria, conjugated to an arylboronic acid that reacts with H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; to form a phenol, MitoP. Quantifying the MitoP/MitoB ratio by liquid chromatography-tandem mass spectrometry enabled measurement of a weighted average of mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; that predominantly reports on thoracic muscle mitochondria within living flies. There was an increase in mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; with age in flies, which was not coordinately altered by interventions that modulated life span. Our findings provide approaches to investigate mitochondrial ROS in vivo and suggest that while an increase in overall mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; correlates with aging, it may not be causative

Reply to “Comments on ‘The North American Regional Climate Change Assessment Program: Overview of Phase I Results\u27”

The authors of Mearns et al. (2012) are aware of the role of driving RCMs with reanalyses and have written extensively on the roles of different types of regional climate models (RCMs) simulations (e.g., Giorgi and Mearns 1999; Leung et al. 2003). Thus, we agree that the skill of dynamical downscaling in which global reanalysis is used to provide boundary conditions in general indicates an upper bound of skill compared to dynamical downscaling in which the boundary conditions come from global climate model simulations. This finding has long been established, as global climate model simulations cannot outperform global reanalysis in providing boundary conditions since the latter is constrained by observations through data assimilation (that is, unless the reanalyses themselves have been shown to have serious deficiences; e.g., Cerezo-Mota et al 2011). The classification of different types of dynamical downscaling introduced by Castro et al. (2005) further adds clarity to this point

Contrasts in China and Soviet reform: sub-national and national causes

Why did reform in China and the former Soviet Union produce drastically different outcomes? Why did some provinces in China embrace faster economic reform than others? This article argues that the state sector and reform initiatives in the sub-national units, reform strategies, entrenchment and maturation of central planning, the size of the defence industry, policy choice and the historical context help explain the differences in Soviet and Chinese reform courses and outcomes. A predominant state sector in the former Soviet republics had stifled local reform initiatives. Gorbachev resorted to democratisation in order to unbolt the gate for popular support for marketisation, yet resulting in the breakup of the Soviet Union and destabilising the economy. In China, some provinces had sizable non-state sectors and were inclined to push forth marketization. Reform resulted in expanding non-state sectors, generating high growth and encouraging the regime to maintain its monopoly of power. China’s reform also benefited from a yet-to-be-entrenched and rudimentary central planning, a small defence sector, popular backlash against past policies, and reformist pragmatic strategy