Loss of abdominal fat and improvement of the cardiovascular risk profile by regular moderate exercise training in patients with NIDDM

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An estimation of the consequences of reinforcing the 2016 and 2019 ESC/EAS guidelines on current lipid-lowering treatment in patients with type 2 diabetes in tertiary care - a SwissDiab study.

BACKGROUND In 2019, the ESC/EAS updated the 2016 guidelines for the management of dyslipidaemias recommending more stringent LDL-cholesterol (LDL-C) targets in diabetes mellitus type 2 (DM2). Based on a real-world patient population, this study aimed to determine the feasibility and cost of attaining guideline-recommended LDL-C targets, and assess cardiovascular benefit. METHODS The Swiss Diabetes Registry is a multicentre longitudinal observational study of outpatients in tertiary diabetes care. Patients with DM2 and a visit 01.01.2018-31.08.2019 that failed the 2016 LDL-C target were identified. The theoretical intensification of current lipid-lowering medication needed to reach the 2016 and 2019 LDL-C target was determined and the cost thereof extrapolated. The expected number of MACE prevented by treatment intensification was estimated. RESULTS 294 patients (74.8%) failed the 2016 LDL-C target. The percentage of patients that theoretically achieved the 2016 and 2019 target with the indicated treatment modifications were: high-intensity statin, 21.4% and 13.3%; ezetimibe, 46.6% and 27.9%; PCSK9 inhibitor (PCSK9i), 30.6% and 53.7%; ezetimibe and PCSK9i, 1.0% and 3.1%, whereas one (0.3%) and five patients (1.7%) failed to reach target, respectively. Achieving the 2016 versus 2019 target would reduce the estimated 4-year MACE from 24.9 to 18.6 versus 17.4 events, at an additional annual cost of medication of 2,140 CHF versus 3,681 CHF per patient, respectively. CONCLUSIONS For 68% of the patients, intensifying statin treatment and/or adding ezetimibe would be sufficient to reach the 2016 target, whereas 57% would require cost-intensive PCSK9i therapy to reach the 2019 target, with limited additional medium-term cardiovascular benefit

Y-family DNA polymerases and their role in tolerance of cellular DNA damage.

The past 15 years have seen an explosion in our understanding of how cells replicate damaged DNA and how this can lead to mutagenesis. The Y-family DNA polymerases lie at the heart of this process, which is commonly known as translesion synthesis. This family of polymerases has unique features that enable them to synthesize DNA past damaged bases. However, as they exhibit low fidelity when copying undamaged DNA, it is essential that they are only called into play when they are absolutely required. Several layers of regulation ensure that this is achieve

Modulation of Cell Surface Receptor Expression by Modified Vaccinia Virus Ankara in Leukocytes of Healthy and HIV-Infected Individuals

Viral vectors are increasingly used as delivery means to induce a specific immunity in humans and animals. However, they also impact the immune system, and it depends on the given context whether this is beneficial or not. The attenuated vaccinia virus strain modified vaccinia virus Ankara (MVA) has been used as a viral vector in clinical studies intended to treat and prevent cancer and infectious diseases. The adjuvant property of MVA is thought to be due to its capability to stimulate innate immunity. Here, we confirmed that MVA induces interleukin-8 (IL-8), and this chemokine was upregulated significantly more in monocytes and HLA-DR(bright)dendritic cells (DCs) of HIV-infected patients on combined antiretroviral therapy (ART) than in cells of healthy persons. The effect of MVA on cell surface receptors is mostly unknown. Using mass cytometry profiling, we investigated the expression of 17 cell surface receptors in leukocytes afterex vivoinfection of human whole-blood samples with MVA. We found that MVA downregulates most of the characteristic cell surface markers in particular types of leukocytes. In contrast, C-X-C motif chemokine receptor 4 (CXCR4) was significantly upregulated in each leukocyte type of healthy persons. Additionally, we detected a relative higher cell surface expression of the HIV-1 co-receptors C-C motif chemokine receptor 5 (CCR5) and CXCR4 in leukocytes of HIV-ART patients than in healthy persons. Importantly, we showed that MVA infection significantly downregulated CCR5 in CD4+ T cells, CD8+ T cells, B cells, and three different DC populations. CD86, a costimulatory molecule for T cells, was significantly upregulated in HLA-(DRDCs)-D-bright after MVA infection of whole blood from HIV-ART patients. However, MVA was unable to downregulate cell surface expression of CD11b and CD32 in monocytes and neutrophils of HIV-ART patients to the same extent as in monocytes and neutrophils of healthy persons. In summary, MVA modulates the expression of many different kinds of cell surface receptors in leukocytes, which can vary in cells originating from persons previously infected with other pathogens

Factors Associated with the Incidence of Type 2 Diabetes Mellitus in HIV-Infected Participants in the Swiss HIV Cohort Study

Background. Human immunodeficiency virus (HIV)-infected persons may be at increased risk for developing type 2 diabetes mellitus because of viral coinfection and adverse effects of treatment. Methods. We studied associations of new-onset diabetes mellitus with hepatitis B virus and hepatitis C virus coinfections and antiretroviral therapy in participants in the Swiss HIV Cohort Study, using Poisson regression. Results. A total of 123 of 6513 persons experienced diabetes mellitus during 27,798 person-years of follow-up (PYFU), resulting in an incidence of 4.4 cases per 1000 PYFU (95% confidence interval [CI], 3.7-5.3 cases per 1000 PYFU). An increased incidence rate ratio (IRR) was found for male subjects (IRR, 2.5; 95% CI, 1.5-4.2), older age (IRR for subjects >60 years old, 4.3; 95% CI, 2.3-8.2), black (IRR, 2.1; 95% CI, 1.1-4.0) and Asian (IRR, 4.9; 95% CI, 2.2-10.9) ethnicity, Centers for Disease Control and Prevention disease stage C (IRR, 1.6; 95% CI, 1.04-2.4), and obesity (IRR, 4.7; 95% CI, 3.1-7.0), but results for hepatitis C virus infection or active hepatitis B virus infection were inconclusive. Strong associations were found for current treatment with nucleoside reverse-transcriptase inhibitors (IRR, 2.22; 95% CI, 1.11-4.45), nucleoside reverse-transcriptase inhibitors plus protease inhibitors (IRR, 2.48; 95% CI, 1.42-4.31), and nucleoside reverse-transcriptase inhibitors plus protease inhibitors and nonnucleoside reverse-transcriptase inhibitors (IRR, 3.25; 95% CI, 1.59-6.67) but were not found for treatment with nucleoside reverse-transcriptase inhibitors plus nonnucleoside reverse-transcriptase inhibitors (IRR, 1.47; 95% CI, 0.77-2.82). Conclusions. In addition to traditional risk factors, current treatment with protease inhibitor- and nucleoside reverse-transcriptase inhibitor-containing regimens was associated with the risk of developing type 2 diabetes mellitus. Our study did not find a significant association between viral hepatitis infection and risk of incident diabete

Replication of the association of HLA-B7 with Alzheimer's disease: a role for homozygosity?

BACKGROUND: There are reasons to expect an association with Alzheimer's disease (AD) within the HLA region. The HLA-B & C genes have, however, been relatively understudied. A geographically specific association with HLA-B7 & HLA-Cw*0702 had been suggested by our previous, small study. METHODS: We studied the HLA-B & C alleles in 196 cases of 'definite' or 'probable' AD and 199 elderly controls of the OPTIMA cohort, the largest full study of these alleles in AD to date. RESULTS: We replicated the association of HLA-B7 with AD (overall, adjusted odds ratio = 2.3, 95% confidence interval = 1.4–3.7, p = 0.001), but not the previously suggested interaction with the ε4 allele of apolipoprotein E. Results for HLA-Cw*0702, which is in tight linkage disequilibrium with HLA-B7, were consistent with those for the latter. Homozygotes of both alleles appeared to be at particularly high risk of AD. CONCLUSION: HLA-B7 and HLA-Cw*0702 are associated with AD in the Oxford population. Because of the contradictions between cohorts in our previous study, we suggest that these results may be geographically specific. This might be because of differences between populations in the structure of linkage disequilibrium or in interactions with environmental, genetic or epigenetic factors. A much larger study will be needed to clarify the role of homozygosity of HLA alleles in AD risk

Ultrastable heterodyne interferometer system using a CMOS modulated light camera

A novel ultrastable widefield interferometer is presented. This uses a modulated light camera (MLC) to capture and stabilise the interferogram in the widefield heterodyne interferometer. This system eliminates the contribution of piston phase to the interferogram without the need for common path optics and results in a highly stable widefield interferometer. The MLC uses quadrature demodulation circuitry built into each pixel to demodulate the light signal and extract phase information using an electronic reference signal. In contrast to the work previously presented [Opt. Express 19, 24546 (2011)], the reference signal is derived from one of the pixels on board the MLC rather than an external source. This local reference signal tracks the instantaneous modulation frequency detected by the other pixels and eliminates the contribution of piston phase to the interferogram, substantially removing the contributions of unwanted vibrations and microphonics to the interferogram. Interferograms taken using the ultrastable system are presented with one of the interferometer mirrors moving at up to 85 mm s−1 over a variety of frequencies from 18 Hz to 20 kHz (giving a variation in optical path length of 220 μm, or 350 wavelengths at 62 Hz). This limit was the result of complex motion in the mirror mount rather than the stability limit of the system. The system is shown to be insensitive to pure piston phase variations equivalent to an object velocity of over 3 m s−1