Circulating proteins as predictors of cardiovascular mortality in endstage renal disease

Introduction: Proteomic profiling of end-stage renal disease (ESRD) patients could lead to improved risk prediction and novel insights into cardiovascular disease mechanisms. Plasma levels of 92 cardiovascular disease-associated proteins were assessed by proximity extension assay (Proseek Multiplex CVD-1, Olink Bioscience, Uppsala, Sweden) in a discovery cohort of dialysis patients, the Mapping of Inflammatory Markers in Chronic Kidney disease cohort [MIMICK; n = 183, 55% women, mean age 63 years, 46 cardiovascular deaths during follow-up (mean 43 months)]. Significant results were replicated in the incident and prevalent hemodialysis arm of the Salford Kidney Study [SKS dialysis study, n = 186, 73% women, mean age 62 years, 45 cardiovascular deaths during follow-up (mean 12 months)], and in the CKD5-LD-RTxcohort with assessments of coronary artery calcium (CAC)-score by cardiac computed tomography (n = 89, 37% women, mean age 46 years). Results: In age and sex-adjusted Cox regression in MIMICK, 11 plasma proteins were nominally associated with cardiovascular mortality (in order of significance: Kidney injury molecule-1 (KIM-1), Matrix metalloproteinase-7, Tumour necrosis factor receptor 2, Interleukin-6, Matrix metalloproteinase-1, Brain-natriuretic peptide, ST2 protein, Hepatocyte growth factor, TNF-related apoptosis inducing ligand receptor-2, Spondin-1, and Fibroblast growth factor 25). Only plasma KIM-1 was associated with cardiovascular mortality after correction for multiple testing, but also after adjustment for dialysis vintage, cardiovascular risk factors and inflammation (hazard ratio) per standard deviation (SD) increase 1.84, 95% CI 1.26–2.69, p = 0.002. Addition of KIM-1, or nine of the most informative proteins to an established risk-score (modified AROii CVM-score) improved discrimination of cardiovascular mortality risk from C = 0.777 to C = 0.799 and C = 0.823, respectively. In the SKS dialysis study, KIM-1 predicted cardiovascular mortality in age and sex adjusted models (hazard ratio per SD increase 1.45, 95% CI 1.03–2.05, p = 0.034) and higher KIM-1 was associated with higher CACscores in the CKD5-LD-RTx-cohort. Conclusions Our proteomics approach identified plasma KIM-1 as a risk marker for cardiovascular mortality and coronary artery calcification in three independent ESRD-cohorts. The improved risk prediction for cardiovascular mortality by plasma proteomics merit further studies.Swedish Research CouncilSwedish Heart–Lung foundationEuropean Union Horizon 2020 (Grant number 634869)Dalarna UniversityUppsala UniversitySwedish Medical Research CouncilNjurfondenEuropean Union’s Horizon 2020 research and innovation programme, Marie Sklodowska-Curie Grant Agreement no. 722609Publishe

Effects on mortality of a nutritional intervention for malnourished HIV-infected adults referred for antiretroviral therapy: a randomised controlled trial.

Malnourished HIV-infected African adults are at high risk of early mortality after starting antiretroviral therapy (ART). We hypothesized that short-course, high-dose vitamin and mineral supplementation in lipid nutritional supplements would decrease mortality

Mercury in the Black Sea:New Insights From Measurements and Numerical Modeling

Redox conditions and organic matter control marine methylmercury (MeHg) production. The Black Sea is the world's largest and deepest anoxic basin and is thus ideal to study Hg species along the extended redox gradient. Here we present new dissolved Hg and MeHg data from the 2013 GEOTRACES MEDBlack cruise (GN04_leg2) that we integrated into a numerical 1-D model, to track the fate and dynamics of Hg and MeHg. Contrary to a previous study, our new data show highest MeHg concentrations in the permanently anoxic waters. Observed MeHg/Hg percentage (range 9-57%) in the anoxic waters is comparable to other subsurface maxima in oxic open-ocean waters. With the modeling we tested for various Hg methylation and demethylation scenarios along the redox gradient. The results show that Hg methylation must occur in the anoxic waters. The model was then used to simulate the time evolution (1850-2050) of Hg species in the Black Sea. Our findings quantify (1) inputs and outputs of Hg-T (similar to 31 and similar to 28 kmol yr(-1)) and MeHgT (similar to 5 and similar to 4 kmol yr(-1)) to the basin, (2) the extent of net demethylation occurring in oxic (similar to 1 kmol yr(-1)) and suboxic water (similar to 6 kmol yr(-1)), (3) and the net Hg methylation in the anoxic waters of the Black Sea (similar to 11 kmol yr(-1)). The model was also used to estimate the amount of anthropogenic Hg (85-93%) in the Black Sea

Icodextrin as salvage therapy in peritoneal dialysis patients with refractory fluid overload

BACKGROUND: Icodextrin is a high molecular weight, starch-derived glucose polymer, which is capable of inducing sustained ultrafiltration over prolonged (12–16 hour) peritoneal dialysis (PD) dwells. The aim of this study was to evaluate the ability of icodextrin to alleviate refractory, symptomatic fluid overload and prolong technique survival in PD patients. METHODS: A prospective, open-label, pre-test/post-test study was conducted in 17 PD patients (8 females/9 males, mean age 56.8 ± 2.9 years) who were on the verge of being transferred to haemodialysis because of symptomatic fluid retention that was refractory to fluid restriction, loop diuretic therapy, hypertonic glucose exchanges and dwell time optimisation. One icodextrin exchange (2.5 L 7.5%, 12-hour dwell) was substituted for a long-dwell glucose exchange each day. RESULTS: Icodextrin significantly increased peritoneal ultrafiltration (885 ± 210 ml to 1454 ± 215 ml, p < 0.05) and reduced mean arterial pressure (106 ± 4 to 96 ± 4 mmHg, p < 0.05), but did not affect weight, plasma albumin concentration, haemoglobin levels or dialysate:plasma creatinine ratio. Diabetic patients (n = 12) also experienced improved glycaemic control (haemoglobin Alc decreased from 8.9 ± 0.7% to 7.9 ± 0.7%, p < 0.05). Overall PD technique survival was prolonged by a mean of 11.6 months (95% CI 6.0–17.3 months). On multivariate Cox proportional hazards analysis, extension of technique survival by icodextrin was only significantly predicted by baseline net daily peritoneal ultrafiltration (adjusted HR 2.52, 95% CI 1.13–5.62, p < 0.05). CONCLUSIONS: Icodextrin significantly improved peritoneal ultrafiltration and extended technique survival in PD patients with symptomatic fluid overload, especially those who had substantially impaired peritoneal ultrafiltration

Short-term regulation of peptide YY secretion by a mixed meal or peritoneal glucose-based dialysate in patients with chronic renal failure

This is a pre-copyedited, author-produced version of an article accepted for publication in "Nephrology Dialysis Trasnplantation" following peer review. The version of the record is avaliable online at Oxford Academic website.Instituto de Salud Carlos III, PI051024Instituto de Salud Carlos III, PI070413Xunta de Galicia, PS07/12Xunta de Galicia, 2006/2

Translation of c-Met targeted image-guided surgery solutions in oral cavity cancer: initial proof of concept data

Simple SummaryTranslation of tumor-specific fluorescent tracers is crucial in the realization intraoperative of tumor identification during fluorescence-guided surgery. Ex vivo assessment of surgical specimens after topical tracer application has the potential to reveal the suitability of a potential surgical target prior to in vivo use in patients. In this study, the c-Met receptor was identified as a possible candidate for fluorescence-guided surgery in oral cavity cancer. Freshly excised tumor specimens obtained from ten patients with squamous cell carcinoma of the tongue were incubated with EMI-137 and imaged with a clinical-grade Cy5 prototype fluorescence camera. In total, 9/10 tumors were fluorescently illuminated, while non-visualization could be linked to non-superficial tumor localization. Immunohistochemistry revealed c-Met expression in all ten specimens. Tumor assessment was improved via video representation of the tumor-to-background ratio.Intraoperative tumor identification (extension/margins/metastases) via receptor-specific targeting is one of the ultimate promises of fluorescence-guided surgery. The translation of fluorescent tracers that enable tumor visualization forms a critical component in the realization of this approach. Ex vivo assessment of surgical specimens after topical tracer application could help provide an intermediate step between preclinical evaluation and first-in-human trials. Here, the suitability of the c-Met receptor as a potential surgical target in oral cavity cancer was explored via topical ex vivo application of the fluorescent tracer EMI-137. Freshly excised tumor specimens obtained from ten patients with squamous cell carcinoma of the tongue were incubated with EMI-137 and imaged with a clinical-grade Cy5 prototype fluorescence camera. In-house developed image processing software allowed video-rate assessment of the tumor-to-background ratio (TBR). Fluorescence imaging results were related to standard pathological evaluation and c-MET immunohistochemistry. After incubation with EMI-137, 9/10 tumors were fluorescently illuminated. Immunohistochemistry revealed c-Met expression in all ten specimens. Non-visualization could be linked to a more deeply situated lesion. Tumor assessment was improved via video representation of the TBR (median TBR: 2.5 (range 1.8-3.1)). Ex vivo evaluation of tumor specimens suggests that c-Met is a possible candidate for fluorescence-guided surgery in oral cavity cancer.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Holocene dynamics of the Southern Hemisphere westerly winds and possible links to CO2 outgassing

The Southern Hemisphere westerly winds (SHW) play an important role in regulating the capacity of the Southern Ocean carbon sink. They modulate upwelling of carbon-rich deep water and, with sea ice, determine the ocean surface area available for air–sea gas exchange. Some models indicate that the current strengthening and poleward shift of these winds will weaken the carbon sink. If correct, centennial- to millennial-scale reconstructions of the SHW intensity should be linked with past changes in atmospheric CO2, temperature and sea ice. Here we present a 12,300-year reconstruction of wind strength based on three independent proxies that track inputs of sea-salt aerosols and minerogenic particles accumulating in lake sediments on sub-Antarctic Macquarie Island. Between about 12.1 thousand years ago (ka) and 11.2 ka, and since about 7 ka, the wind intensities were above their long-term mean and corresponded with increasing atmospheric CO2. Conversely, from about 11.2 to 7.2 ka, the wind intensities were below their long-term mean and corresponded with decreasing atmospheric CO2. These observations are consistent with model inferences of enhanced SHW contributing to the long-term outgassing of CO2 from the Southern Ocean

Barriers to antiretroviral therapy adherence in rural Mozambique

<p>Abstract</p> <p>Background</p> <p>HIV is treated as a chronic disease, but high lost-to-follow-up rates and poor adherence to medication result in higher mortality, morbidity, and viral mutation. Within 18 clinical sites in rural Zambézia Province, Mozambique, patient adherence to antiretroviral therapy has been sub-optimal.</p> <p>Methods</p> <p>To better understand barriers to adherence, we conducted 18 community and clinic focus groups in six rural districts. We interviewed 76 women and 88 men, of whom 124 were community participants (CP; 60 women, 64 men) and 40 were health care workers (HCW; 16 women, 24 men) who provide care for those living with HIV.</p> <p>Results</p> <p>While there was some consensus, both CP and HCW provided complementary insights. CP focus groups noted a lack of confidentiality and poor treatment by hospital staff (42% CP vs. 0% HCW), doubt as to the benefits of antiretroviral therapy (75% CP vs. 0% HCW), and sharing medications with family members (66% CP vs. 0%HCW). Men expressed a greater concern about poor treatment by HCW than women (83% men vs. 0% women). Health care workers blamed patient preference for traditional medicine (42% CP vs. 100% HCW) and the side effects of medication for poor adherence (8% CP vs. 83% CHW).</p> <p>Conclusions</p> <p>Perspectives of CP and HCW likely reflect differing sociocultural and educational backgrounds. Health care workers must understand community perspectives on causes of suboptimal adherence as a first step toward effective intervention.</p