Holocene climate and environmental change in north-eastern Kamchatka (Russian Far East), inferred from a multi-proxy study of lake sediments

The study was supported by the Swedish Research Council through grants 621-2004-5224 and 621-2005-4444 to K.D. Bennett. A. Self and N. Solovieva acknowledge S. Brooks and V. Jones and were supported by NERC grant NE/H008160/1.A sediment record from a small lake in the north-eastern part of the Kamchatka Peninsula has been investigated in a multi-proxy study to gain knowledge of Holocene climatic and environmental change. Pollen, diatoms, chironomids and selected geochemical parameters were analysed and the sediment record was dated with radiocarbon. The study shows Holocene changes in the terrestrial vegetation as well as responses of the lake ecosystem to catchment maturity and multiple stressors, such as climate change and volcanic eruptions. Climate change is the major driving force resulting in the recorded environmental changes in the lake, although recurrent tephra deposition events also contributed. The sediment record has an age at the base of about 10,000 cal yrs BP, and during the first 400 years the climate was cold and the lake exhibited extensive ice-cover during winter and relatively low primary production. Soils in the catchment were poor with shrub alder and birches dominating the vegetation surrounding the lake. At about 9600–8900 cal yrs BP the climate was cold and moist, and strong seasonal wind stress resulted in reduced ice-cover and increased primary production. After ca. 8900 cal yrs BP the forest density increased around the lake, runoff decreased in a generally drier climate resulting in decreased primary production in the lake until ca. 7000 cal yrs BP. This generally dry climate was interrupted by a brief climatic perturbation, possibly attributed to the 8.2 ka event, indicating increasingly windy conditions with thick snow cover, reduced ice-cover and slightly elevated primary production in the lake. The diatom record shows maximum thermal stratification at ca. 6300–5800 cal yrs BP and indicates together with the geochemical proxies a dry and slightly warmer climate resulting in a high productive lake. The most remarkably change in the catchment vegetation occurred at ca. 4200 cal yrs BP in the form of a conspicuous increase in Siberian dwarf pine (Pinus pumila), indicating a shift to a cooler climate with a thicker and more long-lasting snow cover. This vegetational change was accompanied by marked shifts in the diatom and chironomid stratigraphies, which are also indicative of colder climate and more extensive ice-cover.Publisher PDFPeer reviewe

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Late Holocene expansion of Siberian dwarf pine (Pinus pumila) in Kamchatka in response to increased snow cover as inferred from lacustrine oxygen-isotope records

Holocene records of cellulose-inferred lake-water delta O-8 were produced from two lake-sediment sequences obtained in central and northern Kamchatka, Russian Far East. The sediment records share similar fluctuations in delta O-8 during the interval of ca. 5000-800 cal yr BP that correspond (inversely) with changes in K+ content of the GISP2 ice-core record from Greenland, a proxy for the relative strength of the Siberian High, suggesting control by climate-related variability in delta O-8 of regional precipitation. The dramatic expansion of Siberian dwarf pine (Pinus pumila) in northern and central Kamchatka between ca. 5000 and 4000 cal yr BP, as inferred from pollen records from the same and neighbouring sites, appears to have occurred at a time of progressively declining delta O-8 of precipitation. This development is interpreted as reflecting a regional cooling trend accompanied by increasing winter snowfall related to gradual intensification of the Siberian High from ca. 5000 to ca. 3000 cal yr BP. A thicker and more long-lasting snow cover can be assumed to have favoured P. pumila by providing a competitive advantage over other boreal and subalpine tree and shrub species in the region during the later part of the Holocene. These results, which are the first of their kind from Kamchatka, provide novel insight into the Holocene vegetational and climatic development in eastemmost Asia, as well as long-term atmospheric circulation dynamics in Beringia. (C) 2015 Elsevier B.V. All rights reserved

Distinct subcellular autophagy impairments in induced neurons from patients with Huntington's disease.

Huntington's disease is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling Huntington's disease is challenging, as rodent and cellular models poorly recapitulate the disease as seen in ageing humans. To address this, we generated induced neurons through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. Huntington's disease induced neurons (HD-iNs) displayed profound deficits in autophagy, characterized by reduced transport of late autophagic structures from the neurites to the soma. These neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites specifically in HD-iNs. CRISPRi-mediated silencing of HTT did not rescue this phenotype but rather resulted in additional autophagy alterations in control induced neurons, highlighting the importance of wild-type HTT in normal neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in adult patient derived Huntington's disease neurons and provides a new rationale for future development of autophagy activation therapies