Sedentary behavior is emerging as an independent risk factor for chronic disease and mortality. However, the evidence relating television (TV) viewing and other sedentary behaviors to cancer risk has ...not been quantitatively summarized.
We performed a comprehensive electronic literature search in Cochrane, EMBASE, Medline, and SciSearch databases through February 2014 for published articles investigating sedentary behavior in relation to cancer incidence. Because randomized controlled trials are difficult to perform on this topic, we focused on observational studies that met uniform inclusion criteria. Data were extracted independently by both authors and summarized using random-effects meta-analysis and meta-regression. All statistical tests were two-sided.
Data from 43 observational studies including a total of 68936 cancer cases were analyzed. Comparing the highest vs lowest levels of sedentary time, the relative risks (RRs) for colon cancer were 1.54 (95% confidence interval CI = 1.19 to 1.98) for TV viewing time, 1.24 (95% CI = 1.09 to 1.41) for occupational sitting time, and 1.24 (95% CI = 1.03 to 1.50) for total sitting time. For endometrial cancer, the relative risks were 1.66 (95% CI = 1.21 to 2.28) for TV viewing time and 1.32 (95% CI = 1.08 to 1.61) for total sitting time. A positive association with overall sedentary behavior was also noted for lung cancer (RR = 1.21; 95% CI = 1.03 to 1.43). Sedentary behavior was unrelated to cancers of the breast, rectum, ovaries, prostate, stomach, esophagus, testes, renal cell, and non-Hodgkin lymphoma.
Prolonged TV viewing and time spent in other sedentary pursuits is associated with increased risks of certain types of cancer.
Sedentary behavior is related to increased mortality risk. Whether such elevated risk can be offset by enhanced physical activity has not been examined using accelerometry data.
We examined the ...relations of sedentary time and physical activity to mortality from any cause using accelerometry data among 1,677 women and men aged 50 years or older from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 cycle with follow-up through December 31, 2006.
During an average follow-up of 34.67 months and 4,845.42 person-years, 112 deaths occurred. In multivariate Cox proportional hazard models, greater sedentary time (≥ median of 8.60 hours/day) was associated with increased risk of mortality from any cause (relative risk (RR) = 2.03; 95% confidence interval (CI) = 1.09-3.81). Low level of moderate to vigorous physical activity (< median of 6.60 minutes/day) was also related to enhanced all-cause mortality risk (RR = 3.30; 95% CI = 1.33-8.17). In combined analyses, greater time spent sedentary and low levels of moderate to vigorous physical activity predicted a substantially elevated all-cause mortality risk. As compared with the combination of a low sedentary level and a high level of moderate to vigorous physical activity, the risks of mortality from all causes were 4.38 (95% CI = 1.26-15.16) for low levels of both sedentary time and physical activity, 2.79 (95% CI = 0.77-10.12) for greater time spent sedentary and high physical activity level, and 7.79 (95% CI = 2.26-26.82) for greater time spent sedentary and low physical activity level. The interaction term between sedentary time and moderate to vigorous physical activity was not statistically significant (p = 0.508).
Both high levels of sedentary time and low levels of moderate to vigorous physical activity are strong and independent predictors of early death from any cause. Whether a high physical activity level removes the increased risk of all-cause mortality related to sedentariness requires further investigation.
Targeted delivery of compounds to particular cell subsets can enhance therapeutic index by concentrating their action on the cells of interest. Because attempts to target tumors directly have yielded ...limited benefit, we instead target endogenous immune cell subsets in the circulation that can migrate actively into tumors. We describe antibody-targeted nanoparticles that bind to CD8
T cells in the blood, lymphoid tissues, and tumors of mice. PD-1
T cells are successfully targeted in the circulation and tumor. The delivery of an inhibitor of TGFβ signaling to PD-1-expressing cells extends the survival of tumor-bearing mice, whereas free drugs have no effect at such doses. This modular platform also enables PD-1-targeted delivery of a TLR7/8 agonist to the tumor microenvironment, increasing the proportion of tumor-infiltrating CD8
T cells and sensitizing tumors to subsequent anti-PD-1. Targeted delivery of immunotherapy to defined subsets of endogenous leukocytes may be superior to administration of free drugs.
We aim to identify those measures that effectively control the spread of SARS-CoV-2 in Austrian schools. Using cluster tracing data we calibrate an agent-based epidemiological model and consider ...situations where the B1.617.2 (delta) virus strain is dominant and parts of the population are vaccinated to quantify the impact of non-pharmaceutical interventions (NPIs) such as room ventilation, reduction of class size, wearing of masks during lessons, vaccinations, and school entry testing by SARS-CoV2-antigen tests. In the data we find that 40% of all clusters involved no more than two cases, and 3% of the clusters only had more than 20 cases. The model shows that combinations of NPIs together with vaccinations are necessary to allow for a controlled opening of schools under sustained community transmission of the SARS-CoV-2 delta variant. For plausible vaccination rates, primary (secondary) schools require a combination of at least two (three) of the above NPIs.
Superspreading events shaped the coronavirus disease 2019 (COVID-19) pandemic, and their rapid identification and containment are essential for disease control. Here, we provide a national-scale ...analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) superspreading during the first wave of infections in Austria, a country that played a major role in initial virus transmissions in Europe. Capitalizing on Austria's well-developed epidemiological surveillance system, we identified major SARS-CoV-2 clusters during the first wave of infections and performed deep whole-genome sequencing of more than 500 virus samples. Phylogenetic-epidemiological analysis enabled the reconstruction of superspreading events and charts a map of tourism-related viral spread originating from Austria in spring 2020. Moreover, we exploited epidemiologically well-defined clusters to quantify SARS-CoV-2 mutational dynamics, including the observation of low-frequency mutations that progressed to fixation within the infection chain. Time-resolved virus sequencing unveiled viral mutation dynamics within individuals with COVID-19, and epidemiologically validated infector-infectee pairs enabled us to determine an average transmission bottleneck size of 10
SARS-CoV-2 particles. In conclusion, this study illustrates the power of combining epidemiological analysis with deep viral genome sequencing to unravel the spread of SARS-CoV-2 and to gain fundamental insights into mutational dynamics and transmission properties.
A remarkable excess mortality has coincided with the COVID-19 pandemic in Europe. We present preliminary pooled estimates of all-cause mortality for 24 European countries/federal states participating ...in the European monitoring of excess mortality for public health action (EuroMOMO) network, for the period March-April 2020. Excess mortality particularly affected ≥ 65 year olds (91% of all excess deaths), but also 45-64 (8%) and 15-44 year olds (1%). No excess mortality was observed in 0-14 year olds.
Physical activity is related to decreased endometrial cancer risk. However, a comprehensive investigation of activity domains, intensities, time periods in life, and potential interaction with body ...mass index is unavailable. We performed a meta-analysis of physical activity and endometrial cancer studies published through October 2014. We identified 33 eligible studies comprising 19,558 endometrial cancer cases. High versus low physical activity was related to reduced endometrial cancer risk relative risk (RR) = 0.80; 95 % confidence interval (CI) 0.75-0.85. The corresponding RRs for recreational activity, occupational activity, household activity, and walking were 0.84 (95 % CI 0.78-0.91), 0.81 (95 % CI 0.75-0.87), 0.70 (95 % CI 0.47-1.02), and 0.82 (95 % CI 0.69-0.97), respectively (Pdifference = 0.88). Walking/biking for transportation, walking for recreation, and walking without specification revealed summary RRs of 0.70 (95 % CI 0.58-0.85), 0.94 (95 % CI 0.76-1.17), and 0.88 (95 % CI 0.52-1.50), respectively Pdifference = 0.13). Inverse associations were noted for light (RR 0.65; 95 % CI 0.49-0.86), moderate to vigorous (RR 0.83; 95 % CI 0.71-0.96), and vigorous activity (RR 0.80; 95 % CI 0.72-0.90; Pdifference = 0.35). A statistically significant inverse relation was found for postmenopausal (RR 0.81; 95 % CI 0.67-0.97), but not premenopausal women (RR 0.74; 95 % CI 0.49-1.13; Pdifference = 0.78). Physical activity performed during childhood/adolescence, young adulthood/midlife, and older age yielded RRs of 0.94 (95 % CI 0.82-1.08), 0.77 (95 % CI 0.58-1.01), and 0.69 (95 % CI 0.37-1.28), respectively Pdifference = 0.51). An inverse relation was evident in overweight/obese (RR 0.69; 95 % CI 0.52-0.91), but not normal weight women (RR 0.97; 95 % CI 0.84-1.13; Pdifference = 0.07). In conclusion, recreational physical activity, occupational physical activity, and walking/biking for transportation are related to decreased endometrial cancer risk. Inverse associations are evident for physical activity of light, moderate to vigorous, and vigorous intensities. The inverse relation with physical activity is limited to women who are overweight or obese.
Listeria monocytogenes
(
L. monocytogenes
) is a ubiquitous organism that can easily enter the food chain. Infection with
L. monocytogenes
can cause invasive listeriosis. Since 2014, in Austria,
L. ...monocytogenes
isolates from human and food/food-associated samples have been provided on a mandatory basis by food producers and laboratories to the National Reference Laboratory. Since 2017, isolates undergo routinely whole genome sequencing (WGS) and core genome Multilocus Sequence Typing (cgMLST) for cluster analyses. Aims of this study were to characterize isolates and clusters of 2017 by using WGS data and to assess the usefulness of this isolate-based surveillance for generating hypotheses on sources of invasive listeriosis in real-time. WGS data from 31 human and 1744 non-human isolates originating from 2017, were eligible for the study. A cgMLST-cluster was defined as two or more isolates differing by ≤10 alleles. We extracted the sequence types (STs) from the WGS data and analyzed the food subcategories meat, fish, vegetable and diary for associations with the ten most prevalent STs among food, through calculating prevalence ratios (PR) with 95% confidence intervals (CI). The three most frequent STs among the human isolates were ST1 (7/31; 22.6%), ST155 (4/31; 12.9%) and ST451 (3/31; 9.7%) and among the non-human isolates ST451 (614/1744; 35.2%), ST8 (173/1744, 10.0%) and ST9 (117/1744; 6.7%). We found ST21 associated with vegetables (PR: 11.39, 95% CI: 8.32–15.59), ST121 and ST155 with fish (PR: 7.05, 95% CI: 4.88–10.17, PR: 3.29, 95% CI: 1.86–5.82), and ST511, ST7 and ST451 with dairy products (PR: 8.55, 95% CI: 6.65–10.99; PR: 5.05, 95% CI: 3.83–6.66, PR: 3.03, 95% CI: 2.02–4.55). We identified 132 cgMLST-clusters. Six clusters contained human isolates (ST155, ST1, ST101, ST177, ST37 and ST7) and for five of those cgMLST-based cluster analyses solely was able to hypothesize the source: an Austrian meat processing company, two Austrian cheese manufacturers and two vegetable processing companies, one based in Austria and the other in Belgium. Determining routinely STs in food isolates by WGS allows to associate STs with food products. Real-time WGS of
L. monocytogenes
isolates provided mandatorily, proved to be useful in promptly generating hypotheses on sources of invasive listeriosis.
Abstract
Locked nucleic acid based antisense oligonucleotides (LNA-ASOs) can reach their intracellular RNA targets without delivery modules. Functional cellular uptake involves vesicular accumulation ...followed by translocation to the cytosol and nucleus. However, it is yet unknown how many LNA-ASO molecules need to be delivered to achieve target knock down. Here we show by quantitative fluorescence imaging combined with LNA-ASO microinjection into the cytosol or unassisted uptake that ∼105 molecules produce >50% knock down of their targets, indicating that a substantial amount of LNA-ASO escapes from endosomes. Microinjected LNA-ASOs redistributed within minutes from the cytosol to the nucleus and remained bound to nuclear components. Together with the fact that RNA levels for a given target are several orders of magnitude lower than the amounts of LNA-ASO, our data indicate that only a minor fraction is available for RNase H1 mediated reduction of target RNA. When non-specific binding sites were blocked by co-administration of non-related LNA-ASOs, the amount of target LNA-ASO required was reduced by an order of magnitude. Therefore, dynamic processes within the nucleus appear to influence the distribution and activity of LNA-ASOs and may represent important parameters for improving their efficacy and potency.
Summary Background Variations in testing for Clostridium difficile infection can hinder patients' care, increase the risk of transmission, and skew epidemiological data. We aimed to measure the ...underdiagnosis of C difficile infection across Europe. Methods We did a questionnaire-based study at 482 participating hospitals across 20 European countries. Hospitals were questioned about their methods and testing policy for C difficile infection during the periods September, 2011, to August, 2012, and September, 2012, to August, 2013. On one day in winter, 2012–13 (December, 2012, or January, 2013), and summer, 2013 (July or August), every hospital sent all diarrhoeal samples submitted to their microbiology laboratory to a national coordinating laboratory for standardised testing of C difficile infection. Our primary outcome measures were the rates of testing for and cases of C difficile infection per 10 000 patient bed-days. Results of local and national C difficile infection testing were compared with each other. If the result was positive at the national laboratory but negative at the local hospital, the result was classified as undiagnosed C difficile infection. We compared differences in proportions with the Mann-Whitney test, or McNemar's test if data were matched. Findings During the study period, participating hospitals reported a mean of 65·8 tests (country range 4·6–223·3) for C difficile infection per 10 000 patient-bed days and a mean of 7·0 cases (country range 0·7–28·7) of C difficile infection per 10 000 patient-bed days. Only two-fifths of hospitals reported using optimum methods for testing of C difficile infection (defined by European guidelines), although the number of participating hospitals using optimum methods increased during the study period, from 152 (32%) of 468 in 2011–12 to 205 (48%) of 428 in 2012–13. Across all 482 European hospitals on the two sampling days, 148 (23%) of 641 samples positive for C difficile infection (as determined by the national laboratory) were not diagnosed by participating hospitals because of an absence of clinical suspicion, equating to about 74 missed diagnoses per day. Interpretation A wide variety of testing strategies for C difficile infection are used across Europe. Absence of clinical suspicion and suboptimum laboratory diagnostic methods mean that an estimated 40 000 inpatients with C difficile infection are potentially undiagnosed every year in 482 European hospitals. Funding Astellas Pharmaceuticals Europe.
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