Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and ...meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.Systematic review registration PROSPERO CRD42014013953.
This review paper serves to describe the composition and activity of a biologically active carbon (BAC) biofilm used in water purification. An analysis of several physical–chemical, biochemical and ...microbiological methods (indicators) used to characterize the BAC biofilm's composition and activity is provided. As well, the ability of the biofilm to remove and biodegrade waterborne organic substances and pollutants will be reviewed, with context to other industrial processes such as pre-ozonation and post-membrane filtration. Strategies to control the growth of the BAC biofilm, such as varying the nutrient loading rate, manipulating influent DO and pH levels, altering the frequency of BAC filter backwashing and applying oxidative disinfection, will be described in detail along with their respective process control challenges.
Abstract
We present predictions for the quenching of star formation in satellite galaxies of the Local Group from a suite of 30 cosmological zoom simulations of Milky Way-like host galaxies. The ...Auriga simulations resolve satellites down to the luminosity of the classical dwarf spheroidal galaxies of the Milky Way. We find strong mass-dependent and distance-dependent quenching signals, where dwarf systems beyond 600 kpc are only strongly quenched below a stellar mass of 107 M⊙. Ram pressure stripping appears to be the dominant quenching mechanism and 50 per cent of quenched systems cease star formation within 1 Gyr of first infall. We demonstrate that systems within a host galaxy’s R200 radius are comprised of two populations: (i) a first infall population that has entered the host halo within the past few Gyrs and (ii) a population of returning ‘backsplash’ systems that have had a much more extended interaction with the host. Backsplash galaxies that do not return to the host galaxy by redshift zero exhibit quenching properties similar to galaxies within R200 and are distinct from other external systems. The simulated quenching trend with stellar mass has some tension with observations, but our simulations are able reproduce the range of quenching times measured from resolved stellar populations of Local Group dwarf galaxies.
BACKGROUND OSA is a common condition that has been associated with atrial fibrillation (AF), but there is a paucity of data from large longitudinal cohorts to establish whether OSA is a risk factor ...for AF independent of obesity and other established risk factors. METHODS We studied patients attending a sleep clinic referred for in-laboratory polysomnography for possible OSA between 1989 and 2001. Whole-population hospital data in Western Australia for 1970 to 2009 were linked to sleep study cases to determine incident AF hospitalization to 2009. Cox regression analyses were used to assess the independent association of OSA with incident AF. RESULTS Study case subjects (6,841) were predominantly middle aged (48.3 ± 12.5 years old) and men (77%), and 455 developed AF during a median 11.9 years of follow-up. Univariate predictors of AF included age, BMI, hypertension, diabetes, valvular heart disease, coronary or peripheral artery disease, heart failure, and COPD (all P .001). After multivariable adjustment, independent predictors of incident AF were an apnea/hypopnea index (AHI) > 5/h (hazard ratio HR, 1.55; 95% CI, 1.21-2.00), log (AHI 1 1) (HR, 1.15; 95% CI, 1.06-1.26), and log (time with oxygen saturation < 90% 1 1) (HR, 1.12; 95% CI, 1.06-1.19). There were no interactions between age, sex, or BMI and AHI for AF development. CONCLUSIONS OSA diagnosis and severity are independently associated with incident AF. Clinical trials are required to determine if treatment of OSA will reduce the burden of AF.
New Zealand, a geographically remote Pacific island with easily sealable borders, implemented a nationwide 'lockdown' of all non-essential services to curb the spread of COVID-19. Here, we generate ...649 SARS-CoV-2 genome sequences from infected patients in New Zealand with samples collected during the 'first wave', representing 56% of all confirmed cases in this time period. Despite its remoteness, the viruses imported into New Zealand represented nearly all of the genomic diversity sequenced from the global virus population. These data helped to quantify the effectiveness of public health interventions. For example, the effective reproductive number, R
of New Zealand's largest cluster decreased from 7 to 0.2 within the first week of lockdown. Similarly, only 19% of virus introductions into New Zealand resulted in ongoing transmission of more than one additional case. Overall, these results demonstrate the utility of genomic pathogen surveillance to inform public health and disease mitigation.
While genetic mutation is a hallmark of cancer, many cancers also acquire epigenetic alterations during tumorigenesis including aberrant DNA hypermethylation of tumor suppressors, as well as changes ...in chromatin modifications as caused by genetic mutations of the chromatin-modifying machinery. However, the extent of epigenetic alterations in cancer cells has not been fully characterized. Here, we describe complete methylome maps at single nucleotide resolution of a low-passage breast cancer cell line and primary human mammary epithelial cells. We find widespread DNA hypomethylation in the cancer cell, primarily at partially methylated domains (PMDs) in normal breast cells. Unexpectedly, genes within these regions are largely silenced in cancer cells. The loss of DNA methylation in these regions is accompanied by formation of repressive chromatin, with a significant fraction displaying allelic DNA methylation where one allele is DNA methylated while the other allele is occupied by histone modifications H3K9me3 or H3K27me3. Our results show a mutually exclusive relationship between DNA methylation and H3K9me3 or H3K27me3. These results suggest that global DNA hypomethylation in breast cancer is tightly linked to the formation of repressive chromatin domains and gene silencing, thus identifying a potential epigenetic pathway for gene regulation in cancer cells.
Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the ...potential to identify factors that may explain this heterogeneity.
To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect.
MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry.
Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D
or vitamin D
of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected.
Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.
We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity
< 0.001. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10;
= 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D 25(OH)D concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95;
= 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20;
= 0.83). The body of evidence contributing to these analyses was assessed as being of high quality.
Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately.
Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes.
This study is registered as PROSPERO CRD42014013953.
The National Institute for Health Research Health Technology Assessment programme.
Assessing genuine extracellular vesicle (EV) uptake is crucial for understanding the functional roles of EVs. This study measured the bona fide labelling of EVs utilising two commonly used ...fluorescent dyes, PKH26 and C5-maleimide-Alexa633. MCF7 EVs tagged with mEmerald-CD81 were isolated from conditioned media by size exclusion chromatography (SEC) and characterised using Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM), MACsPlex immunocapture assay and immunoblots. These fluorescently tagged EVs were subsequently stained with C5-maleimide-Alexa633 or PKH26, according to published protocols. Colocalisation of dual-labelled EVs was assessed by confocal microscopy and quantified using the Rank-Weighted Colocalisation (RWC) algorithm. We observed strikingly poor colocalisation between mEmerald-CD81-tagged EVs and C5-Maleimide-Alexa633 (5.4% ± 1.8) or PKH26 (4.6% ± 1.6), that remained low even when serum was removed from preparations. Our data confirms previous work showing that some dyes form contaminating aggregates. Furthermore, uptake studies showed that maleimide and mEmerald-CD81-tagged EVs can be often located into non-overlapping subcellular locations. By using common methods to isolate and stain EVs we observed that most EVs remained unstained and most dye signal does not appear to be EV associated. Our work shows that there is an urgent need for optimisation and standardisation in how EV researchers use these tools to assess genuine EV signals.
Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the ...cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.
IMPORTANCE: Sex-based income disparities are well documented in medicine and most pronounced in surgery. These disparities are commonly attributed to differences in hours worked. One proposed ...solution to close the earnings gap is a fee-for-service payment system, which is theoretically free of bias. However, it is unclear whether a sex-based earnings gap persists in a fee-for-service system when earnings are measured on the basis of hours worked. OBJECTIVE: To determine whether male and female surgeons have similar earnings for each hour spent operating in a fee-for-service system. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, population-based study used administrative databases from a fee-for-service, single-payer health system in Ontario, Canada. Surgeons who submitted claims for surgical procedures performed between January 1, 2014, and December 31, 2016, were included. Data analysis took place from February 2018 to December 2018. EXPOSURES: Surgeon sex. MAIN OUTCOMES AND MEASURES: This study compared earnings per hour spent operating between male and female surgeons and earnings stratified by surgical specialty in a matched analysis. We explored factors potentially associated with earnings disparities, including differences in procedure duration and type between male and female surgeons and hourly earnings for procedures performed primarily on male vs female patients. RESULTS: We identified 1 508 471 surgical procedures claimed by 3275 surgeons. Female surgeons had practiced fewer years than male surgeons (median interquartile range, 8.4 2.9-16.6 vs 14.7 5.9-25.7 years; P < .001), and the largest proportion of female surgeons practiced gynecology (400 of 819 female surgeons 48.8%). Hourly earnings for female surgeons were 24% lower than for male surgeons (relative rate, 0.76 95% CI, 0.74-0.79; P < .001). This disparity persisted after adjusting for specialty and in matched analysis stratified by specialty, with the largest mean differences in cardiothoracic surgery (in US dollars: $59.64/hour) and orthopedic surgery ($55.45/hour). There were no differences in time taken by male and female surgeons to perform common procedures; however, female surgeons more commonly performed procedures with the lowest hourly earnings. CONCLUSIONS AND RELEVANCE: Even within a fee-for-service system, male and female surgeons do not have equal earnings for equal hours spent working, suggesting that the opportunity to perform the most lucrative surgical procedures is greater for men than women. These findings call for a comprehensive analysis of drivers of sex-based earning disparities, including referral patterns, and highlight the need for systems-level solutions.
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