American Burn Association Clinical Practice Guidelines on Burn Shock Resuscitation.

This Clinical Practice Guideline (CPG) addresses the topic of acute fluid resuscitation during the first 48 hours following a burn injury for adults with burns ≥20% of the total body surface area (%TBSA). The listed authors formed an investigation panel and developed clinically relevant PICO (Population, Intervention, Comparator, Outcome) questions. A systematic literature search returned 5978 titles related to this topic and after 3 levels of screening, 24 studies met criteria to address the PICO questions and were critically reviewed. We recommend that clinicians consider the use of human albumin solution, especially in patients with larger burns, to lower resuscitation volumes and improve urine output. We recommend initiating resuscitation based on providing 2 mL/kg/% TBSA burn in order to reduce resuscitation fluid volumes. We recommend selective monitoring of intra-abdominal and intraocular pressure during burn shock resuscitation. We make a weak recommendation for clinicians to consider the use of computer decision support software to guide fluid titration and lower resuscitation fluid volumes. We do not recommend the use of transpulmonary thermodilution-derived variables to guide burn shock resuscitation. We are unable to make any recommendations on the use of high-dose vitamin C (ascorbic acid), fresh frozen plasma (FFP), early continuous renal replacement therapy, or vasopressors as adjuncts during acute burn shock resuscitation. Mortality is an important outcome in burn shock resuscitation, but it was not formally included as a PICO outcome because the available scientific literature is missing studies of sufficient population size and quality to allow us to confidently make recommendations related to the outcome of survival at this time.

Less Agricultural Phosphorus Applied in 2019 Led to Less Dissolved Phosphorus Transported to Lake Erie.

Extreme precipitation events affect water quantity and quality in various regions of the world. Heavy precipitation in 2019 resulted in a record high area of unplanted agricultural fields in the U.S. and especially in the Maumee River Watershed (MRW). March-July phosphorus (P) loads from the MRW drive harmful algal bloom (HAB) severity in Lake Erie; hence changes in management that influence P export can ultimately affect HAB severity. In this study, we found that the 2019 dissolved reactive P (DRP) load from March-July was 29% lower than predicted, while the particulate P (PP) load was similar to the predicted value. Furthermore, the reduced DRP load resulted in a less severe HAB than predicted based on discharge volume. The 29% reduction in DRP loss in the MRW occurred with a 62% reduction in applied P, emphasizing the strong influence of recently applied P and subsequent incidental P losses on watershed P loading. Other possible contributing factors to this reduced load include lower precipitation intensity, altered tillage practices, and effects of fallow soils, but more data is needed to assess their importance. We recommend conservation practices focusing on P application techniques and timing and improving resiliency against extreme precipitation events.

Recent Patterns in Lake Erie Phosphorus and Chlorophyll a Concentrations in Response to Changing Loads.

Despite the initial success of extensive efforts to reduce phosphorus (P) loading to Lake Erie as a part of the Great Lakes Water Quality Agreement, Lake Erie appears to be undergoing a re-eutrophication and it is plagued by harmful algal blooms. To offer insights into potential lake responses under differing Maumee River loads and reveal recent changes with time, we explored patterns in phosphorus and chlorophyll a data from 2008 to 2018 collected in western Lake Erie near the mouth of the Maumee River. We found high, but relatively stable Maumee River and lake concentrations of total P (TP) and soluble reactive P (SRP) with no discernable annual or seasonal patterns. Maumee spring TP load was not strongly related to lake TP, and lake SRP concentrations were positively but weakly related to SRP loads. Lake TP was a strong predictor of chlorophyll a, but the relationship was weaker at sites closer to the Maumee. These results highlight spatial differences both in P concentration and the relationship between TP and chlorophyll a, and these indicate that spring phosphorus loads are a weak algal biomass predictor in the portion of the western basin of Lake Erie represented by these sampling stations.

The impact of integrated disease management in high-risk COPD patients in primary care.

Patients with chronic obstructive pulmonary disease (COPD) have a reduced quality of life (QoL) and exacerbations that drive health service utilization (HSU). A majority of patients with COPD are managed in primary care. Our objective was to evaluate an integrated disease management, self-management, and structured follow-up intervention (IDM) for high-risk patients with COPD in primary care. This was a one-year multi-center randomized controlled trial. High-risk, exacerbation-prone COPD patients were randomized to IDM provided by a certified respiratory educator and physician, or usual physician care. IDM received case management, self-management education, and skills training. The primary outcome, COPD-related QoL, was measured using the COPD Assessment Test (CAT). Of 180 patients randomized from 8 sites, 81.1% completed the study. Patients were 53.6% women, mean age 68.2 years, post-bronchodilator FEV1 52.8% predicted, and 77.4% were Global Initiative for Obstructive Lung Disease Stage D. QoL-CAT scores improved in IDM patients, 22.6 to 14.8, and worsened in usual care, 19.3 to 22.0, adjusted difference 9.3 (p < 0.001). Secondary outcomes including the Clinical COPD Questionnaire, Bristol Knowledge Questionnaire, and FEV1 demonstrated differential improvements in favor of IDM of 1.29 (p < 0.001), 29.6% (p < 0.001), and 100 mL, respectively (p = 0.016). Compared to usual care, significantly fewer IDM patients had a severe exacerbation, -48.9% (p < 0.001), required an urgent primary care visit for COPD, -30.2% (p < 0.001), or had an emergency department visit, -23.6% (p = 0.001). We conclude that IDM self-management and structured follow-up substantially improved QoL, knowledge, FEV1, reduced severe exacerbations, and HSU, in a high-risk primary care COPD population. Clinicaltrials.gov NCT02343055.

Transforming soil phosphorus fertility management strategies to support the delivery of multiple ecosystem services from agricultural systems.

Despite greater emphasis on holistic phosphorus (P) management, current nutrient advice delivered at farm-scale still focuses almost exclusively on agricultural production. This limits our ability to address national and international strategies for the delivery of multiple ecosystem services (ES). Currently there is no operational framework in place to manage P fertility for multiple ES delivery and to identify the costs of potentially sacrificing crop yield and/or quality. As soil P fertility plays a central role in ES delivery, we argue that soil test phosphorus (STP) concentration provides a suitable common unit of measure by which delivering multiple ES can be economically valued relative to maximum potential yield, in $ ha-1 yr-1 units. This value can then be traded, or payments made against one another, at spatio-temporal scales relevant for farmer and national policy objectives. Implementation of this framework into current P fertility management strategies would allow for the integration and interaction of different stakeholder interests in ES delivery on-farm and in the wider landscape. Further progress in biophysical modeling of soil P dynamics is needed to inform its adoption across diverse landscapes.

Changes in Water Quality of Grand Lake St. Marys Watershed Following Implementation of a Distressed Watershed Rules Package.

Grand Lake St. Marys watershed has drawn attention over the past decade as water quality issues resulting from nutrient loading have come to the forefront of public opinion, political concern, and scientific study. The objective of this study was to assess long-term changes in water quality (nutrient and sediment concentrations) following the distressed watershed rules package instituted in 2011. Since that time, a variety of rules (e.g., winter manure ban) and best management practices (cover crops, manure storage or transfers, buffers, etc.) have been implemented. We used a general linear model to assess variation in total suspended solids, particulate phosphorus, soluble reactive phosphorus (SRP), nitrate N, and total Kjeldahl nitrogen concentrations from daily Chickasaw Creek (drains ∼25% of watershed) samples spanning 2008 to 2016. Parameters were related to flow (higher values during high flows), timing (lower values during winter months), and the implementation of the distressed watershed rules package (lower values following implementation). Overall, reductions following the distressed designation for all parameters ranged from 5 to 35% during medium and high flow periods (with exception of SRP). Reductions were even more pronounced during winter months covered by the manure ban, where all parameters (including SRP) exhibited decreases at medium and high flows between 20 and 60%. While the reductions seen in this study are significant, concentrations are still highly elevated and continue to be a problem. We are optimistic that this study will serve to inform future management in the region and elsewhere.

Phosphorus Availability in Western Lake Erie Basin Drainage Waters: Legacy Evidence across Spatial Scales.

The Western Lake Erie Basin (WLEB) was inundated with precipitation during June and July 2015 (two to three times greater than historical averages), which led to significant nutrient loading and the largest in-lake algal bloom on record. Using discharge and concentration data from three spatial scales (0.18-16,000 km), we contrast the patterns in nitrate (NO-N) and dissolved reactive phosphorus (DRP) concentration dynamics and discuss potential management implications. Across all scales, NO-N concentration steadily declined with each subsequent rainfall event as it was flushed from the system. In contrast, DRP concentration persisted, even on soils at or below agronomic P levels, suggesting that legacy P significantly contributes to nutrient loads in the WLEB. These findings highlight the need to revisit current P fertility recommendations and soil testing procedures to increase P fertilizer use efficiency and to more holistically account for legacy P.

Increased Soluble Phosphorus Loads to Lake Erie: Unintended Consequences of Conservation Practices?

Cumulative daily load time series show that the early 2000s marked a step-change increase in riverine soluble reactive phosphorus (SRP) loads entering the Western Lake Erie Basin from three major tributaries: the Maumee, Sandusky, and Raisin Rivers. These elevated SRP loads have been sustained over the last 12 yr. Empirical regression models were used to estimate the contributions from (i) increased runoff from changing weather and precipitation patterns and (ii) increased SRP delivery (the combined effects of increased source availability and/or increased transport efficiency of labile phosphorus [P] fractions). Approximately 65% of the SRP load increase after 2002 was attributable to increased SRP delivery, with higher runoff volumes accounting for the remaining 35%. Increased SRP delivery occurred concomitantly with declining watershed P budgets. However, within these watersheds, there have been long-term, largescale changes in land management: reduced tillage to minimize erosion and particulate P loss, and increased tile drainage to improve field operations and profitability. These practices can inadvertently increase labile P fractions at the soil surface and transmission of soluble P via subsurface drainage. Our findings suggest that changes in agricultural practices, including some conservation practices designed to reduce erosion and particulate P transport, may have had unintended, cumulative, and converging impacts contributing to the increased SRP loads, reaching a critical threshold around 2002.

Can Contrast-Enhanced Sonography Detect Bowel Wall Fibrosis in Mixed Inflammatory and Fibrotic Crohn Disease Lesions in an Animal Model?

OBJECTIVES: To determine whether contrast-enhanced sonographic quantitative perfusion parameters can detect bowel wall fibrosis in the setting of mixed inflammatory and fibrotic lesions in a Crohn disease animal model. METHODS: This study was approved by the institutional Committee on the Use and Care of Animals. Multiple (range, 1-5) 2,4,6-trinitrobenzenesulfonic acid-ethanol enemas were used to create intestinal inflammatory lesions with variable fibrosis in female Lewis rats. Low-mechanical index contrast-enhanced sonography was performed 3 days after the final enema using a 0.2-mL bolus of sulfur hexafluoride microbubbles injected through a tail vein. Contrast-enhanced sonographic data were analyzed with software that converts video data into echo-power (linearized) data. Colorectal lesions were scored for histopathologic inflammation and fibrosis; bowel wall collagen was quantified by Western blotting. The Spearman correlation was used to assess associations between contrast-enhanced sonographic quantitative parameters and bowel wall collagen; the Kruskal-Wallis test was used to compare continuous results between histopathologic groups. RESULTS: Thirty-one animals were included in our analysis. Animals were placed into 3 histopathologic cohorts: (1) severe bowel wall inflammation/minimal or no fibrosis (n = 11); (2) severe bowel wall inflammation/moderate fibrosis (n = 9); and (3) severe bowel wall inflammation/severe fibrosis (n = 11). Western blotting showed a significant difference in bowel wall collagen between histopathologic cohorts (P = .0001). There was no correlation between any contrast-enhanced sonographic quantitative parameter and bowel wall collagen (P > .05). There was no difference between histopathologic cohorts for any contrast-enhanced sonographic quantitative parameter (P > .05). CONCLUSIONS: Contrast-enhanced sonographic quantitative perfusion parameters failed to effectively detect bowel wall fibrosis in the setting of superimposed inflammation in a Crohn disease animal model.

Vertical Stratification of Soil Phosphorus as a Concern for Dissolved Phosphorus Runoff in the Lake Erie Basin.

During the re-eutrophication of Lake Erie, dissolved reactive phosphorus (DRP) loading and concentrations to the lake have nearly doubled, while particulate phosphorus (PP) has remained relatively constant. One potential cause of increased DRP concentrations is P stratification, or the buildup of soil-test P (STP) in the upper soil layer (<5 cm). Stratification often accompanies no-till and mulch-till practices that reduce erosion and PP loading, practices that have been widely implemented throughout the Lake Erie Basin. To evaluate the extent of P stratification in the Sandusky Watershed, certified crop advisors were enlisted to collect stratified soil samples (0-5 or 0-2.5 cm) alongside their normal agronomic samples (0-20 cm) ( = 1758 fields). The mean STP level in the upper 2.5 cm was 55% higher than the mean of agronomic samples used for fertilizer recommendations. The amounts of stratification were highly variable and did not correlate with agronomic STPs (Spearman's = 0.039, = 0.178). Agronomic STP in 70% of the fields was within the buildup or maintenance ranges for corn ( L.) and soybeans [ (L.) Merr.] (0-46 mg kg Mehlich-3 P). The cumulative risks for DRP runoff from the large number of fields in the buildup and maintenance ranges exceeded the risks from fields above those ranges. Reducing stratification by a one-time soil inversion has the potential for larger and quicker reductions in DRP runoff risk than practices related to drawing down agronomic STP levels. Periodic soil inversion and mixing, targeted by stratified STP data, should be considered a viable practice to reduce DRP loading to Lake Erie.

Optimisation of Intestinal Fibrosis and Survival in the Mouse S. Typhimurium Model for Anti-fibrotic Drug Discovery and Preclinical Applications.

BACKGROUND AND AIMS: Intestinal fibrosis is a frequent complication in Crohn's disease [CD]. The mouse Salmonella typhimurium model, due to its simplicity, reproducibility, manipulability, and penetrance, is an established fibrosis model for drug discovery and preclinical trials. However, the severity of fibrosis and mortality are host- and bacterial strain-dependent, thus limiting the original model. We re-evaluated the S. typhimurium model to optimise fibrosis and survival, using commercially available mouse strains. METHODS: Fibrotic and inflammatory markers were evaluated across S. typhimurium ΔaroA:C57bl/6 studies performed in our laboratory. A model optimisation study was performed using three commercially available mouse strains [CBA/J, DBA/J, and 129S1/SvImJ] infected with either SL1344 or ΔaroA S. typhimurium. Fibrotic penetrance was determined by histopathology, gene expression, and αSMA protein expression. Fibrosis severity, penetrance, and survival were analysed across subsequent CBA studies. RESULTS: Fibrosis severity and survival are both host- and bacterial strain-dependent. Marked tissue fibrosis and 100% survival occurred in the CBA/J strain infected with SL1344. Subsequent experiments demonstrated that CBA/J mice develop extensive intestinal fibrosis, characterised by transmural tissue fibrosis, a Th1/Th17 cytokine response, and induction of pro-fibrotic genes and extracellular matrix proteins. A meta-analysis of subsequent SL1344:CBA/J studies demonstrated that intestinal fibrosis is consistent and highly penetrant across histological, protein, and gene expression markers. As proof-of-concept, we tested the utility of the SL1344:CBA/J fibrosis model to evaluate efficacy of CCG-203971, a novel anti-fibrotic drug. CONCLUSION: The S. typhimurium SL1344:CBA/J model is an optimised model for the study of intestinal fibrosis.

The effect of high dose oral manganese exposure on copper, iron and zinc levels in rats.

Manganese is an essential dietary nutrient and trace element with important roles in mammalian development, metabolism, and antioxidant defense. In healthy individuals, gastrointestinal absorption and hepatobiliary excretion are tightly regulated to maintain systemic manganese concentrations at physiologic levels. Interactions of manganese with other essential metals following high dose ingestion are incompletely understood. We previously reported that gavage manganese exposure in rats resulted in higher tissue manganese concentrations when compared with equivalent dietary or drinking water manganese exposures. In this study, we performed follow-up evaluations to determine whether oral manganese exposure perturbs iron, copper, or zinc tissue concentrations. Rats were exposed to a control diet with 10 ppm manganese or dietary, drinking water, or gavage exposure to approximately 11.1 mg manganese/kg body weight/day for 7 or 61 exposure days. While manganese exposure affected levels of all metals, particularly in the frontal cortex and liver, copper levels were most prominently affected. This result suggests an under-appreciated effect of manganese exposure on copper homeostasis which may contribute to our understanding of the pathophysiology of manganese toxicity.

Prebiotics Modulate the Effects of Antibiotics on Gut Microbial Diversity and Functioning in Vitro.

Intestinal bacteria carry out many fundamental roles, such as the fermentation of non-digestible dietary carbohydrates to produce short chain fatty acids (SCFAs), which can affect host energy levels and gut hormone regulation. Understanding how to manage this ecosystem to improve human health is an important but challenging goal. Antibiotics are the front line of defence against pathogens, but in turn they have adverse effects on indigenous microbial diversity and function. Here, we have investigated whether dietary supplementation--another method used to modulate gut composition and function--could be used to ameliorate the side effects of antibiotics. We perturbed gut bacterial communities with gentamicin and ampicillin in anaerobic batch cultures in vitro. Cultures were supplemented with either pectin (a non-fermentable fibre), inulin (a commonly used prebiotic that promotes the growth of beneficial bacteria) or neither. Although antibiotics often negated the beneficial effects of dietary supplementation, in some treatment combinations, notably ampicillin and inulin, dietary supplementation ameliorated the effects of antibiotics. There is therefore potential for using supplements to lessen the adverse effects of antibiotics. Further knowledge of such mechanisms could lead to better therapeutic manipulation of the human gut microbiota.

Pharmacokinetic evaluation of the equivalency of gavage, dietary, and drinking water exposure to manganese in F344 rats.

Concerns exist as to whether individuals may be at greater risk for neurotoxicity following increased manganese (Mn) oral intake. The goals of this study were to determine the equivalence of 3 methods of oral exposure and the rate (mg Mn/kg/day) of exposure. Adult male rats were allocated to control diet (10 ppm), high manganese diet (200 ppm), manganese-supplemented drinking water, and manganese gavage treatment groups. Animals in the drinking water and gavage groups were given the 10 ppm manganese diet and supplemented with manganese chloride (MnCl(2)) in drinking water or once-daily gavage to provide a daily manganese intake equivalent to that seen in the high-manganese diet group. No statistically significant difference in body weight gain or terminal body weights was seen. Rats were anesthetized following 7 and 61 exposure days, and samples of bile and blood were collected. Rats were then euthanized and striatum, olfactory bulb, frontal cortex, cerebellum, liver, spleen, and femur samples were collected for chemical analysis. Hematocrit was unaffected by manganese exposure. Liver and bile manganese concentrations were elevated in all treatment groups on day 61 (relative to controls). Increased cerebellum manganese concentrations were seen in animals from the high-manganese diet group (day 61, relative to controls). Increased (relative to all treatment groups) femur, striatum, cerebellum, frontal cortex, and olfactory bulb manganese concentrations were also seen following gavage suggesting that dose rate is an important factor in the pharmacokinetics of oral manganese. These data will be used to refine physiologically based pharmacokinetic models, extending their utility for manganese risk assessment by including multiple dietary exposures.

Long-term and seasonal trend decomposition of Maumee River nutrient inputs to western Lake Erie.

Cyanobacterial blooms in western Lake Erie have recently garnered widespread attention. Current evidence indicates that a major source of the nutrients that fuel these blooms is the Maumee River. We applied a seasonal trend decomposition technique to examine long-term and seasonal changes in Maumee River discharge and nutrient concentrations and loads. Our results indicate similar long-term increases in both regional precipitation and Maumee River discharge (1975-2013), although changes in the seasonal cycles are less pronounced. Total and dissolved phosphorus concentrations declined from the 1970s into the 1990s; since then, total phosphorus concentrations have been relatively stable, while dissolved phosphorus concentrations have increased. However, both total and dissolved phosphorus loads have increased since the 1990s because of the Maumee River discharge increases. Total nitrogen and nitrate concentrations and loads exhibited patterns that were almost the reverse of those of phosphorus, with increases into the 1990s and decreases since then. Seasonal changes in concentrations and loads were also apparent with increases since approximately 1990 in March phosphorus concentrations and loads. These documented changes in phosphorus, nitrogen, and suspended solids likely reflect changing land-use practices. Knowledge of these patterns should facilitate efforts to better manage ongoing eutrophication problems in western Lake Erie.

Implementing agricultural phosphorus science and management to combat eutrophication.

Experience with implementing agricultural phosphorus (P) strategies highlights successes and uncertainty over outcomes. We examine case studies from the USA, UK, and Sweden under a gradient of voluntary, litigated, and regulatory settings. In the USA, voluntary strategies are complicated by competing objectives between soil conservation and dissolved P mitigation. In litigated watersheds, mandated manure export has not wrought dire consequences on poultry farms, but has adversely affected beef producers who fertilize pastures with manure. In the UK, regulatory and voluntary approaches are improving farmer awareness, but require a comprehensive consideration of P management options to achieve downstream reductions. In Sweden, widespread subsidies sometime hinder serious assessment of program effectiveness. In all cases, absence of local data can undermine recommendations from models and outside experts. Effective action requires iterative application of existing knowledge of P fate and transport, coupled with unabashed description and demonstration of tradeoffs to local stakeholders.

Comparison of noncontrast MRI magnetization transfer and T2 -Weighted signal intensity ratios for detection of bowel wall fibrosis in a Crohn's disease animal model.

PURPOSE: To compare the abilities of magnetization transfer magnetic resonance imaging (MT-MRI) and T2 -weighted signal intensity (T2 WSI) ratios to detect intestinal fibrosis in a Crohn's disease animal model. MATERIALS AND METHODS: Ten rats ("Group 1") received one trinitrobenzenesulfonic acid enema to induce acute colonic inflammation, while 10 additional animals ("Group 2") received multiple enemas to induce colonic inflammation and fibrosis. Gradient recalled-echo MT-MRI (5 and 10 kHz off-resonance) and T2 -weighted spin-echo imaging were performed 2 days after the last enema. MT ratios (MTR) and T2 WSI ratios were calculated in the area of greatest colonic thickening. Bowel wall MTR, bowel wall MTR normalized to paraspinous muscle MTR ("normalized MTR"), and T2 WSI ratios were compared between animal groups using Student's t-test. RESULTS: At 10 kHz off-resonance, mean bowel wall MTR for Group 1 was 24.8 ± 3.1% vs. 30.3 ± 3.2% for Group 2 (P = 0.001). Mean normalized MTR was 0.45 ± 0.05 for Group 1 and 0.58 ± 0.08 for Group 2 (P = 0.0003). At 5 kHz off-resonance, mean bowel wall MTR for Group 1 was 34.7 ± 5.2% vs. 40.3 ± 3.6% for Group 2 (P = 0.015). Mean normalized MTR was 0.53 ± 0.08 for Group 1 and 0.64 ± 0.07 for Group 2 (P = 0.003). Mean T2 WSI ratio was 5.32 ± 0.98 for Group 1 and 3.01 ± 0.66 for group 2 (P < 0.0001). Mean T2 WSI ratio/MTR (10 kHz off-resonance) was 12.06 ± 2.70 for Group 1 and 5.22 ± 1.29 for Group 2 (P < 0.0001), with an ROC c-statistic of 0.98. CONCLUSION: MTR and T2 WSI ratios detect bowel wall fibrosis in a Crohn's disease animal model.

Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis.

BACKGROUND: Guidelines advocate changes in fatty acid consumption to promote cardiovascular health. PURPOSE: To summarize evidence about associations between fatty acids and coronary disease. DATA SOURCES: MEDLINE, Science Citation Index, and Cochrane Central Register of Controlled Trials through July 2013. STUDY SELECTION: Prospective, observational studies and randomized, controlled trials. DATA EXTRACTION: Investigators extracted data about study characteristics and assessed study biases. DATA SYNTHESIS: There were 32 observational studies (530,525 participants) of fatty acids from dietary intake; 17 observational studies (25,721 participants) of fatty acid biomarkers; and 27 randomized, controlled trials (103,052 participants) of fatty acid supplementation. In observational studies, relative risks for coronary disease were 1.02 (95% CI, 0.97 to 1.07) for saturated, 0.99 (CI, 0.89 to 1.09) for monounsaturated, 0.93 (CI, 0.84 to 1.02) for long-chain ω-3 polyunsaturated, 1.01 (CI, 0.96 to 1.07) for ω-6 polyunsaturated, and 1.16 (CI, 1.06 to 1.27) for trans fatty acids when the top and bottom thirds of baseline dietary fatty acid intake were compared. Corresponding estimates for circulating fatty acids were 1.06 (CI, 0.86 to 1.30), 1.06 (CI, 0.97 to 1.17), 0.84 (CI, 0.63 to 1.11), 0.94 (CI, 0.84 to 1.06), and 1.05 (CI, 0.76 to 1.44), respectively. There was heterogeneity of the associations among individual circulating fatty acids and coronary disease. In randomized, controlled trials, relative risks for coronary disease were 0.97 (CI, 0.69 to 1.36) for α-linolenic, 0.94 (CI, 0.86 to 1.03) for long-chain ω-3 polyunsaturated, and 0.89 (CI, 0.71 to 1.12) for ω-6 polyunsaturated fatty acid supplementations. LIMITATION: Potential biases from preferential publication and selective reporting. CONCLUSION: Current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats. PRIMARY FUNDING SOURCE: British Heart Foundation, Medical Research Council, Cambridge National Institute for Health Research Biomedical Research Centre, and Gates Cambridge.

Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.

OBJECTIVE: To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with mortality from cardiovascular, cancer, or other conditions, under various circumstances. DESIGN: Systematic review and meta-analysis of observational studies and randomised controlled trials. DATA SOURCES: Medline, Embase, Cochrane Library, and reference lists of relevant studies to August 2013; correspondance with investigators. STUDY SELECTION: Observational cohort studies and randomised controlled trials in adults, which reported associations between vitamin D (measured as circulating 25-hydroxyvitamin D concentration or vitamin D supplement given singly) and cause specific mortality outcomes. DATA EXTRACTION: Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study specific relative risks from 73 cohort studies (849,412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30,716 participants) were meta-analysed using random effects models and were grouped by study and population characteristics. RESULTS: In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods. CONCLUSIONS: Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk.

GM-CSF knockout mice for preclinical testing of agents with antimicrobial activity against Mycobacterium abscessus.

OBJECTIVES: Of the non-tuberculous mycobacteria, Mycobacterium abscessus is particularly refractory to antimicrobial therapy and new agents with activity against these pathogens are urgently needed. The screening of candidate antimicrobial agents against M. abscessus requires a relevant and reproducible animal model of chronic infection. Granulocyte-macrophage colony-stimulating factor knockout (GM-CSF KO) mice were used to develop a new animal model of chronic pulmonary M. abscessus infection that can be used for preclinical efficacy testing of antimicrobial drugs. METHODS: GM-CSF KO mice were infected with a clinical isolate of M. abscessus via intrapulmonary aerosol delivery using a microsprayer device. The clinical condition, histology and cfu of M. abscessus-infected GM-CSF KO mice were evaluated over a period of 4 months. Mice were treated with azithromycin (100 mg/kg) by oral gavage and the clinical condition, histology and bacterial burden was determined after 2 weeks of treatment. RESULTS: We show that pulmonary infection of GM-CSF KO mice with M. abscessus results in a chronic pulmonary infection that lends itself to preclinical testing of new antimicrobial drugs against this bacterium. Azithromycin treatment of M. abscessus-infected GM-CSF KO mice resulted in a lower bacterial burden in the lungs and spleen, weight gain and significant improvement in lung pathology. CONCLUSIONS: Intrapulmonary aerosol infection of GM-CSF KO mice with M. abscessus is a useful animal model for studying pathogenesis as well as pre-clinical testing of new compounds against M. abscessus in acute or chronic phases of infection.