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Importance: Survival probability among individuals critically buried by avalanche is highly time dependent, which was demonstrated 30 years ago. However, it remains unclear whether avalanche survival probability has changed over time., Objective: To assess the avalanche survival rate and probability as well as the rescue probability over the past 4 decades., Design, Setting, and Participants: In this cohort study, avalanche data from Switzerland that were collected by the WSL Institute for Snow and Avalanche Research (SLF) in Davos were analyzed from the winter beginning in 1981 to that beginning in 2020 and compared with data from the period 1981 to 1990. Data were analyzed from January to April 2024., Exposure: Critical avalanche burial (ie, burial involving the head and chest)., Main Outcomes and Measures: Survival rate among individuals critically buried by avalanche, survival probability, and rescue probability in relation to time buried under the avalanche., Results: The study included 1643 individuals critically buried by avalanche (mean [SD] age, 37 [13.7] years; 1090 of 1342 with known sex [81.2%] were male) among 3805 avalanches involving 7059 persons. Compared with the period from 1981 to 1990, the total survival rate over the full study period increased from 43.5% (95% CI, 38.8%-48.3%) to 53.4% (95% CI, 51.0%-55.8%). Survival probability remained high at 91% (95% CI, 80%-100%) for rescue during the first 10 minutes but then decreased to 31% (95% CI, 11%-51%) for rescue between 10 and 30 minutes. The survival rate among those buried long term (>130 minutes) increased from 2.6% (95% CI, 0.7%-6.9%) to 7.3% (95% CI, 4.8%-10.7%). The median rescue time decreased from 45 (IQR, 15-148) minutes to 25 (IQR, 10-85) minutes. Survival rates among individuals rescued from avalanche by organized rescue teams increased from 14.0% (28 of 200) to 22.9% (161 of 704)., Conclusions and Relevance: This cohort study of 1643 individuals critically buried by avalanche found that over the past 4 decades, total survival rates considerably increased and rescue times decreased. Survival rates among those buried long term (>130 minutes) also increased. These findings are likely attributable to collaborative efforts among stakeholders to enhance avalanche search-and-rescue techniques and medical interventions.

Agriculture is the largest source of methane globally, and enteric methane accounts for 32% of methane emissions globally. Dairy-beef is an increasingly important contributor to the beef industry. The objective of this study was to investigate if supplementation with a blend of essential oils (Agolin Ruminant) reduced enteric methane emissions from dairy-bred steers. Methane was measured from thirty-six Holstein Friesian steers (18 control and 18 treatment) in open-circuit respiration chambers, at three time-points relative to the introduction of Agolin Ruminant: (i) -3 (pre-additive introduction co-variate), (ii) 46 days after introduction, and (iii) 116 days after introduction. A significantly lower methane yield was observed in treated animals compared to control animals at both 46 days ( p < 0.05) and 116 days ( p < 0.01) after the introduction of Agolin Ruminant, although there was no difference in methane production (g/day). Control animals appeared to be more affected by isolation in respiration chambers than animals receiving Agolin Ruminant, as indicated by a significant reduction in dry matter intake by control animals in respiration chambers.

Introduction: We aimed to investigate the relationship between the time of the day and the probability of survival of completely buried avalanche victims. We explored the frequency of avalanche burials occurring after sunset, and described victims' characteristics, duration of burial and rescue circumstances compared to daytime avalanches., Methods: In this retrospective, observational study, we analysed avalanche data from the registry of the Swiss Institute for Snow and Avalanche Research, from 1998 to 2020., Results: A total of 3892 avalanche victims were included in the analysis, with 72 of the accidents (1.85%) occurring in the nighttime. Nearly 50% of the victims involved in nighttime avalanche accidents were completely buried, compared to about 25% of victims in daytime avalanches. Completely buried victims were rescued by a companion less often at night than in the daytime (15% vs. 51%, p <.001). The search and rescue of completely buried avalanche victims took longer during the nighttime compared to the daytime (median 89 min vs 20 min, p =.002). The probability of survival decreased as the day progressed; it was highest at around midday (63.0%), but decreased at sunset (40.4%) and was the lowest at midnight (28.7%)., Conclusions: Avalanche accidents at night are a rare event, and probability of survival after complete burial is lower during the nighttime compared to the daytime. The most relevant reason for this is the longer duration of burial, which is explained in part by the lower rate of companion rescue and the lower rate of victim localisation with an avalanche transceiver., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: To compare the binding and agonistic activity of Acthar ® Gel and synthetic melanocortin receptor (MCR) agonists and examine how the activity of select agonists affects the in vivo production of corticosterone., Materials and Methods: In vitro binding was determined using concentration-dependent displacement of the ligand [ 125 I]Nle 4 , D-Phe 7 -α-melanocyte-stimulating hormone (α-MSH) on cells expressing MC1R, MC3R, MC4R, or MC5R. Functional activity was determined using a time-resolved fluorescence cyclic adenosine monophosphate (cAMP) assay in cells expressing MC1R, MC2R, MC3R, MC4R, or MC5R. In vivo corticosterone analyses were performed by measuring plasma corticosterone levels in Sprague Dawley rats., Results: Acthar Gel and synthetic MCR agonists exhibited the highest binding at MC1R, lowest binding at MC5R, and moderate binding at MC3R and MC4R. Acthar Gel stimulated the production of cAMP in all 5 MCR-expressing cell lines, with MC2R displaying the lowest level of full agonist activity, 3-, 6.6-, and 10-fold lower than MC1R, MC3R, and MC4R, respectively. Acthar Gel was a partial agonist at MC5R. The synthetic MCR agonists induced full activity at all 5 MCRs, with the exception of α-MSH having no activity at MC2R. Acthar Gel treatment had less of an impact on in vivo production of corticosterone compared with synthetic ACTH 1-24 depot., Conclusions: Acthar Gel bound to and activated each MCR tested in this study, with partial agonist activity at MC5R and the lowest level of full agonist activity at MC2R, which distinguished it from synthetic MCR agonists. The minimal activity of Acthar Gel at MC2R corresponded to lower endogenous corticosteroid production.

There is an increasing pressure to identify feed additives which increase productivity or decrease methane emissions. This paper aims to elucidate the effects of supplementing a specific essential oils blend Agolin ® Ruminant on the productivity of dairy cows in comparison to non-treated animals. A total of 23 in vivo studies were identified in which Agolin was supplemented at 1 g/d per cow; then a meta-analysis was performed to determine the response ratio on milk yield, rumen fermentation, methane emissions and health. Results indicated that an adaptation period of at least 4 weeks of treatment is required. Whereas short-term studies showed minor and inconsistent effects of Agolin, long-term studies (>4 weeks of treatment) revealed that Agolin supplementation increases milk yield (+3.6%), fat and protein corrected milk (+4.1%) and feed efficiency (+4.4%) without further changes in milk composition and feed intake. Long-term treatment also decreased methane production per day (-8.8%), per dry matter intake (-12.9%) and per fat and protein corrected milk yield (-9.9%) without changes in rumen fermentation pattern. In conclusion, despite the mode of action is still unclear and the small number of studies considered, these findings show that Agolin represents an encouraging alternative to improve productivity in dairy cows.

Essential oils (EO) are widely used in foods as flavoring and preservative agents. Many of the biological activities of EO have been attributed to major essential oil compounds (EOC) but their direct interaction with colonic epithelial cells and their genotoxic and genoprotective effects are not well established. In this study, the cytotoxicity and genotoxicity of EOC including nerolidol, thymol, geraniol, methylisoeugenol, eugenol, linalool, and a commercial blend (Agolin) were determined. Furthermore, the genoprotective effects of EOC against oxidative and methylating damage were assessed using the comet assay in HT-29 colorectal adenocarcinoma cells. The majority of EOC were cytotoxic to HT-29 cells at or above 250 ppm after 24 hr exposure. At noncytotoxic doses, none of the EOC was genotoxic in the comet assay. Genoprotection against oxidative DNA damage was observed for nerolidol (at 62.5 ppm), thymol (at 12.5 ppm), geraniol, and methylisoeugenol (both at 125 ppm), as well as linalool and Agolin (both at 250 ppm). Thymol was the most protective compound against oxidative DNA damage and geraniol (at 125 ppm) also protected cells against methylating DNA damage. This study highlights the potential of EOC such as thymol to protect the colonic epithelium against oxidative DNA damage and geraniol against methylating DNA damage. Further in vivo studies are needed to confirm these findings for safety and efficacy to exploit their potential pharmaceutical or nutraceutical uses for colonic health., (© 2019 Institute of Food Technologists®.)

Aim: To calculate the first Austrian avalanche survival curve and update a Swiss survival curve to explore survival patterns in the Alps., Methods: Avalanche accidents occurring between 2005/06 and 2012/13 in Austria and Switzerland were collected. Completely buried victims (i.e. burial of the head and chest) in open terrain with known outcome (survived or not survived) were included in the analysis. Extrication and survival curves were calculated using the Turnbull algorithm, as in previous studies., Results: 633 of the 796 completely buried victims were included (Austria n=333, Switzerland n=300). Overall survival was 56% (Austria 59%; Switzerland 52%; p=0.065). Time to extrication was shorter in Austria for victims buried ≤60min (p<0.001). The survival curves were similar and showed a rapid initial drop in survival probability and a second drop to 25-28% survival probability after burial duration of ca. 35min, where an inflection point exists and the curve levels off. In a logistic regression analysis, both duration of burial and burial depth had an independent effect on survival. Victims with an air pocket were more likely to survive, especially if buried >15min., Conclusion: The survival curves resembled those previously published and support the idea that underlying survival patterns are reproducible. The results are in accordance with current recommendations for management of avalanche victims and serve as a reminder that expedient companion rescue within a few minutes is critical for survival. An air pocket was shown to be a positive prognostic factor for survival., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Avalanches are the primary hazard for winter backcountry recreationists and cause numerous deaths and injuries annually. Although recreationists usually travel in groups, there is little empirical knowledge on group-related risk factors. This study aims to explore the relative risk of avalanche accidents with respect to group size and to discuss underlying reasons for different risk levels., Methods: We compared backcountry usage data in regions in Switzerland and Italy with avalanche accident data in these regions., Results: We found higher avalanche risk for groups of 4 or more people and lower risk for people traveling alone and in groups of 2. The relative risk of group size 4, 5, and 6 was higher compared with the reference group size of 2 in the Swiss and Italian dataset. The relative risk for people traveling alone was not significantly different compared with the reference group size of 2 in the Italian dataset but was lower in the Swiss dataset., Conclusions: These findings are in accordance with avalanche safety recommendations regarding the higher risk of large groups but not regarding lower risks of people traveling alone in avalanche terrain, which is not recommended and requires great caution. Further studies on backcountry usage are necessary to improve our understanding of human behavior and risk factors. New techniques (eg, video monitoring) may be useful for acquiring reliable data on backcountry usage., (Copyright © 2016 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

A static batch culture system inoculated with human faeces was used to determine the influence of essential oil compounds (EOCs) on mixed faecal microbiota. Bacteria were quantified using quantitative PCR of 16S rRNA genes. Incubation for 24 h of diluted faeces from six individuals caused enrichment of Bifidobacterium spp., but proportions of other major groups were unaffected. Thymol and geraniol at 500 p.p.m. suppressed total bacteria, resulting in minimal fermentation. Thymol at 100 p.p.m. had no effect, nor did eugenol or nerolidol at 100 or 500 p.p.m. except for a slight suppression of Eubacterium hallii. Methyl isoeugenol at 100 or 500 p.p.m. suppressed the growth of total bacteria, accompanied by a large fall in the molar proportion of propionate formed. The relative abundance of Faecalibacterium prausnitzii was unaffected except with thymol at 500 p.p.m. The ability of EOCs to control numbers of the pathogen Clostridium difficile was investigated in a separate experiment, in which the faecal suspensions were amended by the addition of pure culture of C. difficile. Numbers of C. difficile were suppressed by thymol and methyl isoeugenol at 500 p.p.m. and to a lesser extent at 100 p.p.m. Eugenol and geraniol gave rather similar suppression of C. difficile numbers at both 100 and 500 p.p.m. Nerolidol had no significant effect. It was concluded from these and previous pure-culture experiments that thymol and geraniol at around 100 p.p.m. could be effective in suppressing pathogens in the small intestine, with no concern for beneficial commensal colonic bacteria in the distal gut., (© 2015 The Authors.)

Aim: Asphyxia is the primary cause of death among avalanche victims. Avalanche airbags can lower mortality by directly reducing grade of burial, the single most important factor for survival. This study aims to provide an updated perspective on the effectiveness of this safety device., Methods: A retrospective analysis of avalanche accidents involving at least one airbag user between 1994 and 2012 in Austria, Canada, France, Norway, Slovakia, Switzerland and the United States. A multivariate analysis was used to calculate adjusted absolute risk reduction and estimate the effectiveness of airbags on grade of burial and mortality. A univariate analysis was used to examine causes of non-deployment., Results: Binomial linear regression models showed main effects for airbag use, avalanche size and injuries on critical burial, and for grade of burial, injuries and avalanche size on mortality. The adjusted risk of critical burial is 47% with non-inflated airbags and 20% with inflated airbags. The adjusted mortality is 44% for critically buried victims and 3% for non-critically buried victims. The adjusted absolute mortality reduction for inflated airbags is -11 percentage points (22% to 11%; 95% confidence interval: -4 to -18 percentage points) and adjusted risk ratio is 0.51 (95% confidence interval: 0.29 to 0.72). Overall non-inflation rate is 20%, 60% of which is attributed to deployment failure by the user., Conclusion: Although the impact on survival is smaller than previously reported, these results confirm the effectiveness of airbags. Non-deployment remains the most considerable limitation to effectiveness. Development of standardized data collection protocols is encouraged to facilitate further research., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

It is known that cyclooxygenase-2 (COX-2) inhibition elicits significant renal hemodynamics alterations when sodium intake is low. However, the mechanisms involved in these renal changes are not well known. Our objective was to evaluate the role of angiotensin II and 5-lipooxygenase-derived metabolites in the renal effects induced by prolonged COX-2 inhibition when sodium intake is low. Conscious dogs were treated during 7 days with a COX-2 inhibitor (1 mg·kg·d, SC75416), and either a vehicle, an AT1 receptor antagonist (0.4 mg · kg · d, candesartan) or a selective 5-lipooxygenase inhibitor (PF-150, 20 and 60 mg · kg · d). The administration of SC75416 alone induced significant changes in renal blood flow (219 ± 14 to 160 ± 10 mL/min), glomerular filtration rate (51 ± 2 to 42 ± 3 mL/min), and plasma potassium (pK) (4.3 ± 0.1 to 4.6 ± 0.1 mEq/L). Similar decrements in renal blood flow (27%) and glomerular filtration rate (20%) and a similar increment in pK (7%) were found when SC75416 was administered in candesartan-pretreated dogs. However, SC75416 administration did not elicit significant changes in renal hemodynamics and pK in dogs pretreated with each dose of PF-150. Our data suggest that leukotrienes but not angiotensin II are involved in the renal effects induced by COX-2 inhibition when sodium intake is low.

Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure-activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties. Further SAR studies of the benzoxazole ring substituents lead to a novel series of highly potent compounds with improved PK profile, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Based on its excellent in vitro and in vivo pharmacological, pharmacokinetic and safety profile and ease of synthesis, compound 26 (PF-4693627) was advanced to clinical studies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The microbiota of the intestinal tract plays an important role in colonic health, mediating many effects of dietary components on colonic health and during enteric infections. In the context of the increasing incidence of antibiotic resistance in gut bacteria, complementary therapies are required for the prevention and treatment of enteric infections. Here we report the potential application of essential oils (EO) and pure EO compounds to improve human gut health. Nerolidol, thymol, eugenol and geraniol inhibited growth of the pathogens Escherichia coli O157 : H7(VT(-)), Clostridium difficile DSM1296, Clostridium perfringens DSM11780, Salmonella typhimurium 3530 and Salmonella enteritidis S1400 at a half-maximal inhibitory concentration (IC(50)) varying from 50 to 500 p.p.m. Most EO showed greater toxicity to pathogens than to commensals. However, the beneficial commensal Faecalibacterium prausnitzii was sensitive to EO at similar or even lower concentrations than the pathogens. The EO showed dose-dependent effects on cell integrity, as measured using propidium iodide, of Gram-positive bacteria. These effects were not strongly correlated with growth inhibition, however, suggesting that cell membrane damage occurred but was not the primary cause of growth inhibition. Growth inhibition of Gram-negative bacteria, in contrast, occurred mostly without cell integrity loss. Principal component analysis showed clustering of responses according to bacterial species rather than to the identity of the EO, with the exception that responses to thymol and nerolidol clustered away from the other EO. In conclusion, the selective effects of some EO might have beneficial effects on gut health if chosen carefully for effectiveness against different species.

Autotaxin is the enzyme responsible for the production of lysophosphatidic acid (LPA) from lysophosphatidyl choline (LPC), and it is up-regulated in many inflammatory conditions, including but not limited to cancer, arthritis, and multiple sclerosis. LPA signaling causes angiogenesis, mitosis, cell proliferation, and cytokine secretion. Inhibition of autotaxin may have anti-inflammatory properties in a variety of diseases; however, this hypothesis has not been tested pharmacologically because of the lack of potent inhibitors. Here, we report the development of a potent autotaxin inhibitor, PF-8380 [6-(3-(piperazin-1-yl)propanoyl)benzo[d]oxazol-2(3H)-one] with an IC(50) of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood. PF-8380 has adequate oral bioavailability and exposures required for in vivo testing of autotaxin inhibition. Autotaxin's role in producing LPA in plasma and at the site of inflammation was tested in a rat air pouch model. The specific inhibitor PF-8380, dosed orally at 30 mg/kg, provided >95% reduction in both plasma and air pouch LPA within 3 h, indicating autotaxin is a major source of LPA during inflammation. At 30 mg/kg PF-8380 reduced inflammatory hyperalgesia with the same efficacy as 30 mg/kg naproxen. Inhibition of plasma autotaxin activity correlated with inhibition of autotaxin at the site of inflammation and in ex vivo whole blood. Furthermore, a close pharmacokinetic/pharmacodynamic relationship was observed, which suggests that LPA is rapidly formed and degraded in vivo. PF-8380 can serve as a tool compound for elucidating LPA's role in inflammation.

Background: Within Europe and North America, the median annual mortality from snow avalanches between 1994 and 2003 was 141. There are two commonly used rescue devices: the avalanche transceiver, which is intended to speed up locating a completely buried person, and the avalanche airbag, which aims to prevent the person from being completely buried., Objective: This retrospective study aimed to evaluate whether these avalanche rescue devices had an effect on mortality., Methods: The study population was 1504 persons who were involved in 752 avalanches either in Switzerland from 1990 to 2000 and from 2002 to 2003 (1296 persons, 86.2%) or in Austria from 1998 to 2004 (208 persons, 13.8%)., Results: Persons equipped with an avalanche airbag had a lower chance of dying (2.9% versus 18.9%; P=0.026, OR 0.09, n=1504). In persons who were completely buried, without visible or audible signs at the surface and who did not rescue themselves (n=317), we found a lower median duration of burial (25min versus 125min; P<0.001) and mortality (55.2% versus 70.6%; P<0.001, OR 0.26) in those using an avalanche transceiver than in those not using the device., Conclusions: Our data showed that both the avalanche airbag and the avalanche transceiver reduce mortality. However, to improve the evaluation of rescue devices in the future, the data collection procedures should be reviewed and prospective trials should be considered, as the reliability of retrospective studies is limited.

Cyclooxygenase-2 (COX-2) overexpression is a widely recognized feature of human breast cancer and inhibitors of the enzyme have antitumor effects in a subset of tumor settings. Previously, we demonstrated that direct overexpression of COX-2 under control of the mammary-specific MMTV promoter/enhancer, was itself oncogenic and lead to the induction of mammary tumors in multiparous, outbred CD1 mice. In the present study, we provide evidence that COX-2 dependent tumor progression can also be studied in FVB/N, an inbred strain widely used for analysis of breast cancer progression. In these mice, the human COX-2 transgene was strongly induced during pregnancy/lactation and mammary tumors developed after multiple pregnancies. However, crossing the COX-2 FVB/N mice with the C57BL6 strain resulted in loss of the mammary tumorigenic phenotype despite the fact that the human COX-2 gene was induced. Treatment of the COX-2 transgenic mice in the FVB/N strain with celecoxib (1600 ppm), a COX-2 selective inhibitor, resulted significant reduction in tumor size and multiplicity when compared to transgenic mice fed with control chow. SC-560 (20 ppm), a COX-1 selective inhibitor did not have significant effect on tumorigenesis. These studies suggest that FVB/N is a susceptible mouse strain well suited to the study of COX-2 mediated tumor progression and may provide a tool for the identification of interacting genes and therapeutic treatments for this clinically important target.

We provide evidence that cyclooxygenase (COX)-2-derived prostaglandins contribute to tumor growth by inducing newly formed blood vessels (neoangiogenesis) that sustain tumor cell viability and growth. COX-2 is expressed within human tumor neovasculature as well as in neoplastic cells present in human colon, breast, prostate, and lung cancer biopsy tissue. COX-1 is broadly distributed in normal, as well as in neoplastic, tissues. The contribution of COX-2 to human tumor growth was indicated by the ability of celecoxib, an agent that inhibits the COX-2 enzyme, to suppress growth of lung and colon tumors implanted into recipient mice. Mechanistically, celecoxib demonstrated a potent antiangiogenic activity. In a rat model of angiogenesis, we observe that corneal blood vessel formation is suppressed by celecoxib, but not by a COX-1 inhibitor. These and other data indicate that COX-2 and COX-2-derived prostaglandins may play a major role in development of cancer through numerous biochemical mechanisms, including stimulation of tumor cell growth and neovascularization. The ability of celecoxib to block angiogenesis and suppress tumor growth suggests a novel application of this anti-inflammatory drug in the treatment of human cancer.