Sex-specific associations of environmental exposures with prevalent diabetes and obesity - Results from the KORA Fit study.

Promising evidence suggests a link between environmental factors, particularly air pollution, and diabetes and obesity. However, it is still unclear whether men and women are equally susceptible to environmental exposures. Therefore, we aimed to assess sex-specific long-term effects of environmental exposures on metabolic diseases. We analyzed cross-sectional data from 3,034 participants (53.7% female, aged 53-74 years) from the KORA Fit study (2018/19), a German population-based cohort. Environmental exposures, including annual averages of air pollutants [nitrogen oxides (NO2, NOx), ozone, particulate matter of different diameters (PM10, PMcoarse, PM2.5), PM2.5abs, particle number concentration], air temperature and surrounding greenness, were assessed at participants' residences. We evaluated sex-specific associations of environmental exposures with prevalent diabetes, obesity, body-mass-index (BMI) and waist circumference using logistic or linear regression models with an interaction term for sex, adjusted for age, lifestyle factors and education. Further effect modification, in particular by urbanization, was assessed in sex-stratified analyses. Higher annual averages of air pollution, air temperature and greenness at residence were associated with diabetes prevalence in men (NO2: Odds Ratio (OR) per interquartile range increase in exposure: 1.49 [95% confidence interval (CI): 1.13, 1.95], air temperature: OR: 1.48 [95%-CI: 1.15, 1.90]; greenness: OR: 0.78 [95%-CI: 0.59, 1.01]) but not in women. Conversely, higher levels of air pollution, temperature and lack of greenness were associated with lower obesity prevalence and BMI in women. After including an interaction term for urbanization, only higher greenness was associated with higher BMI in rural women, whereas higher air pollution was associated with higher BMI in urban men. To conclude, we observed sex-specific associations of environmental exposures with metabolic diseases. An additional interaction between environmental exposures and urbanization on obesity suggests a higher susceptibility to air pollution among urban men, and higher susceptibility to greenness among rural women, which needs corroboration in future studies.

Coronary angiography after cardiac arrest.

PURPOSE OF REVIEW: Acute coronary syndromes represent the commonest cause of out-of-hospital cardiac arrest (OHCA) in adults. Coronary angiography (CAG) followed by percutaneous coronary intervention (PCI) has been established as the treatment strategy for these patients. In this review, we aim first to discuss the potential risks and expected benefits from it, the caveats in its implementation, and the current tools for patient selection. Then summarize the recent evidence on the group of patients without ST-segment elevation on post-return of spontaneous circulation (ROSC) ECG. RECENT FINDINGS: The implementation of this strategy still shows a wide variation among the various systems of care.The presence of ST-segment elevation on post-ROSC ECG remains the most reliable tool for patient selection for immediate CAG.A primary PCI strategy is currently recommended for patients with ST-segment elevation on post-ROSC ECG regardless of the conscious state of patients.Recently several randomised studies including patients without ST-segment elevation on post-ROSC ECG showed no benefit with immediate CAG compared to delayed/ elective CAG. This has led to a substantial although not uniform change in current recommendations. SUMMARY: Recent studies show no benefit with immediate CAG in groups of patients without ST-segment elevation on post-ROSC ECG. Further refinements in selecting the appropriate patients for immediate CAG seem necessary.

Effects of Short- And Medium-Term Exposures to Lower Air Temperature on 71 Novel Biomarkers of Subclinical Inflammation: Results from the KORA F4 Study.

Increasing evidence has revealed that exposure to low temperatures is linked to a higher risk of chronic diseases and death; however, the mechanisms underlying the observed associations are still poorly understood. We performed a cross-sectional analysis with 1115 participants from the population-based KORA F4 study, which was conducted in Augsburg, Germany, from 2006 to 2008. Seventy-one inflammation-related protein biomarkers were analyzed in serum using proximity extension assay technology. We employed generalized additive models to explore short- and medium-term effects of air temperature on biomarkers of subclinical inflammation at cumulative lags of 0-1 days, 2-6 days, 0-13 days, 0-27 days, and 0-55 days. We found that short- and medium-term exposures to lower air temperature were associated with higher levels in 64 biomarkers of subclinical inflammation, such as Protein S100-A12 (EN-RAGE), Interleukin-6 (IL-6), Interleukin-10 (IL-10), C-C motif chemokine 28 (CCL28), and Neurotrophin-3 (NT-3). More pronounced associations between lower air temperature and higher biomarker of subclinical inflammation were observed among older participants, people with cardiovascular disease or prediabetes/diabetes, and people exposed to higher levels of air pollution (PM2.5, NO2, and O3). Our findings provide intriguing insight into how low air temperature may cause adverse health effects by activating inflammatory pathways.

High-resolution spatiotemporal modeling of daily near-surface air temperature in Germany over the period 2000-2020.

The commonly used weather stations cannot fully capture the spatiotemporal variability of near-surface air temperature (Tair), leading to exposure misclassification and biased health effect estimates. We aimed to improve the spatiotemporal coverage of Tair data in Germany by using multi-stage modeling to estimate daily 1 × 1 km minimum (Tmin), mean (Tmean), maximum (Tmax) Tair and diurnal Tair range during 2000-2020. We used weather station Tair observations, satellite-based land surface temperature (LST), elevation, vegetation and various land use predictors. In the first stage, we built a linear mixed model with daily random intercepts and slopes for LST adjusted for several spatial predictors to estimate Tair from cells with both Tair and LST available. In the second stage, we used this model to predict Tair for cells with only LST available. In the third stage, we regressed the second stage predictions against interpolated Tair values to obtain Tair countrywide. All models achieved high accuracy (0.91 ≤ R2 ≤ 0.98) and low errors (1.03 °C ≤ Root Mean Square Error (RMSE) ≤ 2.02 °C). Validation with external data confirmed the good performance, locally, i.e., in Augsburg for all models (0.74 ≤ R2 ≤ 0.99, 0.87 °C ≤ RMSE ≤ 2.05 °C) and countrywide, for the Tmean model (0.71 ≤ R2 ≤ 0.99, 0.79 °C ≤ RMSE ≤ 1.19 °C). Annual Tmean averages ranged from 8.56 °C to 10.42 °C with the years beyond 2016 being constantly hotter than the 21-year average. The spatial variability within Germany exceeded 15 °C annually on average following patterns including mountains, rivers and urbanization. Using a case study, we showed that modeling leads to broader Tair variability representation for exposure assessment of participants in health cohorts. Our results indicate the proposed models as suitable for estimating nationwide Tair at high resolution. Our product is critical for temperature-based epidemiological studies and is also available for other research purposes.

Improved daily estimates of relative humidity at high resolution across Germany: A random forest approach.

The lack of readily available methods for estimating high-resolution near-surface relative humidity (RH) and the incapability of weather stations to fully capture the spatiotemporal variability can lead to exposure misclassification in studies of environmental epidemiology. We therefore aimed to predict German-wide 1 × 1 km daily mean RH during 2000-2021. RH observations, longitude and latitude, modelled air temperature, precipitation and wind speed as well as remote sensing information on topographic elevation, vegetation, and the true color band composite were incorporated in a Random Forest (RF) model, in addition to date for capturing the temporal variations of the response-explanatory variables relationship. The model achieved high accuracy (R2 = 0.83) and low errors (Root Mean Square Error (RMSE) of 5.07%, Mean Absolute Percentage Error (MAPE) of 5.19% and Mean Percentage Error (MPE) of - 0.53%), calculated via ten-fold cross-validation. A comparison of our RH predictions with measurements from a dense monitoring network in the city of Augsburg, South Germany confirmed the good performance (R2 ≥ 0.86, RMSE ≤ 5.45%, MAPE ≤ 5.59%, MPE ≤ 3.11%). The model displayed high German-wide RH (22y-average of 79.00%) and high spatial variability across the country, exceeding 12% on yearly averages. Our findings indicate that the proposed RF model is suitable for estimating RH for a whole country in high-resolution and provide a reliable RH dataset for epidemiological analyses and other environmental research purposes.

Higher Daily Air Temperature Is Associated with Shorter Leukocyte Telomere Length: KORA F3 and KORA F4.

Higher air temperature is associated with increased age-related morbidity and mortality. To date, short-term effects of air temperature on leukocyte telomere length have not been investigated in an adult population. We aimed to examine the short-term associations between air temperature and leukocyte telomere length in an adult population-based setting, including two independent cohorts. This population-based study involved 5864 participants from the KORA F3 (2004-2005) and F4 (2006-2008) cohort studies conducted in Augsburg, Germany. Leukocyte telomere length was assessed by a quantitative PCR-based method. We estimated air temperature at each participant's residential address through a highly resolved spatiotemporal model. We conducted cohort-specific generalized additive models to explore the short-term effects of air temperature on leukocyte telomere length at lags 0-1, 2-6, 0-6, and 0-13 days separately and pooled the estimates by fixed-effects meta-analysis. Our study found that between individuals, an interquartile range (IQR) increase in daily air temperature was associated with shorter leukocyte telomere length at lags 0-1, 2-6, 0-6, and 0-13 days (%change: -2.96 [-4.46; -1.43], -2.79 [-4.49; -1.07], -4.18 [-6.08; -2.25], and -6.69 [-9.04; -4.27], respectively). This meta-analysis of two cohort studies showed that between individuals, higher daily air temperature was associated with shorter leukocyte telomere length.

ILCOR Scientific Knowledge Gaps and Clinical Research Priorities for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: A Consensus Statement.

Despite significant advances in the field of resuscitation science, important knowledge gaps persist. Current guidelines for resuscitation are based on the International Liaison Committee on Resuscitation 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations, which includes treatment recommendations supported by the available evidence. The writing group developed this consensus statement with the goal of focusing future research by addressing the knowledge gaps identified during and after the 2015 International Liaison Committee on Resuscitation evidence evaluation process. Key publications since the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations are referenced, along with known ongoing clinical trials that are likely to affect future guidelines.

Arrhythmic risk stratification in heart failure: Time for the next step?

BACKGROUND: Primary prevention of sudden cardiac death by means of implantable cardioverter-defibrillators constitutes the holy grail of arrhythmology. However, current risk stratification algorithms lead to suboptimal outcomes, by both allocating ICDs to patients not deriving any meaningful survival benefit and withholding them from those erroneously considered as low-risk for arrhythmic mortality. METHODS: In the present review article we will attempt to present shortcomings of contemporary guidelines regarding sudden death prevention in ischemic and dilated cardiomyopathy patients and present available data suggesting encouraging results following implementation of multifactorial approaches, by using multiple modalities, both noninvasive and invasive. Invasive electrophysiological testing, namely programmed ventricular stimulation, will be discussed in greater length to highlight both its potential usefulness and currently ongoing multicenter studies aiming to provide evidence necessary to make the next step in sudden death risk stratification. RESULTS: Promising findings have been reported by multiple study groups regarding novel strategies for both negative selection of low and positive selection of relatively preserved ejection fraction patients as candidates for ICD implantation. CONCLUSIONS: The era of ejection fraction as the sole risk stratifier for arrhythmic risk in heart failure appears to be drawing to an end, especially if current underway large studies validate previous findings.

Part 2: Evidence Evaluation and Management of Conflicts of Interest: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.

The process for evaluating the resuscitation science has evolved considerably over the past 2 decades. The current process, which incorporates the use of the GRADE methodology, culminated in the 2015 CoSTR publication, which in turn will inform the international resuscitation councils' guideline development processes. Over the next few years, the process will continue to evolve as ILCOR moves toward a more continuous evaluation of the resuscitation science.

Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle.

Obesity is increasingly prevalent, strongly associated with nonalcoholic liver disease, and a risk factor for numerous cancers. Here, we describe the liver-related consequences of long-term diet-induced obesity. Mice were exposed to an extended obesity model comprising a diet high in trans-fats and fructose corn syrup concurrent with a sedentary lifestyle. Livers were assessed histologically using the nonalcoholic fatty liver disease (NAFLD) activity score (Kleiner system). Mice in the American Lifestyle-Induced Obesity Syndrome (ALIOS) model developed features of early nonalcoholic steatohepatitis at 6 months (mean NAFLD activity score = 2.4) and features of more advanced nonalcoholic steatohepatitis at 12 months, including liver inflammation and bridging fibrosis (mean NAFLD activity score = 5.0). Hepatic expression of lipid metabolism and insulin signaling genes were increased in ALIOS mice compared with normal chow-fed mice. Progressive activation of the mouse hepatic stem cell niche in response to ALIOS correlated with steatosis, fibrosis, and inflammation. Hepatocellular neoplasms were observed in 6 of 10 ALIOS mice after 12 months. Tumors displayed cytological atypia, absence of biliary epithelia, loss of reticulin, alteration of normal perivenular glutamine synthetase staining (absent or diffuse), and variable α-fetoprotein expression. Notably, perivascular tumor cells expressed hepatic stem cell markers. These studies indicate an adipogenic lifestyle alone is sufficient for the development of nonalcoholic steatohepatitis, hepatic stem cell activation, and hepatocarcinogenesis in wild-type mice.

Inert ambient annealing effect on MANOS capacitor memory characteristics.

In this work we report on the influence of nitrogen ambient thermal effects on the performance of Pt/Al2O3/Si3N4/SiO2/Si memory capacitors. Two post deposition annealing (PDA) furnace steps were employed, at 850 and 1050 °C both for 15 min. The alumina films were deposited by atomic layer deposition using TMA/H2O at 250 °C. The structural characteristics of the stacks were evaluated by transmission electron microscopy and x-ray reflectivity measurements. The memory performance of the stacks was evaluated by write/erase and erase/write measurements, endurance and retention testing. It was found that in as-deposited state the Al2O3 layer is defective resulting in strong leakage currents, controlled by deep defects states. Thus, this behavior inhibits the memory functionality of the stacks. PDA crystallizes and condenses the Al2O3 transforming the layer from amorphous to polycrystalline. During this transformation the Al2O3 electrical quality improves greatly indicating that a significant number of these deep defects have been removed during annealing. Physical reasoning implies that the most plausible origin of these deep defects is hydrogen. However, the polycrystalline Al2O3 films showed inferior retention characteristics which are attributed to grain boundary related shallow defects. The findings of this work could pave the way for more efficient annealing schemes, in which an important factor is the time interval for hydrogen out-diffusion from the Al2O3 layer.

Towards a survival risk prediction model for metastatic NSCLC patients on durvalumab using whole-lung CT radiomics.

Background: Existing criteria for predicting patient survival from immunotherapy are primarily centered on the PD-L1 status of patients. We tested the hypothesis that noninvasively captured baseline whole-lung radiomics features from CT images, baseline clinical parameters, combined with advanced machine learning approaches, can help to build models of patient survival that compare favorably with PD-L1 status for predicting 'less-than-median-survival risk' in the metastatic NSCLC setting for patients on durvalumab. With a total of 1062 patients, inclusive of model training and validation, this is the largest such study yet. Methods: To ensure a sufficient sample size, we combined data from treatment arms of three metastatic NSCLC studies. About 80% of this data was used for model training, and the remainder was held-out for validation. We first trained two independent models; Model-C trained to predict survival using clinical data; and Model-R trained to predict survival using whole-lung radiomics features. Finally, we created Model-C+R which leveraged both clinical and radiomics features. Results: The classification accuracy (for median survival) of Model-C, Model-R, and Model-C+R was 63%, 55%, and 68% respectively. Sensitivity analysis of survival prediction across different training and validation cohorts showed concordance indices ([95 percentile]) of 0.64 ([0.63, 0.65]), 0.60 ([0.59, 0.60]), and 0.66 ([0.65,0.67]), respectively. We additionally evaluated generalization of these models on a comparable cohort of 144 patients from an independent study, demonstrating classification accuracies of 65%, 62%, and 72% respectively. Conclusion: Machine Learning models combining baseline whole-lung CT radiomic and clinical features may be a useful tool for patient selection in immunotherapy. Further validation through prospective studies is needed.

Associations between medium- and long-term exposure to air temperature and epigenetic age acceleration.

Climate change poses a serious threat to human health worldwide, while aging populations increase. However, no study has ever investigated the effects of air temperature on epigenetic age acceleration. This study involved 1,725 and 1,877 participants from the population-based KORA F4 (2006-2008) and follow-up FF4 (2013-2014) studies, respectively, conducted in Augsburg, Germany. The difference between epigenetic age and chronological age was referred to as epigenetic age acceleration and reflected by Horvath's epigenetic age acceleration (HorvathAA), Hannum's epigenetic age acceleration (HannumAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), and Epigenetic Skin and Blood Age acceleration (SkinBloodAA). Daily air temperature was estimated using hybrid spatiotemporal regression-based models. To explore the medium- and long-term effects of air temperature modeled in time and space on epigenetic age acceleration, we applied generalized estimating equations (GEE) with distributed lag non-linear models, and GEE, respectively. We found that high temperature exposure based on the 8-week moving average air temperature (97.5th percentile of temperature compared to median temperature) was associated with increased HorvathAA, HannumAA, GrimAA, and SkinBloodAA: 1.83 (95% CI: 0.29-3.37), 11.71 (95% CI: 8.91-14.50), 2.26 (95% CI: 1.03-3.50), and 5.02 (95% CI: 3.42-6.63) years, respectively. Additionally, we found consistent results with high temperature exposure based on the 4-week moving average air temperature was associated with increased HannumAA, GrimAA, and SkinBloodAA: 9.18 (95% CI: 6.60-11.76), 1.78 (95% CI: 0.66-2.90), and 4.07 (95% CI: 2.56-5.57) years, respectively. For the spatial variation in annual average temperature, a 1 °C increase was associated with an increase in all five measures of epigenetic age acceleration (HorvathAA: 0.41 [95% CI: 0.24-0.57], HannumAA: 2.24 [95% CI: 1.95-2.53], PhenoAA: 0.32 [95% CI: 0.05-0.60], GrimAA: 0.24 [95%: 0.11-0.37], and SkinBloodAA: 1.17 [95% CI: 1.00-1.35] years). In conclusion, our results provide first evidence that medium- and long-term exposures to high air temperature affect increases in epigenetic age acceleration.

Management of comatose survivors of out-of-hospital cardiac arrest in Europe: current treatment practice and adherence to guidelines. A joint survey by the Association for Acute CardioVascular Care (ACVC) of the ESC, the European Resuscitation Council (ERC), the European Society for Emergency Medicine (EUSEM), and the European Society of Intensive Care Medicine (ESICM).

AIMS: International guidelines give recommendations for the management of comatose out-of-hospital cardiac arrest (OHCA) survivors. We aimed to investigate adherence to guidelines and disparities in the treatment of OHCA in hospitals in Europe. METHODS AND RESULTS: A web-based, multi-institutional, multinational survey in Europe was conducted using an electronic platform with a predefined questionnaire developed by experts in post-resuscitation care. The survey was disseminated to all members of the societies via email, social media, websites, and newsletters in June 2021. Of 252 answers received, 237 responses from different units were included and 166 (70%) were from cardiac arrest centres. First-line vasopressor used was noradrenaline in 195 (83%) and the first-line inotrope was dobutamine in 148 (64%) of the responses. Echocardiography is available 24/7 in 204 (87%) institutions. Targeted temperature management was used in 160 (75%) institutions for adult comatose survivors of OHCA with an initial shockable rhythm. Invasive or external cooling methods with feedback were used in 72 cardiac arrest centres (44%) and 17 (24%) non-cardiac arrest centres (P < 0.0003). A target temperature between 32 and 34°C was preferred by 46 centres (21%); a target between 34 and 36°C by 103 centres (52%); and <37.5°C by 35 (16%). Multimodal neuroprognostication was poorly implemented and a follow-up at 3 months after discharge was done in 71 (30%) institutions. CONCLUSION: Post-resuscitation care is not well established and varies among centres in European hospitals. Cardiac arrest centres have a higher coherence with guidelines compared with respondents from non-cardiac arrest centres. The overall inconsistency in approaches and deviation from recommendations could be a focus for improvement.

Assessment of short-term heat effects on cardiovascular mortality and vulnerability factors using small area data in Europe.

BACKGROUND: Short-term associations between heat and cardiovascular disease (CVD) mortality have been examined mostly in large cities. However, different vulnerability and exposure levels may contribute to spatial heterogeneity. This study assessed heat effects on CVD mortality and potential vulnerability factors using data from three European countries, including urban and rural settings. METHODS: We collected daily counts of CVD deaths aggregated at the small-area level in Norway (small-area level: municipality), England and Wales (lower super output areas), and Germany (district) during the warm season (May-September) from 1996 to 2018. Daily mean air temperatures estimated by spatial-temporal models were assigned to each small area. Within each country, we applied area-specific Quasi-Poisson regression using distributed lag nonlinear models to examine the heat effects at lag 0-1 days. The area-specific estimates were pooled by random-effects meta-analysis to derive country-specific and overall heat effects. We examined individual- and area-level heat vulnerability factors by subgroup analyses and meta-regression, respectively. RESULTS: We included 2.84 million CVD deaths in analyses. For an increase in temperature from the 75th to the 99th percentile, the pooled relative risk (RR) for CVD mortality was 1.14 (95% CI: 1.03, 1.26), with the country-specific RRs ranging from 1.04 (1.00, 1.09) in Norway to 1.24 (1.23, 1.26) in Germany. Heat effects were stronger among women [RRs (95% CIs) for women and men: 1.18 (1.08, 1.28) vs. 1.12 (1.00, 1.24)]. Greater heat vulnerability was observed in areas with high population density, high degree of urbanization, low green coverage, and high levels of fine particulate matter. CONCLUSION: This study provides evidence for the heat effects on CVD mortality in European countries using high-resolution data from both urban and rural areas. Besides, we identified individual- and area-level heat vulnerability factors. Our findings may facilitate the development of heat-health action plans to increase resilience to climate change.

Quality indicators for post-resuscitation care after out-of-hospital cardiac arrest: a joint statement from the Association for Acute Cardiovascular Care of the European Society of Cardiology, the European Resuscitation Council, the European Society of Intensive Care Medicine, and the European Society for Emergency Medicine.

AIMS: Quality of care (QoC) is a fundamental tenet of modern healthcare and has become an important assessment tool for healthcare authorities, stakeholders and the public. However, QoC is difficult to measure and quantify because it is a multifactorial and multidimensional concept. Comparison of clinical institutions can be challenging when QoC is estimated solely based on clinical outcomes. Thus, measuring quality through quality indicators (QIs) can provide a foundation for quality assessment and has become widely used in this context. QIs for the evaluation of QoC in acute myocardial infarction are now well-established, but no such indicators exist for the process from resuscitation of cardiac arrest and post-resuscitation care in Europe. METHODS AND RESULTS: The Association of Acute Cardiovascular Care of the European Society Cardiology, the European Resuscitation Council, European Society of Intensive Care Medicine and the European Society for Emergency Medicine, have reflected on the measurement of QoC in cardiac arrest. A set of QIs have been proposed, with the scope to unify and evolve QoC for the management of cardiac arrest across Europe. CONCLUSION: We present here the list of QIs (6 primary QIs and 12 secondary Qis), with descriptions of the methodology used, scientific justification and motives for the choice for each measure with the aim that this set of QIs will enable assessment of the quality of postout-of-hospital cardiac arrest management across Europe.

11ß-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial.

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regenerates active glucocorticoid, we investigated whether 11ß-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn't met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.

ERC-ESICM guidelines on temperature control after cardiac arrest in adults.

The aim of these guidelines is to provide evidence­based guidance for temperature control in adults who are comatose after resuscitation from either in-hospital or out-of-hospital cardiac arrest, regardless of the underlying cardiac rhythm. These guidelines replace the recommendations on temperature management after cardiac arrest included in the 2021 post-resuscitation care guidelines co-issued by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM). The guideline panel included thirteen international clinical experts who authored the 2021 ERC-ESICM guidelines and two methodologists who participated in the evidence review completed on behalf of the International Liaison Committee on Resuscitation (ILCOR) of whom ERC is a member society. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations. The panel provided suggestions on guideline implementation and identified priorities for future research. The certainty of evidence ranged from moderate to low. In patients who remain comatose after cardiac arrest, we recommend continuous monitoring of core temperature and actively preventing fever (defined as a temperature > 37.7 °C) for at least 72 hours. There was insufficient evidence to recommend for or against temperature control at 32-36 °C or early cooling after cardiac arrest. We recommend not actively rewarming comatose patients with mild hypothermia after return of spontaneous circulation (ROSC) to achieve normothermia. We recommend not using prehospital cooling with rapid infusion of large volumes of cold intravenous fluids immediately after ROSC.

ERC-ESICM guidelines on temperature control after cardiac arrest in adults.

The aim of these guidelines is to provide evidence­based guidance for temperature control in adults who are comatose after resuscitation from either in-hospital or out-of-hospital cardiac arrest, regardless of the underlying cardiac rhythm. These guidelines replace the recommendations on temperature management after cardiac arrest included in the 2021 post-resuscitation care guidelines co-issued by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM). The guideline panel included thirteen international clinical experts who authored the 2021 ERC-ESICM guidelines and two methodologists who participated in the evidence review completed on behalf of the International Liaison Committee on Resuscitation (ILCOR) of whom ERC is a member society. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations. The panel provided suggestions on guideline implementation and identified priorities for future research. The certainty of evidence ranged from moderate to low. In patients who remain comatose after cardiac arrest, we recommend continuous monitoring of core temperature and actively preventing fever (defined as a temperature > 37.7 °C) for at least 72 h. There was insufficient evidence to recommend for or against temperature control at 32-36 °C or early cooling after cardiac arrest. We recommend not actively rewarming comatose patients with mild hypothermia after return of spontaneous circulation (ROSC) to achieve normothermia. We recommend not using prehospital cooling with rapid infusion of large volumes of cold intravenous fluids immediately after ROSC.

Acute intermittent hypoxia drives hepatic de novo lipogenesis in humans and rodents.

Background and aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. Methods: Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. Results: Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. Conclusions: These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD.