CMB-S4

We describe the stage 4 cosmic microwave background ground-based experiment CMB-S4

Physiological and Performance Effects of Altitude Training for Elite Athletes: A Systematic Review and Meta-Analysis

Background: At the elite level, minute variances in performance can be the difference between a podium finish and competing in a final. As such, coaches are continuously looking at developing ways to improve performance. One strategy used by athletes in order to facilitate physiologic and exercise performance improvement is through hypoxic exposure. Two models appear to dominate the discussion: live high, train low (LHTL) and live high, train high (LHTH). The former proposes living at altitude (2000m – 3000m) but training at or near sea level (600m – 1200m). Whilst the LHTH model requires athletes to live and train at altitude ranges beyond (1250 to 3000m) Objectives: To identify the physiological and performance adaptations associated with LHTL or LHTH for elite endurance athletes. Methods: 1) A narrative review of the literature was carried out to address and explore current literature within altitude training. 2) A systematic review and meta-analysis were performed to determine how altitude training (both LHTL and LHTH) influences the physiological and performance effects in elite and high performing athletes, contrasting different models of altitude exposure. Results: 1) Narrative review: key results for physiological and performance adaptations for the narrative review seem to indicate that an optimal height of 2000 – 2500m for 3 – 4 weeks for LHTH, while under models adopting a train low component (LHTL), optimal adaptation height should range between 2500 – 3000m for 3 – 4 weeks (>12 h·day-1). 12 h·day-1). 2) Systematic review and meta-analysis: 24 studies were included in the final analysis. Improvements in tHbmass, HCT and lactate were found. For hemoglobin mass, a small increase was found following altitude training (g = 0.23; 95% CI = 0.09 to 0.36; P P = 0.07). Finally, in relation to lactate, following altitude training, athletes produced moderately more favourable lactate responses to exercise than control (g = 0.55; 95% CI = -0.01 to 1.10; P = 0.05). Despite moderate improvements in some physiological markers (tHbmass, HCT and lactate), results did not demonstrate enhanced exercise performance improvements (TT: g = 0.12; 95% CI = -0.13 to 0.37; P = 0.35; Oxygen consumption: g = 0.13; 95% CI = -0.08 to 0.35; P = 0.22; PPO: g = 0.09; 95% CI = -0.13 to 0.32; P = 0.42). Conclusion Improvements in tHbmass, HCT and lactate were found. Altitude training modalities (LHTL and LHTH) should be used by well-trained and elite athletes to enhance physiological adaptations. However, the degree to which these physiological markers improve performance outcomes needs further investigation. The moderate number of studies examined within the current meta-analysis limits the confidence of these findings, and it is likely this training modality has a broader effect on physiology and hence performance than this

CMB-S4 Decadal Survey APC White Paper

We provide an overview of the science case, instrument configuration and project plan for the next-generation ground-based cosmic microwave background experiment CMB-S4, for consideration by the 2020 Decadal Survey

CMB-S4 Science Case, Reference Design, and Project Plan

We present the science case, reference design, and project plan for the Stage-4 ground-based cosmic microwave background experiment CMB-S4

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score.

BACKGROUND Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. METHODS We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. FINDINGS 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). INTERPRETATION We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. FUNDING UK Medical Research Council and University of Milan-Bicocca

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score.

BACKGROUND: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. METHODS: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. FINDINGS: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). INTERPRETATION: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. FUNDING: UK Medical Research Council and University of Milan-Bicocca

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score

Background: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p&lt;0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p&lt;0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p&lt;0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p&lt;0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79–0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=–0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). Interpretation: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. Funding: UK Medical Research Council and University of Milan-Bicocca

CMB-S4 Decadal Survey APC White Paper

International audienceWe provide an overview of the science case, instrument configuration and project plan for the next-generation ground-based cosmic microwave background experiment CMB-S4, for consideration by the 2020 Decadal Survey

CMB-S4 Science Case, Reference Design, and Project Plan

We present the science case, reference design, and project plan for the Stage-4 ground-based cosmic microwave background experiment CMB-S4

CMB-S4 decadal survey APC white paper

We provide an overview of the science case, instrument configuration and project plan for the next-generation ground-based cosmic microwave background experiment CMB-S4, for consideration by the 2020 Decadal Survey