Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis.

BACKGROUND: Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels. METHODS: In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, -0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25. RESULTS: A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-D ClinicalTrials.gov number, NCT02879305.).

Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis.

BACKGROUND: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS: In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.).

A practical guide to the appropriate analysis of eGFR data over time: A simulation study.

In several therapeutic areas, including chronic kidney disease (CKD) and immunoglobulin A nephropathy (IgAN), there is a growing interest in how best to analyze estimated glomerular filtration rate (eGFR) data over time in randomized clinical trials including how to best accommodate situations where the rate of change is not anticipated to be linear over time, often due to possible short term hemodynamic effects of certain classes of interventions. In such situations, concerns have been expressed by regulatory authorities that the common application of single slope analysis models may induce Type I error inflation. This article aims to offer practical advice and guidance, including SAS codes, on the statistical methodology to be employed in an eGFR rate of change analysis and offers guidance on trial design considerations for eGFR endpoints. A two-slope statistical model for eGFR data over time is proposed allowing for an analysis to simultaneously evaluate short term acute effects and long term chronic effects. A simulation study was conducted under a range of credible null and alternative hypotheses to evaluate the performance of the two-slope model in comparison to commonly used single slope random coefficients models as well as to non-slope based analyses of change from baseline or time normalized area under the curve (TAUC). Importantly, and contrary to preexisting concerns, these simulations demonstrate the absence of alpha inflation associated with the use of single or two-slope random coefficient models, even when such models are misspecified, and highlight that any concern regarding model misspecification relates to power and not to lack of Type I error control.

Conditional power and information fraction calculations at an interim analysis for random coefficient models.

Random coefficient (RC) models are commonly used in clinical trials to estimate the rate of change over time in longitudinal data. Trials utilizing a surrogate endpoint for accelerated approval with a confirmatory longitudinal endpoint to show clinical benefit is a strategy implemented across various therapeutic areas, including immunoglobulin A nephropathy. Understanding conditional power (CP) and information fraction calculations of RC models may help in the design of clinical trials as well as provide support for the confirmatory endpoint at the time of accelerated approval. This paper provides calculation methods, with practical examples, for determining CP at an interim analysis for a RC model with longitudinal data, such as estimated glomerular filtration rate (eGFR) assessments to measure rate of change in eGFR slope.

Theory of Mind and Social Informant Discrepancy in Autism.

When autistic youth are asked to assess their own social skills, they frequently rate themselves more favorably than their parents rate them. The magnitude of this informant discrepancy has been shown to relate to key clinical outcomes such as treatment response. It has been proposed that this discrepancy arises from difficulties with Theory of Mind. Participants were 167 youth 11 to 17 years old; 72% male, and their parents. Youth completed self-report measures of social skills and social cognitive tasks, while their parents completed questionnaires regarding social skills. A repeated-measures ANOVA indicated both non-autistic and autistic youth rated themselves more favorably than their parents rated them across all measures. Zero-order correlations revealed that raw differences between parent- and participant-report were negatively correlated with scores on parent-reported Theory of Mind measures. However, polynomial analysis did not indicate interaction effects between parent- and participant-report on any of the measures used. Polynomial regression revealed that increases in parent-reported social skill predicted larger increases in parent-report Theory of Mind at low levels of parent-reported social skill compared to high levels of parent-reported social skill. Participant-report social skills predicted performance on a behavioral Theory of Mind test in a curvilinear fashion, such that the relationship was positive at low levels of participant-reported social skills, but negative at high levels. This study replicates the finding that raw difference score analyses may result in illusory effects that are not supported when using more contemporary analysis methods, and that more complex and subtle relationships between social insight and perspective-taking exist within autistic youth.

Combined Accentuated Eccentric Loading and Rest Redistribution in High-Volume Back Squat: Acute Kinetics and Kinematics.

ABSTRACT: Chae, S, Long, SA, Lis, RP, McDowell, KW, Wagle, JP, Carroll, KM, Mizuguchi, S, and Stone, MH. Combined accentuated eccentric loading and rest redistribution in high-volume back squat: Acute kinetics and kinematics. J Strength Cond Res 38(4): 640-647, 2024-The purpose of this study was to explore acute kinetic and kinematic responses to combined accentuated eccentric loading and rest redistribution (AEL + RR). Resistance-trained men ( n = 12, 25.6 ± 4.4 years, 1.77 ± 0.06 m, and 81.7 ± 11.4 kg) completed a back squat (BS) 1 repetition maximum (1RM) and weight releaser familiarization session. Three BS exercise conditions (sets × repetitions × eccentric/concentric loading) consisted of (a) 3 × (5 × 2) × 110/60% (AEL + RR 5), (b) 3 × (2 × 5) × 110/60% (AEL + RR 2), and (c) 3 × 10 × 60/60% 1RM (traditional sets [TS]). Weight releasers (50% 1RM) were attached to every first repetition of each cluster set (every first, third, fifth, seventh, and ninth repetition in AEL + RR 5 and every first and sixth repetition in AEL + RR 2). The AEL + RR 5 resulted in significantly ( p < 0.05) greater concentric peak velocity (PV) (1.18 ± 0.17 m·s -1 ) and peak power (PP) (2,304 ± 499 W) compared with AEL + RR 2 (1.11 ± 0.19 m·s -1 and 2,148 ± 512 W) and TS (1.10 ± 0.14 m·s -1 and 2,079 ± 388 W). Furthermore, AEL + RR 5 resulted in significantly greater PV and PP across all 10 repetitions compared with TS. Although AEL + RR 5 resulted in significantly greater concentric mean force (MF) (1,706 ± 224 N) compared with AEL + RR 2 (1,697 ± 209 N) and TS (1,685 ± 211 N), no condition by set or repetition interactions existed. In conclusion, AEL + RR 5 increases PV and PP but has little effect on MF. Coaches might consider prescribing AEL + RR 5 to increase especially peak aspects of velocity and power outcomes.

Combined Accentuated Eccentric Loading and Rest Redistribution in High-Volume Back Squat: Acute Stimulus and Fatigue.

ABSTRACT: Chae, S, Long, SA, Lis, RP, McDowell, KW, Wagle, JP, Carroll, KM, Mizuguchi, S, and Stone, MH. Combined accentuated eccentric loading and rest redistribution in high-volume back squat: Acute stimulus and fatigue. J Strength Cond Res 38(4): 648-655, 2024-The purpose of this study was to examine acute stimulus and fatigue responses to combined accentuated eccentric loading and rest redistribution (AEL + RR). Resistance-trained men ( n = 12, 25.6 ± 4.4 years, 1.77 ± 0.06 m, and 81.7 ± 11.4 kg) completed a back squat (BS) 1 repetition maximum (1RM) and weight releaser familiarization session. Three BS exercise conditions (sets × repetitions × eccentric-concentric loading) consisted of (a) 3 × (5 × 2) × 110/60% (AEL + RR 5), (b) 3 × (2 × 5) × 110/60% (AEL + RR 2), and (c) 3 × 10 × 60/60% 1RM (traditional sets [TS]). Weight releasers (50% 1RM) were attached to every first repetition of each cluster set (every first, third, fifth, seventh, and ninth repetition in AEL + RR 5 and every first and sixth repetition in AEL + RR 2). The AEL + RR 5 resulted in greater total volume load (sets × repetitions × eccentric + concentric loading) (6,630 ± 1,210 kg) when compared with AEL + RR 2 (5,944 ± 1,085 kg) and TS (5,487 ± 1,002 kg). In addition, AEL + RR 5 led to significantly ( p < 0.05) greater rating of perceived exertion (RPE) after set 2 and set 3 and lower blood lactate (BL) after set 3 and 5, 15, and 25 minutes postexercise than AEL + RR 2 and TS. There was a main effect of condition for BL between AEL + RR 5 (5.11 ± 2.90 mmol·L -1 ), AEL + RR 2 (6.23 ± 3.22 mmol·L -1 ), and TS (6.15 ± 3.17 mmol·L -1 ). In summary, AEL + RR 5 results in unique stimulus and fatigue responses. Although it may increase perceived exertion, coaches could use AEL + RR 5 to achieve greater back squat total volume load while reducing BL accumulation.

Epigenetic Regulation of Cancer Immune Cells.

The epigenetic regulation of immune response involves reversible and heritable changes that do not alter the DNA sequence. Though there have been extensive studies accomplished relating to epigenetic changes in cancer cells, recent focus has been shifted on epigenetic-mediated changes in the immune cells including T cells, Macrophages, Natural Killer cells and anti-tumor immune responses. This review compiles the most relevant and recent literature related to the role of epigenetic mechanisms including DNA methylation and histone modifications in immune cells of wide range of cancers. We also include recent research with respect to role of the most relevant transcription factors that epigenetically control the anti-tumor immune response. Finally, a statement of future direction that promises to look forward for strategies to improve immunotherapy in cancer.

Nanoliposome C6-Ceramide in combination with anti-CTLA4 antibody improves anti-tumor immunity in hepatocellular cancer.

Combination therapy represents an effective therapeutic approach to overcome hepatocellular cancer (HCC) resistance to immune checkpoint blockade (ICB). Based upon previous work demonstrating that nanoliposome C6-ceramide (LipC6) not only induces HCC apoptosis but also prevents HCC-induced immune tolerance, we now investigate the potential of LipC6 in combination with ICB in HCC treatment. We generated orthotopic HCC-bearing mice, which have typical features in common with human patients, and then treated them with LipC6 in combination with the antibodies (Abs) for programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte antigen 4 (CTLA4). The tumor growth was monitored by magnetic resonance imaging (MRI) and the intrahepatic immune profiles were checked by flow cytometry in response to the treatments. Realtime PCR (qPCR) was used to detect the expression of target genes. The results show that LipC6 in combination with anti-CTLA4 Ab, but not anti-PD-1 Ab, significantly slowed tumor growth, enhanced tumor-infiltrating CD8+ T cells, and suppressed tumor-resident CD4+ CD25+ FoxP3+ Tregs. Further molecular investigation indicates that the combinational treatment suppressed transcriptional factor Krüppel-like Factor 2 (KLF2), forkhead box protein P3 (FoxP3), and CTLA4. Our studies suggest that LipC6 in combination with anti-CTLA4 Ab represents a novel therapeutic approach with significant potential in activating anti-HCC immune response and suppressing HCC growth.

Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents-post hoc analyses of the ASCEND-ND and ASCEND-D trials.

BACKGROUND: The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305). METHODS: ASCEND-ND randomized 3872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2964 patients to daprodustat or conventional erythropoiesis-stimulating agents (ESAs). In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks). The prespecified on-treatment approach examined relative risks for cancer AEs up to the last dose date + 1 day. In these analyses, owing to different dosing intervals between arms, Cox models were used to estimate the daprodustat effect by various follow-up periods (censoring at last dose date, last dose date + dosing intervals, or end of study). RESULTS: In ASCEND-ND, the safety of daprodustat vs darbepoetin on cancer-related AEs depended on the duration of follow-up after last dose date: hazard ratio (HR) 1.04 [95% confidence interval (CI) 0.77, 1.40] at end of study [HR 1.12 (95% CI 0.81, 1.56) for last dose date + dosing interval; HR 1.50 (95% CI 1.04, 2.15) for last dose date + 1 day]. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined. CONCLUSIONS: Prespecified on-treatment analyses for cancer-related AEs appeared to result in biased risk estimates in ASCEND-ND by preferentially under-counting events from patients assigned to darbepoetin. Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat. TRIAL REGISTRATION: The ASCEND-ND trial is registered with ClinicalTrials.gov (NCT02876835); the ASCEND-D trial is registered with ClinicalTrials.gov (NCT02879305).

Two Days Versus Four Days of Training Cessation Following a Step-Taper in Powerlifters.

ABSTRACT: Burke, BI, Carroll, KM, Travis, SK, Stone, ME, and Stone, MH. Two days versus four days of training cessation following a step-taper in powerlifters. J Strength Cond Res 37(12): e625-e632, 2023-Tapering and training cessation are methods of training load management aimed at optimizing athlete preparedness leading into competition. Such practices are often used by strength sport athletes such as powerlifters (i.e., athletes who compete in the back squat [BS], bench press [BP], and deadlift [DL]). The purpose of this study was to compare the differences in maximal strength, subjective recovery and stress state, and body composition alterations in strength athletes undergoing a 1-week step-taper followed by either a 2-day (2D) or 4-day (4D) period of training cessation. Twelve powerlifters (22.3 ± 2.1 yrs; 92.1 ± 20.4 kg; 174.8 ± 7.5 cm) completed a 6-week training protocol aimed at peaking 1 repetition maximum (1RM) strength on BS, BP, and DL. Body composition, subjective recovery and stress state, and 1RM on BS, BP, and DL were assessed before an overreach week (T1) and after the periods of training cessation (T2) for each group. Alpha criterion was set at p ≤ 0.05. There were significant increases in BP ( p = 0.032, g = 0.10), powerlifting total ( p = 0.014, g = 0.11), and DOTS score ( p = 0.006, g = 0.12) after 2D of cessation. However, after 4D of cessation, significant increases were only observed in DL ( p = 0.019, g = 0.11) along with significant decreases in BP ( p = 0.003, g = -0.13). There were no statistically significant changes in any other variable for either group indicating that BS, psychometric, and body composition data were maintained between T1 and T2. The results of this study support the use of 1-week step-tapers, followed by a short period of training cessation (2-4D) to maintain or improve maximal strength performance.

Tumorigenic circulating tumor cells from xenograft mouse models of non-metastatic NSCLC patients reveal distinct single cell heterogeneity and drug responses.

BACKGROUND: Circulating tumor cells (CTCs) are liquid biopsies that represent micrometastatic disease and may offer unique insights into future recurrences in non-small cell lung cancer (NSCLC). Due to CTC rarity and limited stability, no stable CTC-derived xenograft (CDX) models have ever been generated from non-metastatic NSCLC patients directly. Alternative strategies are needed to molecularly characterize CTCs and means of potential future metastases in this potentially curable patient group. METHODS: Surgically resected NSCLC primary tumor tissues from non-metastatic patients were implanted subcutaneously in immunodeficient mice to establish primary tumor patient-derived xenograft (ptPDX) models. CTCs were isolated as liquid biopsies from the blood of ptPDX mice and re-implanted subcutaneously into naïve immunodeficient mice to generate liquid biopsy CTC-derived xenograft (CDX) tumor models. Single cell RNA sequencing was performed and validated in an external dataset of non-xenografted human NSCLC primary tumor and metastases tissues. Drug response testing in CDX models was performed with standard of care chemotherapy (carboplatin/paclitaxel). Blockade of MYC, which has a known role in drug resistance, was performed with a MYC/MAX dimerization inhibitor (10058-F4). RESULTS: Out of ten ptPDX, two (20%) stable liquid biopsy CDX mouse models were generated. Single cell RNA sequencing analysis revealed an additional regenerative alveolar epithelial type II (AT2)-like cell population in CDX tumors that was also identified in non-xenografted NSCLC patients' metastases tissues. Drug testing using these CDX models revealed different treatment responses to carboplatin/paclitaxel. MYC target genes and c-MYC protein were upregulated in the chemoresistant CDX model, while MYC/MAX dimerization blocking could overcome chemoresistance to carboplatin/paclitaxel. CONCLUSIONS: To overcome the lack of liquid biopsy CDX models from non-metastatic NSCLC patients, CDX models can be generated with CTCs from ptPDX models that were originally established from patients' primary tumors. Single cell analyses can identify distinct drug responses and cell heterogeneities in CDX tumors that can be validated in NSCLC metastases tissues. CDX models deserve further development and study to discover personalized strategies against micrometastases in non-metastatic NSCLC patients.

Single Circulating-Tumor-Cell-Targeted Sequencing to Identify Somatic Variants in Liquid Biopsies in Non-Small-Cell Lung Cancer Patients.

Non-small-cell lung cancer (NSCLC) accounts for most cancer-related deaths worldwide. Liquid biopsy by a blood draw to detect circulating tumor cells (CTCs) is a tool for molecular profiling of cancer using single-cell and next-generation sequencing (NGS) technologies. The aim of the study was to identify somatic variants in single CTCs isolated from NSCLC patients by targeted NGS. Thirty-one subjects (20 NSCLC patients, 11 smokers without cancer) were enrolled for blood draws (7.5 mL). CTCs were identified by immunofluorescence, individually retrieved, and DNA-extracted. Targeted NGS was performed to detect somatic variants (single-nucleotide variants (SNVs) and insertions/deletions (Indels)) across 65 oncogenes and tumor suppressor genes. Cancer-associated variants were classified using OncoKB database. NSCLC patients had significantly higher CTC counts than control smokers (p = 0.0132; Mann-Whitney test). Analyzing 23 CTCs and 13 white blood cells across seven patients revealed a total of 644 somatic variants that occurred in all CTCs within the same subject, ranging from 1 to 137 per patient. The highest number of variants detected in ≥1 CTC within a patient was 441. A total of 18/65 (27.7%) genes were highly mutated. Mutations with oncogenic impact were identified in functional domains of seven oncogenes/tumor suppressor genes (NF1, PTCH1, TP53, SMARCB1, SMAD4, KRAS, and ERBB2). Single CTC-targeted NGS detects heterogeneous and shared mutational signatures within and between NSCLC patients. CTC single-cell genomics have potential for integration in NSCLC precision oncology.

Study design and baseline characteristics of patients on dialysis in the ASCEND-D trial.

BACKGROUND: The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is noninferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: hemoglobin (Hb) efficacy and cardiovascular (CV) safety. METHODS: We report the trial design, key demographic, clinical and laboratory findings, and baseline therapies of 2964 patients randomized in the open-label (sponsor-blinded) active-controlled, parallel-group, randomized ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large CV outcome trials (CVOTs) and in the most relevant registries. RESULTS: The median age of patients was 58 years, 43% were female; 67% were White and 16% were Black. The median Hb at baseline was 10.4 g/dL. Among randomized patients, 89% were receiving hemodialysis and 11% peritoneal dialysis. Among key comorbidities, 42% reported a history of diabetes mellitus and 45% a history of CV disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron uses were noted in 64 and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries. CONCLUSIONS: ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anemia with CKD G5D.This trial is registered with ClinicalTrials.gov: NCT02879305. EudraCT Number: 2016-000541-31; Sponsor Protocol Number: 200807.

The ASCEND-ND trial: study design and participant characteristics.

BACKGROUND: Anaemia is common in chronic kidney disease (CKD) and assessment of the risks and benefits of new therapies is important. METHODS: The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3-5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8-10 g/dL or receiving ESAs with screening Hb of 8-12 g/dL. Participants were randomized to daprodustat or darbepoetin alfa (1:1) in an open-label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28-52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials. RESULTS: Overall, 3872 patients were randomized from 39 countries (median age 67 years, 56% female, 56% White, 27% Asian and 10% Black). The median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and estimated glomerular filtration rate was 18 mL/min/1.73 m2. Among randomized patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin-angiotensin system blockers, 55% were taking statins and 49% were taking oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials. CONCLUSION: ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis.

Utility of a Shortened Isometric Midthigh Pull Protocol for Assessing Rapid Force Production in Athletes.

ABSTRACT: Suarez, DG, Carroll, KM, Slaton, JA, Rochau, KG, Davis, MW, and Stone, MH. Utility of a shortened isometric midthigh pull protocol for assessing rapid force production in athletes. J Strength Cond Res 36(7): 1819-1825, 2022-The purpose of this investigation was to determine the magnitude of difference, reliability, and relationship to performance of a shortened isometric midthigh pull (IMTP) protocol. Fourteen strength-trained men (age: 26.8 ± 5.0 years, height: 176.3 ± 6.9 cm, body mass: 86.8 ± 13.9 kg, and training age: 8.5 ± 6.9 years) performed 1-second (SHORT) and traditional (TRAD) IMTP protocols during consecutive weeks. Peak force (PF), instantaneous force (90 & 200 ms), rate of force development (RFD) (0-90 ms & 0-200 ms), and impulse (0-90 ms & 0-200 ms) from each protocol were collected. Paired samples t test and Hedge's g were calculated to determine the magnitude of difference in each variable between protocols. Within-session and between-session reliability was assessed with intraclass correlation coefficient, coefficient of variation, and 95% confidence intervals. Static jumps were performed to compare relationships of the IMTP variables from each protocol with jumping performance. There was no statistically significant (p > 0.05) difference in PF between the protocols (p = 0.345; g = -0.07). All early force-time variables were significantly higher in the SHORT protocol (p = <0.001-0.018; g = 0.38-0.79). The SHORT protocol resulted in more reliable RFD measures within-session. Correlations with jumping performance were mostly similar between protocols (r = 0.253-0.660). The SHORT IMTP protocol resulted in comparable PF values and considerably higher early force-time characteristics despite a restrained time to produce force and shorter rest. The SHORT protocol allows for an accurate assessment of rapid force-generating abilities while necessitating shorter collection periods than typical IMTP protocols.

Subsequent urinary stone events are predicted by the magnitude of urinary oxalate excretion in enteric hyperoxaluria.

Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone events in those with enteric hyperoxaluria (EH) are limited. Therefore, we assessed the relationship between UOx excretion and risk of kidney stone events in a retrospective population-based EH cohort. In all, 297 patients from Olmsted County, Minnesota were identified with EH based upon having a 24-h UOx ≥40 mg/24 h preceded by a diagnosis or procedure associated with malabsorption. Diagnostic codes and urologic procedures consistent with kidney stones during follow-up after baseline UOx were considered a new stone event. Logistic regression and accelerated failure time modeling were performed as a function of UOx excretion to predict the probability of new stone event and the annual rate of stone events, respectively, with adjustment for urine calcium and citrate. Mean ± standard deviation age was 51.4 ± 11.4 years and 68% were female. Median (interquartile range) UOx was 55.4 (46.6-73.0) mg/24 h and 81 patients had one or more stone event during a median follow-up time of 4.9 (2.8-7.8) years. Higher UOx was associated with a higher probability of developing a stone event (P < 0.01) and predicted an increased annual risk of kidney stones (P = 0.001). Estimates derived from these analyses suggest that a 20% decrease in UOx is associated with 25% reduction in the annual odds of a future stone event. Thus, these data demonstrate an association between baseline UOx and stone events in EH patients and highlight the potential benefit of strategies to reduce UOx in this patient group. BACKGROUND: Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone events in those with enteric hyperoxaluria (EH) are limited. METHODS: We assessed the relationship between UOx excretion and risk of kidney stone events in a retrospective population-based EH cohort. In all, 297 patients from Olmsted County, Minnesota were identified with EH based upon having a 24-h UOx ≥40 mg/24 h preceded by a diagnosis or procedure associated with malabsorption. Diagnostic codes and urologic procedures consistent with kidney stones during follow-up after baseline UOx were considered a new stone event. Logistic regression and accelerated failure time modeling were performed as a function of UOx excretion to predict the probability of new stone event and the annual rate of stone events, respectively, with adjustment for urine calcium and citrate. RESULTS: Mean ± SD age was 51.4 ± 11.4 years and 68% were female. Median (interquartile range) UOx was 55.4 (46.6-73.0) mg/24 h and 81 patients had ≥1 stone event during a median follow-up time of 4.9 (2.8-7.8) years. Higher UOx was associated with a higher probability of developing a stone event (P < 0.01) and predicted an increased annual risk of kidney stones (P = 0.001). Estimates derived from these analyses suggest that a 20% decrease in UOx is associated with 25% reduction in the annual odds of a future stone event. CONCLUSIONS: These data demonstrate an association between baseline UOx and stone events in EH patients and highlight the potential benefit of strategies to reduce UOx in this patient group.

Development and evaluation of an outbreak surveillance system integrating whole genome sequencing data for non-typhoidal Salmonella in London and South East of England, 2016-17.

An outbreak surveillance system for Salmonella integrating whole genome sequencing (WGS) and epidemiological data was developed in South East and London in 2016-17 to assess local WGS clusters for triage and investigation. Cases genetically linked within a 5 single-nucleotide polymorphism (SNP) single linkage cluster were assessed using a set of locally agreed thresholds based on time, person and place, for reporting to local health protection teams (HPTs). Between September 2016 and September 2017, 230 unique 5-SNP clusters (442 weekly reports) of non-typhoidal Salmonella 5-SNP WGS clusters were identified, of which 208 unique 5-SNP clusters (316 weekly reports) were not reported to the HPTs. In the remaining 22 unique clusters (126 weekly clusters) reported to HPTs, nine were known active outbreak investigations, seven were below locally agreed thresholds and six exceeded local thresholds. A common source or vehicle was identified in four of six clusters that exceeded locally agreed thresholds. This work demonstrates that a threshold-based surveillance system, taking into account time, place and genetic relatedness, is feasible and effective in directing the use of local public health resources for risk assessment and investigation of non-typhoidal Salmonella clusters.

Astaxanthin Prevents Diet-Induced NASH Progression by Shaping Intrahepatic Immunity.

Dietary change leads to a precipitous increase in non-alcoholic fatty liver disease (NAFLD) from simple steatosis to the advanced form of non-alcoholic steatohepatitis (NASH), affecting approximately 25% of the global population. Although significant efforts greatly advance progress in clarifying the pathogenesis of NAFLD and identifying therapeutic targets, no therapeutic agent has been approved. Astaxanthin (ASTN), a natural antioxidant product, exerts an anti-inflammation and anti-fibrotic effect in mice induced with carbon tetrachloride (CCl4) and bile duct ligation (BDL); thus, we proposed to further investigate the potential effect of ASTN on a diet-induced mouse NASH and liver fibrosis, as well as the underlying cellular and molecular mechanisms. By treating pre-development of NASH in mice induced with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), we have demonstrated that oral administration ASTN preventively ameliorated NASH development and liver fibrosis by modulating the hepatic immune response, liver inflammation, and oxidative stress. Specifically, ASTN treatment led to the reduction in liver infiltration of monocyte-derived macrophages, hepatic stellate cell (HSC) activation, oxidative stress response, and hepatocyte death, accompanied by the decreased hepatic gene expression of proinflammatory cytokines such as TNF-α, TGF-ß1, and IL-1ß. In vitro studies also demonstrated that ASTN significantly inhibited the expression of proinflammatory cytokines and chemokine CCL2 in macrophages in response to lipopolysaccharide (LPS) stimulation. Overall, in vivo and in vitro studies suggest that ASTN functions as a promising therapeutic agent to suppress NASH and liver fibrosis via modulating intrahepatic immunity.

Accentuated Eccentric Loading and Cluster Set Configurations in the Back Squat: A Kinetic and Kinematic Analysis.

ABSTRACT: Wagle, JP, Cunanan, AJ, Carroll, KM, Sams, ML, Wetmore, A, Bingham, GE, Taber, CB, DeWeese, BH, Sato, K, Stuart, CA, and Stone, MH. Accentuated eccentric loading and cluster set configurations in the back squat: a kinetic and kinematic analysis. J Strength Cond Res 35(2): 420-427, 2021-This study examined the kinetic and kinematic differences between accentuated eccentric loading (AEL) and cluster sets in trained male subjects (age = 26.1 ± 4.1 years, height = 183.5 ± 4.3 cm, body mass = 92.5 ± 10.5 kg, and back squat to body mass ratio = 1.8 ± 0.3). Four load condition sessions consisted of traditionally loaded (TL) "straight sets," TL cluster (TLC) sets, AEL cluster (AEC) sets, and AEL "straight sets" where only the first repetition had eccentric overload (AEL1). An interrepetition rest interval of 30 seconds was prescribed for both TLC and AEC. Concentric intensity for all load conditions was 80% 1 repetition maximum (1RM). Accentuated eccentric loading was applied to repetitions using weight releasers with total eccentric load equivalent to 105% of concentric 1RM. Traditionally loaded cluster had statistically greater concentric outputs than TL. Furthermore, statistically greater eccentric and concentric outputs were observed during AEC compared with TL with the exception of peak power. Statistically greater concentric characteristics were observed in TLC compared with AEL1, but statistically greater eccentric outputs were observed in AEL1. In the 2 cluster set conditions, statistically greater concentric rate of force development (RFDCON) (d = 0.470, p < 0.001) and average velocity (vavg) (d = 0.560, p < 0.001) in TLC compared with AEC were observed. However, statistically greater eccentric work (WECC) (d = 2.096, p < 0.001) and eccentric RFD (RFDECC) (d = 0.424, p < 0.001) were observed in AEC compared with TLC. Overall, eccentric overload demonstrated efficacy as a means of increasing eccentric work and RFD, but not as a means of potentiating concentric output. Finally, interrepetition rest seems to have the largest influence on concentric power output and RFD.