Updated protocol and guest participant results from the ACCeRT clinical study

Introduction Cancer cachexia is a condition often seen at diagnosis, throughout chemotherapeutic treatments and in end stage Non-Small Cell Lung Cancer patients. These patients often experience a shorter life-expectancy and deterioration in performance status and reduced quality of life. New multi˗targeted regimens are required to be tested in this population to address these issues. Materials and methods The ACCeRT study is an open label, prospective, randomised controlled feasibility study investigating the use of eicosapentaenoic acid and COX-2 inhibitor (celecoxib) versus eicosapentaenoic acid, COX-2 inhibitor (celecoxib), progressive resistance training followed by ingestion of essential amino acids high in leucine in Non-Small Cell Lung Cancer cachectic patients. The study protocol was published in November 2011. Due to study participants and study team preferences a number of changes were made. Firstly, a change from a bolus drink containing 20 g of essential amino acids to an encapsulated form in divided doses over three days. Secondly, a change in leg strength analysis from utilising a leg/back dynamometry to a customised chair with a load cell testing extension isometric force. Thirdly, study drug dose reductions were now permitted. Fourthly, addition of two study sites which allowed participants to attend progressive resistance training sessions in their local area. Finally, a change in inclusion criteria to include participants that had received any first-line anti-cancer treatment. A guest participant was invited onto the study in April 2012, followed by the first study participant in June 2012. Results The guest participant showed trends in efficacy in a number of outcomes; stable fat free mass in the context of decreasing total body weight, with stable FAACT˗PWB, MFSI-SF physical, and WHOQOL-BREF QOL scores at week 20, all during documented disease progression now termed refractory cachexia. There were no treatment or exercise-related adverse events. Conclusion Publishing feasibility study protocols allows transparency in study interventions and assessments. The above ACCeRT regimen stabilised fat free mass and a number of physical/performance indicators and QOL in the guest participant

A multi-targeted treatment approch to cancer cachexia: Auckland's Cancer Cachexia evaluating Resistance Training (ACCeRT) trial

Abstract Background Cancer cachexia is a condition often seen at diagnosis, throughout anti-cancer treatments and in end-stage nonsmall- cell lung cancer patients. Methods and results Participants with late-stage non-small-cell lung cancer and cachexia (defined as ≥5% weight loss within 12 months) were randomly assigned 1:2 to 2.09 g of eicosapentaenoic acid (EPA) and 300 mg of cyclo-oxygenase-2 inhibitor celecoxib orally once daily vs. same dosing of EPA, celecoxib, plus two sessions per week of progressive resistance training and 20 g of oral essential amino acids high in leucine in a split dose over 3 days, after each session. Primary endpoint was the acceptability of the earlier multi-targeted approach. Main secondary endpoints included change in body weight and fat-free mass, by bioelectric impedance analysis and total quadriceps muscle volume by magnetic resonance imaging over 20 weeks. Sixty-nine patients were screened resulting in 20 patients being enrolled. Acceptability scored high, with 4.5/5 (Arm A) and 5/5 (Arm B) for EPA and 5/5 for celecoxib within both arms and 4.8/5 for progressive resistance training sessions and 4.5/5 for essential amino acids within Arm B, all at Week 20. Results showed a net gain in bioelectric impedance analysis fat-free mass of +1.3 kg, n = 2 (Arm A), compared with +0.7 kg, n = 7 (Arm B) at Week 12, and —1.5 kg, n = 2 (Arm A), compared with —1.7 kg, n = 4 (Arm B) at Week 20. Trends in efficacy in terms of improvement and/or stability in cachexia markers were seen within magnetic resonance imaging muscle volume, albumin, and C-reactive protein levels within both arms. There were no exercise-related adverse events, with one possible related adverse event of asymptomatic atrial fibrillation in one participant within Arm A. Conclusions Non-small-cell lung cancer cachectic patients are willing to be enrolled onto a multi-targeted treatment regimen and may benefit from cachexia symptom management even during the late/refractory stage

IL32 downregulation lowers triglycerides and type I collagen in di-lineage human primary liver organoids

Steatotic liver disease (SLD) prevails as the most common chronic liver disease yet lack approved treatments due to incomplete understanding of pathogenesis. Recently, elevated hepatic and circulating interleukin 32 (IL -32) levels were found in individuals with severe SLD. However, the mechanistic link between IL -32 and intracellular triglyceride metabolism remains to be elucidated. We demonstrate in vitro that incubation with IL -32b protein leads to an increase in intracellular triglyceride synthesis, while downregulation of IL32 by small interfering RNA leads to lower triglyceride synthesis and secretion in organoids from human primary hepatocytes. This reduction requires the upregulation of Phospholipase A2 group IIA (PLA2G2A). Furthermore, downregulation of IL32 results in lower intracellular type I collagen levels in di -lineage human primary hepatic organoids. Finally, we identify a genetic variant of IL32 (rs76580947) associated with lower circulating IL -32 and protection against SLD measured by non-invasive tests. These data suggest that IL32 downregulation may be beneficial against SLD

An expanded evaluation of protein function prediction methods shows an improvement in accuracy

Background: A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. Results: We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. Conclusions: The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent. Keywords: Protein function prediction, Disease gene prioritizationpublishedVersio

An Expanded Evaluation of Protein Function Prediction Methods Shows an Improvement In Accuracy

Background: A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. Results: We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. Conclusions: The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Acceptability, Compliance, and Safety of Non-small Cell Lung Cancer Cachectic Participants Continuing Compassionate Access in the ACCeRT Clinical Study

Objective: Cancer cachexia is defined as: a ‘multifactorial syndrome’, and it has been suggested that a multitargeted approach is required in its management. High prevalence is seen within non-small cell lung cancer, and patients may continue to experience cachexia post end of anti-cancer treatment, and in the late/end stage. Material and Methods: Participants who had completed week 20/End of Trial visit in the main Auckland’s Cancer Cachexia evaluating Resistance Training (ACCeRT) study were invited to continue with treatment under compassionate use. Participants could continue with 2.09 g of eicosapentaenoic acid (EPA), 300 mg COX-2 inhibitor (celecoxib), once daily; plus two sessions per week of progressive resistance training (PRT), and 20 g oral essential amino acids (EAA); high in leucine, in a split dose over three days post each session. Data was collected on the acceptability, compliance and adherence to medication/PRT sessions. Secondary endpoints included: change in body weight and fat free mass, handgrip and leg strength, the Functional Assessment of Anorexia/Cachexia Therapy, Multidimensional Fatigue Symptom Inventory-Short Form, World Health Organization Quality of Life — BREF, Glasgow prognostic score, and pro-inflammatory cytokines. Results: All six participants, who completed the main ACCeRT study, opted to continue with compassionate use. Acceptability remained high, with overall compliance to last study/PRT visit of 81.0% for EPA, 98.8% for celecoxib, 78.9% for PRT and 77.2% for EAA. Participants continued to lose body weight and Fat-Free Mass, along with reduced albumin and increased C-Reactive protein levels. Mean time on compassionate study treatment was 78 days, and with a mean overall survival of 257 days (140 + 117). Conclusion: Non-small cell lung cancer (NSCLC) cachectic patients are willing to be enrolled onto a multi-targeted treatment regimen, and may benefit from cachexia symptom management even during their late/refractory stage