A case-control study of the clinical and economic impact of infections caused by Carbapenemase-producing Enterobacterales (CPE).

PURPOSE: The aim was to analyse the clinical and economic impact of carbapenemase-producing Enterobacterales (CPE) infections. METHODS: Case-control study. Adult patients with CPE infections were considered cases, while those with non-CPE infections were controls. Matching criteria were age (± 5 years), sex, source of infection and microorganism (ratio 1:2). Primary outcome was 30-day mortality. Secondary outcomes were 90-day mortality, clinical failure, hospitalisation costs and resource consumption. RESULTS: 246 patients (82 cases and 164 controls) were included. Klebsiella pneumoniae OXA-48 was the most common microorganism causing CPE infections. CPE cases had more prior comorbidities (p = 0.007), septic shock (p = 0.003), and were more likely to receive inappropriate empirical and definitive antibiotic treatment (both p < 0.001). Multivariate analysis identified septic shock and inappropriate empirical treatment as independent predictors for 7-day and end-of-treatment clinical failure, whereas Charlson Index and septic shock were associated with 30- and 90-day mortality. CPE infection was independently associated with early clinical failure (OR 2.18, 95% CI, 1.03-4.59), but not with end-of-treatment clinical failure or 30- or 90-day mortality. In terms of resource consumption, hospitalisation costs for CPE were double those of the non-CPE group. CPE cases had longer hospital stay (p < 0.001), required more long-term care facilities (p < 0.001) and outpatient parenteral antibiotic therapy (p = 0.007). CONCLUSIONS: The CPE group was associated with worse clinical outcomes, but this was mainly due to a higher comorbidity burden, more severe illness, and more frequent inappropriate antibiotic treatment rather than resistance patterns as such. However, the CPE group consumed more healthcare resources and incurred higher costs.

Nursing students' attitude toward euthanasia following its legalization in Spain.

BACKGROUND: Euthanasia is a controversial practice in many countries. Since Spain's Euthanasia Law came into effect on March 24, 2021, healthcare providers have faced a new challenge since they must inform patients, provide care, accompany them, and implement the law. It also represents a new stumbling block at universities, which must adapt to regulatory changes and educate future professionals accordingly. Little is known about the attitude of nursing students in Spain toward euthanasia since this law was implemented. OBJECTIVE: This study aims to answer the following research questions: What is the attitude of nursing students toward euthanasia? What factors influence this attitude? RESEARCH DESIGN: A cross-sectional study was conducted using an online questionnaire. PARTICIPANTS AND RESEARCH CONTEXT: The study population comprised all nursing students at a public university in Barcelona (n = 444), Spain, during the 2022-2023 academic year. The validated Spanish version of the Euthanasia Attitude Scale was employed. A bivariate analysis was performed. ETHICAL CONSIDERATIONS: The university Ethics Committee (CEEAH 6247) approved this study. All participating students signed an informed consent form. Participation was voluntary, and data anonymity and confidentiality were guaranteed. RESULTS: Two hundred and forty-four nursing students responded to the questionnaire. The mean total score was 79.64. Participants with religious beliefs presented lower scores, indicating a more negative attitude toward euthanasia. Participants in their second, third, or fourth year of the nursing degree scored higher, demonstrating a more positive attitude. CONCLUSIONS: The attitude of nursing students toward euthanasia was remarkably positive. Working on ethical content during the degree course and clinical practice are factors that help to develop a more positive attitude. In addition, nursing education should encourage professional aspects to prevail over religious beliefs in euthanasia situations.

[The provision of assisted death in the context of the desire to anticipate death]. / La prestación de ayuda a morir en el contexto del deseo de anticipar la muerte.

The entry into force of the Organic Law on the Regulation of Euthanasia in June 2021 obliges clinicians to reconsider their professional work, in the face of a new service that expands the limits of what was considered correct until then. This new service affects the entire healthcare system, but especially primary care professionals. Beyond the procedural and moral aspects, it is necessary to rethink the assessment of the patient who expresses a wish to die. In this review, we start with the relatively recent definition of the wish to hasten death (WTHD), its causes, epidemiology and differential diagnosis. Then, we examine the different mental frameworks found in the process of dying and the concept of a «good death¼. Finally, we analyse the paths that can lead to the provision of aid in dying within the framework of current legislation. The WTHD is specific to requests in case of «serious and advanced illness¼, not in other cases contemplated by the Law. When faced with a request to activate the Aid in Dying Prestation in the context of WTHD (that is, in the proximity of death), it becomes necessary to increase the patient's sense of control and begin to work on grief. Besides, in the face of an administrative process that will necessarily be long, adapting the therapeutic efforts and sedation should be considered as possible options. We understand that it is essential not to create false expectations for patients/families and not to overload healthcare professionals with administrative tasks that will be futile. It is difficult to balance these in the face of a request for a right to which the patient should always have access.

Evaluation of OMOP CDM, i2b2 and ICGC ARGO for supporting data harmonization in a breast cancer use case of a multicentric European AI project.

OBJECTIVE: Observational research in cancer poses great challenges regarding adequate data sharing and consolidation based on a homogeneous data semantic base. Common Data Models (CDMs) can help consolidate health data repositories from different institutions minimizing loss of meaning by organizing data into a standard structure. This study aims to evaluate the performance of the Observational Medical Outcomes Partnership (OMOP) CDM, Informatics for Integrating Biology & the Bedside (i2b2) and International Cancer Genome Consortium, Accelerating Research in Genomic Oncology (ICGC ARGO) for representing non-imaging data in a breast cancer use case of EuCanImage. METHODS: We used ontologies to represent metamodels of OMOP, i2b2, and ICGC ARGO and variables used in a cancer use case of a European AI project. We selected four evaluation criteria for the CDMs adapted from previous research: content coverage, simplicity, integration, implementability. RESULTS: i2b2 and OMOP exhibited higher element completeness (100% each) than ICGC ARGO (58.1%), while the three achieved 100% domain completeness. ICGC ARGO normalizes only one of our variables with a standard terminology, while i2b2 and OMOP use standardized vocabularies for all of them. In terms of simplicity, ICGC ARGO and i2b2 proved to be simpler both in terms of ontological model (276 and 175 elements, respectively) and in the queries (7 and 20 lines of code, respectively), while OMOP required a much more complex ontological model (615 elements) and queries similar to those of i2b2 (20 lines). Regarding implementability, OMOP had the highest number of mentions in articles in PubMed (130) and Google Scholar (1,810), ICGC ARGO had the highest number of updates to the CDM since 2020 (4), and i2b2 is the model with more tools specifically developed for the CDM (26). CONCLUSION: ICGC ARGO proved to be rigid and very limited in the representation of oncologic concepts, while i2b2 and OMOP showed a very good performance. i2b2's lack of a common dictionary hinders its scalability, requiring sites that will share data to explicitly define a conceptual framework, and suggesting that OMOP and its Oncology extension could be the more suitable choice. Future research employing these CDMs with actual datasets is needed.

Attenuation of Tumor Burden in Response to Rucaparib in Lung Adenocarcinoma: The Contribution of Oxidative Stress, Apoptosis, and DNA Damage.

In cancer, overactivation of poly (ADPribose) polymerases (PARP) plays a relevant role in DNA repair. We hypothesized that treatment with the PARP inhibitor rucaparib may reduce tumor burden via several biological mechanisms (apoptosis and oxidative stress) in mice. In lung tumors (LP07 lung adenocarcinoma) of mice treated/non-treated (control animals) with PARP inhibitor (rucaparib,150 mg/kg body weight/24 h for 20 day), PARP activity and expression, DNA damage, apoptotic nuclei, cell proliferation, and redox balance were measured using immunoblotting and immunohistochemistry. In lung tumors of rucaparib-treated mice compared to non-treated animals, tumor burden, PARP activity, and cell proliferation decreased, while DNA damage, TUNEL-positive nuclei, protein oxidation, and superoxide dismutase content (SOD)2 increased. In this experiment on lung adenocarcinoma, the pharmacological PARP inhibitor rucaparib elicited a significant improvement in tumor size, probably through a reduction in cell proliferation as a result of a rise in DNA damage and apoptosis. Oxidative stress and SOD2 also increased in response to treatment with rucaparib within the tumor cells of the treated mice. These results put the line forward to the contribution of PARP inhibitors to reduced tumor burden in lung adenocarcinoma. The potential implications of these findings should be tested in clinical settings of patients with lung tumors.

Comparison of Hospitalized Coronavirus Disease 2019 and Influenza Patients Requiring Supplemental Oxygen in a Cohort Study: Clinical Impact and Resource Consumption.

BACKGROUND: To compare clinical characteristics, outcomes, and resource consumption of patients with coronavirus disease 2019 (COVID-19) and seasonal influenza requiring supplemental oxygen. METHODS: Retrospective cohort study conducted at a tertiary-care hospital. Patients admitted because of seasonal influenza between 2017 and 2019, or with COVID-19 between March and May 2020 requiring supplemental oxygen were compared. Primary outcome: 30-day mortality. Secondary outcomes: 90-day mortality and hospitalization costs. Attempted sample size to detect an 11% difference in mortality was 187 patients per group. RESULTS: COVID-19 cases were younger (median years of age, 67; interquartile range [IQR] 54-78 vs 76 [IQR 64-83]; P < .001) and more frequently overweight, whereas influenza cases had more hypertension, immunosuppression, and chronic heart, respiratory, and renal disease. Compared with influenza, COVID-19 cases had more pneumonia (98% vs 60%, <.001), higher Modified Early Warning Score (MEWS) and CURB-65 (confusion, blood urea nitrogen, respiratory rate, systolic blood pressure, and age >65 years) scores and were more likely to show worse progression on the World Health Organization ordinal scale (33% vs 4%; P < .001). The 30-day mortality rate was higher for COVID-19 than for influenza: 15% vs 5% (P = .001). The median age of nonsurviving cases was 81 (IQR 74-88) and 77.5 (IQR 65-84) (P = .385), respectively. COVID-19 was independently associated with 30-day (hazard ratio [HR], 4.6; 95% confidence interval [CI], 2-10.4) and 90-day (HR, 5.2; 95% CI, 2.4-11.4) mortality. Sensitivity and subgroup analyses, including a subgroup considering only patients with pneumonia, did not show different trends. Regarding resource consumption, COVID-19 patients had longer hospital stays and higher critical care, pharmacy, and complementary test costs. CONCLUSIONS: Although influenza patients were older and had more comorbidities, COVID-19 cases requiring supplemental oxygen on admission had worse clinical and economic outcomes.

Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency.

Opa1 participates in inner mitochondrial membrane fusion and cristae morphogenesis. Here, we show that muscle-specific Opa1 ablation causes reduced muscle fiber size, dysfunctional mitochondria, enhanced Fgf21, and muscle inflammation characterized by NF-κB activation, and enhanced expression of pro-inflammatory genes. Chronic sodium salicylate treatment ameliorated muscle alterations and reduced the muscle expression of Fgf21. Muscle inflammation was an early event during the progression of the disease and occurred before macrophage infiltration, indicating that it is a primary response to Opa1 deficiency. Moreover, Opa1 repression in muscle cells also resulted in NF-κB activation and inflammation in the absence of necrosis and/or apoptosis, thereby revealing that the activation is a cell-autonomous process and independent of cell death. The effects of Opa1 deficiency on the expression NF-κB target genes and inflammation were absent upon mitochondrial DNA depletion. Under Opa1 deficiency, blockage or repression of TLR9 prevented NF-κB activation and inflammation. Taken together, our results reveal that Opa1 deficiency in muscle causes initial mitochondrial alterations that lead to TLR9 activation, and inflammation, which contributes to enhanced Fgf21 expression and to growth impairment.

Anti-myeloperoxidase and proteinase 3 antibodies for nephritis flare prediction in anti-neutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: The value of myeloperoxidase (MPO) and proteinase 3 (PR3) antibody titres in the assessment of renal disease activity and flare prediction in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is not well known. METHODS: We performed a retrospective study including 113 AVV patients with renal biopsy-proven pauci-immune necrotizing glomerulonephritis from seven Spanish hospitals. The main inclusion criteria were assessment of MPO antibodies using multiplex flow immunoassay and PR3 antibody measurements using immunoassay chemiluminescence with an identical range of values for all participating centres. RESULTS: Serum MPO antibodies 3 ± 1.2 months before relapse were higher in patients who relapsed [19.2 ± 12.2 versus 3.2 ± 5.1 antibody index (AI); P < 0.001]. The discrimination value of MPO antibodies 3 months before renal relapse had an area under the receiver operating characteristics curve (AUC) of 0.82 [95% confidence interval (CI) 0.73-0.92; P < 0.001]. ΔMPO antibodies (change in antibodies titration 6 months before relapse) were higher in patients who relapsed (8.3 ± 12 versus 0.9 ± 3.1 AI; P = 0.001). The discrimination value of ΔMPO had an AUC of 0.76 (95% CI 0.63-0.88; P < 0.001). The positive predictive value of renal relapse in PR3 patients is 100% and the negative predictive value of renal relapse in patients with PR3-positive titres is 57.1%. Serum PR3 antibodies were higher in patients who relapsed 2.8 ± 1.4 months before relapse (58.6 ± 24.6 versus 2.0 ± 0.6 AI; P < 0.001). CONCLUSIONS: MPO level monitoring using multiplex flow immunoassay and PR3 measurements using immunoassay chemiluminescence are useful and sensitive tools for the prediction of renal relapse in the follow-up of AAV patients with renal disease and relevant surrogate markers of renal disease activity.

Multidimensional predictors of negative symptoms in antipsychotic-naive first-episode psychosis.

BACKGROUND: Despite a large body of schizophrenia research, we still have no reliable predictors to guide treatment from illness onset. The present study aimed to identify baseline clinical or neurobiological factors - including peripheral brain-derived neurotrophic factor (BDNF) levels and amygdala or hippocampal relative volumes - that could predict negative symptomatology and persistent negative symptoms in first-episode psychosis after 1 year of follow-up. METHODS: We recruited 50 drug-naive patients with first-episode psychosis and 50 age- and sex-matched healthy controls to study brain volumes. We performed univariate and multiple and logistic regression analyses to determine the association between baseline clinical and neurobiological variables, score on the PANSS negative subscale and persistent negative symptoms after 1 year of follow-up. RESULTS: Low baseline serum BDNF levels (p = 0.011), decreased left amygdala relative volume (p = 0.001) and more severe negative symptomatology (p = 0.021) predicted the severity of negative symptoms at 1 year, as measured by the PANSS negative subscale. Low baseline serum BDNF levels (p = 0.012) and decreased left amygdala relative volume (p = 0.010) predicted persistent negative symptoms at 1 year. LIMITATIONS: We were unable to assess negative symptoms and their dimensions with next-generation scales, which were not available when the study was initiated. CONCLUSION: This study shows that a set of variables at baseline, including low BDNF levels, smaller left amygdala relative volume and score on the PANSS negative subscale are significant predictors of outcomes in first-episode psychosis. These findings might offer an initial step for tailoring treatments in first-episode psychosis.

Predictors and changes of physical activity in idiopathic pulmonary fibrosis.

BACKGROUND: Different clinical predictors of physical activity (PA) have been described in idiopathic pulmonary fibrosis (IPF), but studies are lacking evaluating the potential role of muscle strength and anxiety and depression symptoms in PA limitation. Moreover, little is known about the impact of changes in PA in the course of the disease. The aim of the present study was to investigate the relationship between baseline PA and a wide range of variables in IPF, to assess its longitudinal changes at 12 months and its impact on progression free-survival. METHODS: PA was assessed by accelerometer and physiological, clinical, psychological factors and health-related quality of life were evaluated in subjects with IPF at baseline and at 12 month follow-up. Predictors of PA were determined at baseline, evolution of PA parameters was described and the prognostic role of PA evolution was also established. RESULTS: Forty participants with IPF were included and 22 completed the follow-up. At baseline, subjects performed 5765 (3442) daily steps and spent 64 (44) minutes/day in moderate to vigorous PA. Multivariate regression models showed that at baseline, a lower six-minute walked distance, lower quadriceps strength (QMVC), and a higher depression score in the Hospital Anxiety and Depression scale were associated to lower daily step number. In addition, being in (Gender-Age-Physiology) GAP III stage, having a BMI ≥ 25 kg/m2 and lower QMVC or maximum inspiratory pressure were factors associated with sedentary behaviour. Adjusted for age, gender and forced vital capacity (FVC) (%pred.) a lower progression-free survival was evidenced in those subjects that decreased PA compared to those that maintained, or even increased it, at 12 months [HR 12.1 (95% CI, 1.9-78.8); p = 0.009]. CONCLUSION: Among a wide range of variables, muscle strength and depression symptoms have a predominant role in PA in IPF patients. Daily PA behaviour and its evolution should be considered in IPF clinical assessment and as a potential complementary indicator of disease prognosis.

OntoPharma: ontology based clinical decision support system to reduce medication prescribing errors.

BACKGROUND: Clinical decision support systems (CDSS) have been shown to reduce medication errors. However, they are underused because of different challenges. One approach to improve CDSS is to use ontologies instead of relational databases. The primary aim was to design and develop OntoPharma, an ontology based CDSS to reduce medication prescribing errors. Secondary aim was to implement OntoPharma in a hospital setting. METHODS: A four-step process was proposed. (1) Defining the ontology domain. The ontology scope was the medication domain. An advisory board selected four use cases: maximum dosage alert, drug-drug interaction checker, renal failure adjustment, and drug allergy checker. (2) Implementing the ontology in a formal representation. The implementation was conducted by Medical Informatics specialists and Clinical Pharmacists using Protégé-OWL. (3) Developing an ontology-driven alert module. Computerised Physician Order Entry (CPOE) integration was performed through a REST API. SPARQL was used to query ontologies. (4) Implementing OntoPharma in a hospital setting. Alerts generated between July 2020/ November 2021 were analysed. RESULTS: The three ontologies developed included 34,938 classes, 16,672 individuals and 82 properties. The domains addressed by ontologies were identification data of medicinal products, appropriateness drug data, and local concepts from CPOE. When a medication prescribing error is identified an alert is shown. OntoPharma generated 823 alerts in 1046 patients. 401 (48.7%) of them were accepted. CONCLUSIONS: OntoPharma is an ontology based CDSS implemented in clinical practice which generates alerts when a prescribing medication error is identified. To gain user acceptance OntoPharma has been designed and developed by a multidisciplinary team. Compared to CDSS based on relational databases, OntoPharma represents medication knowledge in a more intuitive, extensible and maintainable manner.

The Impact of Motivational Interviewing on Self-care and Health-Related Quality of Life in Patients With Chronic Heart Failure.

BACKGROUND: Self-care is an integral component of successful chronic heart failure (HF) management. Structured educational programs have already been shown to be effective in improving self-care, but some patients show resistance and little motivation for change. OBJECTIVE: The objective of this study was to compare efficacy in improving self-care and health-related quality of life (HRQoL) for an educational intervention based on motivational interviewing (MI) compared with a conventional educational intervention. METHODS: This experimental pretest-posttest study with an equivalent historical control group included 93 patients in the intervention group and 93 matched patients in the control group. Participants attended a first visit after HF hospitalization discharge and 6 to 7 follow-up visits during 6 months. The European Heart Failure Self-care Behavior scale and the Minnesota Living with Heart Failure Questionnaire were used to assess self-care and HRQoL, respectively. Data on mortality and hospital readmissions were collected as adverse events. RESULTS: Self-care improved significantly more in the MI-based intervention group than in the control group ( P = .005). Although both self-care and HRQoL improved in both groups over time ( P < .05), there was no significant between-group difference in terms of HRQoL improvement over time ( P = .13). CONCLUSIONS: Our findings suggest that MI delivered by MI-trained nurses is effective in significantly improving self-care by patients with HF. Nonetheless, further studies are required to evaluate the impact of MI on other outcomes, such as HRQoL and adverse clinical events.

Intra-rater reliability and feasibility of the HexCom advanced disease complexity assessment model.

AIM: To study the intra-rater reliability and feasibility of the HexCom complexity assessment model by analyzing internal consistency, intra-rater reliability and response time. DESIGN: Test-retest study with a selection of 11 clinical situations that cover the full scope of situations assessed by the HexCom model and which are responded to individually. LOCATION: Home care, primary care, hospital and sociosanitary care. Two specialized palliative home care teams (PADES). PARTICIPANTS: A total of 20 professionals comprising 10 experts in palliative home care (PADES) and 10 professionals from general palliative care (primary care, hospital and sociosanitary care). These professionals came from the fields of family medicine (5), internal medicine (2), geriatrics (2), nursing (9), psychology (1) and social work (1). MAIN MEASUREMENTS: Cronbach's alpha, weighted kappa, response time. RESULTS: Cronbach's alpha of 0.91 for HexCom-Red and 0.87 for HexCom-Clin. Intra-rater reliability ranging from good to very good for HexCom-Red (kappa: 0.78-1) and from moderate to very good for HexCom-Clin (kappa: 0.58-0.91). Average response time of 0:57 for HexCom-Red and 3:80min for HexComClin. CONCLUSIONS: HexCom-Red and HexCom-Clin are reliable tools and feasible for use by all professionals involved in both general and specialized palliative care at different levels.

Predictor factors for conservative management of cervical intraepithelial neoplasia grade 2: Cytology and HPV genotyping.

OBJECTIVE: The purpose of this study was to evaluate the role of HPV genotyping and previous cytology result to predict the evolution of CIN2 histological lesions managed conservatively. METHODS: A prospective observational study was conducted at Hospital del Mar in Barcelona from January 2012 to May 2017. Women with new diagnosis of CIN2 were invited to undergo conservative management for 24 months. Complete regression, partial regression, persistence and progression to CIN3 were defined as final outcomes. Univariate and multivariate analyses combining HPV genotyping and cytology were used to establish progression predictors of CIN2. RESULTS: A total of 300 patients were included in the study, and 291 patients completed the 24-months follow-up. Of them, 214 patients (73.5%) showed regression; 43 (14.8%) persistence to CIN2, and 34 (11.7%) progression to CIN3. In multivariable analysis, HPV-16 infection (odds ratio [OR] 1.97, [95% confidence interval {CI} 1.13-3.43]) and previous HSIL cytology (OR 3.46, [95% CI 1.99-6.02]) significantly increased the risk of persistence or progression (CIN2+) of CIN2 lesions. In contrast, all HPV-negative lesions regressed (p < 0.001). CONCLUSIONS: The regression rate of CIN2 lesions supports conservative management in selected patients regardless of their age. Patients with a CIN2 biopsy and negative HPV test had a high rate of regression and should be offered follow-up without excisional treatment. In contrast, patients with HPV-16 and HSIL cytology had an increased risk of CIN2+, their treatment should be individualized and excisional treatment should be considered. The age may not be considered a criterion to decide the best management. New markers may help in the future to select the best management of CIN2.

Prevalence and risk factors for serositis in patients with systemic lupus erythematosus: A case-control study.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune multisystemic disease with a wide variety of clinical manifestations. One of its symptoms, associated to high morbidity, is serositis. Its prevalence ranges between 11% and 54%, and little is known about factors associated to this manifestation. The aim of this study is to determine the prevalence of serositis in SLE patients visited at the outpatient Lupus Unit of the Hospital del Mar and identify risk factors that can be used as predictors of this manifestation. METHODS: A retrospective case-control study was performed based on the review of 297 medical records of SLE patients. Twenty-eight patients were identified to have suffered serositis (cases) and were age- and sex-matched with 2 controls with SLE without serositis. RESULTS: The overall prevalence of serositis in our cohort was 9.42%, being higher in men than in women, 30% versus 7.9% (p = 0.001, 95% CI: 1.7-42.4%). In 40.7%, it was the first manifestation of the disease. When looking for serositis-associated factors, an association was found with anti-dsDNA antibodies measured by the Crithidia method (p = 0.016), and different measures of corticosteroids, where cases had required higher maximum doses and more pulses than controls throughout the disease, although this last correlation was lost when adjusting for confounding variables as nephritis and arthritis. Cases also received more mycophenolic acid (p = 0.021) and, marginally, more belimumab (p = 0.056). CONCLUSION: The overall prevalence of serositis was 9.42%, being significantly higher in men (30%). Therefore, male gender constitutes a risk factor for serositis, and almost one third of men will develop this manifestation, so greater awareness is required in SLE men. CrithidiaDNA+ was also identified as a risk factor, and it should be determined in all SLE patients. Cases significantly received more corticosteroid pulses and higher maximum doses in relation to other SLE severe manifestations, which could imply a more aggressive form of SLE in patients with serositis.

Impact of high-flow oxygen therapy during exercise in idiopathic pulmonary fibrosis: a pilot crossover clinical trial.

BACKGROUND: Supplemental oxygen delivered with standard oxygen therapy (SOT) improves exercise capacity in patients with idiopathic pulmonary fibrosis (IPF). Although high-flow nasal cannula oxygen therapy (HFNC) improves oxygenation in other respiratory diseases, its impact on exercise performance has never been evaluated in IPF patients. We hypothesized that HFNC may improve exercise capacity in IPF subjects compared to SOT. METHODS: This was a prospective, crossover, pilot randomized trial that compared both oxygenation methods during a constant submaximal cardiopulmonary exercise test (CPET) in IPF patients with exertional oxygen saturation (SpO2) ≤ 85% in the 6-min walking test. The primary outcome was endurance time (Tlim). Secondary outcomes were muscle oxygen saturation (StO2) and respiratory and leg symptoms. RESULTS: Ten IPF patients [71.7 (6) years old, 90% males] were included. FVC and DLCO were 58 ± 11% and 31 ± 13% pred. respectively. Tlim during CPET was significantly greater using HFNC compared to SOT [494 ± 173 vs. 381 ± 137 s, p = 0.01]. HFNC also associated with a higher increase in inspiratory capacity (IC) [19.4 ± 14.2 vs. 7.1 ± 8.9%, respectively; p = 0.04], and a similar trend was observed in StO2 during exercise. No differences were found in respiratory or leg symptoms between the two oxygen devices. CONCLUSIONS: This is the first study demonstrating that HFNC oxygen therapy improves exercise tolerance better than SOT in IPF patients with exertional desaturation. This might be explained by changes in ventilatory mechanics and muscle oxygenation. Further and larger studies are needed to confirm the benefits of HFNC in IPF patients and its potential usefulness in rehabilitation programs.

Curcumin and Resveratrol Improve Muscle Function and Structure through Attenuation of Proteolytic Markers in Experimental Cancer-Induced Cachexia.

Muscle wasting and cachexia are prominent comorbidities in cancer. Treatment with polyphenolic compounds may partly revert muscle wasting. We hypothesized that treatment with curcumin or resveratrol in cancer cachectic mice may improve muscle phenotype and total body weight through attenuation of several proteolytic and signaling mechanisms in limb muscles. In gastrocnemius and soleus muscles of cancer cachectic mice (LP07 adenocarcinoma cells, N = 10/group): (1) LC-induced cachexia, (2) LC-cachexia+curcumin, and (3) LC-cachexia + resveratrol, muscle structure and damage (including blood troponin I), sirtuin-1, proteolytic markers, and signaling pathways (NF-κB and FoxO3) were explored (immunohistochemistry and immunoblotting). Compared to nontreated cachectic mice, in LC-cachexia + curcumin and LC-cachexia + resveratrol groups, body and muscle weights (gastrocnemius), limb muscle strength, muscle damage, and myofiber cross-sectional area improved, and in both muscles, sirtuin-1 increased, while proteolysis (troponin I), proteolytic markers, and signaling pathways were attenuated. Curcumin and resveratrol elicited beneficial effects on fast- and slow-twitch limb muscle phenotypes in cachectic mice through sirtuin-1 activation, attenuation of atrophy signaling pathways, and proteolysis in cancer cachectic mice. These findings have future therapeutic implications as these natural compounds, separately or in combination, may be used in clinical settings of muscle mass loss and dysfunction including cancer cachexia.

Circulating ADAMs are associated with renal and cardiovascular outcomes in chronic kidney disease patients.

BACKGROUND: A disintegrin and metalloproteinase (ADAM) 17, also known as tumour necrosis factor α-converting enzyme (TACE), is a metalloproteinase that releases the ectodomains of most growth factors, cytokines, receptors and enzymes and has been associated with the presence of chronic kidney disease (CKD) and cardiovascular (CV) disease. The role of circulating ADAMs in the progression of renal function and CV events in CKD patients is unknown. METHODS: A total of 2570 subjects from an observational and multicentre study with CKD Stages 3-5, CKD Stage 5D and controls without any history of CV disease were studied. Circulating ADAM activity was assessed using a fluorometric technique. Progression of renal disease was defined as a 30% increase in serum creatinine or dialysis requirement after 24 months of follow-up. CV outcomes were assessed after 48 months of follow-up. RESULTS: Patients with advanced CKD had higher ADAM activity as compared with patients with moderate CKD or controls. Male patients with progression of CKD had higher ADAM levels at baseline compared with patients with stable renal function {22.19 relative fluorescence units/µL/h [95% confidence interval (CI) 11.22-37.32] versus 12.15 (7.02-21.50)}. After multivariate adjustment, higher ADAM activity was identified as a risk factor for progression of CKD in male patients [30% increase in the creatinine odds ratio (OR) 2.72 (95% CI 1.58-4.68), P < 0.001; dialysis requirement OR 3.00 (95% CI 1.65-5.46), P < 0.001; dialysis requirement or 30% increase in the creatinine OR 3.15 (95% CI 2.06-4.81), P < 0.001]. ADAM activity was also identified as an independent risk factor for CV events [hazard ratio (HR) 1.68 (95% CI 1.20-2.36), P = 0.003]. CONCLUSIONS: High ADAMs activity levels are independently associated with CKD progression in males and with CV events in CKD patients.

Relevance of KDPI value and acute rejection on kidney transplant outcomes in recipients with delayed graft function - a retrospective study.

Delayed graft function (DGF) is associated with poorer graft survival and higher rate of acute rejection (AR). It is unknown whether this negative influence relies on the increased risk of AR or the DGF itself. The different Kidney Donor Profile Index (KDPI) values may also play a role in this interaction. Retrospective study aimed to evaluate the impact of DGF on graft function and graft survival in a subset of KT recipients (2004-2017). We also analyzed the relationship between KDPI and DGF. The study includes 601 KT, 226 of them (37%) developed DGF. Graft survival was lower in patients with DGF compared with non-DGF patients. Multivariable analysis revealed DGF as risk factor for graft loss, independently of the presence or not of acute rejection. Between DGF patients, we observed poorer graft survival in patients with higher KDPI value (>85%). We observed a trend of a greater impact of KDPI in patients with DGF, although this interaction was not statistically significant. Additionally, we observed poorer 12-month graft function in DGF patients. DGF is related to poorer graft survival independently of the developed acute rejection. This negative impact might be influenced by high KDPI values.

Prolonged Immobilization Exacerbates the Loss of Muscle Mass and Function Induced by Cancer-Associated Cachexia through Enhanced Proteolysis in Mice.

We hypothesized that in mice with lung cancer (LC)-induced cachexia, periods of immobilization of the hindlimb (7 and 15 days) may further aggravate the process of muscle mass loss and function. Mice were divided into seven groups (n = 10/group): (1) non-immobilized control mice, (2) 7-day unloaded mice (7-day I), (3) 15-day unloaded mice (15-day I), (4) 21-day LC-cachexia group (LC 21-days), (5) 30-day LC-cachexia group (LC 30-days), (6) 21-day LC-cachexia group besides 7 days of unloading (LC 21-days + 7-day I), (7) 30-day LC-cachexia group besides 15 days of unloading (LC 30-days + 15-day I). Physiological parameters, body weight, muscle and tumor weights, phenotype and morphometry, muscle damage (including troponin I), proteolytic and autophagy markers, and muscle regeneration markers were identified in gastrocnemius muscle. In LC-induced cachexia mice exposed to hindlimb unloading, gastrocnemius weight, limb strength, fast-twitch myofiber cross-sectional area, and muscle regeneration markers significantly decreased, while tumor weight and area, muscle damage (troponin), and proteolytic and autophagy markers increased. In gastrocnemius of cancer-cachectic mice exposed to unloading, severe muscle atrophy and impaired function was observed along with increased muscle proteolysis and autophagy, muscle damage, and impaired muscle regeneration.