A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study.

BACKGROUND AND PURPOSE: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies. EXPERIMENTAL APPROACH: Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses. KEY RESULTS: In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability. CONCLUSIONS AND IMPLICATIONS: The novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.

Enhanced Donor Antigen Presentation by B Cells Predicts Acute Cellular Rejection and Late Outcomes After Transplantation.

Background: Enhanced B-cell presentation of donor alloantigen relative to presentation of HLA-mismatched reference alloantigen is associated with acute cellular rejection (ACR), when expressed as a ratio called the antigen presenting index (API) in an exploratory cohort of liver and intestine transplant (LT and IT) recipients. Methods: To test clinical performance, we measured the API using the previously described 6-h assay in 84 LT and 54 IT recipients with median age 3.3 y (0.05-23.96). Recipients experiencing ACR within 60 d after testing were termed rejectors. Results: We first confirmed that B-cell uptake and presentation of alloantigen induced and thus reflected the alloresponse of T-helper cells, which were incubated without and with cytochalasin and primaquine to inhibit antigen uptake and presentation, respectively. Transplant recipients included 76 males and 62 females. Rejectors were tested at median 3.6 d before diagnosis. The API was higher among rejectors compared with nonrejectors (2.2 ±â€…0.2 versus 0.6 ±â€…0.04, P value = 1.7E-09). In logistic regression and receiver-operating-characteristic analysis, API ≥1.1 achieved sensitivity, specificity, and positive and negative predictive values for predicting ACR in 99 training set samples. Corresponding metrics ranged from 80% to 88% in 32 independent posttransplant samples, and 73% to 100% in 20 independent pretransplant samples. In time-to-event analysis, API ≥1.1 predicted higher incidence of late donor-specific anti-HLA antibodies after API measurements in LT recipients (P = 0.011) and graft loss in IT recipients (P = 0.008), compared with recipients with API <1.1, respectively. Conclusions: Enhanced donor antigen presentation by circulating B cells predicts rejection after liver or intestine transplantation as well as higher incidence of DSA and graft loss late after transplantation.

Ribonucleicacid interference or small molecule inhibition of Runx1 in the border zone prevents cardiac contractile dysfunction following myocardial infarction.

AIMS: Myocardial infarction (MI) is a major cause of death worldwide. Effective treatments are required to improve recovery of cardiac function following MI, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile region bordering an infarct is functionally distinct from the remote surviving myocardium and is a determinant of adverse remodelling and cardiac contractility. Expression of the transcription factor RUNX1 is increased in the border zone 1-day after MI, suggesting potential for targeted therapeutic intervention. OBJECTIVE: This study sought to investigate whether an increase in RUNX1 in the border zone can be therapeutically targeted to preserve contractility following MI. METHODS AND RESULTS: In this work we demonstrate that Runx1 drives reductions in cardiomyocyte contractility, calcium handling, mitochondrial density, and expression of genes important for oxidative phosphorylation. Both tamoxifen-inducible Runx1-deficient and essential co-factor common ß subunit (Cbfß)-deficient cardiomyocyte-specific mouse models demonstrated that antagonizing RUNX1 function preserves the expression of genes important for oxidative phosphorylation following MI. Antagonizing RUNX1 expression via short-hairpin RNA interference preserved contractile function following MI. Equivalent effects were obtained with a small molecule inhibitor (Ro5-3335) that reduces RUNX1 function by blocking its interaction with CBFß. CONCLUSIONS: Our results confirm the translational potential of RUNX1 as a novel therapeutic target in MI, with wider opportunities for use across a range of cardiac diseases where RUNX1 drives adverse cardiac remodelling.

Local Data Quality Assessments on EHR-Based Real-World Data for Rare Diseases.

The project "Collaboration on Rare Diseases" CORD-MI connects various university hospitals in Germany to collect sufficient harmonized electronic health record (EHR) data for supporting clinical research in the field of rare diseases (RDs). However, the integration and transformation of heterogeneous data into an interoperable standard through Extract-Transform-Load (ETL) processes is a complex task that may influence the data quality (DQ). Local DQ assessments and control processes are needed to ensure and improve the quality of RD data. We therefore aim to investigate the impact of ETL processes on the quality of transformed RD data. Seven DQ indicators for three independent DQ dimensions were evaluated. The resulting reports show the correctness of calculated DQ metrics and detected DQ issues. Our study provides the first comparison results between the DQ of RD data before and after ETL processes. We found that ETL processes are challenging tasks that influence the quality of RD data. We have demonstrated that our methodology is useful and capable of evaluating the quality of real-world data stored in different formats and structures. Our methodology can therefore be used to improve the quality of RD documentation and to support clinical research.

Rare Diseases in Hospital Information Systems-An Interoperable Methodology for Distributed Data Quality Assessments.

BACKGROUND: Multisite research networks such as the project "Collaboration on Rare Diseases" connect various hospitals to obtain sufficient data for clinical research. However, data quality (DQ) remains a challenge for the secondary use of data recorded in different health information systems. High levels of DQ as well as appropriate quality assessment methods are needed to support the reuse of such distributed data. OBJECTIVES: The aim of this work is the development of an interoperable methodology for assessing the quality of data recorded in heterogeneous sources to improve the quality of rare disease (RD) documentation and support clinical research. METHODS: We first developed a conceptual framework for DQ assessment. Using this theoretical guidance, we implemented a software framework that provides appropriate tools for calculating DQ metrics and for generating local as well as cross-institutional reports. We further applied our methodology on synthetic data distributed across multiple hospitals using Personal Health Train. Finally, we used precision and recall as metrics to validate our implementation. RESULTS: Four DQ dimensions were defined and represented as disjunct ontological categories. Based on these top dimensions, 9 DQ concepts, 10 DQ indicators, and 25 DQ parameters were developed and applied to different data sets. Randomly introduced DQ issues were all identified and reported automatically. The generated reports show the resulting DQ indicators and detected DQ issues. CONCLUSION: We have shown that our approach yields promising results, which can be used for local and cross-institutional DQ assessments. The developed frameworks provide useful methods for interoperable and privacy-preserving assessments of DQ that meet the specified requirements. This study has demonstrated that our methodology is capable of detecting DQ issues such as ambiguity or implausibility of coded diagnoses. It can be used for DQ benchmarking to improve the quality of RD documentation and to support clinical research on distributed data.

[Uncovering rare diseases in medical data-coding]. / Seltene Erkrankungen in den Daten sichtbar machen ­ Kodierung.

The ICD-10-GM coding system used in the German healthcare system only captures a minority of rare disease diagnoses. Therefore, information on the incidence and prevalence of rare diseases as well as necessary (financial) resources for the expert care required for evidence-based decisions by health insurers, care providers, and politicians are lacking. Furthermore, the missing information complicates and sometimes even precludes the generation of scientific knowledge on rare diseases. Therefore, starting in 2023, all in-patient cases in Germany with a rare disease diagnosis must be coded by an ORPHAcode using the Alpha-ID-SE file.The file Alpha-ID-SE links the ICD-10-GM codes to the internationally established ORPHAcodes for rare diseases. Commercially available software tools progressively support the coding of rare diseases. In several centers for rare diseases linked to university hospitals, IT tools and procedures were established to realize a complete coding of rare diseases. These include financial incentives for the institutions providing rare disease codes, systematic queries asking for rare disease codes during the coding process, and a semi-automated coding process for all patients with a rare disease previously seen at the institution. A combination of the different approaches probably results in the most complete coding.To get the complete picture of rare disease epidemiology and care requirements, a specific and unique coding of out-patient cases is also desirable. Furthermore, a structured reporting of phenotype is required, especially for complex rare diseases and for yet undiagnosed cases.

Secondary task engagement, risk-taking, and safety-related equipment use in German bicycle and e-scooter riders - An observation.

The behavioral safety of e-bike and e-scooter riders is a significant concern in traffic safety. In an observational study in Braunschweig, Germany, 4,514 bicycle and e-scooter riders were observed concerning their used vehicles type, secondary task engagement, use of additional safety equipment, and traffic rule violation. Overall, 13.4% of all riders were engaged in any secondary task, wearing headphones or earphones being the most frequent behavior (6.7%), followed by conversations with other cyclists (3.7%). Banned mobile phone use was low (0.8%). Secondary task engagement was positively correlated with traffic rule violations and at-fault conflicts and negatively with the use of additional safety equipment. Cluster analysis on vehicle types and behaviors revealed five groups of riders, two with relatively high numbers of risky behaviors: young and middle-aged, predominantly male riders of conventional bicycles, and a group of demographically similar users of electric bikes and e-scooters. Campaigns targeted at these specific groups may help reduce risky behaviors.

Preclinical models of myocardial infarction: from mechanism to translation.

Approximately 7 million people are affected by acute myocardial infarction (MI) each year, and despite significant therapeutic and diagnostic advancements, MI remains a leading cause of mortality worldwide. Preclinical animal models have significantly advanced our understanding of MI and have enabled the development of therapeutic strategies to combat this debilitating disease. Notably, some drugs currently used to treat MI and heart failure (HF) in patients had initially been studied in preclinical animal models. Despite this, preclinical models are limited in their ability to fully reproduce the complexity of MI in humans. The preclinical model must be carefully selected to maximise the translational potential of experimental findings. This review describes current experimental models of MI and considers how they have been used to understand drug mechanisms of action and support translational medicine development. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.

Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size.

AIMS: Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury. METHODS AND RESULTS: We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis. CONCLUSION: Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.

Azospira inquinata sp. nov., a nitrate-reducing bacterium of the family Rhodocyclaceae isolated from contaminated groundwater.

Two novel Gram-stain-negative bacterial strains, Azo-3T and Azo-2, were isolated from a toluene-producing enrichment culture that originated from contaminated groundwater at a site in southeast Louisiana (USA). Cells are non-spore forming straight to curved rods with single polar flagella. Strains Azo-3T and Azo-2 are oxidase-positive, catalase-negative, use nitrate and nitrite as electron acceptors, and are able to fix nitrogen. Poly-ß-hydroxybutyrate storage granules are produced. Dominant fatty acids when grown in R2A medium at 37 °C are C16:0, summed feature 3 (C16:1 ω7c and/or C15:0 iso 2OH), C17:0 cyclo and C18:1 ω7c. 16S rRNA gene sequence based phylogenetic analysis indicated that the strains cluster within the family Rhodocyclaceae, class Betaproteobacteria, most closely related to but distinct from type strains of the species Azospira oryzae (96.94% similarity) and Azospira restricta (95.10% similarity). Complete genome sequences determined for strains Azo-3T and Azo-2 revealed DNA G+C content of 62.70 mol%. Genome-wide comparisons based on average nucleotide identity by orthology and estimated DNA-DNA hybridization values combined with phenotypic and chemotaxonomic traits and phylogenetic analysis indicate that strains Azo-3T and Azo-2 represent a novel species within the genus Azospira for which the name Azospira inquinata sp. nov. is proposed. The type strain of Azospira inquinata is Azo-3T (=NRRL B-65590T=DSM 112046T).

INFLIXIMAB AND ADALIMUMAB SERUM TROUGH CONCENTRATIONS THRESHOLD ASSOCIATED WITH DEEP REMISSION IN INFLAMMATORY BOWEL DISEASE.

OBJECTIVE: Deep remission (DR) defined by clinical-biomarker remission and mucosal healing (MH) has emerged as a new therapeutic target in inflammatory bowel disease (IBD). The aim of this study was to define an optimal cut-off concentration for IFX and ADA during maintenance therapy associated with DR. The secondary objective, was to evaluate the influence of variables on anti-TNF concentrations and DR. METHODS: Retrospective study including 120 and 122 patients IBD diagnosed who received maintenance therapy with IFX and ADA. Biomarker remission was considered by C-reactive protein (CRP)<5 mg/L and fecal calprotectin (CF)<100 mcg/g. Crohn's disease (CD) clinical remission was defined by a Harvey Bradshaw score<5 and MH by a simple endoscopic score for CD (SES-CD)<3.  In ulcerative colitis (UC), it was defined as a Mayo total score<3 and Mayo endoscopic subscore<2. Receiver operating characteristic (ROC) test was performed to determine drug concentration thresholds associated with DR. Anti-TNF concentrations were classified into quartiles. X2 and Kruskal-Wallis test were used to compare discrete and continuous variables between quartile groups. Multivariate logistic regression was performed to identify patient characteristics and serological factors associated with DR. RESULTS: Anti-TNF concentrations were higher in patients with DR, in IFX (4.4, IQR: 3.3-6.5 vs 2.3, IQR: 1.1-4.2 µg/mL, P<0.005) and ADA (6.3, IQR: 4.2-8.2 vs 3.9, IQR: 2.4-5.5 µg/mL, P<0.005). A ROC identified a concentration threshold of 3.1 µg/mL in IFX (area under the ROC curve [AUROC], 0.72) and 6.3 µg/mL in ADA (AUROC, 0.75) associated with DR. Factors associated with the highest quartiles of serum IFX concentration were: elevated body mass index (BMI), absence of previous IBD-surgery, CRP<5 mg/L, and FC<100 µg/g. In ADA, higher quartiles were related to concomitant immunosuppressants, low BMI, absence of previous IBD-surgery, and CRP<5 mg/L and FC<100 µg/g. Multivariate regression identified FC<100 µg/g, CRP<5mg/L, IFX ≥3.1µg/mL and ADA concentrations ≥6.3µg/mL as factors significantly associated with DR.  CONCLUSIONS: Trough IFX and ADA concentrations, CRP<5mg/L and FC<100 µg/g are associated with DR during maintenance therapy. Cutoff point of 3.1 and 6.3 g/mL for IFX and ADA respectively, were identified as DR predictors.

Objetivo: La remisión profunda, definida como remisión clínico-analítica y  curación de la mucosa, es el objetivo terapéutico en la enfermedad inflamatoria intestinal. En este estudio se define el punto de  corte óptimo de concentración valle de infliximab y adalimumab asociado a  remisión profunda en fase de mantenimiento. El objetivo secundario es  evaluar las covariables relacionadas con las concentraciones de antifactor de necrosis tumoral y la remisión profunda.Método: Estudio retrospectivo que incluyó 120 y 122 pacientes  diagnosticados de enfermedad inflamatoria intestinal tratados con infliximab y adalimumab. La proteína C reactiva < 5 mg/l y la calprotectina  fecal < 100 µg/g se consideró para remisión analítica. En la enfermedad de Crohn, la remisión clínica se definió mediante puntuación Harvey  Bradshaw < 5; la curación de la mucosa por puntuación endoscópica simple para enfermedad de Crohn < 3; en colitis ulcerosa, por índice total de Mayo < 3 e índice subendoscópico de Mayo < 2. Se realizó un análisis por  curva de eficacia diagnóstica para determinar el cutoff asociado  a remisión profunda. Las concentraciones de antifactor de necrosis tumoral se clasificaron en cuartiles. Se utilizó la prueba X2 y Kruskal-Wallis para comparar variables discretas o continuas. Se realizó una  regresión  logística multivariante para identificar las características de  pacientes y serológicas asociadas a remisión profunda.Resultados: Las concentraciones de antifactor de necrosis tumoral fueron  superiores en remisión profunda en comparación con los que no la  alcanzaron en infliximab (4,4; rango intercuartílico: 3,3-6,5 versus 2,3;  rango intercuartílico: 1,1-4,2 µg/ml; P < 0,005) y adalimumab (6,3; rango  intercuartílico: 4,2-8,2 versus 3,9; rango intercuartílico: 2,4-5,5 µg/ml; P <  0,005). Se identificó un cutoff de 3,1 µg/ml en infliximab (área bajo la curva  de eficacia diagnóstica 0,72), y 6,3 µg/ml en adalimumab (área bajo la curva de eficacia diagnóstica 0,75). Los factores asociados a concentraciones  más elevadas de infliximab fueron: elevado índice de masa  corporal, ausencia de cirugía previa de enfermedad inflamatoria intestinal,  proteína C reactiva < 5 mg/l y calprotectina fecal < 100 µg/g. En  adalimumab, concentraciones más altas se relacionaron con  oadministración  de inmunosupresores, bajo índice de masa corporal,  ausencia de cirugía previa, proteína C reactiva < 5 mg/l y calprotectina fecal  < 100 µg/g. Se identificó calprotectina fecal < 100 µg/g, proteína C reactiva  < 5 mg/l, infliximab ≥ 3,1 µg/ml y adalimumab ≥ 6,3 µg/ml como factores  asociados a remisión profunda.logística multivariante para identificar las características de pacientes yserológicas asociadas a remisión profunda.Resultados: Las concentraciones de antifactor de necrosis tumoral fueronsuperiores en remisión profunda en comparación con los que no la alcanzaronen infliximab (4,4; rango intercuartílico: 3,3-6,5 versus 2,3; rango intercuartílico:1,1-4,2 µg/ml; P < 0,005) y adalimumab (6,3; rango intercuartílico:4,2-8,2 versus 3,9; rango intercuartílico: 2,4-5,5 µg/ml; P < 0,005).Se identificó un cutoff de 3,1 µg/ml en infliximab (área bajo la curva deeficacia diagnóstica 0,72), y 6,3 µg/ml en adalimumab (área bajo la curvade eficacia diagnóstica 0,75). Los factores asociados a concentraciones máselevadas de infliximab fueron: elevado índice de masa corporal, ausenciade cirugía previa de enfermedad inflamatoria intestinal, proteína C reactiva< 5 mg/l y calprotectina fecal < 100 µg/g. En adalimumab, concentracionesmás altas se relacionaron con coadministración de inmunosupresores,bajo índice de masa corporal, ausencia de cirugía previa, proteína C reactiva< 5 mg/l y calprotectina fecal < 100 µg/g. Se identificó calprotectinafecal < 100 µg/g, proteína C reactiva < 5 mg/l, infliximab ≥ 3,1 µg/ml yadalimumab ≥ 6,3 µg/ml como factores asociados a remisión profunda.Conclusiones: Las concentraciones valle de infliximab y adalimumab, proteínaC reactiva < 5 mg/l y calprotectina fecal < 100 µg/g se asocian a remisiónprofunda. Se identifican concentraciones cutoff de 3,1 y 6,3 µg/ml en infliximaby adalimumab, respectivamente, como predictoras de remisión profunda.

Los niveles séricos de infliximab y adalimumab están asociados con remisión profunda en la enfermedad inflamatoria intestinal / Serum levels of infliximab and adalimumab are associated with deep remission in inflammatory bowel disease

Objetivo: La remisión profunda, definida como remisión clínico-analíticay curación de la mucosa, es el objetivo terapéutico en la enfermedadinflamatoria intestinal. En este estudio se define el punto de corte óptimode concentración valle de infliximab y adalimumab asociado a remisiónprofunda en fase de mantenimiento. El objetivo secundario es evaluarlas covariables relacionadas con las concentraciones de antifactor denecrosis tumoral y la remisión profunda.Método: Estudio retrospectivo que incluyó 120 y 122 pacientes diagnosticados de enfermedad inflamatoria intestinal tratados con infliximaby adalimumab. La proteína C reactiva < 5 mg/l y la calprotectina fecal< 100 µg/g se consideró para remisión analítica. En la enfermedad deCrohn, la remisión clínica se definió mediante puntuación Harvey Bradshaw < 5; la curación de la mucosa por puntuación endoscópica simplepara enfermedad de Crohn < 3; en colitis ulcerosa, por índice total deMayo < 3 e índice subendoscópico de Mayo < 2. Se realizó un análisispor curva de eficacia diagnóstica para determinar el cutoff asociado aremisión profunda. Las concentraciones de antifactor de necrosis tumoral se clasificaron en cuartiles. Se utilizó la prueba X2 y Kruskal-Wallispara comparar variables discretas o continuas. Se realizó una regresión logística multivariante para identificar las características de pacientes yserológicas asociadas a remisión profunda.Resultados: Las concentraciones de antifactor de necrosis tumoral fueronsuperiores en remisión profunda en comparación con los que no la alcanzaron en infliximab (4,4; rango intercuartílico: 3,3-6,5 versus 2,3; rango intercuartílico: 1,1-4,2 μg/ml; P < 0,005) y adalimumab (6,3; rango intercuartílico: 4,2-8,2 versus 3,9; rango intercuartílico: 2,4-5,5 μg/ml; P < 0,005).Se identificó un cutoff de 3,1 μg/ml en infliximab (área bajo la curva deeficacia diagnóstica 0,72), y 6,3 μg/ml en adalimumab (área bajo la curvade eficacia diagnóstica 0,75). (AU)

Objective: Deep remission defined by clinical-biomarker remissionand mucosal healing has emerged as a new therapeutic target in inflammatory bowel disease. The aim of this study was to define an optimalcut-off concentration for infliximab and adalimumab during maintenancetherapy associated with deep remission. The secondary objective, wasto evaluate the influence of variables on anti tumor necrosis factor-alphaconcentrations and deep remission.Method: Retrospective study including 120 and 122 patients inflammatory bowel disease diagnosed who received maintenance therapywith infliximab and adalimumab. Biomarker remission was consideredby C-reactive protein < 5 mg/L and fecal calprotectin < 100 µg/g.Crohn’s disease clinical remission was defined by a Harvey Bradshawscore < 5 and mucosal healing by a simple endoscopic score for Crohn'sdisease< 3. In ulcerative colitis, it was defined as a Mayo total score < 3and Mayo endoscopic subscore < 2. Receiver operating characteristictest was performed to determine drug concentration thresholds associatedwith deep remission. Anti tumor necrosis factor-alpha concentrations wereclassified into quartiles. X2 and Kruskal-Wallis test were used to comparediscrete and continuous variables between quartile groups. Multivariate logistic regression was performed to identify patient characteristics andserological facto C-reactive protein rs associated with deep remission.Results: Anti tumor necrosis factor-alpha concentrations were higher inpatients with deep remission, in infliximab (4.4, interquartile range: 3.3-6.5vs 2.3, interquartile range: 1.1-4.2 μg/mL, P < 0.005) and adalimumab(6.3, interquartile range: 4.2-8.2 vs 3.9, interquartile range: 2.4-5.5 μg/mL,P < 0.005). (AU)

Nursing's Response to the Executive Order to Advance American Kidney Health.

The state of American kidney health is currently under the microscope. In the United States, approximately 20,000 persons advance to end-stage renal disease annually. Trends indicate accelerating increases in cost of care and a high mortality rate among patients with end-stage renal disease, with only 57% of patients surviving after 3 years. An executive order by the White House has placed the transformation of kidney care at the forefront of the country's health care agenda. The order focuses on key issues including improving outcomes, reducing treatment-related expenditures and increasing kidney donations. Mobilization of health care resources directed toward policymaking, workforce growth and development, and research will be critical to effectively achieve this executive order. Nursing's response, as the health care profession with the most members, will be crucial to achieving response implementation and success of the order. This article describes immediate and future actions including policy, leadership, clinical, educational, and research initiatives that the nursing profession should take to advance kidney health. It calls for specific actions by nursing and focuses on nursing organizations, nursing research, quality improvement initiatives, nursing innovation, advanced practice nursing, and the nephrology and transplant nursing workforce in order to improve kidney health nationally. The impact of the SARS-CoV-2 pandemic on kidney health and the implications for the profession of nursing are outlined. Although there are still many unknowns about the pandemic, nursing's voice is necessary to ensure the ongoing delivery of high-quality care.

Signalling pathways linking cysteine cathepsins to adverse cardiac remodelling.

Adverse cardiac remodelling clinically manifests as deleterious changes to heart architecture (size, mass and geometry) and function. These changes, which include alterations to ventricular wall thickness, chamber dilation and poor contractility, are important because they progressively drive patients with cardiac disease towards heart failure and are associated with poor prognosis. Cysteine cathepsins contribute to key signalling pathways involved in adverse cardiac remodelling including synthesis and degradation of the cardiac extracellular matrix (ECM), cardiomyocyte hypertrophy, impaired cardiomyocyte contractility and apoptosis. In this review, we highlight the role of cathepsins in these signalling pathways as well as their translational potential as therapeutic targets in cardiac disease.

Therapeutic drug monitoring of levetiracetam in daily clinical practice: high-performance liquid chromatography versus immunoassay.

Objectives: Although levetiracetam presents an easy dosing and tolerability, therapeutic drug monitoring may be recommended in certain situations. Measurement of levetiracetam in serum plasma is commonly done by high performance liquid chromatography (HPLC). After ARK Diagnostics marketed an enzyme immunoassay (IA) for levetiracetam in serum or plasma, automated determinations are possible. In this study, the performance of this immunoassay and the impact of automation on the follow-up in patients treated with levetiracetam is evaluated. We also detected those subpopulations of patients who may benefit the most from this therapeutic drug monitoring. Methods: Samples from 50 outpatients diagnosed with epilepsy and treated with levetiracetam were collected. This new IA was performed on the Architect c4000 analyser and compared with the HPLC. Then, a retrospective observational study that included serum samples of levetiracetam for 24 months, was conducted to evaluate the impact of automattion and the influence of some variables (age, sex, renal function, and co-administration of valproic acid and glucuronidation-inducing drugs) in levetiracetam apparent oral clearance (CLp/F) by a multivariate linear regression. Results: The mean high-performance liquid chromatography quantified concentration (CpHPLC) was 18.43 mcg/mL (95% CI: 15.48 to 21.39) and immunoassay concentration (CpEI) was 18.35 mcg/mL (95% CI: 15.20 to 21.50) (P=0.861). The Pearson's linear correlation coefficient obtained in the analysis was r2=0.88, according to the following equation: CpHPLC=-0.29+1.01 CpEI. The intraclass correlation coefficient was 0.95 (95% CI: 0.91 to 0.97). After IA implementation, the number of levetiracetam determinations increased in 76.27%. The median of Clp/F was higher (P<0.001) in inducers (4.36 L/h; IQR:3.29-5.44) and lower (P<0.001) in glomerular filtration rate (GFR) <60 mL/min (2.7 L/h; IQR: 0.58-3.85). Conclusions: The Ark method performed on the Architect is fully acceptable and can be used routinely to measure levetiracetam plasmatic concentration levels. It has demonstrated the need for closer monitoring in patients with renal failure or co-administration of glucuronidation-inducing drugs.

RUNX1: an emerging therapeutic target for cardiovascular disease.

Runt-related transcription factor-1 (RUNX1), also known as acute myeloid leukaemia 1 protein (AML1), is a member of the core-binding factor family of transcription factors which modulate cell proliferation, differentiation, and survival in multiple systems. It is a master-regulator transcription factor, which has been implicated in diverse signalling pathways and cellular mechanisms during normal development and disease. RUNX1 is best characterized for its indispensable role for definitive haematopoiesis and its involvement in haematological malignancies. However, more recently RUNX1 has been identified as a key regulator of adverse cardiac remodelling following myocardial infarction. This review discusses the role RUNX1 plays in the heart and highlights its therapeutic potential as a target to limit the progression of adverse cardiac remodelling and heart failure.

The organochlorine pesticides pentachlorophenol and dichlorodiphenyltrichloroethane increase secretion and production of interleukin 6 by human immune cells.

The environmental contaminants pentachlorophenol (PCP) and 4, 4'-dichlorodiphenyltrichloroethane (DDT) are detected in some human blood samples at levels as high as 5 µM (PCP) and 260 nM (DDT). Several cancers are associated with exposures to these contaminants. IL-6 is a pro-inflammatory cytokine that when dysregulated stimulates inflammatory diseases and tumor progression. Immune cells exposed to PCP at 0.05-5 µM and DDT at 0.025-2.5 µM showed increased secretion of IL-6 when the cell preparations contained either T lymphocytes or monocytes. Increased IL-6 secretion was due to PCP and DDT induced cellular production of the cytokine and was dependent on MAP kinase signaling pathways (in the case of PCP). Compound-induced increases in IL-6 production were in part due to increases in either the transcription of and/or stability of its mRNA. Thus, both PCP and DDT have the potential to produce chronic inflammation by stimulating production of IL-6 by immune cells.

Vancomycin dose optimisation comparing a pharmacokinetic/pharmacodynamic model versus the pharmacokinetic model.

OBJECTIVES: To compare vancomycin dosage adjustment by evaluating trough concentrations (Ctrough) of vancomycin and its pharmacokinetic/pharmacodynamic (PK/PD) correlation (AUC/MIC ≥400). METHODS: A retrospective study of 52 adult haematological patients and 29 ICU patients was carried out. Dosage adjustment was performed in routine clinical practice with Ctrough​​ and then compared using a PK/PD model. The probability of achieving the PK/PD target associated with the success of antimicrobial therapy was evaluated. When the susceptibility of the organism responsible for infection is not known, Monte Carlo simulation calculates the cumulative fraction of response (CFR) from the distribution of MIC values. Values of CFR >90% represent an optimal achieved regimen against a population of microorganisms. RESULTS: According to dosage adjustment performed ​​with Ctrough, in haematological patients the dose of vancomycin was increased in 65.4% compared with an increase in 53.8% of patients with the PK/PD model. No dose adjustment was needed in 21.1% of patients using Ctrough compared with 7.7% with the PK/PD model and in 13.5% of patients using Ctrough determination and in 38.5% of patients with the PK/PD model the dose was reduced. For ICU patients the dosage adjustment made ​​with Ctrough resulted in an increased dose of vancomycin in 79.4% of patients compared with 41.4% with the PK/PD model. No dose adjustment was needed in 3.4% of patients using Ctrough in comparison with 13.8% with the PK/PD model, and the dose was reduced in 17.2% of patients using Ctrough determination and in 44.8% with the PK/PD model. CONCLUSIONS: Data for bacterial susceptibility combined with measured data for antibiotic concentrations using a PK/PD model predict and improve the dosage adjustment for individual patients. A larger study with more complete datasets are needed for validation before it can be fully introduced into clinical practice.

Exposures to the environmental contaminants pentachlorophenol and dichlorodiphenyltrichloroethane increase production of the proinflammatory cytokine, interleukin-1ß, in human immune cells.

Pentachlorophenol (PCP) and dichlorodiphenyltrichloroethane (DDT) are organochlorine environmental contaminants found in human blood at very significant levels (as high as 5 µm for PCP and 260 nm for DDT). Cancers of the blood (lymphoma and myeloma) and kidney as well as others have been associated with exposure to these contaminants. Interleukin (IL)-1ß is a proinflammatory cytokine and is involved in stimulating cell proliferation. High levels of IL-1ß are associated with inflammatory diseases and tumor progression. Previous studies showed that PCP and DDT at certain concentrations were able to stimulate secretion of IL-1ß. This study shows that the increased secretion of IL-1ß seen with both contaminants is due to compound-induced increases in the production of this cytokine. Increased production began within 6 hours of exposure to PCP and continued to increase up to 24 hours. DDT-induced stimulation of IL-1ß appeared to be maximal after 6 hours of exposure and then diminished by 24 hours. The increases seen in IL-1ß production stimulated by PCP appear to be at least partially due to compound-induced increases in IL-1ß mRNA. Although DDT caused increased production of IL-1ß, it did not appear to cause consistent increases in its mRNA. PCP- and DDT-induced increases in IL-1ß production were dependent primarily on the p38 mitogen-activated protein kinase pathway. These results indicate that both PCP and DDT are able to increase IL-1ß production in a p38 mitogen-activated protein kinase-dependent manner, which may have the potential to influence chronic inflammation.

Distribution and status of living colonies of Acropora spp. in the reef crests of a protected marine area of the Caribbean (Jardines de la Reina National Park, Cuba).

The reef crests of the Jardines de la Reina National Park (JRNP) are largely formed by Acropora palmata, but colonies of A. cervicornis and the hybrid A. prolifera are also present. This study shows spatial distribution of colonies, thickets and live fragments of these species in the fore reefs. Snorkeling was used to perform the direct observations. The maximum diameter of 4,399 colonies of A. palmata was measured and the health of 3,546 colonies was evaluated. The same was done to 168 colonies of A. cervicornis and 104 colonies of A. prolifera. The influence of the location and marine currents on a number of living colonies of A. palmata was analyzed. For such purpose, reef crests were divided into segments of 500 m. The marine park was divided into two sectors: East and West. The Caballones Channel was used as the reference dividing line. The park was also divided into five reserve zones. We counted 7,276 live colonies of Acropora spp. 1.4% was A. prolifera, 3.5% A. cervicornis and 95.1% A. palmata. There were 104 thickets of A. palmata, ranging from eight to 12 colonies, and 3,495 fragments; 0.6% was A. cervicornis and the rest A. palmata (99.4%). In the East sector, 263 colonies (3.8% of the total), six thickets (5.8%) and 32 fragments (1%) of A. palmate were recorded. In the same sector, there were 11 fragments (50%) of A.cervicornis and two (2%) colonies of A. prolifera. Health of A. palmata was evaluated as good and not so good in the study area. Health of A. cervicornis was critical and health of A. prolifera was good in all five reserve zones. There was a significant increase in the number of colonies from east to west (Χ2 = 11.5, gl = 3.0, p = 0.009). This corroborates the existence of an important abundance differences between the eastern and the western region of the JRNP. A negative relationship was observed between the number of colonies and the distance from the channel (Χ2 = 65.0, df = 3.0, p < 0.001). The influence of the channel, for the live colonies of A. palmata is greater within the first 2,000 m. It then decreases until approximately 6,000 m, and no significant increase beyond. The orientation of the reef crests significantly influenced the abundance of the colonies (Χ2 = 15.5, df = 2.9, p = 0.001). The results presented here provide a baseline for future research on the status of the populations of Acropora spp., considering that there has been a certain recovery of the species A. palmata during the last 10-16 years. Given the current status of the populations of Acropora spp., conservation actions focusing A. cervicornis should be prioritized.