Construct, Face, and Predictive Validity of Parkinson's Disease Rodent Models.

Parkinson's disease (PD) is the second most common neurodegenerative disease globally. Current drugs only alleviate symptoms without halting disease progression, making rodent models essential for researching new therapies and understanding the disease better. However, selecting the right model is challenging due to the numerous models and protocols available. Key factors in model selection include construct, face, and predictive validity. Construct validity ensures the model replicates pathological changes seen in human PD, focusing on dopaminergic neurodegeneration and a-synuclein aggregation. Face validity ensures the model's symptoms mirror those in humans, primarily reproducing motor and non-motor symptoms. Predictive validity assesses if treatment responses in animals will reflect those in humans, typically involving classical pharmacotherapies and surgical procedures. This review highlights the primary characteristics of PD and how these characteristics are validated experimentally according to the three criteria. Additionally, it serves as a valuable tool for researchers in selecting the most appropriate animal model based on established validation criteria.

Carbon Fiber Paper Sensor for Determination of Trimethoprim Antibiotic in Fish Samples.

The increase in anthropogenic pollution raises serious concerns regarding contamination of water bodies and aquatic species with potential implications on human health. Pharmaceutical compounds are a type of contaminants of emerging concern that are increasingly consumed and, thus, being frequently found in the aquatic environment. In this sense, an electrochemical sensor based on an unmodified and untreated carbon fiber paper (CPS-carbon paper sensor) was simply employed for the analysis of trimethoprim antibiotic in fish samples. First, the analytical conditions were thoroughly optimized in order for the CPS to achieve maximum performance in trimethoprim determination. Therefore, an electrolyte (0.1 M Britton-Robinson buffer) pH of 7 was selected and for square wave voltammetry parameters, optimum values of amplitude, frequency and step potential corresponded to 0.02 V, 50 Hz, and 0.015 V, respectively, whereas the deposition of analyte occurred at +0.7 V for 60 s. In these optimum conditions, the obtained liner range (0.05 to 2 µM), sensitivity (48.8 µA µM-1 cm-2), and LOD (0.065 µM) competes favorably with the commonly used GCE-based sensors or BDD electrodes that employ nanostructuration or are more expensive. The CPS was then applied for trimethoprim determination in fish samples after employing a solid phase extraction procedure based on QuEChERS salts, resulting in recoveries of 105.9 ± 1.8% by the standard addition method.

The Sequential Organ Failure Assessment (SOFA) Score: has the time come for an update?

The Sequential Organ Failure Assessment (SOFA) score was developed more than 25 years ago to provide a simple method of assessing and monitoring organ dysfunction in critically ill patients. Changes in clinical practice over the last few decades, with new interventions and a greater focus on non-invasive monitoring systems, mean it is time to update the SOFA score. As a first step in this process, we propose some possible new variables that could be included in a SOFA 2.0. By so doing, we hope to stimulate debate and discussion to move toward a new, properly validated score that will be fit for modern practice.

Criteria, Processes, and Determination of Competence in Basic Critical Care Echocardiography Training: A Delphi Process Consensus Statement by the Learning Ultrasound in Critical Care (LUCC) Initiative.

BACKGROUND: With the paucity of high-quality studies on longitudinal basic critical care echocardiography (BCCE) training, expert opinion guidelines have guided BCCE competence educational standards and processes. However, existing guidelines lack precise detail due to methodological flaws during guideline development. RESEARCH QUESTIONS: To formulate methodologically robust guidelines on BCCE training using evidence and expert opinion, detailing specific criteria for every step, we conducted a modified Delphi process using the principles of the validated AGREE-II tool. Based on systematic reviews, the following domains were chosen: components of a longitudinal BCCE curriculum; pass-grade criteria for image-acquisition and image-interpretation; and formative/summative assessment and final competence processes. STUDY DESIGN AND METHODS: Between April 2020 and May 2021, a total of 21 BCCE experts participated in four rounds. Rounds 1 and 2 used five web-based questionnaires, including branching-logic software for directed questions to individual panelists. In round 3 (videoconference), the panel finalized the recommendations by vote. During the journal peer-review process, Round 4 was conducted as Web-based questionnaires. Following each round, the agreement threshold for each item was determined as ≥ 80% for item inclusion and ≤ 30% for item exclusion. RESULTS: Following rounds 1 and 2, agreement was reached on 62 of 114 items. To the 49 unresolved items, 12 additional items were added in round 3, with 56 reaching agreement and five items remaining unresolved. There was agreement that longitudinal BCCE training must include introductory training, mentored formative training, summative assessment for competence, and final cognitive assessment. Items requiring multiple rounds included two-dimensional views, Doppler, cardiac output, M-mode measurement, minimum scan numbers, and pass-grade criteria. Regarding objective criteria for image-acquisition and image-interpretation quality, the panel agreed on maintaining the same criteria for formative and summative assessment, to categorize BCCE findings as major vs minor and a standardized approach to errors, criteria for readiness for summative assessment, and supervisory options. INTERPRETATION: In conclusion, this expert consensus statement presents comprehensive evidence-based recommendations on longitudinal BCCE training. However, these recommendations require prospective validation.

Carbon paper as a promising sensing material: Characterization and electroanalysis of ketoprofen in wastewater and fish.

In the present work, the exceptional electrochemical properties of carbon paper were characterized and explored in the development of a sensor for the anti-inflammatory drug, ketoprofen. An initial electrochemical characterization of the carbon paper with a redox indicator revealed much higher voltammetric peaks in comparison with other carbon-based electrodes, namely, screen-printed carbon electrode, boron-doped diamond electrode, glassy carbon electrode, pyrolytic graphite electrode, and pencil graphite electrode, predicting a good sensing performance. Ketoprofen showed a pronounced cathodic peak around -1.1 V vs Ag/AgCl (KCl, 3 M) at pH 5 in Britton-Robinson buffer, presenting a diffusion-controlled process. An optimized differential pulse voltammetry procedure was employed for ketoprofen determination achieving a limit of detection of 0.11 ± 0.01 µM, a linearity up to 6.02 µM, and a high sensitivity of 24 ± 4 or 35 ± 3 µA µM-1 cm-2 (depending on the calibration range: 0.088-1.96 µM or 1.96-6.02 µM, respectively) with acceptable (6-15% relative standard deviation) reproducibility and repeatability considering the challenging conditions of its detection in aqueous solutions. The sensor revealed to be highly selective in the presence of common interferents and other widely consumed anti-inflammatory drugs. Moreover, the developed sensor reached good accuracy in wastewater and fish samples with recoveries varying from 82.3 ± 4.4 to 88.6 ± 4.5%.

Is there a clinically meaningful difference in patient reported dyspnea in acute heart failure? An analysis from URGENT Dyspnea.

BACKGROUND: Dyspnea is the most common presenting symptom in patients with acute heart failure (AHF), but is difficult to quantify as a research measure. The URGENT Dyspnea study compared 3 scales: (1) 10 cm VAS, (2) 5-point Likert, and (3) a 7-point Likert (both VAS and 5-point Likert were recorded in the upright and supine positions). However, the minimal clinically important difference (MCID) to patients has not been well established. METHODS: We performed a secondary analysis from URGENT Dyspnea, an observational, multi-center study of AHF patients enrolled within 1 h of first physician assessment in the ED. Using the anchor-based method to determine the MCID, a one-category change in the 7-point Likert was used as the criterion standard ('minimally improved or worse'). The main outcome measures were the change in visual analog scale (VAS) and 5-point Likert scale from baseline to 6-h assessment relative to a 1-category change response in the 7-point Likert scale ('minimally worse', 'no change', or 'minimally better'). RESULTS: Of the 776 patients enrolled, 491 had a final diagnosis of AHF with responses at both time points. A 10.5 mm (SD 1.6 mm) change in VAS was the MCID for improvement in the upright position, and 14.5 mm (SD 2.0 mm) in the supine position. However, there was no MCID for worsening, as few patients reported worse dyspnea. There was also no significant MCID for the 5-point Likert scale. CONCLUSION: A 10.5 mm change is the MCID for improvement in dyspnea over 6 h in ED patients with AHF.

Soluble CD146, a new endothelial biomarker of acutely decompensated heart failure.

BACKGROUND: The present study involved both human cohorts and animal experiments to explore the performance of soluble CD146 (sCD146), a marker of endothelial function, as a diagnostic marker of acutely decompensated heart failure (ADHF), to determine the influence of patients' characteristics on that performance and to explore the potential application of CD146 in the pathophysiology of ADHF. METHODS AND RESULTS: NT-proBNP and sCD146 were measured in three hundred ninety-one patients admitted to the emergency department for acute dyspnea. ROC curve analysis demonstrated that AUCs for ADHF diagnosis in dyspneic patients were 0.86 (95% CI: 0.82-0.90) for sCD146 and 0.90 (95% CI: 0.86-0.92) for NT-proBNP. Subgroup analyses demonstrated that adding sCD146 to NT-proBNP improved the diagnostic performance for patients lying in the gray zone of NT-proBNP (p=0.02) and could be especially useful for ruling-out ADHF. An experimental model of ADHF in rats using thoracic aortic constriction suggests that CD146 is expressed in the intima of large arteries and associated with both left ventricular function and organ congestion. CONCLUSIONS: sCD146, a marker of endothelial function, seems to be as powerful as NT-proBNP is used to detect the cardiac origin of an acute dyspnea. The combination of sCD146 and NT-proBNP may have better performance than NT-proBNP used alone in particular for patients underlying in the "gray" zone and could therefore be an improved option for ruling-out ADHF. Both experimental and human data suggest that CD146 is related to systolic left ventricular function and to organ congestion.

Assessment of dyspnea early in acute heart failure: patient characteristics and response differences between likert and visual analog scales.

BACKGROUND: Dyspnea is the most common symptom in acute heart failure (AHF), yet how to best measure it has not been well defined. Prior studies demonstrate differences in dyspnea improvement across various measurement scales, yet these studies typically enroll patients well after the emergency department (ED) phase of management. OBJECTIVES: The aim of this study was to determine predictors of early dyspnea improvement for three different, commonly used dyspnea scales (i.e., five-point absolute Likert scale, 10-cm visual analog scale [VAS], or seven-point relative Likert scale). METHODS: This was a post hoc analysis of URGENT Dyspnea, an observational study of 776 patients in 17 countries enrolled within 1 hour of first physician encounter. Inclusion criteria were broad to reflect real-world clinical practice. Prior literature informed the a priori definition of clinically significant dyspnea improvement. Resampling-based multivariable models were created to determine patient characteristics significantly associated with dyspnea improvement. RESULTS: Of the 524 AHF patients, approximately 40% of patients did not report substantial dyspnea improvement within the first 6 hours. Baseline characteristics were similar between those who did or did not improve, although there were differences in history of heart failure, coronary artery disease, and initial systolic blood pressure. For those who did improve, patient characteristics differed across all three scales, with the exception of baseline dyspnea severity for the VAS and five-point Likert scale (c-index ranged from 0.708 to 0.831 for each scale). CONCLUSIONS: Predictors of early dyspnea improvement differ from scale to scale, with the exception of baseline dyspnea. Attempts to use one scale to capture the entirety of the dyspnea symptom may be insufficient.

Unbiased plasma proteomics for novel diagnostic biomarkers in cardiovascular disease: identification of quiescin Q6 as a candidate biomarker of acutely decompensated heart failure.

AIMS: Biochemical marker testing has improved the evaluation and management of patients with cardiovascular diseases over the past decade. Natriuretic peptides (NPs), used in clinical practice to assess cardiac dysfunction, exhibit many limitations, however. We used an unbiased proteomics approach for the discovery of novel diagnostic plasma biomarkers of heart failure (HF). METHODS AND RESULTS: A proteomics pipeline adapted for very low-abundant plasma proteins was applied to clinical samples from patients admitted with acute decompensated HF (ADHF). Quiescin Q6 (QSOX1), a protein involved in the formation of disulfide bridges, emerged as the best performing marker for ADHF (with an area under the receiver operator characteristic curve of 0.86, 95% confidence interval: 0.79-0.92), and novel isoforms of NPs were also identified. Diagnostic performance of QSOX1 for ADHF was confirmed in 267 prospectively collected subjects of whom 76 had ADHF. Combining QSOX1 to B-type NP (BNP) significantly improved diagnostic accuracy for ADHF by particularly improving specificity. Using thoracic aortic constriction in rats, QSOX1 was specifically induced within both left atria and ventricles at the time of HF onset. CONCLUSION: The novel biomarker QSOX1 accurately identifies ADHF, particularly when combined with BNP. Through both clinical and experimental studies we provide lines of evidence for a link between ADHF and cardiovascular production of QSOX1.

Letters from relatives: a source of information providing rich insight into the experience of the family in palliative care.

Studies on the effectiveness and efficiency of palliative care (PC) services that use a methodology similar to that used by studies in other medical specialties face serious limitations, since the goals of PC are substantially different. Qualitative research methods can make an important contribution to our understanding of the features of palliative care (PC) that are most relevant to patients and their relatives. The goal of this study was to understand the reasons behind the gratitude shown in letters from bereaved relatives sent to two PC units, one in Spain and one in Portugal. A thematic analysis of the content of the letters was independently carried out by three researchers, who later collaborated to write up the results. Relatives appeared grateful primarily for the humane attitude, professional treatment, and emotional support that their loved ones received from the PC team; they thanked the team for creating a special atmosphere and offering holistic care, and they talked about the contrast between PC and other forms of care. The unsolicited gratitude expressed in their letters constitutes a valid and particularly rich source of information about the contribution that a PC team can make.

International variations in the clinical, diagnostic, and treatment characteristics of emergency department patients with acute heart failure syndromes.

AIMS: Results from investigations in one area of the world may not translate to another if patient characteristics and practices differ. We examine differences in the presentation and management of emergency department (ED) patients with dyspnoea from acute heart failure syndromes (AHFS) between the USA, Western Europe, and Eastern Europe. METHODS AND RESULTS: The URGENT Dyspnoea study was a multinational prospective observational study of dyspnoeic ED patients with AHFS from 18 countries. Acute heart failure syndrome patients from the USA and Western and Eastern Europe underwent dyspnoea assessments within 1 h of the first physician evaluation. Patient characteristics, evaluation, and treatments were compared between geographical regions using analysis of variance and χ(2) tests. Four hundred and ninety-three patients with AHFS met the inclusion criteria. Participants in the USA were more frequently non-white, younger, on chronic beta-blocker therapy, and with an ejection fraction ≤40% when compared with Eastern and Western Europe. Patients from Eastern Europe were more likely to present with de novo heart failure and have ischaemic electrocardiogram changes. Pulmonary oedema was more common on chest radiograph in Western Europe, but natriuretic peptide levels were elevated in all three regions. Diuretic use was similar across all the regions. Intravenous nitroglycerin was used more frequently in Eastern (32.8%) and Western Europe (24.4%) compared with the USA (2.5%). CONCLUSION: International differences in AHFS presentations and management between regions suggest results from clinical trials in one region may not translate directly to another. These differences should be considered when designing trials and interpreting the results from clinical investigations.

The impact of early standard therapy on dyspnoea in patients with acute heart failure: the URGENT-dyspnoea study.

AIMS: The vast majority of acute heart failure (AHF) trials to date have targeted dyspnoea. However, they enrolled patients relatively late and did not standardize their methods of dyspnoea measurement. URGENT Dyspnoea was designed to determine changes in dyspnoea in response to initial, standard therapy in patients presenting with AHF using a standardized approach. METHODS AND RESULTS: URGENT Dyspnoea was an international, multi-centre, observational cohort study of AHF patients managed conventionally and enrolled within 1 h of first hospital medical evaluation. Patient-assessed dyspnoea was recorded in the sitting position at baseline and at 6 hours by Likert and visual analog scales. Less symptomatic patients were placed supine to determine whether this provoked worsening dyspnoea (orthopnoea). Of the 524 patients with AHF, the mean age was 68 years, 43% were women, and 83% received intravenous diuretics. On a 5-point Likert scale, dyspnoea improvement was reported by 76% of patients after 6 h of standard therapy. Supine positioning (orthopnoea test) led to worse dyspnoea in 47% of patients compared to sitting upright. CONCLUSION: When sitting upright, dyspnoea in the sitting position improves rapidly and substantially in patients with AHF after administration of conventional therapy, mainly intra-venous diuretics. However, many patients remain orthopnoeic. Improving the methodology of clinical trials in AHF by standardizing the conditions under which dyspnoea is assessed could enhance their ability to identify effective treatments. Relief of orthopnoea is clinically valuable and may represent a useful goal for clinical trials.

Design and rationale of the URGENT Dyspnea study: an international, multicenter, prospective study.

BACKGROUND: Dyspnea is a key target in both clinical management and clinical trials of acute heart failure syndromes and its relief important to patients, clinicians, investigators, and regulatory approval agencies. Despite its importance, the impact of early therapy on dyspnea is not well known. The severity of dyspnea may also be influenced by the conditions under which it is measured (ie, sitting up or lying down). URGENT Dyspnea (Ularitide Global Evaluation in Acute Decompensated Heart Failure) is a prospective multicenter study designed to address these issues. METHODS AND RESULTS: Consenting adult patients with dyspnea secondary to acute heart failure syndromes are eligible. Patients must be interviewed within one hour of first physician evaluation, typically in an emergency department or acute care setting, with dyspnea assessed by the patient using both a 5-point Likert scale and 10-point visual analog scale in the sitting (60 degrees) and then supine (20 degrees ) position if symptomatically able. Improvement of dyspnea by change in Likert and visual analog scale scores at 6 h is the primary endpoint. CONCLUSIONS: Timing of dyspnea measurement and the conditions under which it is measured may influence dyspnea severity and this may have significant implications for future acute heart failure syndromes clinical trial design that target dyspnea.

Levosimendan use in several scenarios of acute heart failure.

In countries where it is available, early levosimendan infusion can be considered for patients who remain symptomatic with dyspnea at rest despite initial therapy, particularly those with a history of chronic heart failure or chronically treated with beta-blockers. Hypotensive patients or patients with active ischemia are not the best candidates for levosimendan administration and should have these problems addressed first.

A proposal to standardize dyspnoea measurement in clinical trials of acute heart failure syndromes: the need for a uniform approach.

Dyspnoea is the most common presenting symptom amongst patients with acute heart failure syndromes (AHFS). It is distressing to patients and therefore an important target for treatment in clinical practice, clinical trials, and for regulatory approval of novel agents. Despite its importance as a treatment target, no consensus exists on how to assess dyspnoea in this setting. There is a considerable uncertainty about the reproducibility of the various instruments used to measure dyspnoea, their ability to reflect changes in symptoms and whether they accurately reflect the patient's experience. Little attempt has been made to ensure consistent implementation with respect to patients' posture during assessment or timing in relationship to therapy. There is also limited understanding of how rapidly and completely dyspnoea responds to standard therapy. A standardized method with which to assess dyspnoea is required for clinical trials of AHFS in order to ensure uniform collection of data on a key endpoint. We propose the Provocative Dyspnoea Assessment, a method of measurement that combines sequential dyspnoea provocation by positioning and walking with a dyspnoea self assessment using a five-point Likert scale, to yield a final Dyspnoea Severity Score. This proposed tool requires detailed validation but has face validity for the uniform assessment of dyspnoea.

Uso de levosimendana em diversos quadros de insuficiência cardíaca aguda: [revisão] / Levosimendan use in several scenarios of acute heart failure: [review]

Nos países em que é comercializada, a administração precoce de levosimendana deve ser considerada em pacientes que permanecem sintomáticos e com dispnéia em repouso apesar da terapia inicial, principalmente aqueles com história de insuficiência cardíaca crônica ou em tratamento prolongado com betabloqueadores. Pacientes hipotensos ou com isquemia ativa não são os melhores candidatos para receber infusão de levosimendana e precisam, primeiro, ter esses problemas tratados.

In countries where it is available, early levosimendan infusion can be considered for patients who remain symptomatic with dyspnea at rest despite initial therapy, particularly those with a history of chronic heart failure or chronically treated with beta-blockers. Hypotensive patients or patients with active ischemia are not the best candidates for levosimendan administration and should have these problems addressed first.

New pharmacologic therapies for acute heart failure.

Given the limitations of high-dose diuretics and vasodilators and the increasing literature showing that inotropes, regardless of the dose used, have a detrimental effect on mortality, a variety of new agents are under investigation for the treatment of pulmonary and systemic congestion and restoration of cardiac output in the setting of acute heart failure syndromes. The new therapeutic approach is based on two goals: short-term improvement in symptoms together with long-term improvement of cardiac function. This review describes new agents that are in preclinical and in clinical phases with realistic prospects: anti-endothelin, natriuretic peptides, istaroxime, levosimendan, myosin activators, and vasopressin antagonists. Those new therapeutic strategies aim to act at the cellular level to improve vessel and heart functions, with minimal side effects, together with improved sodium and water balance.

Algorithm for therapeutic management of acute heart failure syndromes.

As for other critically ill diseases, two key factors may markedly improved morbidity and mortality of acute heart failure syndromes (AHFS): early initiation of treatment and tailored therapy. Early initiation aims to stop the negative cascade of heart dysfunction. Tailored therapy should be based on the level of systolic blood pressure at admission and fluid retention. Indeed, EFICA and OPTIMIZE-HF showed that patients with high systolic blood pressure have a left ventricular systolic function that is likely preserved and those with low systolic blood pressure have a lower left ventricular ejection fraction and frequent signs of organ's hypoperfusion. Among the proposed treatments, non-invasive ventilation is the only treatment that was consistently proven to be beneficial on morbidity and mortality in almost all types of AHFS. Concerning pharmacological agents, actions should be taken to increase the use of vasodilators and reduce the use of diuretics.