Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series.

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease.

Importance: Numerous studies have established the association of the common APOE ε2 and APOE ε4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction. Objective: To determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk. Design, Setting, and Participants: Case-control study including 31 929 participants and using a sequenced discovery sample (Alzheimer Disease Sequencing Project; stage 1) followed by 2 microarray imputed data sets derived from the Alzheimer Disease Genetic Consortium (stage 2, internal replication) and the Million Veteran Program (stage 3, external validation). This study combined case-control, family-based, population-based, and longitudinal AD cohorts, which recruited participants (1991-2022) in primarily US-based studies with 1 US/Nigerian study. Across all stages, individuals included in this study were of African ancestry. Exposures: Two APOE missense variants (R145C and R150H) were assessed, stratified by APOE genotype. Main Outcomes and Measures: The primary outcome was AD case-control status, and secondary outcomes included age at AD onset. Results: Stage 1 included 2888 cases (median age, 77 [IQR, 71-83] years; 31.3% male) and 4957 controls (median age, 77 [IQR, 71-83] years; 28.0% male). In stage 2, across multiple cohorts, 1201 cases (median age, 75 [IQR, 69-81] years; 30.8% male) and 2744 controls (median age, 80 [IQR, 75-84] years; 31.4% male) were included. In stage 3, 733 cases (median age, 79.4 [IQR, 73.8-86.5] years; 97.0% male) and 19 406 controls (median age, 71.9 [IQR, 68.4-75.8] years; 94.5% male) were included. In ε3/ε4-stratified analyses of stage 1, R145C was present in 52 individuals with AD (4.8%) and 19 controls (1.5%); R145C was associated with an increased risk of AD (odds ratio [OR], 3.01; 95% CI, 1.87-4.85; P = 6.0 × 10-6) and was associated with a reported younger age at AD onset (ß, -5.87 years; 95% CI, -8.35 to -3.4 years; P = 3.4 × 10-6). Association with increased AD risk was replicated in stage 2 (R145C was present in 23 individuals with AD [4.7%] and 21 controls [2.7%]; OR, 2.20; 95% CI, 1.04-4.65; P = .04) and was concordant in stage 3 (R145C was present in 11 individuals with AD [3.8%] and 149 controls [2.7%]; OR, 1.90; 95% CI, 0.99-3.64; P = .051). Association with earlier AD onset was replicated in stage 2 (ß, -5.23 years; 95% CI, -9.58 to -0.87 years; P = .02) and stage 3 (ß, -10.15 years; 95% CI, -15.66 to -4.64 years; P = 4.0 × 10-4). No significant associations were observed in other APOE strata for R145C or in any APOE strata for R150H. Conclusions and Relevance: In this exploratory analysis, the APOE ε3[R145C] missense variant was associated with an increased risk of AD among individuals of African ancestry with the ε3/ε4 genotype. With additional external validation, these findings may inform AD genetic risk assessment in individuals of African ancestry.

Culture, sex and social context influence brain-to-brain synchrony: an fNIRS hyperscanning study.

BACKGROUND: Unique interpersonal synchrony occurs during every social interaction, and is shaped by characteristics of participating individuals in these social contexts. Additionally, depending on context demands, interpersonal synchrony is also altered. The study therefore aims to investigate culture, sex, and social context effects simultaneously in a novel role-play paradigm. Additionally, the effect of personality traits on synchrony was investigated across cultures, and a further exploratory analysis on the effects of these variables on pre- and post-session empathy changes was conducted. METHODS: 83 dyads were recruited in two waves from Singapore and Italy and took part in a within-subjects session where they interacted with each other as themselves (Naturalistic Conversation) and as others (Role-Play and Role Reversal). Big Five Inventory (administered pre-session) and Interpersonal Reactivity Index (administered pre- and post-session) were used as measures of personality and empathy respectively, while synchrony was measured using hyperscanning functional near-infrared spectroscopy in the prefrontal cortex. After data-preprocessing and preliminary analyses, a mixture of multiple linear regression and exploratory forward stepwise regression models were used to address the above study aims. RESULTS: Results revealed significant main and interaction effects of culture, sex and social context on brain-to-brain synchrony, particularly in the medial left cluster of the prefrontal cortex, and a unique contribution of extraversion and openness to experience to synchrony in the Italian cohort only. Finally, culture-driven differences in empathy changes were identified, where significant increases in empathy across sessions were generally only observed within the Singaporean cohort. CONCLUSIONS: Main findings indicate lowered brain-to-brain synchrony during role-playing activities that is moderated by the dyad's sex make-up and culture, implying differential processing of social interactions that is also influenced by individuals' background factors. Findings align with current literature that role-playing is a cognitively demanding activity requiring greater levels of self-regulation and suppression of self-related cognition as opposed to interpersonal co-regulation characterized by synchrony. However, the current pattern of results would be better supported by future studies investigating multimodal synchronies and corroboration.

The NeuroAiD II (MLC901) in vascular cognitive impairment study (NEURITES).

BACKGROUND: A substantial proportion of patients after nondisabling stroke are cognitively impaired compared to age- and education-matched community-dwelling controls. Moreover, poststroke patients who have 'vascular cognitive impairment no dementia' (VCIND) of moderate severity have a high risk of incident dementia, dependency and death. Further studies are urgently needed to demonstrate effective cognition-enhancing therapies in VCIND given the scarcity of evidence-based treatment options. NeuroAiD is a traditional Chinese medicine that has been shown to induce neuroplasticity, promote cell proliferation and stimulate the development of dense axonal and dendritic networks in animal stroke models. NeuroAiD may improve cerebral blood flow and functional recovery after stroke in patients. OBJECTIVE: To investigate the effects and tolerability of NeuroAiD II in patients with VCIND. METHODS: The NeuroAiD II (MLC901) in Vascular Cognitive Impairment Study (NEURITES) is a 24-week, double-blind, randomized, placebo-controlled phase II study of NeuroAiD II in patients with VCIND. The primary outcome is executive function as measured by the Verbal Fluency test. Secondary outcomes include cognitive assessments such as the ADAS-Cog, MoCA, MMSE and Cognitive Battery: activities of daily living as measured by the Alzhei-mer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scale for mild cognitive impairment, behavior as measured by the Neuropsychiatric Inventory, and depression as measured by the Geriatric Depression Scale and the Beck Depression Scale. In addition, there will be novel exploratory outcomes: (a) magnetic resonance imaging of lesion location (structural imaging), structural integrity of white matter pathways (diffusion tensor imaging), neuronal function (resting studies) and perfusion (arterial spin labeling and MR angiography), and (b) retinal and optic nerve imaging. Safety and tolerability will be assessed using adverse events, laboratory tests and vital signs. CONCLUSIONS: NEURITES has the potential to set new standards for the systematic evaluation of Asian traditional medicine for integration into standard medicine practice and establishing a novel therapeutic approach for improving cognition after stroke.

Do Types of Information in an Animated Video Intervention Affect University Students' Autism Knowledge and Openness Towards Peers on the Autism Spectrum?

This pre-test post-test control group design sought to compare the effectiveness of delivering different types of information ([1] factual information vs. [2] factual information + descriptive and explanatory information vs. [3] factual information + descriptive, explanatory + directive information) in an animated video intervention in increasing university students' autism knowledge and openness toward peers on the autism spectrum. The sample consisted of 92 undergraduates (27 males, 65 females; age range = 18-36) from various universities in Singapore. Participants were randomly assigned to one of the three experimental conditions/videos, where they completed a measure of their autism knowledge and openness scale, before viewing a 5-minute long animated video containing different types of information about autism. After which, participants completed the measure of autism knowledge and openness scale again, followed by a measure of their empathy level. Results indicated that participants' autism knowledge improved following the viewing of the animated video. However, the three different videos containing different types of information did not differ in influencing participants' openness toward peers on the autism spectrum. Nevertheless, qualitative responses proposed that the video containing factual information, with descriptive, explanatory, and directive information was useful in helping participants to know how to interact with their peers on the autism spectrum. The findings of this study provide preliminary support for the most effective method to educate and raise awareness about autism, among the general student population in order to foster a supportive and inclusive environment.

Understanding Women's Knowledge, Awareness, and Perceptions of STIs/STDs in Asia: A Scoping Review.

OBJECTIVE: This study aimed to conduct a scoping review to collect current literature on the knowledge, awareness, and perception (KAP) of sexually transmitted infections/diseases (STIs/STDs) among women in Asia. METHODOLOGY: The PRISMA-Scoping methodology was used in this study to extract papers from four databases published between 2018 and 2022. Sixty-eight articles were included after screening and elimination. RESULTS: The studies on KAP of STIs/STDs among women were largely undertaken in Southeast Asia (Indonesia, Malaysia, and Vietnam) and South Asia (India, Pakistan, and Bangladesh). Regardless of the specific cohort of women studied, research indicates consistently low levels of knowledge and awareness across Asia. This trend seems to be more prevalent among female commercial sex workers, women with lower educational levels, and those in poorer socioeconomic positions. In South Asia, cultural, sociological, economic, and gender inequalities, particularly male domination, all have a significant impact on KAP levels. CONCLUSION: As education is a major factor that influences health behaviour, this review underscores the need to allocate more resources to educational initiatives, particularly targeting vulnerable groups such as sex workers, transgender women, pregnant women, and rural housewives. This strategic focus may contribute significantly to preventing STIs/STDs, particularly in less developed regions/countries.

Potential cognitive and neural benefits of a computerised cognitive training programme based on Structure Learning in healthy adults: study protocol for a randomised controlled trial.

BACKGROUND: Cognitive flexibility refers to the capacity to shift between conceptual representations particularly in response to changes in instruction and feedback. It enables individuals to swiftly adapt to changes in their environment and has significant implications for learning. The present study focuses on investigating changes in cognitive flexibility following an intervention programme-Structure Learning training. METHODS: Participants are pseudo-randomised to either the Training or Control group, while matched on age, sex, intelligence and cognitive flexibility performance. In the Training group, participants undergo around 2 weeks of training (at least 13 sessions) on Structure Learning. In the Control group, participants do not have to undergo any training and are never exposed to the Structure Learning task. The effects of Structure Learning training are investigated at both the behavioural and neural level. We measured covariates that can influence an individual's training performance before the training phase and outcome measures that can potentially show training benefits after the training phase. At the behavioural level, we investigated outcomes in both cognitive and social aspects with a primary focus on executive functions. At the neural level, we employed a multimodality approach and investigated potential changes to functional connectivity patterns, neurometabolite concentration in the frontal brain regions, and brain microstructure and myelination. DISCUSSION: We reported the development of a novel training programme based on Structure Learning that aims to hone a general learning ability to potentially achieve extensive transfer benefits across various cognitive constructs. Potential transfer benefits can be exhibited through better performance in outcome measures between Training and Control participants, and positive associations between training performance and outcomes after the training in Training participants. Moreover, we attempt to substantiate behavioural findings with evidence of neural changes across different imaging modalities by the Structure Learning training. TRIAL REGISTRATION: National Institutes of Health U.S. National Library of Medicine ClinicalTrials.gov NCT05611788. Registered on 7 November 2022. PROTOCOL VERSION: 11 May 2023.

Study protocol: How does cognitive flexibility relate to other executive functions and learning in healthy young adults?

BACKGROUND: Cognitive flexibility (CF) enables individuals to readily shift from one concept or mode of practice/thoughts to another in response to changes in the environment and feedback, making CF vital to optimise success in obtaining goals. However, how CF relates to other executive functions (e.g., working memory, response inhibition), mental abilities (e.g., creativity, literacy, numeracy, intelligence, structure learning), and social factors (e.g., multilingualism, tolerance of uncertainty, perceived social support, social decision-making) is less well understood. The current study aims to (1) establish the construct validity of CF in relation to other executive function skills and intelligence, and (2) elucidate specific relationships between CF, structure learning, creativity, career decision making and planning, and other life skills. METHODS: This study will recruit up to 400 healthy Singaporean young adults (age 18-30) to complete a wide range of cognitive tasks and social questionnaires/tasks. The richness of the task/questionnaire battery and within-participant administration enables us to use computational modelling and structural equation modelling to examine connections between the latent constructs of interest. SIGNIFICANCE AND IMPACT: The current study is the first systematic investigation into the construct validity of CF and its interrelationship with other important cognitive skills such as learning and creativity, within an Asian context. The study will further explore the concept of CF as a non-unitary construct, a novel theoretical proposition in the field. The inclusion of a structure learning paradigm is intended to inform future development of a novel intervention paradigm to enhance CF. Finally, the results of the study will be useful for informing classroom pedagogy and the design of lifelong learning policies and curricula, as part of the wider remit of the Cambridge-NTU Centre for Lifelong Learning and Individualised Cognition (CLIC).

IcyHot analgesic topical cream limits cardiac injury in rodents.

Little is known whether topical analgesic creams, whose natural products enter the blood stream after application, affect myocardial infarct size. Here we tested whether topical analgesic creams can trigger remote cardioprotection and the mechanism involved. Male Sprague Dawley rats were used for an in vivo rodent model consisting of 30 minutes left anterior descending coronary artery ischemia and 2 hours of reperfusion followed by infarct size assessment. The topical analgesic IcyHot, applied to the abdomen prior to ischemia, reduced myocardial infarct size versus control (41 ± 3* vs 62 ± 1, n= 6/group, *P < 0.001). In contrast, the topical analgesic creams Preparation H, Aspercreme Heat, or Tiger Balm did not alter infarct size. IcyHot, unlike Preparation H, increased circulating methyl salicylate levels during reperfusion (3.0 ± 0.6 vs 0.4 ± 0.2 mg/dL, n = 6, *P < 0.001, measured at the internal jugular vein). Methyl salicylate (10 µM) applied to isolated adult cardiac myocytes during reoxygenation reduced cell death when compared to vehicle (21% ± 2%* vs 30% ± 2% of trypan blue positive cells, n = 9/group, *P < 0.01). Further, treatment with the TRP ankyrin 1 (TRPA1) inhibitors TCS-5861528 (1 µM) or AP-18 (1 µM) blocked the methyl salicylate-induced protective effect in isolated adult cardiomyocytes. In intact rodents, either of the TRPA1 inhibitors (1 mg/kg, intravenous) given prior to IcyHot topical application blocked IcyHot-induced infarct size reduction. IcyHot also reduced infarct size when applied 24 hours prior to myocardial ischemia or during myocardial ischemia versus control. Together, these findings support IcyHot analgesic cream can trigger remote cardioprotection through releasing methyl salicylate into the bloodstream with cardioprotection occurring by a TRPA1-dependent mechanism.

Association of atrial fibrillation and amino-terminal pro-brain natriuretic peptide concentrations in dyspneic subjects with and without acute heart failure: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study.

BACKGROUND: Amino-terminal pro-brain natriuretic peptide (NT-proBNP) testing is useful for diagnosis or exclusion of heart failure (HF) in dyspneic patients. Atrial fibrillation (AF) may cause dyspnea in the absence of acute HF and may also affect plasma levels of NT-proBNP. METHODS: We prospectively enrolled 599 patients presenting with dyspnea to the emergency department and obtained a blood sample for NT-proBNP measurement. The diagnosis of AF was identified via presentation electrocardiogram. A final diagnosis of HF was determined by blinded study physicians using all available hospital records for each subject through 60 days of follow-up. We assessed the association between the presence of AF and level of NT-proBNP in subsets of patients with and without HF. RESULTS: Of 599 dyspneic patients, 75 (13%) were in AF at presentation; these patients had significantly higher median NT-proBNP levels when compared with those without AF (2934 vs 294 pg/mL, P < .0001). Among patients with acute HF, AF was present in 28%; NT-proBNP levels were lower in those with AF versus those without (3488 vs 4492 pg/mL, P < .001), but AF was not independently associated with NT-proBNP after multivariable adjustment. In patients without acute HF, median NT-proBNP concentrations were significantly higher in those with AF than in those without (932 vs 121 pg/mL, P = .02); in these subjects, AF was the strongest predictor of an NT-proBNP concentration in a range consistent with acute HF (odds ratio 9.94, 95% CI 2.97-33.3, P < .001). CONCLUSION: Atrial fibrillation is associated with higher NT-proBNP concentrations in dyspneic patients, particularly in those without acute HF.

Usefulness of aminoterminal pro-brain natriuretic peptide testing for the diagnostic and prognostic evaluation of dyspneic patients with diabetes mellitus seen in the emergency department (from the PRIDE Study).

Despite widespread testing, the utility of aminoterminal pro-brain natriuretic peptide (NT-pro-BNP) for diagnosis or risk assessment in patients with diabetes mellitus (DM) in the emergency department (ED) remains unclear. NT-pro-BNP was measured in subjects with dyspnea in the ED. A final diagnosis of acute heart failure (HF) was determined by blinded study physicians using all available hospital records. Vital status was assessed at 1 year; independent predictors of death were identified using Cox analysis. Of 599 subjects, 157 (26.2%) had DM, which was an independent predictor of a final diagnosis of acute HF. In patients diagnosed with acute HF, median concentrations of NT-pro-BNP were similar in patients with and without DM (4,784 vs 3,382 pg/ml, respectively, p = 0.93). In dyspneic subjects without acute HF, median concentrations of NT-pro-BNP were significantly higher in patients with DM (242 vs 115 pg/ml, p = 0.01), but this difference was no longer significant after adjusting for relevant covariates. The area under the curve for NT-pro-BNP to diagnose acute HF in subjects with DM was 0.94 (p <0.001). Using age-adjusted cutpoints, NT-pro-BNP was 92% sensitive and 90% specific for the diagnosis of HF in diabetic subjects. In diabetic patients, a NT-pro-BNP level > or =986 pg/ml was independently associated with an increased risk of death at 1 year (hazard ratio 3.42, 95% confidence interval 1.09 to 10.7, p <0.001). In conclusion, NT-pro-BNP testing offers valuable diagnostic and prognostic information in the evaluation of dyspneic patients with DM in the ED, using identical cutpoints as the population as whole.

A validated clinical and biochemical score for the diagnosis of acute heart failure: the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Acute Heart Failure Score.

BACKGROUND: No method integrating amino-terminal pro-brain natriuretic peptide (NT-proBNP) testing with clinical assessment for the evaluation of patients with suspected acute heart failure (HF) has been described. METHODS: Amino-terminal pro-brain natriuretic peptide results and clinical factors from 599 patients with dyspnea were analyzed. The beta coefficients of the 8 independent predictors of HF were used to assign a weighted integeric score for predictor. The sum of these integers provided a diagnostic HF "score" for each patient. Receiver operating characteristic curve analysis determined the optimal cut point for the diagnosis of acute HF. The performance of the score was evaluated in the development cohort and subsequently in a patient population from a separate clinical trial of patients with dyspnea conducted in Christchurch, New Zealand. RESULTS: Eight factors comprised the score: elevated NT-proBNP (4 points), interstitial edema on chest x-ray (2 points), orthopnea (2 points), absence of fever (2 points), loop diuretic use, age > 75 years, rales, and absence of cough (all 1 point). Median scores in patients with acute HF were higher than those without acute HF (9 vs 3 points, P < .001). At a cut point of > or = 6 points, the score had a sensitivity of 96% and a specificity of 84% for the diagnosis of acute HF (P < .001). The score improved diagnostic accuracy over NT-proBNP testing alone and retained discriminative capacity in patients in whom clinical uncertainty was present. Lastly, the accuracy of the score was validated in the external data set of patients with suspected acute HF. CONCLUSION: We report a simple and accurate scoring system combining NT-proBNP testing and clinical assessment for the diagnosis or exclusion of acute HF in patients with dyspnea.

Acute predictors of subacute complete heart block after alcohol septal ablation for obstructive hypertrophic cardiomyopathy.

Acute and subacute complete heart block (CHB) are sequelae of alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy. Temporary pacemakers are routinely placed at the time of ASA, but there are no widely accepted guidelines for their management. This study examined acute predictors of subacute CHB in 52 consecutive ASA procedures in 48 patients without preexisting permanent pacemakers. Acute CHB occurred during 32 ASA procedures (62%), with the return of atrioventricular conduction on the day of ASA in all cases. New intraventricular conduction defects (IVCDs) were noted after 32 procedures (62%); in 9 of these, there was new first-degree atrioventricular block as well. CHB recurred subacutely 36 +/- 22 hours after 13 ASA procedures (25%). In 5 of these cases, there was absent or inconsistent ventricular escape rhythm. Subacute CHB did not occur in 9 cases without acute CHB during ASA or new IVCDs after ASA. Acute CHB during ASA, new IVCDs after ASA, and new first-degree atrioventricular block after ASA incrementally increased the risk for subacute CHB. In conclusion, patients with acute CHB during ASA or new IVCDs after ASA are at high risk for developing subacute CHB, sometimes without a reliable escape rhythm; these patients should therefore have temporary pacing support for > or = 48 hours after ASA or the last occurrence of CHB. Patients without acute CHB during ASA or new IVCDs after ASA are at low risk for subacute CHB.

Neither race nor gender influences the usefulness of amino-terminal pro-brain natriuretic peptide testing in dyspneic subjects: a ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) substudy.

BACKGROUND: Amino-terminal pro-brain natriuretic peptide (NT-proBNP) is useful for the diagnosis and exclusion of congestive heart failure (HF). Little is known about the effect of race on NT-proBNP concentrations. Also, NT-proBNP levels may be higher in apparently well women, but the effect of gender on NT-proBNP concentrations in dyspneic patients is not known. METHODS AND RESULTS: NT-proBNP (Elecsys proBNP, Roche, Indianapolis, IN) was measured in 599 dyspneic patients in a prospective study. Of these, 44 were African American; 295 were female. NT-proBNP levels were examined according to race and gender in patients with and without acute HF using analysis of covariance. Receiver operating characteristic (ROC) curves assessed NT-proBNP by race and gender. Cutpoints for diagnosis (450, 900, and 1800 pg/mL for ages < 50, 50 to 75, and > 75 years) and exclusion (300 pg/mL) were examined in African-American and female subjects. There was no difference in the rates of acute HF between African-American and non-African-American (30% versus 35%, P = .44) or male and female (35% versus 35%, P = .86) subjects. In subjects with HF, there was no difference in median NT-proBNP concentrations between African American and non-African American (6196 versus 3597 pg/mL, P = .37). In subjects without HF, unadjusted NT-proBNP levels were lower in African-American subjects than in non-African-American subjects (68 versus 148 pg/mL, P < .03); however, when adjusted for factors known to influence NT-proBNP concentrations (age, prior HF, creatinine clearance, atrial fibrillation, and body mass index), race no longer significantly affected NT-proBNP concentrations. There was no statistical difference in median NT-proBNP concentrations between male and female subjects with (4686 versus 3622 pg/mL, P = .53) or without HF (116 pg/mL versus 150 pg/mL, P = .62). Among African Americans, NT-proBNP had an area under the ROC for acute HF of 0.96 (P < .0001), and at optimal cutpoints, had a sensitivity of 100% and a specificity of 90%. Among females, NT-proBNP had an area under the ROC for acute HF of 0.95 (P < .0001), and had a sensitivity of 89% and a specificity of 88%; 300 pg/mL had negative predictive value of 100% in African Americans and females. CONCLUSION: NT-proBNP is useful for the diagnosis and exclusion of acute HF in dyspneic subjects, irrespective of race or gender.

Amino-terminal pro-brain natriuretic peptide for the diagnosis of acute heart failure in patients with previous obstructive airway disease.

STUDY OBJECTIVE: We evaluate results from amino-terminal pro-brain natriuretic peptide (NT-proBNP) testing with or without those of clinical judgment for the evaluation of dyspneic patients with previous chronic obstructive pulmonary disease or asthma. METHODS: As a secondary analysis of previously collected observational data from a convenience sample of 599 breathless patients, 216 patients with previous chronic obstructive pulmonary disease or asthma who presented to the emergency department were analyzed according to results of NT-proBNP, clinical impression, and their final diagnosis. Test performance of NT-proBNP in these patients with chronic obstructive pulmonary disease or asthma was examined for the group as a whole, as well as in patients with and without previous heart failure. NT-proBNP results were compared to clinician-estimated likelihood for heart failure using receiver operating curves and as a function of NT-proBNP plus clinical evaluation. The final diagnosis was determined by 2 independent cardiologists blinded to NT-proBNP using all available data from the 60-day follow-up period. RESULTS: Overall, 55 patients (25%) had acute heart failure; the median value of NT-proBNP was higher in these patients compared with those without acute heart failure (2,238 vs 178 pg/mL); use of cut points of 450 pg/mL for patients younger than 50 years and 900 pg/mL for patients 50 years or older yielded a sensitivity of 87% (95% confidence interval [CI] 72% to 93%) and a specificity of 84% (95% CI 76% to 88%). In patients without previous heart failure (n=164), median NT-proBNP levels were also higher in patients with heart failure of new onset compared with those with chronic obstructive pulmonary disease or asthma exacerbation (1561 versus 168 pg/mL). High clinical suspicion for acute heart failure (probability >80%) detected only 23% of patients with new-onset heart failure, whereas 82% of these patients had elevated NT-proBNP levels. In patients who had both previous acute heart failure and chronic obstructive pulmonary disease or asthma (n=52), median NT-proBNP levels were significantly higher in those with acute heart failure (4,435 pg/mL) than patients with chronic obstructive pulmonary disease or asthma exacerbation (536 pg/mL). In patients with acute-on-chronic heart failure, NT-proBNP levels were elevated in 91%, whereas clinical impression considered only 39% of cases as high likelihood for acute heart failure. CONCLUSION: NT-proBNP may be a useful adjunct to standard clinical evaluation of dyspneic patients with previous obstructive airway disease.

Effect of body mass index on natriuretic peptide levels in patients with acute congestive heart failure: a ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) substudy.

BACKGROUND: Obesity is associated with lower B-type natriuretic peptide (BNP) levels in healthy individuals and patients with chronic congestive heart failure (CHF). Neither the mechanism of natriuretic peptide suppression in the obese patient nor whether obesity affects natriuretic peptide levels among patients with acute CHF is known. METHODS: The associations of amino-terminal pro-BNP (NT-proBNP), BNP, and body mass index (BMI) were examined in 204 subjects with acute CHF. Multivariable regression analyses were performed to identify factors independently related to NT-proBNP and BNP levels. RESULTS: Across clinical strata of normal (<25 kg/m2), overweight (25-29.9 kg/m2), and obese (> or =30 kg/m2) patients, median NT-proBNP and BNP levels decreased with increasing BMI (both P values < .001). In multivariable analyses adjusting for covariates known to affect BNP levels, the inverse relationship between BMI and both NT-proBNP and BNP remained ( P < .05 for both). Using a cut point of 900 pg/mL, NT-proBNP was falsely negative in up to 10% of CHF cases in overweight patients (25-29.9 kg/m2) and 15% in obese patients (> or =30 kg/m2). Using the standard cut point of 100 pg/mL, BNP testing was falsely negative in 20% of CHF cases in both overweight and obese patients. The assays for NT-proBNP and BNP exhibited similar overall sensitivity for the diagnosis of CHF. CONCLUSIONS: When adjusted for relevant covariates, compared with normal counterparts, overweight and obese patients with acute CHF have lower circulating NT-proBNP and BNP levels, suggesting a BMI-related defect in natriuretic peptide secretion. NT-proBNP fell below the diagnostic cutoff for CHF less often than BNP in overweight and obese individuals; however, when used as a diagnostic tool to identify CHF in such patients, both markers may have reduced sensitivity.

Combined use of amino terminal-pro-brain natriuretic peptide levels and QRS duration to predict left ventricular systolic dysfunction in patients with dyspnea.

The combination of elevated amino-terminal pro-brain natriuretic peptide levels and wide QRS duration was highly sensitive and specific for the prediction of impaired left ventricular systolic function among a group of patients presenting with dyspnea to the emergency department. This strategy can be used to predict depressed function and target more formal evaluation with echocardiography in patients with dyspnea.

The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study.

The utility of aminoterminal pro-brain natriuretic peptide (NT-proBNP) testing in the emergency department to rule out acute congestive heart failure (CHF) and the optimal cutpoints for this use are not established. We conducted a prospective study of 600 patients who presented in the emergency department with dyspnea. The clinical diagnosis of acute CHF was determined by study physicians who were blinded to NT-proBNP results. The primary end point was a comparison of NT-proBNP results with the clinical assessment of the managing physician for identifying acute CHF. The median NT-proBNP level among 209 patients (35%) who had acute CHF was 4,054 versus 131 pg/ml among 390 patients (65%) who did not (p <0.001). NT-proBNP at cutpoints of >450 pg/ml for patients <50 years of age and >900 pg/ml for patients >or=50 years of age were highly sensitive and specific for the diagnosis of acute CHF (p <0.001). An NT-proBNP level <300 pg/ml was optimal for ruling out acute CHF, with a negative predictive value of 99%. Increased NT-proBNP was the strongest independent predictor of a final diagnosis of acute CHF (odds ratio 44, 95% confidence interval 21.0 to 91.0, p <0.0001). NT-proBNP testing alone was superior to clinical judgment alone for diagnosing acute CHF (p = 0.006); NT-proBNP plus clinical judgment was superior to NT-proBNP or clinical judgment alone. NT-proBNP measurement is a valuable addition to standard clinical assessment for the identification and exclusion of acute CHF in the emergency department setting.

Echocardiographic measures of acute haemodynamic response after cardiac resynchronization therapy predict long-term clinical outcome.

AIMS: Although acute haemodynamic improvement in response to cardiac resynchronization therapy (CRT) is reflective of a favourable cardiac contractile response, there is limited information regarding not only its ability to predict long-term clinical outcome but also cardiac-substrate-specific differences in the prognostic value of this measure. METHODS AND RESULTS: Fifty-three heart failure patients (69 +/- 11 years) with low left ventricle ejection fraction (LVEF) (22 +/- 6%), wide QRS (169 +/- 31 ms), and indications for CRT were included. There were no significant differences in age, New York Heart Association (NYHA) class, medications, QRS width, or LVEF between ischaemic (n = 37) and non-ischaemic (n = 16) groups. Echocardiograms were performed within 24 h of implantation with device OFF and ON. Acute haemodynamic response was measured as LV dP/dt derived from the CW Doppler of mitral regurgitation. Percentage change in dP/dt was used to classify patients: high- (HR: DeltadP/dt > 25%) or poor-responders (PR: DeltadP/dt