Using the HER2/CEP17 FISH Ratio to Predict Pathologic Complete Response Following Neoadjuvant Anti-HER2 Doublet Therapy in HER2+ Breast Cancer.

BACKGROUND: Clinical trials of HER2-directed therapy that omit neoadjuvant conventional chemotherapy for HER+ breast cancer demonstrate that a subset of patients still obtains a pCR. Identifying tumor characteristics which predict pCR may help select patients for de-escalated neoadjuvant dual HER2-targeted treatment without chemotherapy. This is the first study evaluating the HER2/CEP17 ratio by FISH as a biomarker to predict pCR among patients who received neoadjuvant anti-HER2 regimens without chemotherapy. PATIENTS AND METHODS: Data from patients with locally advanced HER2+ breast cancer who received neoadjuvant dual HER2-targeted therapy without conventional chemotherapy from a single center was retrospectively reviewed. All patients were enrolled in one of 3 clinical trials evaluating chemotherapy de-escalation. Logistic regression modeling assessed for a relationship between the HER2/CEP17 FISH ratio obtained from baseline tissue biopsy and pCR based on pathology at the time of definitive breast surgery following neoadjuvant treatment. RESULTS: Following neoadjuvant treatment with dual HER2-targeted therapies in 56 patients, the probability of pCR was 73% among patients with a HER2 ratio of 13.1 compared to a probability of 38% among patients with HER2 ratio of 5.5 (OR 4.14, 95% CI 1.44-11.89; P = .012). This positive association persisted after controlling for different treatment regimens administered (OR 2.87, 95% CI 0.9-9.18, P = .020). CONCLUSIONS: These data found a positive association between the HER2/CEP17 FISH ratio and pCR following neoadjuvant dual HER2-targeted therapy without chemotherapy. Larger prospective studies are needed to validate the HER2 ratio as a biomarker to select patients for neoadjuvant dual anti-HER2 therapy without chemotherapy.

The Brain-Heart Axis: Neuroinflammatory Interactions in Cardiovascular Disease.

PURPOSE OF REVIEW: The role of neuroimmune modulation and inflammation in cardiovascular disease has been historically underappreciated. Physiological connections between the heart and brain, termed the heart-brain axis (HBA), are bidirectional, occur through a complex network of autonomic nerves/hormones and cytokines, and play important roles in common disorders. RECENT FINDINGS: At the molecular level, advances in the past two decades reveal complex crosstalk mediated by the sympathetic and parasympathetic nervous systems, the renin-angiotensin aldosterone and hypothalamus-pituitary axes, microRNA, and cytokines. Afferent pathways amplify proinflammatory signals via the hypothalamus and brainstem to the periphery, promoting neurogenic inflammation. At the organ level, while stress-mediated cardiomyopathy is the prototypical disorder of the HBA, cardiac dysfunction can result from a myriad of neurologic insults including stroke and spinal injury. Atrial fibrillation is not necessarily a causative factor for cardioembolic stroke, but a manifestation of an abnormal atrial substrate, which can lead to the development of stroke independent of AF. Central and peripheral neurogenic proinflammatory factors have major roles in the HBA, manifesting as complex bi-directional relationships in common conditions such as stroke, arrhythmia, and cardiomyopathy.

The Promise and Illusion of Continuous, Cuffless Blood Pressure Monitoring.

PURPOSE OF REVIEW: Blood pressure (BP) fluctuations outside of clinic are increasingly recognized for their role in the development of cardiovascular disease, syncope, and premature death and as a promising target for tailored hypertension treatment. However, current cuff-based BP devices, including home and ambulatory devices, are unable to capture the breadth of BP variability across human activities, experiences, and contexts. RECENT FINDINGS: Cuffless, wearable BP devices offer the promise of beat-to-beat, continuous, noninvasive measurement of BP during both awake and sleep periods with minimal patient inconvenience. Importantly, cuffless BP devices can characterize BP variability, allowing for the identification of patient-specific triggers of BP surges in the home environment. Unfortunately, the pace of evidence, regulation, and validation testing has lagged behind the pace of innovation and direct consumer marketing. We provide an overview of the available technologies and devices for cuffless BP monitoring, considerations for the calibration and validation of these devices, and the promise and pitfalls of the cuffless BP paradigm.

Orthostatic Hypotension, Hypertension Treatment, and Cardiovascular Disease: An Individual Participant Meta-Analysis.

Importance: There are ongoing concerns about the benefits of intensive vs standard blood pressure (BP) treatment among adults with orthostatic hypotension or standing hypotension. Objective: To determine the effect of a lower BP treatment goal or active therapy vs a standard BP treatment goal or placebo on cardiovascular disease (CVD) or all-cause mortality in strata of baseline orthostatic hypotension or baseline standing hypotension. Data Sources: Individual participant data meta-analysis based on a systematic review of MEDLINE, EMBASE, and CENTRAL databases through May 13, 2022. Study Selection: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) with orthostatic hypotension assessments. Data Extraction and Synthesis: Individual participant data meta-analysis extracted following PRISMA guidelines. Effects were determined using Cox proportional hazard models using a single-stage approach. Main Outcomes and Measures: Main outcomes were CVD or all-cause mortality. Orthostatic hypotension was defined as a decrease in systolic BP of at least 20 mm Hg and/or diastolic BP of at least 10 mm Hg after changing position from sitting to standing. Standing hypotension was defined as a standing systolic BP of 110 mm Hg or less or standing diastolic BP of 60 mm Hg or less. Results: The 9 trials included 29 235 participants followed up for a median of 4 years (mean age, 69.0 [SD, 10.9] years; 48% women). There were 9% with orthostatic hypotension and 5% with standing hypotension at baseline. More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline orthostatic hypotension (hazard ratio [HR], 0.81; 95% CI, 0.76-0.86) similarly to those with baseline orthostatic hypotension (HR, 0.83; 95% CI, 0.70-1.00; P = .68 for interaction of treatment with baseline orthostatic hypotension). More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline standing hypotension (HR, 0.80; 95% CI, 0.75-0.85), and nonsignificantly among those with baseline standing hypotension (HR, 0.94; 95% CI, 0.75-1.18). Effects did not differ by baseline standing hypotension (P = .16 for interaction of treatment with baseline standing hypotension). Conclusions and Relevance: In this population of hypertension trial participants, intensive therapy reduced risk of CVD or all-cause mortality regardless of orthostatic hypotension without evidence for different effects among those with standing hypotension.

A metabolomics approach identified toxins associated with uremic symptoms in advanced chronic kidney disease.

Uremic symptoms are common in patients with advanced chronic kidney disease, but the toxins that cause these symptoms are unknown. To evaluate this, we performed a cross-sectional study of the 12 month post-randomization follow-up visit of Modification of Diet in Renal Disease (MDRD) participants reporting uremic symptoms who also had available stored serum. We quantified 1,163 metabolites by liquid chromatography-tandem mass spectrometry. For each uremic symptom, we calculated a score as the severity multiplied by the number of days the symptom was experienced. We analyzed the associations of the individual symptom scores with metabolites using linear models with empirical Bayesian inference, adjusted for multiple comparisons. Among 695 participants, the mean measured glomerular filtration rate (mGFR) was 28 mL/min/1.73 m2. Uremic symptoms were more common in the subgroup of 214 patients with an mGFR under 20 mL/min/1.73 m2 (mGFR under 20 subgroup) than in the full group. For all metabolites with significant associations, the direction of the association was concordant in the full group and the subgroup. For gastrointestinal symptoms (bad taste, loss of appetite, nausea, and vomiting), eleven metabolites were associated with symptoms. For neurologic symptoms (decreased alertness, falling asleep during the day, forgetfulness, lack of pep and energy, and tiring easily/weakness), seven metabolites were associated with symptoms. Associations were consistent across sensitivity analyses. Thus, our proof-of-principle study demonstrates the potential for metabolomics to understand metabolic pathways associated with uremic symptoms. Larger, prospective studies with external validation are needed.

Effects of Intensive Blood Pressure Treatment on Orthostatic Hypotension : A Systematic Review and Individual Participant-based Meta-analysis.

BACKGROUND: Although intensive blood pressure (BP)-lowering treatment reduces risk for cardiovascular disease, there are concerns that it might cause orthostatic hypotension (OH). PURPOSE: To examine the effects of intensive BP-lowering treatment on OH in hypertensive adults. DATA SOURCES: MEDLINE, EMBASE, and Cochrane CENTRAL from inception through 7 October 2019, without language restrictions. STUDY SELECTION: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) that involved more than 500 adults with hypertension or elevated BP and that were 6 months or longer in duration. Trial comparisons were groups assigned to either less intensive BP goals or placebo, and the outcome was measured OH, defined as a decrease of 20 mm Hg or more in systolic BP or 10 mm Hg or more in diastolic BP after changing position from seated to standing. DATA EXTRACTION: 2 investigators independently abstracted articles and rated risk of bias. DATA SYNTHESIS: 5 trials examined BP treatment goals, and 4 examined active agents versus placebo. Trials examining BP treatment goals included 18 466 participants with 127 882 follow-up visits. Trials were open-label, with minimal heterogeneity of effects across trials. Intensive BP treatment lowered risk for OH (odds ratio, 0.93 [95% CI, 0.86 to 0.99]). Effects did not differ by prerandomization OH (P for interaction = 0.80). In sensitivity analyses that included 4 additional placebo-controlled trials, overall and subgroup findings were unchanged. LIMITATIONS: Assessments of OH were done while participants were seated (not supine) and did not include the first minute after standing. Data on falls and syncope were not available. CONCLUSION: Intensive BP-lowering treatment decreases risk for OH. Orthostatic hypotension, before or in the setting of more intensive BP treatment, should not be viewed as a reason to avoid or de-escalate treatment for hypertension. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute, National Institutes of Health. (PROSPERO: CRD42020153753).

Predicting Sepsis Mortality in a Population-Based National Database: Machine Learning Approach.

BACKGROUND: Although machine learning (ML) algorithms have been applied to point-of-care sepsis prognostication, ML has not been used to predict sepsis mortality in an administrative database. Therefore, we examined the performance of common ML algorithms in predicting sepsis mortality in adult patients with sepsis and compared it with that of the conventional context knowledge-based logistic regression approach. OBJECTIVE: The aim of this study is to examine the performance of common ML algorithms in predicting sepsis mortality in adult patients with sepsis and compare it with that of the conventional context knowledge-based logistic regression approach. METHODS: We examined inpatient admissions for sepsis in the US National Inpatient Sample using hospitalizations in 2010-2013 as the training data set. We developed four ML models to predict in-hospital mortality: logistic regression with least absolute shrinkage and selection operator regularization, random forest, gradient-boosted decision tree, and deep neural network. To estimate their performance, we compared our models with the Super Learner model. Using hospitalizations in 2014 as the testing data set, we examined the models' area under the receiver operating characteristic curve (AUC), confusion matrix results, and net reclassification improvement. RESULTS: Hospitalizations of 923,759 adults were included in the analysis. Compared with the reference logistic regression (AUC: 0.786, 95% CI 0.783-0.788), all ML models showed superior discriminative ability (P<.001), including logistic regression with least absolute shrinkage and selection operator regularization (AUC: 0.878, 95% CI 0.876-0.879), random forest (AUC: 0.878, 95% CI 0.877-0.880), xgboost (AUC: 0.888, 95% CI 0.886-0.889), and neural network (AUC: 0.893, 95% CI 0.891-0.895). All 4 ML models showed higher sensitivity, specificity, positive predictive value, and negative predictive value compared with the reference logistic regression model (P<.001). We obtained similar results from the Super Learner model (AUC: 0.883, 95% CI 0.881-0.885). CONCLUSIONS: ML approaches can improve sensitivity, specificity, positive predictive value, negative predictive value, discrimination, and calibration in predicting in-hospital mortality in patients hospitalized with sepsis in the United States. These models need further validation and could be applied to develop more accurate models to compare risk-standardized mortality rates across hospitals and geographic regions, paving the way for research and policy initiatives studying disparities in sepsis care.

Higher Carbohydrate Amount and Lower Glycemic Index Increase Hunger, Diet Satisfaction, and Heartburn in Overweight and Obese Adults in the OmniCarb Randomized Clinical Trial.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet, a high-carbohydrate diet, is highly recommended based on its cardiovascular risk benefits, yet adherence remains persistently low. How subjective impressions of this diet contribute to adherence has not been thoroughly explored. The OmniCarb trial, which compared DASH-style diets varying in glycemic index (GI) and carbohydrate amount, surveyed subjective impressions of such diets. OBJECTIVES: We examined the effects of GI and carbohydrate amount on qualitative aspects of diet acceptability through secondary outcomes in the OmniCarb trial. METHODS: OmniCarb was a randomized, crossover trial of 4 DASH-style diets varying by GI (≥65 compared with ≤45) and carbohydrate amount (40% compared with 58% kcal) in overweight or obese (BMI ≥25 kg/m2) adults (n = 163). Participants consumed each diet in random order over 5-wk periods, separated by 2-wk washouts. At baseline and the end of each feeding period, participants rated hunger, diet satisfaction, and gastrointestinal symptoms (diarrhea/loose stools, constipation, bloating, nausea, and heartburn). RESULTS: Participant mean age was 52 y, with 52% women, 51% non-Hispanic black, and 56% obese (BMI ≥30). Compared with baseline, all intervention diets decreased heartburn, increased diarrhea/loose stools, and increased bloating, but did not significantly affect constipation or nausea. Compared with lower carbohydrate diets, higher carbohydrate diets increased hunger (RR: 1.16; 95% CI: 1.04, 1.30), increased diet satisfaction (RR: 1.10; 95% CI: 1.01, 1.20), and increased heartburn (RR: 1.49; 95% CI: 1.09, 2.04). Compared with lower GI diets, higher GI diets did not affect hunger (RR: 0.92; 95% CI: 0.83, 1.02), decreased diet satisfaction (RR: 0.83; 95% CI: 0.75, 0.92), and did not affect heartburn (RR: 0.89; 95% CI: 0.70, 1.13). There were no between-diet differences for diarrhea/loose stools, constipation, bloating, and nausea. CONCLUSIONS: Although a higher carbohydrate amount in DASH-style diets can increase diet satisfaction, it can also decrease satiety and increase heartburn in adults with overweight or obesity.This trial is registered at clinicaltrials.gov as NCT00608049.

Cardiovascular Effects of Androgen Deprivation Therapy in Prostate Cancer: Contemporary Meta-Analyses.

Androgen deprivation therapy is a cornerstone of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and antagonism, androgen receptor inhibition, and CYP17 (cytochrome P450 17A1) inhibition. Studies in the past decade have raised concerns about the potential for androgen deprivation therapy to increase the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors. In this review, we summarize existing data on the cardiovascular effects of androgen deprivation therapy. Among the therapies, abiraterone stands out for increasing risk of cardiac events in meta-analyses of both randomized controlled trials and observational studies. We find a divergence between observational studies, which show consistent positive associations between androgen deprivation therapy use and cardiovascular disease, and randomized controlled trials, which do not show these associations reproducibly.

Metabolomics reveals the impact of Type 2 diabetes on local muscle and vascular responses to ischemic stress.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) reduces exercise capacity, but the mechanisms are incompletely understood. We probed the impact of ischemic stress on skeletal muscle metabolite signatures and T2DM-related vascular dysfunction. METHODS: we recruited 38 subjects (18 healthy, 20 T2DM), placed an antecubital intravenous catheter, and performed ipsilateral brachial artery reactivity testing. Blood samples for plasma metabolite profiling were obtained at baseline and immediately upon cuff release after 5 min of ischemia. Brachial artery diameter was measured at baseline and 1 min after cuff release. RESULTS: as expected, flow-mediated vasodilation was attenuated in subjects with T2DM (P<0.01). We confirmed known T2DM-associated baseline differences in plasma metabolites, including homocysteine, dimethylguanidino valeric acid and ß-alanine (all P<0.05). Ischemia-induced metabolite changes that differed between groups included 5-hydroxyindoleacetic acid (healthy: -27%; DM +14%), orotic acid (healthy: +5%; DM -7%), trimethylamine-N-oxide (healthy: -51%; DM +0.2%), and glyoxylic acid (healthy: +19%; DM -6%) (all P<0.05). Levels of serine, betaine, ß-aminoisobutyric acid and anthranilic acid were associated with vessel diameter at baseline, but only in T2DM (all P<0.05). Metabolite responses to ischemia were significantly associated with vasodilation extent, but primarily observed in T2DM, and included enrichment in phospholipid metabolism (P<0.05). CONCLUSIONS: our study highlights impairments in muscle and vascular signaling at rest and during ischemic stress in T2DM. While metabolites change in both healthy and T2DM subjects in response to ischemia, the relationship between muscle metabolism and vascular function is modified in T2DM, suggesting that dysregulated muscle metabolism in T2DM may have direct effects on vascular function.

Impact of post-sepsis cardiovascular complications on mortality in sepsis survivors: a population-based study.

BACKGROUND: It remains unclear whether sepsis-related cardiovascular complications have an adverse impact on survival independent of pre-existing comorbidities. To investigate the survival impact of post-sepsis cardiovascular complications among sepsis survivors, we conducted a population-based study using the National Health Insurance Database of Taiwan. METHODS: We identified sepsis patients from the National Health Insurance Research Database of Taiwan using ICD-9-CM codes involving infection and organ dysfunction between 2000 and 2011. Post-sepsis incident myocardial infarction (MI) and stroke were ascertained by ICD-9-CM codes and antiplatelet treatment. We constructed a non-sepsis comparison cohort using propensity score matching to ascertain the association between sepsis and cardiovascular complications. Furthermore, we compared the 180-day mortality and 365-day mortality between patients surviving sepsis with or without post-sepsis MI or stroke within 70 days of hospital discharge. We constructed Cox regression models adjusting for pre-existing comorbidities to evaluate the independent survival impact of post-sepsis MI or stroke among sepsis survivors. RESULTS: We identified 42,316 patients hospitalized for sepsis, from which we matched 42,151 patients 1:1 with 42,151 patients hospitalized without sepsis. Compared to patients hospitalized without sepsis, patients hospitalized with sepsis had an increased risk of MI or stroke (adjusted odds ratio 1.72, 95% CI 1.60-1.85). Among 42,316 patients hospitalized for sepsis, 486 (1.15%) patients developed incident stroke and 108 (0.26%) developed incident MI within 70 days of hospital discharge. Compared to sepsis survivors without cardiovascular complications, sepsis survivors with incident MI or stroke had a higher mortality rate at 180 days (11.68% vs. 4.44%, P = 0.003) and at 365 days (16.75% vs. 7.11%, P = 0.005). Adjusting for age, sex, and comorbidities, post-sepsis MI or stroke was independently associated with increased 180-day (adjusted hazard ratio [HR] 2.16, 95% CI 1.69-2.76) and 365-day (adjusted HR 1.90, 95% CI 1.54-2.32) mortality. CONCLUSIONS: Compared to sepsis patients without incident MI or stroke, sepsis patients with incident MI or stroke following hospital discharge had an increased risk of mortality for up to 365 days of follow-up. This increased risk cannot be explained by pre-sepsis comorbidities.

Serum metabolites are associated with all-cause mortality in chronic kidney disease.

Chronic kidney disease (CKD) involves significant metabolic abnormalities and has a high mortality rate. Because the levels of serum metabolites in patients with CKD might provide insight into subclinical disease states and risk for future mortality, we determined which serum metabolites reproducibly associate with mortality in CKD using a discovery and replication design. Metabolite levels were quantified via untargeted liquid chromatography and mass spectroscopy from serum samples of 299 patients with CKD in the Modification of Diet in Renal Disease (MDRD) study as a discovery cohort. Six among 622 metabolites were significantly associated with mortality over a median follow-up of 17 years after adjustment for demographic and clinical covariates, including urine protein and measured glomerular filtration rate. We then replicated associations with mortality in 963 patients with CKD from the African American Study of Kidney Disease and Hypertension (AASK) cohort over a median follow-up of ten years. Three of the six metabolites identified in the MDRD cohort replicated in the AASK cohort: fumarate, allantoin, and ribonate, belonging to energy, nucleotide, and carbohydrate pathways, respectively. Point estimates were similar in both studies and in meta-analysis (adjusted hazard ratios 1.63, 1.59, and 1.61, respectively, per doubling of the metabolite). Thus, selected serum metabolites were reproducibly associated with long-term mortality in CKD beyond markers of kidney function in two well characterized cohorts, providing targets for investigation.

The public health dimension of chronic kidney disease: what we have learnt over the past decade.

Much progress has been made in chronic kidney disease (CKD) epidemiology in the last decade to establish CKD as a condition that is common, harmful and treatable. The introduction of the new equations for estimating glomerular filtration rate (GFR) and the publication of international reference standards for creatinine and cystatin measurement paved the way for improved global estimates of CKD prevalence. The addition of albuminuria categories to the staging of CKD paved the way for research linking albuminuria and GFR to a wide range of renal and cardiovascular adverse outcomes. The advent of genome-wide association studies ushered in insights into genetic polymorphisms underpinning some types of CKD. Finally, a number of new randomized clinical trials and meta-analyses have informed evidence-based guidelines for the treatment and prevention of CKD. In this review, we discuss the lessons learnt from epidemiological investigations of the staging, etiology, prevalence and prognosis of CKD between 2007 and 2016.

Cellular mechanisms of alpha herpesvirus egress: live cell fluorescence microscopy of pseudorabies virus exocytosis.

Egress of newly assembled herpesvirus particles from infected cells is a highly dynamic process involving the host secretory pathway working in concert with viral components. To elucidate the location, dynamics, and molecular mechanisms of alpha herpesvirus egress, we developed a live-cell fluorescence microscopy method to visualize the final transport and exocytosis of pseudorabies virus (PRV) particles in non-polarized epithelial cells. This method is based on total internal reflection fluorescence (TIRF) microscopy to selectively image fluorescent virus particles near the plasma membrane, and takes advantage of a virus-encoded pH-sensitive probe to visualize the precise moment and location of particle exocytosis. We performed single-particle tracking and mean squared displacement analysis to characterize particle motion, and imaged a panel of cellular proteins to identify those spatially and dynamically associated with viral exocytosis. Based on our data, individual virus particles travel to the plasma membrane inside small, acidified secretory vesicles. Rab GTPases, Rab6a, Rab8a, and Rab11a, key regulators of the plasma membrane-directed secretory pathway, are present on the virus secretory vesicle. These vesicles undergo fast, directional transport directly to the site of exocytosis, which is most frequently near patches of LL5ß, part of a complex that anchors microtubules to the plasma membrane. Vesicles are tightly docked at the site of exocytosis for several seconds, and membrane fusion occurs, displacing the virion a small distance across the plasma membrane. After exocytosis, particles remain tightly confined on the outer cell surface. Based on recent reports in the cell biological and alpha herpesvirus literature, combined with our spatial and dynamic data on viral egress, we propose an integrated model that links together the intracellular transport pathways and exocytosis mechanisms that mediate alpha herpesvirus egress.

A murine model to characterize the antithrombotic effect of molecules targeting human von Willebrand factor.

von Willebrand factor (VWF) is a promising target for developing antithrombotic drugs. The absence of accessible animal models impedes the study of specific human VWF (huVWF) targeting molecules in thrombosis. huVWF is not functional in the mouse because of a lack of interaction between huVWF and murine glycoprotein Ib. Using site-directed mutagenesis, we have replaced single or multiple amino acids in huVWF with their murine counterparts to eliminate species incompatibility. Using hydrodynamic injection, we have expressed the different chimeric VWF constructs into VWF(-/-) mice. Only huVWF with a complete murine A1 domain insertion was able to correct bleeding in vivo and form occlusive thrombi in mesenteric vessels after FeCl(3) treatment. Using this model, we tested the antithrombotic effect of monoclonal antibodies against huVWF, blocking its interaction with collagens (mAbs 203 and 505) or with glycoprotein IIbIIIa (mAb 9). The 3 mAbs inhibited the thrombotic process in arterioles of VWF(-/-) mice expressing huVWFmuA1. Inhibiting VWF-interaction with collagens was more potent, emphasizing the potential of such a target as an antithrombotic tool. Our results validate our murine model as a simple in vivo tool to evaluate anti-huVWF agents.

Clinical Biochemistry of Serum Troponin.

Accurate measurement and interpretation of serum levels of troponin (Tn) is a central part of the clinical workup of a patient presenting with chest pain suspicious for acute coronary syndrome (ACS). Knowledge of the molecular characteristics of the troponin complex and test characteristics of troponin measurement assays allows for a deeper understanding of causes of false positive and false negative test results in myocardial injury. In this review, we discuss the molecular structure and functions of the constituent proteins of the troponin complex (TnT, TnC, and TnI); review the different isoforms of Tn and where they are from; survey the evolution of clinical Tn assays, ranging from first-generation to high-sensitivity (hs); provide a primer on statistical interpretation of assay results based on different clinical settings; and discuss potential causes of false results. We also summarize the advances in technologies that may lead to the development of future Tn assays, including the development of point of care assays and wearable Tn sensors for real-time continuous measurement.

Sepsis increases the risk of in-hospital cardiac arrest: a population-based analysis.

Sepsis patients have a high risk of developing in-hospital cardiac arrest (IHCA), which portends poor survival. However, little is known about whether the increased incidence of IHCA is due to sepsis itself or to comorbidities harbored by sepsis patients. We conducted a retrospective population-based cohort study comprising 20,022 patients admitted with sepsis to hospitals in Taiwan using the National Health Insurance Research Database (NHIRD). We constructed three non-sepsis comparison cohorts using risk set sampling and propensity score (PS) matching. We used univariate conditional logistic regression to evaluate the risk of IHCA and associated mortality. We identified 12,790 inpatients without infection (matched cohort 1), 12,789 inpatients with infection but without sepsis (matched cohort 2), and 10,536 inpatients with end-organ dysfunction but without sepsis (matched cohort 3). In the three PS-matched cohorts, the odds ratios (OR) for developing ICHA were 21.17 (95% CI 17.19, 26.06), 18.96 (95% CI: 15.56, 23.10), and 1.23 (95% CI: 1.13, 1.33), respectively (p < 0.001 for all ORs). In conclusion, in our study of inpatients across Taiwan, sepsis was independently associated with an increased risk of IHCA. Further studies should focus on identifying the proxy causes of IHCA using real-time monitoring data to further reduce the incidence of cardiopulmonary insufficiency in patients with sepsis.