An integrated magnetic separation enzyme-linked colorimetric sensing platform for field detection of Escherichia coli O157: H7 in food.

An intelligent colorimetric sensing platform integrated with in situ immunomagnetic separation function was developed for ultrasensitive detection of Escherichia coli O157: H7 (E. coli O157: H7) in food. Captured antibody modified magnetic nanoparticles (cMNPs) and detection antibody/horseradish peroxidase (HRP) co-functionalized AuNPs (dHAuNPs) were firstly synthesized for targeted enrichment and colorimetric assay of E. coli O157: H7, in which remarkable signal amplification was realized by loading large amounts of HRP on the surface of AuNPs. Coupling with the optical collimation attachments and embedded magnetic separation module, a highly integrated optical device was constructed, by which in situ magnetic separation and high-quality imaging of 96-well microplates containing E. coli O157: H7 was achieved with a smartphone. The concentration of E. coli O157: H7 could be achieved in one-step by performing digital image colorimetric analysis of the obtained image with a custom-designed app. This biosensor possesses high sensitivity (1.63 CFU/mL), short detecting time (3 h), and good anti-interference performance even in real-sample testing. Overall, the developed method is expected to be a novel field detection platform for foodborne pathogens in water and food as well as for the diagnosis of infections due to its portability, ease of operation, and high feasibility.

B-N Co-Doped Graphene: Stability and Catalytic Activity in Oxygen Reduction Reaction - A Theoretical Insight.

We systematically investigated the stable configurations and catalytic activity in the Oxygen Reduction Reaction (ORR) of graphene co-doped with boron and nitrogen (B-N) using first-principles methods. Compared to single B/N doping, co-doping with BN is energetically favored. We found that intermediate species of ORR process adsorb on boron atoms, which act as catalytic sites. The presence of neighboring nitrogen atoms around boron plays a crucial role in modulating the catalytic activity of boron. For the same adsorption configuration, the adsorption energy of the adsorbate increases with the number of neighboring nitrogen atoms around boron and generally correlates positively with the number of electrons gained by the adsorbate. Regarding the catalytic activity of ORR, excessively strong adsorption of adsorbates impedes their hydrogenation. The best substrates for ORR catalytic activity are B-N-graphene and N-B2-graphene, with the rate-determining step being the hydrogenation of *OO and overpotentials of 0.49 V and 0.54 V, respectively.

Urine multi-index intelligent detection based on polymer/paper hybrid microfluidic biochip for hyperuricemia monitoring.

Hyperuricemia (HUA) has gradually become a public health burden as an independent risk factor for a variety of chronic diseases. Herein, a user-friendly point-of-care (POC) detection system (namely "Smart-HUA-Monitor") based on smartphone-assisted paper-based microfluidic is proposed for colorimetric quantification of HUA urinary markers, including uric acid (UA), creatinine (CR) and pH. The detection limits of UA and CR were 0.0178 and 0.5983 mM, respectively, and the sensitivity of pH were 0.1. The method was successfully validated in artificial urine samples and 100 clinical samples. Bland-Altman plots showed a high consistency between µPAD and the testing instruments (HITACHI 7600 Automatic Analyzer, URIT-500B Urine Analyzer and AU5800B automatic biochemical analyzer) in hospital. Smart-HUA-Monitor provides an accurate quantitative, rapid, low-cost and reliable tool for the monitoring and early diagnosis of HUA urine indicators.

Skin sympathetic nerve activity in symptomatic and asymptomatic paroxysmal atrial fibrillation.

BACKGROUND: The causes of symptoms in patients with paroxysmal atrial fibrillation (AF) remains unclear. OBJECTIVE: The purpose of this study was to correlate the magnitudes of skin sympathetic nerve activity (SKNA) with symptoms in patients with AF. METHODS: We prospectively enrolled patients with symptomatic paroxysmal AF for ambulatory electrocardiography and SKNA recording. Heart rhythms at the time of symptoms were categorized as AF or normal sinus rhythm (NSR). Maximal and average skin sympathetic nerve activity (aSKNA) and heart rate (HR) were compared between symptomatic and asymptomatic AF and NSR episodes using mixed effects models to account for within-patient correlations. RESULTS: Among the 31 enrolled patients, 16 (52%) had at least 1 episode of AF, and 24 (77%) endorsed symptoms during the monitoring period. Compared with asymptomatic AF episodes, symptomatic AF episodes had higher maximal aSKNA (1.260 [interquartile range (IQR) 1.114-1.723] µV vs 1.108 [IQR 0.974-1.312] µV; P <0.001) and higher maximal HR (152 ± 24 bpm vs 132 ± 19 bpm; P <.001). Symptomatic NSR episodes were associated with higher maximal aSKNA (1.612 [IQR 1.287-2.027] µV vs 1.332 [IQR 1.033-1.668] µV; P = .001) and higher maximal HR (152 ± 24 bpm vs 105 ± 16 bpm; P <.001) than asymptomatic NSR episodes. Of the symptomatic episodes, 66 (73%) occurred during NSR and 24 (27%) during AF. All P values were obtained from mixed effects models. CONCLUSION: Symptomatic episodes in patients with paroxysmal AF were more frequently associated with NSR than AF. Symptomatic AF and NSR episodes were associated with higher aSKNA than asymptomatic episodes. In patients with paroxysmal AF, symptoms correlate better with SKNA than heart rhythm.

Patient Comments and Patient Experience Ratings Are Strongly Correlated With Emergency Department Wait Times.

BACKGROUND AND OBJECTIVES: Hospitals and clinicians increasingly are reimbursed based on quality of care through financial incentives tied to value-based purchasing. Patient-centered care, measured through patient experience surveys, is a key component of many quality incentive programs. We hypothesize that operational aspects such as wait times are an important element of emergency department (ED) patient experience. The objectives of this paper are to determine (1) the association between ED wait times and patient experience and (2) whether patient comments show awareness of wait times. METHODS: This is a cross-sectional observational study from January 1, 2019, to December 31, 2020, across 16 EDs within a regional health care system. Patient and operations data were obtained as secondary data through internal sources and merged with primary patient experience data from our data analytics team. Dependent variables are (1) the association between ED wait times in minutes and patient experience ratings and (2) the association between wait times in minutes and patient comments including the term wait (yes/no). Patients rated their "likelihood to recommend (LTR) an ED" on a 0 to 10 scale (categories: "Promoter" = 9-10, "Neutral" = 7-8, or "Detractor" = 0-6). Our aggregate experience rating, or Net Promoter Score (NPS), is calculated by the following formula for each distinct wait time (rounded to the nearest minute): NPS = 100* (# promoters - # detractors)/(# promoters + # neutrals + # detractors). Independent variables for patient age and gender and triage acuity, were included as potential confounders. We performed a mixed-effect multivariate ordinal logistic regression for the rating category as a function of 30 minutes waited. We also performed a logistic regression for the percentage of patients commenting on the wait as a function of 30 minutes waited. Standard errors are adjusted for clustering between the 16 ED sites. RESULTS: A total of 50 833 unique participants completed an experience survey, representing a response rate of 8.1%. Of these respondents, 28.1% included comments, with 10.9% using the term "wait." The odds ratio for association of a 30-minute wait with LTR category is 0.83 [0.81, 0.84]. As wait times increase, the odds of commenting on the wait increase by 1.49 [1.46, 1.53]. We show policy-relevant bubble plot visualizations of these two relationships. CONCLUSIONS: Patients were less likely to give a positive patient experience rating as wait times increased, and this was reflected in their comments. Improving on the factors contributing to ED wait times is essential to meeting health care systems' quality initiatives.

Structure and inhibition of the human lysosomal transporter Sialin.

Sialin, a member of the solute carrier 17 (SLC17) transporter family, is unique in its ability to transport not only sialic acid using a pH-driven mechanism, but also transport mono and diacidic neurotransmitters, such as glutamate and N-acetylaspartylglutamate (NAAG), into synaptic vesicles via a membrane potential-driven mechanism. While most transporters utilize one of these mechanisms, the structural basis of how Sialin transports substrates using both remains unclear. Here, we present the cryogenic electron-microscopy structures of human Sialin: apo cytosol-open, apo lumen-open, NAAG-bound, and inhibitor-bound. Our structures show that a positively charged cytosol-open vestibule accommodates either NAAG or the Sialin inhibitor Fmoc-Leu-OH, while its luminal cavity potentially binds sialic acid. Moreover, functional analyses along with molecular dynamics simulations identify key residues in binding sialic acid and NAAG. Thus, our findings uncover the essential conformational states in NAAG and sialic acid transport, demonstrating a working model of SLC17 transporters.

Sympathetic toggled paroxysmal atrial fibrillation and recurrent premature atrial contractions in ambulatory patients.

BACKGROUND: Autonomic nerve activity is important in the mechanisms of paroxysmal atrial fibrillation (PAF). OBJECTIVE: The purpose of this study was to test the hypothesis that a single burst of skin sympathetic nerve activity (SKNA) can toggle on and off PAF or premature atrial contraction (PAC) clusters. METHODS: Simultaneous recording of SKNA and electrocardiogram (neuECG) recording was performed over 7 days in patients with PAF. RESULTS: In study 1, 8 patients (7 men and 1 woman; age 62 ± 8 years) had 124 episodes of PAF. An SKNA burst toggled both on and off PAF in 8 episodes (6.5%) (type 1), toggled on but not off in 12 episodes (9.7%) (type 2), and toggled on a PAC cluster followed by PAF in 4 episodes (3.2%) (type 3). The duration of these PAF episodes was <10 minutes. The remaining 100 episodes (80.6%) were associated with active SKNA bursts throughout PAF (type 4) and lasted longer than type 1 (P = .0185) and type 2 (P = .0027) PAF. There were 47 PAC clusters. Among them, 24 (51.1%) were toggled on and off, and 23 (48.9%) were toggled on but not off by an SKNA burst. In study 2, 17 patients (9 men and 8 women; age 58 ± 12 years) had <10 minutes of PAF (4, 8, 0, and 31 of types 1, 2, 3, and 4, respectively). There were significant circadian variations of all types of PAF. CONCLUSION: A single SKNA burst can toggle short-duration PAF and PAC cluster episodes on and off. The absence of continued SKNA after the onset might have affected the maintenance of these arrhythmias.

Flexible Strain Sensors Based on an Interlayer Synergistic Effect of Nanomaterials for Continuous and Noninvasive Blood Pressure Monitoring.

The continuous, noninvasive monitoring of human blood pressure (BP) through the accurate detection of pulse waves has extremely stringent requirements on the sensitivity and stability of flexible strain sensors. In this study, a new ultrasensitive flexible strain sensor based on the interlayer synergistic effect was fabricated through drop-casting and drying silver nanowires and graphene films on polydimethylsiloxane substrates and was further successfully applied for continuous monitoring of BP. This strain sensor exhibited ultrahigh sensitivity with a maximum gauge factor of 34357.2 (∼700% sensitivity enhancement over other major sensors), satisfactory response time (∼85 ms), wide strange range (12%), and excellent stability. An interlayer fracture mechanism was proposed to elucidate the working principle of the strain sensor. The real-time BP values can be obtained by analyzing the relationship between the BP and the pulse transit time. To verify our strain sensor for real-time BP monitoring, our strain sensor was compared with a conventional electrocardiogram-photoplethysmograph method and a commercial cuff-based device and showed similar measurement results to BP values from both methods, with only minor differences of 0.693, 0.073, and 0.566 mmHg in the systolic BP, diastolic BP, and mean arterial pressure, respectively. Furthermore, the reliability of the strain sensors was validated by testing 20 human subjects for more than 50 min. This ultrasensitive strain sensor provides a new pathway for continuous and noninvasive BP monitoring.

Wire-Arc Additive Manufacturing of Nano-Treated Aluminum Alloy 2024.

With high strength and good fatigue resistance, Al-Cu alloys such as AA2024 are widely used in the aerospace and automotive industries. However, the system's susceptibility to hot cracking and other solidification defects hinders its development in metal additive manufacturing (AM). A nano-treated AA2024 deposition, with the addition of TiC nanoparticles, is successfully additively manufactured without cracks. Microstructural analysis suggests nanoparticles not only mitigate the hot cracking sensitivity but also significantly refine and homogenize grains, resulting in an average size of 23.2 ± 0.4 µm. Microhardness profiles show consistent mechanical performance along the build direction, regardless of cyclic thermal exposure. Finally, excellent tensile strength and elongation up to 428 MPa and 7.4% were achieved after heat treatment. The combined results show a great promise of nano-treating in high-strength aluminum AM.

Concordance Between Electronic Health Record-Recorded Race and Ethnicity and Patient Report in Emergency Department Patients.

OBJECTIVE: We assessed the concordance of patient-reported race and ethnicity for emergency department (ED) patients compared with what was recorded in the electronic health record. METHODS: We conducted a single-center, prospective, observational study of 744 ED patients (English- and/or Spanish-speaking), asking them to describe their race and ethnicity. We compared the distributions of ethnicity and race between patient-reported and electronic health record data using McNemar's test. We calculated percent agreement and Cohen's kappa, with 95% confidence intervals (CI), for the concordance of patient-reported race and ethnicity with electronic health record data. RESULTS: Of 744 ED patients, 731 participants who completed the survey reported their ethnicity, resulting in 98.2% of electronic health records obtained ethnicities matched self-reported data (kappa = 0.95; 95% CI: 0.92 to 0.98). For those who self-reported as Hispanic, only 92.3% agreement was observed between the self-reported and electronic health record values. For all patients who had race recorded, 85.4% agreement was observed (kappa = 0.75; 95% CI 0.71 to 0.79). High rates of agreement were observed for Black or African American patients (98.7%) and White patients (96.6%), with low rates for those who identified as "More than one race" (22.9%) or "Other" race (1.8%). In the subset of Hispanic patients, low rates of agreement (25.0%) were observed for race (kappa = 0.10; 95% CI 0.01 to 0.19). CONCLUSIONS: Documentation discordance regarding race and ethnicity exists between electronic health records and self-reported data for our ED patients, particularly for ethnically Hispanic and Latino/a patients. Future efforts should focus on ensuring that demographic information in the electronic health record is accurately collected.

Variable selection for latent class analysis in the presence of missing data with application to record linkage.

The Fellegi-Sunter model is a latent class model widely used in probabilistic linkage to identify records that belong to the same entity. Record linkage practitioners typically employ all available matching fields in the model with the premise that more fields convey greater information about the true match status and hence result in improved match performance. In the context of model-based clustering, it is well known that such a premise is incorrect and the inclusion of noisy variables could compromise the clustering. Variable selection procedures have therefore been developed to remove noisy variables. Although these procedures have the potential to improve record matching, they cannot be applied directly due to the ubiquity of the missing data in record linkage applications. In this paper, we modify the stepwise variable selection procedure proposed by Fop, Smart, and Murphy and extend it to account for missing data common in record linkage. Through simulation studies, our proposed method is shown to select the correct set of matching fields across various settings, leading to better-performing algorithms. The improved match performance is also seen in a real-world application. We therefore recommend the use of our proposed selection procedure to identify informative matching fields for probabilistic record linkage algorithms.

Effect of TiC Nanoparticles on a Zn-Al-Cu System for Biodegradable Cardiovascular Stent Applications.

Despite being a weaker metal, zinc has become an increasingly popular candidate for biodegradable implant applications due to its suitable corrosion rate and biocompatibility. Previous studies have experimented with various alloy elements to improve the overall mechanical performance of pure Zn without compromising the corrosion performance and biocompatibility; however, the thermal stability of biodegradable Zn alloys has not been widely studied. In this study, TiC nanoparticles were introduced for the first time to a Zn-Al-Cu system. After hot rolling, TiC nanoparticles were uniformly distributed in the Zn matrix and effectively enabled phase control during solidification. The Zn-Cu phase, which was elongated and sharp in the reference alloy, became globular in the nanocomposite. The strength of the alloy, after introducing TiC nanoparticles, increased by 31% from 259.7 to 340.3 MPa, while its ductility remained high at 49.2% elongation to failure. Fatigue performance also improved greatly by adding TiC nanoparticles, increasing the fatigue limit by 47.6% from 44.7 to 66 MPa. Furthermore, TiC nanoparticles displayed excellent phase control capability during body-temperature aging. Without TiC restriction, Zn-Cu phases evolved into dendritic morphologies, and the Al-rich eutectic grew thicker at grain boundaries. However, both Zn-Cu and Al-rich eutectic phases remained relatively unchanged in shape and size in the nanocomposite. A combination of exceptional tensile properties, improved fatigue performance, better long-term stability with a suitable corrosion rate, and excellent biocompatibility makes this new Zn-Al-Cu-TiC material a promising candidate for biodegradable stents and other biodegradable applications.

Factors associated with the SARS-CoV-2 immunoglobulin-G titer levels in convalescent whole-blood donors: a Chinese cross-sectional study.

Blood transfusions from convalescent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infected patients could be used to treat patients with severe infections or immunocompromised patients. However, it is necessary to select the optimal donors to maximize the utilization of resources. In this study, we investigated the associations among body mass index (BMI), tobacco smoking, exercise frequency and duration, and alcohol consumption with the SARS-CoV-2 immunoglobulin-G (IgG) antibody titer levels with in the Chinese convalescent blood donor population. Here we show that BMI, smoking habits, and exercise frequency appear to be predictive factors for IgG levels in convalescent male blood donors. However, these variables were not observed as predictive of IgG levels in female convalescent blood donors. The findings could be used to optimize the screening for potential blood donors to treat immunocompromised or severely ill COVID-19 patients.

Manual evaluation of record linkage algorithm performance in four real-world datasets.

BACKGROUND: Patient data is fragmented across multiple repositories, yielding suboptimal and costly care. Record linkage algorithms are widely accepted solutions for improving completeness of patient records. However, studies often fail to fully describe their linkage techniques. Further, while many frameworks evaluate record linkage methods, few focus on producing gold standard datasets. This highlights a need to assess these frameworks and their real-world performance. OBJECTIVE: We use real-world datasets and expand upon previous frameworks to evaluate a consistent approach to the manual review of gold standard datasets and measure its impact on algorithm performance. METHODS: We applied the framework, which includes elements for data description, reviewer training and adjudication, and software and reviewer descriptions, to four datasets. Record-pairs were formed and 15,000 records were randomly sampled from these pairs. After training, two reviewers determined match status for each record-pair. If reviewers disagreed, a third reviewer was used for final adjudication. RESULTS: Between the four datasets, the percent discordant rate ranged from 1.8-13.6%. While reviewers' discordance rate typically ranged between 1% and 5%, one exhibited a 59% discordance rate, showing the importance of the third reviewer. The original analysis was compared to three sensitivity analyses. The original analysis most often exhibited the highest predictive values compared to the sensitivity analyses. CONCLUSION: Reviewers vary in their assessment of a gold standard, which can lead to variances in estimates for matching performance. Our analysis demonstrates how a multi-reviewer process can be applied to create gold standards, identify reviewer discrepancies, and evaluate algorithm performance.

Bubbles-Induced Porous Structure-Based Flexible Piezoresistive Sensors for Speech Recognition.

Flexible piezoresistive sensors with a porous structure that are used in the field of speech recognition are seldom characterized by both high sensitivity and ease of preparation. In this study, a piezoresistive sensor with a porous structure that is both highly sensitive and can be prepared by using a simple method is proposed for speech recognition. The preparation process utilizes the interaction of bubbles generated by ethanol evaporation and active agents with polydimethylsiloxane to produce a porous flexible substrate. This preparation process requires neither templates nor harsh experimental conditions such as a low temperature and a low pressure. Furthermore, the prepared piezoresistive sensor has excellent properties, such as a high sensitivity (27.6 kPa-1), a satisfactory response time (800 µs), and a good stability (10,000 cycles). When used for speech recognition, more than 1500 vocalizations and silent speech signals obtained from subjects saying numbers from "0" to "9" were collected by the sensor for training a convolutional neural network model. The average accuracy of the recognition reached 94.8%. The simple preparation process and the excellent performance of the prepared flexible piezoresistive sensor endow it with a wide application prospect in the field of speech recognition.

Short-Stay Units vs Routine Admission From the Emergency Department in Patients With Acute Heart Failure: The SSU-AHF Randomized Clinical Trial.

Importance: More than 80% of patients who present to the emergency department (ED) with acute heart failure (AHF) are hospitalized. With more than 1 million annual hospitalizations for AHF in the US, safe and effective alternatives are needed. Care for AHF in short-stay units (SSUs) may be safe and more efficient than hospitalization, especially for lower-risk patients, but randomized clinical trial data are lacking. Objective: To compare the effectiveness of SSU care vs hospitalization in lower-risk patients with AHF. Design, Setting, and Participants: This multicenter randomized clinical trial randomly assigned low-risk patients with AHF 1:1 to SSU or hospital admission from the ED. Patients received follow-up at 30 and 90 days post discharge. The study began December 6, 2017, and was completed on July 22, 2021. The data were analyzed between March 27, 2020, and November 11, 2023. Intervention: Randomized post-ED disposition to less than 24 hours of SSU care vs hospitalization. Main Outcomes and Measures: The study was designed to detect at least 1-day superiority for a primary outcome of days alive and out of hospital (DAOOH) at 30-day follow-up for 534 participants, with an allowance of 10% participant attrition. Due to the COVID-19 pandemic, enrollment was truncated at 194 participants. Before unmasking, the primary outcome was changed from DAOOH to an outcome with adequate statistical power: quality of life as measured by the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). The KCCQ-12 scores range from 0 to 100, with higher scores indicating better quality of life. Results: Of the 193 patients enrolled (1 was found ineligible after randomization), the mean (SD) age was 64.8 (14.8) years, 79 (40.9%) were women, and 114 (59.1%) were men. Baseline characteristics were balanced between arms. The mean (SD) KCCQ-12 summary score between the SSU and hospitalization arms at 30 days was 51.3 (25.7) vs 45.8 (23.8) points, respectively (P = .19). Participants in the SSU arm had 1.6 more DAOOH at 30-day follow-up than those in the hospitalization arm (median [IQR], 26.9 [24.4-28.8] vs 25.4 [22.0-27.7] days; P = .02). Adverse events were uncommon and similar in both arms. Conclusions and Relevance: The findings show that the SSU strategy was no different than hospitalization with regard to KCCQ-12 score, superior for more DAOOH, and safe for lower-risk patients with AHF. These findings of lower health care utilization with the SSU strategy need to be definitively tested in an adequately powered study. Trial Registration: ClinicalTrials.gov Identifier: NCT03302910.

Role of Autophagy and Pyroptosis in Intervertebral Disc Degeneration.

Intervertebral disc degeneration is a chronic degenerative disease caused by the interaction of genetic and environmental factors, mainly manifested as lower back pain. At present, the diagnosis of intervertebral disc degeneration mainly relies on imaging. However, early intervertebral disc degeneration is usually insidious, and there is currently a lack of relevant clinical biomarkers that can reliably reflect early disease progression. Pyroptosis is a regulatory form of cell death triggered by the activation of inflammatory bodies and caspase, which can induce the formation of plasma membrane pores and cell swelling or lysis. Previous studies have shown that during the progression of intervertebral disc degeneration, sustained activation of inflammasomes leads to nuclear cell pyroptosis, which can occur in the early stages of intervertebral disc degeneration. Moreover, intervertebral disc nucleus pulposus cells adapt to the external environment through autophagy and maintain cellular homeostasis and studying the mechanism of autophagy in IDD and intervening in its pathological and physiological processes can provide new ideas for the clinical treatment of IDD. This review analyzes the effects of pyroptosis and autophagy on IDD by reviewing relevant literature in recent years, in order to explore the relationship between pyroptosis, autophagy and IDD.

Case Series of Men with the Germline APC I1307K variant and Treatment-Emergent Neuroendocrine Prostate Cancer.

INTRODUCTION: Somatic mutations in the Wnt signaling gene Adenomatous Polyposis Coli (APC) promote metastatic prostate cancer (PCa) progression. Less is known regarding the impact of germline APC mutations on PCa outcomes. We sought to investigate the prevalence of aggressive variant PCa (AVPC) and treatment-emergent neuroendocrine PCa (t-NEPC) in patients with the germline APC I1307K variant, an alteration found in 7% of Ashkenazi Jewish men. MATERIALS AND METHODS: We report a retrospective cohort study comparing patients with PCa and either APC I1307K germline mutation, APC somatic mutations, or unselected patients. Proportions of patients with AVPC among all the cases were estimated along with 95% Clopper-Pearson exact confidence intervals (CI). Odds ratios with 95% CI were provided for the prevalence of t-NEPC and AVPC in patients with germline APC I1307K compared to patients with frameshift alterations in APC. RESULTS: From 2016-2022, 18 patients with PCa at 3 institutions with the germline APC (I1307K) mutation were identified. Clinically-defined AVPC was found in 8 of the 15 cases with metastatic disease (53%; 95% CI: 26%-79%). Combined somatic alterations in two or more of RB1, TP53 or PTEN (molecularly-defined AVPC) were found in 5/18 cases (28%; 95% CI: 10%-54%). When compared to 20 patients with APC somatic frameshift mutations, patients with the germline APC I1307K variant had a significantly increased risk of AVPC (OR 7.2; 95% CI 1.27, 40.68). CONCLUSION: PCa that develops in the presence of the germline APC I1307K mutation appear to be enriched for clinically-defined and molecularly-defined AVPC and in particular, for t-NEPC.

Epimeric vitamin D and cardiovascular structure and function in advanced CKD and after kidney transplantation.

BACKGROUND: 25-hydroxyvitamin D can undergo C-3 epimerization to produce 3-epi-25(OH)D3. 3-epi-25(OH)D3 levels decline in chronic kidney disease (CKD), but its role in regulating the cardiovascular system is unknown. Herein, we examined the relationship between 3-epi-25(OH)D3, and cardiovascular functional and structural endpoints in patients with CKD. METHODS: We examined n = 165 patients with advanced CKD from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) study cohort, including those who underwent kidney transplant (KTR, n = 76) and waitlisted patients who did not (NTWC, n = 89). All patients underwent cardiopulmonary exercise testing and echocardiography at baseline, 2 months and 12 months. Serum 3-epi-25(OH)D3 was analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: Patients were stratified into quartiles of baseline 3-epi-25(OH)D3 (Q1: <0.4 ng/mL, n = 51; Q2: 0.4 ng/mL, n = 26; Q3: 0.5-0.7 ng/mL, n = 47; Q4: ≥0.8 ng/mL, n = 41). Patients in Q1 exhibited lower peak oxygen uptake [VO2Peak = 18.4 (16.2-20.8) mL/min/kg] compared with Q4 [20.8 (18.6-23.2) mL/min/kg; P = .009]. Linear mixed regression model showed that 3-epi-25(OH)D3 levels increased in KTR [from 0.47 (0.30) ng/mL to 0.90 (0.45) ng/mL] and declined in NTWC [from 0.61 (0.32) ng/mL to 0.45 (0.29) ng/mL; P < .001]. Serum 3-epi-25(OH)D3 was associated with VO2Peak longitudinally in both groups [KTR: ß (standard error) = 2.53 (0.56), P < .001; NTWC: 2.73 (0.70), P < .001], but was not with left ventricular mass or arterial stiffness. Non-epimeric 25(OH)D3, 24,25(OH)2D3 and the 25(OH)D3:24,25(OH)2D3 ratio were not associated with any cardiovascular outcome (all P > .05). CONCLUSIONS: Changes in 3-epi-25(OH)D3 levels may regulate cardiovascular functional capacity in patients with advanced CKD.

The prognostic value of improving congestion on lung ultrasound during treatment for acute heart failure differs based on patient characteristics at admission.

BACKGROUND: Lung ultrasound congestion scoring (LUS-CS) is a congestion severity biomarker. The BLUSHED-AHF trial demonstrated feasibility for LUS-CS-guided therapy in acute heart failure (AHF). We investigated two questions: 1) does change (∆) in LUS-CS from emergency department (ED) to hospital-discharge predict patient outcomes, and 2) is the relationship between in-hospital decongestion and adverse events moderated by baseline risk-factors at admission? METHODS: We performed a secondary analysis of 933 observations/128 patients from 5 hospitals in the BLUSHED-AHF trial receiving daily LUS. ∆LUS-CS from ED arrival to inpatient discharge (scale -160 to +160, where negative = improving congestion) was compared to a primary outcome of 30-day death/AHF-rehospitalization. Cox regression was used to adjust for mortality risk at admission [Get-With-The-Guidelines HF risk score (GWTG-RS)] and the discharge LUS-CS. An interaction between ∆LUS-CS and GWTG-RS was included, under the hypothesis that the association between decongestion intensity (by ∆LUS-CS) and adverse outcomes would be stronger in admitted patients with low-mortality risk but high baseline congestion. RESULTS: Median age was 65 years, GWTG-RS 36, left ventricular ejection fraction 36 %, and ∆LUS-CS -20. In the multivariable analysis ∆LUS-CS was associated with event-free survival (HR = 0.61; 95 % CI: 0.38-0.97), while discharge LUS-CS (HR = 1.00; 95%CI: 0.54-1.84) did not add incremental prognostic value to ∆LUS-CS alone. As GWTG-RS rose, benefits of LUS-CS reduction attenuated (interaction p < 0.05). ∆LUS-CS and event-free survival were most strongly correlated in patients without tachycardia, tachypnea, hypotension, hyponatremia, uremia, advanced age, or history of myocardial infarction at ED/baseline, and those with low daily loop diuretic requirements. CONCLUSIONS: Reduction in ∆LUS-CS during AHF treatment was most associated with improved readmission-free survival in heavily congested patients with otherwise reassuring features at admission. ∆LUS-CS may be most useful as a measure to ensure adequate decongestion prior to discharge, to prevent early readmission, rather than modify survival.