Search

The optimal hemoglobin threshold to guide red blood cell transfusion for patients with acute myocardial infarction and anemia is uncertain. This prespecified secondary analysis of the MINT (Myocardial Ischemia and Transfusion) trial, which randomly assigned patients to a liberal transfusion threshold versus a more restrictive threshold, used target trial emulation methods to compare 4 transfusion strategies to maintain patients' hemoglobin concentrations at or above thresholds of 10, 9, 8, or 7 g/dL. Visual Abstract. Effect of Four Hemoglobin Transfusion Threshold Strategies in Patients With Acute Myocardial Infarction and Anemia: The optimal hemoglobin threshold to guide red blood cell transfusion for patients with acute myocardial infarction and anemia is uncertain. This prespecified secondary analysis of the MINT (Myocardial Ischemia and Transfusion) trial, which randomly assigned patients to a liberal transfusion threshold versus a more restrictive threshold, used target trial emulation methods to compare 4 transfusion strategies to maintain patients' hemoglobin concentrations at or above thresholds of 10, 9, 8, or 7 g/dL. Background: The optimal hemoglobin threshold to guide red blood cell (RBC) transfusion for patients with acute myocardial infarction (MI) and anemia is uncertain. Objective: To estimate the efficacy of 4 individual hemoglobin thresholds (<10 g/dL [<100 g/L], <9 g/dL [<90 g/L], <8 g/dL [<80 g/L], and <7 g/dL [<70 g/L]) to guide transfusion in patients with acute MI and anemia. Design: Prespecified secondary analysis of the MINT (Myocardial Ischemia and Transfusion) trial using target trial emulation methods. (ClinicalTrials.gov: NCT02981407) Setting: 144 clinical sites in 6 countries. Participants: 3492 MINT trial participants with acute MI and a hemoglobin level below 10 g/dL. Intervention: Four transfusion strategies to maintain patients' hemoglobin concentrations at or above thresholds of 10, 9, 8, or 7 g/dL. Protocol exceptions were permitted for specified adverse clinical events. Measurements: Data from the MINT trial were leveraged to emulate 4 transfusion strategies and estimate per protocol effects on the composite outcome of 30-day death or recurrent MI (death/MI) and 30-day death using inverse probability weighting. Results: The 30-day risk for death/MI was 14.8% (95% CI, 11.8% to 18.4%) for a <10-g/dL strategy, 15.1% (CI, 11.7% to 18.2%) for a <9-g/dL strategy, 15.9% (CI, 12.4% to 19.0%) for a <8-g/dL strategy, and 18.3% (CI, 14.6% to 22.0%) for a <7-g/dL strategy. Absolute risk differences and risk ratios relative to the <10-g/dL strategy for 30-day death/MI increased as thresholds decreased, although 95% CIs were wide. Findings were similar and imprecise for 30-day death. Limitation: Unmeasured confounding may have persisted despite adjustment. Conclusion: The 30-day risks for death/MI and death among patients with acute MI and anemia seem to increase progressively with lower hemoglobin concentration thresholds for transfusion. However, the imprecision around estimates from this target trial analysis precludes definitive conclusions about individual hemoglobin thresholds. Primary Funding Source: National Heart, Lung, and Blood Institute. [ABSTRACT FROM AUTHOR]

Background: Frailty is associated with adverse cardiovascular outcomes independent of age and comorbidities, yet the independent influence of frailty progression on cardiovascular outcomes remains uncertain. Methods: To determine whether frailty progression is associated with adverse cardiovascular outcomes, independent of baseline frailty and age, we evaluated all Medicare Fee‐for‐Service beneficiaries ≥65 years at cohort inception with continuous enrollment from 2003 to 2015. Linear mixed effects models, adjusted for baseline frailty and age, were used to estimate change in a validated claims‐based frailty index (CFI) over a 5‐year period. Survival analysis was used to examine frailty progression and risk of adverse health outcomes. Results: There were 8.9 million unique patients identified, mean age 77.3 ± 7.2 years, 58.7% female, 10.9% non‐White race. In total, 60% had frailty progression and 40% frailty regression over median follow‐up of 2.4 years. Compared to those with frailty regression, when adjusting for age and baseline CFI, those with frailty progression had a significantly greater risk of incident major adverse cardiovascular and cerebrovascular events (MACCE) (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.31–1.31), all‐cause mortality (HR 1.34, 95% CI 1.34–1.34), acute myocardial infarction (HR 1.08, 95% CI 1.07–1.09), heart failure exacerbation (HR 1.30, 95% CI 1.29–1.30), ischemic stroke (HR 1.14, 95% CI 1.14–1.15). There was also a graded increase in risk of each outcome with more rapid progression, as well as significantly fewer days alive at home (DAH) with more rapid progression compared to the slowest progression group (270.4 ± 112.3 vs. 308.6 ± 93.0 days, rate ratio 0.88, 95% CI 0.87–0.88, p < 0.001). Conclusions: In this large, nationwide sample of older Medicare beneficiaries, frailty progression, independent of age and baseline frailty, was associated with fewer DAH and a graded risk of MACCE, all‐cause mortality, myocardial infarction, heart failure, and ischemic stroke compared to those with frailty regression. [ABSTRACT FROM AUTHOR]

The riverine transport and deposition of mud is the primary agent of landscape construction and evolution in many fluvial and coastal environments. Previous efforts exploring this process have raised uncertainty regarding the effects of hydrodynamic and chemical controls on the transport and deposition of mud, and thus the constructions of muddy coastal and upstream environments. As such, direct measurements are necessary to constrain the deposition of mud by river systems. Here, we combine laboratory evidence and a field investigation in the Mississippi River delta to explore the controls on the riverine transport and deposition of mud. We show that the flocculation of mud, with floc diameters greater than 10 μm, in freshwater is a ubiquitous phenomenon, causing the sedimentation of mud to be driven by changes in local hydrodynamics, and thus providing an explanation for how river systems construct landscapes through the deposition of mud in both coastal and upstream environments. Plain Language Summary: Muddy landscapes are some of the most common and vital environments on Earth's surface, such as floodplains, deltas, and estuaries. Due to their small size, and thus easily suspendable nature, mud particles are thought to be extremely difficult to deposit under typical flow conditions in rivers. As such, the means by which rivers deposit mud has been the subject of much study and debate. Canonically, the deposition of cohesive sediment occurs as rivers approach the ocean, where increases in salinity induce the aggregation of clay and silt particles to form heavier floccules, or "flocs." Recent studies have also explored the influence of organic material on mud aggregation. However, the means by which rivers are able to construct muddy landscapes upstream, in the absence of saline or organic‐rich water, remains uncertain. To address this discrepancy, we utilize a combination of laboratory evidence and a field investigation on the Mississippi River delta to show that all mud is transported as flocs, not as individual grains, and as such, the deposition of mud by river systems is controlled by the ability of the river flow to suspend existing mud flocs, and not by abrupt changes in water chemistry inducing flocculation in coastal regions. Key Points: Flocculation of mud in water is a ubiquitous phenomenonSalinity may have little to no effect on mud floc size as rivers enter marine environmentsDeposition of flocculated mud in river systems is driven by changes in hydrodynamic stress [ABSTRACT FROM AUTHOR]

Background: Ultrasound enhancing agents (UEAs) are an invaluable adjunct to stress and transthoracic echocardiography (STE) to improve left ventricular visualization. Despite multiple single center studies evaluating UEA use, investigation into the rates, sources of variation, and outcomes of UEA use on a national level in the United States (US) has been limited by lack of validation of UEA codes for claims analyses. Methods: We conducted a retrospective cross-sectional study, 2019–2022, using linked multicenter electronic medical record (EMR) data from > 30 health systems linked to all-payor claims data representing > 90% of the US population. Individuals receiving STE in both EMR and claims data on the same day during the study window were included. UEA receipt as identified by presence of a Current Procedural Terminology (CPT) or National Drug Code (NDC) for UEA use within 1-day of the index STE event. We evaluated the performance of claims to identify UEA use, using EMR data as the gold standard, stratified by inpatient and outpatient status. Results: Amongst 54,525 individuals receiving STE in both EMR and claims data, 12,853 (23.6%) had a UEA claim in EMR, 10,461 (19.2%) had a UEA claim in claims, and 9140 (16.8%) had a UEA claim in both within the 1-day window. The sensitivity, specificity, accuracy, positive, and negative predictive values for UEA claims were 71.1%, 96.8%, 90.8%, 87.4%. and 91.6% respectively. However, amongst inpatients, the sensitivity of UEA claims was substantially lower (6.8%) compared to outpatients (79.7%). Conclusions: While the overall accuracy of claims to identify UEA use was high, there was substantial under-capture of UEA use by claims amongst inpatients. These results call into question published rates of UEA use amongst inpatients in studies using administrative claims, and highlight ongoing need to improve inpatient coding for UEA use. [ABSTRACT FROM AUTHOR]

Background Frailty is increasingly recognized as a useful measure of vulnerability in older adults. Multiple claims-based frailty indices (CFIs) can readily identify individuals with frailty, but whether 1 CFI improves prediction over another is unknown. We sought to assess the ability of 5 distinct CFIs to predict long-term institutionalization (LTI) and mortality in older Veterans. Methods Retrospective study conducted in U.S. Veterans ≥65 years without prior LTI or hospice use in 2014. Five CFIs were compared: Kim, Orkaby (Veteran Affairs Frailty Index [VAFI]), Segal, Figueroa, and the JEN-FI, grounded in different theories of frailty: Rockwood cumulative deficit (Kim and VAFI), Fried physical phenotype (Segal), or expert opinion (Figueroa and JFI). The prevalence of frailty according to each CFI was compared. CFI performance for the coprimary outcomes of any LTI or mortality from 2015 to 2017 was examined. Because Segal and Kim include age, sex, or prior utilization, these variables were added to regression models to compare all 5 CFIs. Logistic regression was used to calculate model discrimination and calibration for both outcomes. Results A total of 3 million Veterans were included (mean age 75, 98% male participants, 80% White, and 9% Black). Frailty was identified for between 6.8% and 25.7% of the cohort with 2.6% identified as frail by all 5 CFIs. There was no meaningful difference between CFIs in the area under the receiver operating characteristic curve for LTI (0.78–0.80) or mortality (0.77–0.79). Conclusions Based on different frailty constructs, and identifying different subsets of the population, all 5 CFIs similarly predicted LTI or death, suggesting each could be used for prediction or analytics. [ABSTRACT FROM AUTHOR]

The microbiome is known to play a role in many human diseases, but identifying key microbes and their functions generally requires large studies due to the vast number of species and genes, and the high levels of intra-individual and inter-individual variation. 16S amplicon sequencing of the rRNA gene is commonly used for large studies due to its comparatively low sequencing cost, but it has poor taxonomic and functional resolution. Deep shotgun sequencing is a more accurate and comprehensive alternative for small studies, but can be cost-prohibitive for biomarker discovery in large populations. Shallow or moderate-depth shotgun metagenomics may serve as a viable alternative to 16S sequencing for large-scale and/or dense longitudinal studies, but only if resolution and reproducibility are comparable. Here we applied both 16S and shallow shotgun stool microbiome sequencing to a cohort of 5 subjects sampled twice daily and weekly, with technical replication at the DNA extraction and the library preparation/sequencing steps, for a total of 80 16S samples and 80 shallow shotgun sequencing samples. We found that shallow shotgun sequencing produced lower technical variation and higher taxonomic resolution than 16S sequencing, at a much lower cost than deep shotgun sequencing. These findings suggest that shallow shotgun sequencing provides a more specific and more reproducible alternative to 16S sequencing for large-scale microbiome studies where costs prohibit deep shotgun sequencing and where bacterial species are expected to have good coverage in whole-genome reference databases. [ABSTRACT FROM AUTHOR]

Aims: Frailty is associated with increased morbidity and mortality in patients undergoing left atrial appendage closure (LAAC). This study aimed to compare the performance of two claims‐based frailty measures in predicting adverse outcomes following LAAC. Methods: We identified patients 66 years and older who underwent LAAC between October 1, 2016, and December 31, 2019, in Medicare fee‐for‐service claims. Frailty was assessed using the previously validated Hospital Frailty Risk Score (HFRS) and Kim Claims‐based Frailty Index (CFI). Patients were identified as frail based on HFRS ≥5 and CFI ≥0.25. Results: Of the 21,787 patients who underwent LAAC, frailty was identified in 45.6% by HFRS and 15.4% by CFI. There was modest agreement between the two frailty measures (kappa 0.25, Pearson's correlation 0.62). After adjusting for age, sex, and comorbidities, frailty was associated with higher risk of 30‐day mortality, 1‐year mortality, 30‐day readmission, long hospital stay, and reduced days at home (p <.01 for all) regardless of the frailty measure used. The addition of frailty to standard comorbidities significantly improved model performance to predict 1‐year mortality, long hospital stay, and reduced days at home (Delong p‐value <.001). Conclusion: Despite significant variation in frailty detection and modest agreement between the two frailty measures, frailty status remained highly predictive of mortality, readmissions, long hospital stay, and reduced days at home among patients undergoing LAAC. Measuring frailty in clinical practice, regardless of the method used, may provide prognostic information useful for patients being considered for LAAC, and may inform shared decision‐making in this population. [ABSTRACT FROM AUTHOR]

Background: In response to COVID-19 pandemic state restrictions, our institution deferred elective procedures from 3/15/2020 to 6/13/2020, and removed cardiology fellows from the echocardiography rotation to staff clinical services. We assessed the impact of the COVID-19 pandemic on fellow education and echocardiography volumes. Methods: Our institutional database was used to examine volumes of transthoracic (TTE), stress (SE), and transesophageal echocardiograms (TEE) from 7/1/2018 to 10/10/2020. Study volumes were compared in three intervals: pre-pandemic (7/1/2018- 3/14/2020), pandemic (3/15/2020–6/13/2020), and pandemic recovery (6/14/2020–10/10/2020). We examined weekly number of TTEs performed or interpreted by cardiology fellows during the study period, and compared these to the two previous academic years. Results: Weekly TTE volume declined by 54% during the pandemic, and increased by 99% during pandemic recovery, (p < 0.05). SE and TEE revealed similar trends. A strong correlation between weekly TTE volume and inpatient admissions was observed during the study period (rs=0.67, p < 0.05). Weekly fellow TTE scans declined by 78% during the pandemic, with a 380% increase during pandemic recovery (p < 0.05). Weekly fellow TTE interpretations declined by 56% during the pandemic, with a 76% increase during pandemic recovery (p < 0.05). Conclusion: COVID restrictions between 3/15/2020- 6/14/2020 coincided with a marked decline in TTE, SE, and TEE volumes, with an increase similar to near pre-pandemic volumes during the pandemic recovery period. A similar decline with the onset of COVID restrictions, and increase to pre-restriction volumes thereafter was observed with fellow scans and interpretations, but total academic year fellow training volumes remained depressed. With the ongoing COVID-19 pandemic and rise of multiple variants, training programs may need to adjust fellows' clinical responsibilities so as to support achievement of echocardiography training certification. [ABSTRACT FROM AUTHOR]

Aims Prediction of mitral (MR) and tricuspid (TR) regurgitation progression on transthoracic echocardiography (TTE) is needed to personalize valvular surveillance intervals and prognostication. Methods and results Structured TTE report data at Beth Israel Deaconess Medical Center, 26 January 2000–31 December 2017, were used to determine time to progression (≥1+ increase in severity). TTE predictors of progression were used to create a progression score, externally validated at Massachusetts General Hospital, 1 January 2002–31 December 2019. In the derivation sample (MR, N = 34 933; TR, N = 27 526), only 5379 (15.4%) individuals with MR and 3630 (13.2%) with TR had progression during a median interquartile range) 9.0 (4.1–13.4) years of follow-up. Despite wide inter-individual variability in progression rates, a score based solely on demographics and TTE variables identified individuals with a five- to six-fold higher rate of MR/TR progression over 10 years (high- vs. low-score tertile, rate of progression; MR 20.1% vs. 3.3%; TR 21.2% vs. 4.4%). Compared to those in the lowest score tertile, those in the highest tertile of progression had a four-fold increased risk of mortality. On external validation, the score demonstrated similar performance to other algorithms commonly in use. Conclusion Four-fifths of individuals had no progression of MR or TR over two decades. Despite wide interindividual variability in progression rates, a score, based solely on TTE parameters, identified individuals with a five- to six-fold higher rate of MR/TR progression. Compared to the lowest tertile, individuals in the highest score tertile had a four-fold increased risk of mortality. Prediction of long-term MR/TR progression is not only feasible but prognostically important. [ABSTRACT FROM AUTHOR]

Background: While large scientific and medical evidence has demonstrated the increased risk of death and cardiovascular mortality in patients with severe AS, the independent contribution of moderate AS to an increased risk of death remains uncertain. Methods and findings: We conducted a multicenter study including a cohort of 30,865 US patients and another cohort of 217,599 Australian patients with equivalent echocardiographic and aortic valve profiling over the same period (2003–2017). During a median 5.2 years (US) and 4.4 years (Australian) follow-up, the risk of death (hazard ratio) of patients with moderate AS as compared to those without AS was 1.66 (95%CI 1.52–1.80) and 1.37 (95%CI 1.34–1.41) in the US and Australian cohorts, even after adjusting this analysis for age and sex. This increased risk of death and cardiovascular mortality (odds ratio) in patients with moderate AS was consistent also across subgroups of left ventricular ejection fraction (LVEF) (subgroups of LVEF < 40%, 40–49%, 50–59%, and ≥ 60%: OR of moderate AS for CV mortality 2.0 [95%CI 1.4–2.7], 1.7 [95%CI 1.2–2.4], 1.5 [95%CI 1.1–1.9], and 1.4 [95%CI 1.2–1.6], respectively). Conclusions: The findings of this study suggest that patients with moderate AS have a potential increased risk of death and cardiovascular mortality, regardless of age, sex, and LVEF. Hence, these data suggest the need to develop specific strategies to detect and treat individuals with moderate AS. [ABSTRACT FROM AUTHOR]

In response to the coronavirus disease 2019 (COVID-19) pandemic, the Cardio-Oncology and Imaging Councils of the American College of Cardiology offers recommendations to clinicians regarding the cardiovascular care of cardio-oncology patients in this expert consensus statement. Cardio-oncology patients-individuals with an active or prior cancer history and with or at risk of cardiovascular disease-are a rapidly growing population who are at increased risk of infection, and experiencing severe and/or lethal complications by COVID-19. Recommendations for optimizing screening and monitoring visits to detect cardiac dysfunction are discussed. In addition, judicious use of multimodality imaging and biomarkers are proposed to identify myocardial, valvular, vascular, and pericardial involvement in cancer patients. The difficulties of diagnosing the etiology of cardiovascular complications in patients with cancer and COVID-19 are outlined, along with weighing the advantages against risks of exposure, with the modification of existing cardiovascular treatments and cardiotoxicity surveillance in patients with cancer during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Keywords: frailty; peripheral artery disease (PAD); Vascular Quality Initiative (VQI) EN frailty peripheral artery disease (PAD) Vascular Quality Initiative (VQI) 258 260 3 06/14/22 20220601 NES 220601 Commentary on: Al-Damlugi et al. Frailty and outcomes following revascularization of lower-extremity peripheral artery disease: Insights from the Vascular Quality Initiative (VQI). [Extracted from the article]

Background: Limited data exist on the differential ability of variables on transthoracic echocardiogram (TTE) to predict heart failure (HF) readmission across the spectrum of left ventricular (LV) systolic function. Methods: We linked 15 years of TTE report data (1/6/2003-5/3/2018) at Beth Israel Deaconess Medical Center to complete Medicare claims. In those with recent HF, we evaluated the relationship between variables on baseline TTE and HF readmission, stratified by LVEF. Results: After excluding TTEs with uninterpretable diastology, 5,900 individuals (mean age: 76.9 years; 49.1% female) were included, of which 2545 individuals (41.6%) were admitted for HF. Diastolic variables augmented prediction compared to demographics, comorbidities, and echocardiographic structural variables (p < 0.001), though discrimination was modest (c-statistic = 0.63). LV dimensions and eccentric hypertrophy predicted HF in HF with reduced (HFrEF) but not preserved (HFpEF) systolic function, whereas LV wall thickness, NT-proBNP, pulmonary vein D- and Ar-wave velocities, and atrial dimensions predicted HF in HFpEF but not HFrEF (all interaction p < 0.10). Prediction of HF readmission was not different in HFpEF and HFrEF (p = 0.93). Conclusions: In this single-center echocardiographic study linked to Medicare claims, left ventricular dimensions and eccentric hypertrophy predicted HF readmission in HFrEF but not HFpEF and left ventricular wall thickness predicted HF readmission in HFpEF but not HFrEF. Regardless of LVEF, diastolic variables augmented prediction of HF readmission compared to echocardiographic structural variables, demographics, and comorbidities alone. The additional role of medication adherence, readmission history, and functional status in differential prediction of HF readmission by LVEF category should be considered for future study. [ABSTRACT FROM AUTHOR]

Objective: The Appropriate Use Criteria (AUC) has been used to identify individuals who are likely to benefit from percutaneous coronary intervention (PCI) for stable ischaemic heart disease. However, whether physicians reliably grade PCI appropriateness and whether AUC categories stratify symptomatic improvement in real-world practice are unclear.Methods: Patient-reported outcomes measures (PROMs) for angina (Seattle Angina Questionnaire (SAQ-7)), dyspnoea (Rose Dyspnea Scale (RDS)) and depression (Patient Health Questionnaire-2 (PHQ-2)) were collected on patients undergoing elective coronary angiography at an academic medical centre. Retrospectively, two physicians independently determined PCI appropriateness by the AUC criteria.Results: Inter-rater agreement on appropriateness was moderate (κ=0.48, 95% CI 0.32 to 0.63). Of PCI procedures evaluated, 57 (47.1%) were appropriate (A-PCI), 62 (51.2%) were maybe appropriate (MA-PCI) and 2 (1.6%) were rarely appropriate. At baseline, A-PCI compared with MA-PCI patients had worse RDS scores (2.0 vs 1.2, p=0.01). At 30 days, the change in SAQ-7 summary score was similar between groups (A-PCI vs MA-PCI, +27.1 vs +20.7, p=0.11). The mean change in RDS score was greater in A-PCI than MA-PCI (-1.0 vs -0.5, p for group by time interaction=0.03). PHQ-2 scores were similar and did not improve at 30 days.Conclusion: In patients undergoing PCI with PROMs collected before and 30 days after PCI, similar improvements in angina were observed regardless of appropriateness. Inter-rater agreement on PCI appropriateness was only moderate. Use of PROMs may improve reliability of physician assessments of PCI appropriateness. [ABSTRACT FROM AUTHOR]

Aims We sought to identify the prevalence and related outcomes of frail individuals undergoing transcatheter mitral valve repair and transcatheter aortic valve replacement (TAVR). Methods and results Patients aged 65 and older were included in the study if they had at least one procedural code for transcatheter mitral valve repair or TAVR between 1 January 2016 and 31 December 2016 in the Centers for Medicare and Medicaid Services Medicare Provider and Review database. The Hospital Frailty Risk Score, an International Classification of Diseases, Tenth Revision (ICD-10) claims-based score, was used to identify frailty and the primary outcome was all-cause 1-year mortality. A total of 3746 (11.6%) patients underwent transcatheter mitral valve repair and 28 531 (88.4%) underwent TAVR. In the transcatheter mitral valve repair and TAVR populations, respectively, there were 1903 (50.8%) and 14 938 (52.4%) patients defined as low risk for frailty (score <5), 1476 (39.4%) and 11 268 (39.5%) defined as intermediate risk (score 5–15), and 367 (9.8%) and 2325 (8.1%) defined as high risk (score >15). One-year mortality was 12.8% in low-risk patients, 29.7% in intermediate-risk patients, and 40.9% in high-risk patients undergoing transcatheter mitral valve repair (log rank P  < 0.001). In patients undergoing TAVR, 1-year mortality rates were 7.6% in low-risk patients, 17.6% in intermediate-risk patients, and 30.1% in high-risk patients (log rank P  < 0.001). Conclusions This study successfully identified individuals at greater risk of short- and long-term mortality after undergoing transcatheter valve therapies in an elderly population in the USA using the ICD-10 claims-based Hospital Frailty Risk Score. View large Download slide View large Download slide [ABSTRACT FROM AUTHOR]

Hematopoietic stem/progenitor cells (HSPC) are characterized by their unique capacities of self-renewal and multi-differentiation potential. This second property makes them able to adapt their differentiation profile depending on the local environment they reach. Taking advantage of an animal model of peritonitis, induced by injection of the TLR-2 ligand, zymosan, we sought to study the relationship between bone marrow-derived hematopoietic stem/progenitor cells (BM-HSPCs) and innate lymphoid cells (ILCs) regarding their emergence and differentiation at the site of inflammation. Our results demonstrate that the strength of the inflammatory signals affects the capacity of BM-derived HSPCs to migrate and give rise in situ to ILCs. Both low- and high-dose of zymosan injections trigger the appearance of mature ILCs in the peritoneal cavity where the inflammation occurs. Herein, we show that only in low-dose injected mice, the recovered ILCs are dependent on an in situ differentiation of BM-derived HSPCs and/or ILC2 precursors (ILC2P) wherein high-dose, the stronger inflammatory environment seems to be able to induce the emergence of ILCs independently of BM-derived HSPCs. We suggest that a relationship between HSPCs and ILCs seems to be affected by the strength of the inflammatory stimuli opening new perspectives in the manipulation of these early hematopoietic cells. [ABSTRACT FROM AUTHOR]

Objective: To determine the safety and pharmacokinetics of alpha‐1 antitrypsin (AAT) in adults and children. Research design and methods: Short‐term AAT treatment restores euglycemia in the non‐obese mouse model of type 1 diabetes. A phase I multicenter study in 16 subjects with new‐onset type 1 diabetes studied the safety and pharmacokinetics of Aralast NP (AAT). This open‐label, dose‐escalation study enrolled 8 adults aged 16 to 35 years and 8 children aged 8 to 15 years within 100 days of diagnosis, to receive 12 infusions of AAT: a low dose of 45 mg/kg weekly for 6 weeks, followed by a higher dose of 90 mg/kg for 6 weeks. Results: C‐peptide secretion during a mixed meal, hemoglobin A1c (HbA1c), and insulin usage remained relatively stable during the treatment period. At 72 hours after infusion of 90 mg/kg, mean levels of AAT fell below 2.0 g/L for 7 of 15 subjects. To identify a plasma level of AAT likely to be therapeutic, pharmacodynamic ex vivo assays were performed on fresh whole blood from adult subjects. Polymerase chain reaction (PCR) analyses were performed on inhibitor of IKBKE, NOD1, TLR1, and TRAD gene expression, which are important for activation of nuclear factor‐κB (NF‐κB) and apoptosis pathways. AAT suppressed expression dose‐dependently; 50% inhibition was achieved in the 2.5 to 5.0 mg/mL range. Conclusions: AAT was well tolerated and safe in subjects with new‐onset type 1 diabetes. Weekly doses of AAT greater than 90 mg/kg may be necessary for an optimal therapeutic effect. [ABSTRACT FROM AUTHOR]

Summary The common genetic variation at rs8004664 in the FOXN3 gene is independently and significantly associated with fasting blood glucose, but not insulin, in non-diabetic humans. Recently, we reported that primary hepatocytes from rs8004664 hyperglycemia risk allele carriers have increased FOXN3 transcript and protein levels and liver-limited overexpression of human FOXN3, a transcriptional repressor that had not been implicated in metabolic regulation previously, increases fasting blood glucose in zebrafish. Here, we find that injection of glucagon into mice and adult zebrafish decreases liver Foxn3 protein and transcript levels. Zebrafish foxn3 loss-of-function mutants have decreased fasting blood glucose, blood glucagon, liver gluconeogenic gene expression, and α cell mass. Conversely, liver-limited overexpression of foxn3 increases α cell mass. Supporting these genetic findings in model organisms, non-diabetic rs8004664 risk allele carriers have decreased suppression of glucagon during oral glucose tolerance testing. By reciprocally regulating each other, liver FOXN3 and glucagon control fasting glucose. [ABSTRACT FROM AUTHOR]

Background: Readmission rates after hospitalizations for heart failure (HF), acute myocardial infarction (AMI), and pneumonia among Medicare beneficiaries are used to assess quality and determine reimbursement. Whether these measures reflect readmission rates for other conditions or insurance groups is unknown. Objective: To investigate whether hospital-level 30-day readmission measures for publicly reported conditions (HF, AMI, and pneumonia) among Medicare patients reflect those for Medicare patients hospitalized for unreported conditions or non-Medicare patients hospitalized with HF, AMI, or pneumonia. Design: Cross-sectional. Setting: Population-based. Participants: Hospitals in the all-payer Nationwide Readmissions Database in 2013 and 2014. Measurements: Hospital-level 30-day all-cause risk-standardized excess readmission ratios (ERRs) were compared for 3 groups of patients: Medicare beneficiaries admitted for HF, AMI, or pneumonia (Medicare reported group); Medicare beneficiaries admitted for other conditions (Medicare unreported group); and non-Medicare beneficiaries admitted for HF, AMI, or pneumonia (non-Medicare group). Results: Within-hospital differences in ERRs varied widely among groups. Medicare reported ratios differed from Medicare unreported ratios by more than 0.1 for 29% of hospitals and from non-Medicare ratios by more than 0.1 for 46% of hospitals. Among hospitals with higher readmission ratios, ERRs for the Medicare reported group tended to overestimate ERRs for the non-Medicare group but underestimate those for the Medicare unreported group. Limitation: Medicare groups and risk adjustment differed slightly from those used by the Centers for Medicare & Medicaid Services. Conclusion: Hospital ERRs, as estimated by Medicare to determine financial penalties, have poor agreement with corresponding measures for populations and conditions not tied to financial penalties. Current publicly reported measures may not be good surrogates for overall hospital quality related to 30-day readmissions. [ABSTRACT FROM AUTHOR]

Background: Readmission rates after hospitalizations for heart failure (HF), acute myocardial infarction (AMI), and pneumonia among Medicare beneficiaries are used to assess quality and determine reimbursement. Whether these measures reflect readmission rates for other conditions or insurance groups is unknown.Objective: To investigate whether hospital-level 30-day readmission measures for publicly reported conditions (HF, AMI, and pneumonia) among Medicare patients reflect those for Medicare patients hospitalized for unreported conditions or non-Medicare patients hospitalized with HF, AMI, or pneumonia.Design: Cross-sectional.Setting: Population-based.Participants: Hospitals in the all-payer Nationwide Readmissions Database in 2013 and 2014.Measurements: Hospital-level 30-day all-cause risk-standardized excess readmission ratios (ERRs) were compared for 3 groups of patients: Medicare beneficiaries admitted for HF, AMI, or pneumonia (Medicare reported group); Medicare beneficiaries admitted for other conditions (Medicare unreported group); and non-Medicare beneficiaries admitted for HF, AMI, or pneumonia (non-Medicare group).Results: Within-hospital differences in ERRs varied widely among groups. Medicare reported ratios differed from Medicare unreported ratios by more than 0.1 for 29% of hospitals and from non-Medicare ratios by more than 0.1 for 46% of hospitals. Among hospitals with higher readmission ratios, ERRs for the Medicare reported group tended to overestimate ERRs for the non-Medicare group but underestimate those for the Medicare unreported group.Limitation: Medicare groups and risk adjustment differed slightly from those used by the Centers for Medicare & Medicaid Services.Conclusion: Hospital ERRs, as estimated by Medicare to determine financial penalties, have poor agreement with corresponding measures for populations and conditions not tied to financial penalties. Current publicly reported measures may not be good surrogates for overall hospital quality related to 30-day readmissions.Primary Funding Source: Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology. [ABSTRACT FROM AUTHOR]

The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Leprdb/db and Lepob/ob mice with REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor. As expected, REMD 2.59 suppresses hepatic glucose production and improves glycemia. Surprisingly, it also enhances insulin action in both liver and skeletal muscle, coinciding with an increase in AMP-activated protein kinase (AMPK)-mediated lipid oxidation. Furthermore, weekly REMD 2.59 treatment over a period of months protects against diabetic cardiomyopathy. These functional improvements are not derived simply from correcting the systemic milieu; nondiabetic mice with cardiac-specific overexpression of lipoprotein lipase also show improvements in contractile function after REMD 2.59 treatment. These observations suggest that hyperglucagonemia enables lipotoxic conditions, allowing the development of insulin resistance and cardiac dysfunction during disease progression. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear hormone receptor that promotes fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS). We and others have recently shown that PPARα and its target genes are downregulated, and FAO and OXPHOS are impaired in autosomal dominant polycystic kidney disease (ADPKD). However, whether PPARα and FAO/OXPHOS are causally linked to ADPKD progression is not entirely clear. We report that expression of PPARα and FAO/OXPHOS genes is downregulated, and in vivo β-oxidation rate of 3H-labeled triolein is reduced in Pkd1RC/RC mice, a slowly progressing orthologous model of ADPKD that closely mimics the human ADPKD phenotype. To evaluate the effects of upregulating PPARα, we conducted a 5-mo, randomized, preclinical trial by treating Pkd1RC/RC mice with fenofibrate, a clinically available PPARα agonist. Fenofibrate treatment resulted in increased expression of PPARα and FAO/OXPHOS genes, upregulation of peroxisomal and mitochondrial biogenesis markers, and higher β-oxidation rates in Pkd1RC/RC kidneys. MRI-assessed total kidney volume and total cyst volume, kidney-weight-to-body-weight ratio, cyst index, and serum creatinine levels were significantly reduced in fenofibrate-treated compared with untreated littermate Pkd1RC/RC mice. Moreover, fenofibrate treatment was associated with reduced kidney cyst proliferation and infiltration by inflammatory cells, including M2-like macrophages. Finally, fenofibrate treatment also reduced bile duct cyst number, cyst proliferation, and liver inflammation and fibrosis. In conclusion, our studies suggest that promoting PPARα activity to enhance mitochondrial metabolism may be a useful therapeutic strategy for ADPKD. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol-3-kinases (PI3K) γ and δ are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. The effects of PI3Kγ and PI3Kδ on alloimmunity remain underexplored. Here, we show that both PI3Kγ−/− and PI3KδD910A/D910A mice receiving heart allografts have suppression of alloreactive T effector cells and delayed acute rejection. However, PI3Kδ mutation also dampens regulatory T cells (Treg). After treatment with low dose CTLA4-Ig, PI3Kγ−/−, but not PI3ΚδD910A/D910A, recipients exhibit indefinite prolongation of heart allograft survival. PI3KδD910A/D910A Tregs have increased apoptosis and impaired survival. Selective inhibition of PI3Kγ and PI3Kδ (using PI3Kδ and dual PI3Kγδ chemical inhibitors) shows that PI3Kγ inhibition compensates for the negative effect of PI3Kδ inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation. [ABSTRACT FROM AUTHOR]

Few studies have examined rates and causes of short-term readmissions among adults across age and insurance types. We compared rates, characteristics, and costs of 30-day readmission after all-cause hospitalizations across insurance types in the US. We retrospectively evaluated alive patients ≥18 years old, discharged for any cause, 1/1/13-11/31/13, 2006 non-federal hospitals in 21 states in the Nationwide Readmissions Database. The primary stratification variable of interest was primary insurance. Comorbid conditions were assessed based on Elixhauser comorbidities, as defined by administrative billing codes. Additional measures included diagnoses for index hospitalizations leading to rehospitalization. Hierarchical multivariable logistic regression models, with hospital site as a random effect, were used to calculate the adjusted odds of 30-day readmissions by age group and insurance categories. Cost and discharge estimates were weighted per NRD procedures to reflect a nationally representative sample. Diagnoses for index hospitalizations leading to rehospitalization were determined. Among 12,533,551 discharges, 1,818,093 (14.5%) resulted in readmission within 30 days. Medicaid insurance was associated with the highest adjusted odds ratio (AOR) for readmission both in those ≥65 years old (AOR 1.12, 95%CI 1.10–1.14; p <0.001), and 45–64 (AOR 1.67, 95% CI 1.66–1.69; p < 0.001), and Medicare in the 18–44 group (Medicare vs. private insurance: AOR 1.99, 95% CI 1.96–2.01; p <0.001). Discharges for psychiatric or substance abuse disorders, septicemia, and heart failure accounted for the largest numbers of readmissions, with readmission rates of 24.0%, 17.9%, 22.9% respectively. Total costs for readmissions were 50.7 billion USD, highest for Medicare (29.6 billion USD), with non-Medicare costs exceeding 21 billion USD. While Medicare readmissions account for more than half of the total burden of readmissions, costs of non-Medicare readmissions are nonetheless substantial. Medicaid patients have the highest odds of readmission in individuals older than age 44, commonly due to hospitalizations for psychiatric illness and substance abuse disorders. Medicaid patients represent a population at uniquely high risk for readmission. [ABSTRACT FROM AUTHOR]

Diet is a modifiable factor associated with the risk of several cancers, with convincing evidence showing a link between diet and breast cancer. The role of bioactive compounds of food origin, including those found in cruciferous vegetables, is an active area of research in cancer chemoprevention. This review focuses on 3,3'-diindolylmethane (DIM), the major bioactive indole in crucifers. Research of the cancer-preventive activity of DIM has yielded basic mechanistic, animal, and human trial data. Further, this body of evidence is largely supported by observational studies. Bioactive DIM has demonstrated chemopreventive activity in all stages of breast cancer carcinogenesis. This review describes current evidence related to the metabolism and mechanisms of DIM involved in the prevention of breast cancer. Importantly, this review also focuses on current evidence from human observational and intervention trials that have contributed to a greater understanding of exposure estimates that will inform recommendations for DIM intake. [ABSTRACT FROM AUTHOR]

The innate immune system critically shapes diabetogenic adaptive immunity during type 1 diabetes (T1D) pathogenesis. While the role of tissue-infiltrating monocyte-derived macrophages in T1D is well established, the role of their tissue-resident counterparts remains undefined. We now demonstrate that islet resident macrophages (IRMs) from non-autoimmune mice have an immunoregulatory phenotype and powerfully induce FoxP3+ Tregs in vitro. The immunoregulatory phenotype and function of IRMs is compromised by TLR4 activation in vitro. Moreover, as T1D approaches in NOD mice, the immunoregulatory phenotype of IRMs is diminished as is their relative abundance compared to immunostimulatory DCs. Our findings suggest that maintenance of IRM abundance and their immunoregulatory phenotype may constitute a novel therapeutic strategy to prevent and/or cure T1D. [ABSTRACT FROM AUTHOR]