Heart failure (HF)-a serious and costly condition-is increasingly prevalent. We estimated the US burden including emergency department (ED) visits, inpatient hospitalizations and associated costs, ...and mortality.
We analyzed 2006 to 2014 data from the Healthcare Cost and Utilization Project Nationwide Emergency Department Sample, the Healthcare Cost and Utilization Project National (nationwide) Inpatient Sample, and the National Vital Statistics System. International Classification of Disease codes identified HF and comorbidities. Burden was estimated separately for ED visits, hospitalizations, and mortality. In addition, criteria were applied to identify total unique acute events. Rates of primary HF (primary diagnosis or underlying cause of death) and comorbid HF (comorbid diagnosis or contributing cause of death) were calculated, age standardized to the 2010 US population. In 2014, there were an estimated 1 068 412 ED visits, 978 135 hospitalizations, and 83 705 deaths with primary HF. There were 4 071 546 ED visits, 3 370 856 hospitalizations, and 230 963 deaths with comorbid HF. Between 2006 and 2014, the total unique acute event rate for primary HF declined from 536 to 449 per 100 000 (relative percent change of -16%; P for trend, <0.001) but increased for comorbid HF from 1467 to 1689 per 100 000 (relative percentage change, 15%; P for trend, <0.001). HF-related mortality decreased significantly from 2006 to 2009 but did not change meaningfully after 2009. For hospitalizations with primary HF, the estimated mean cost was $11 552 in 2014, totaling an estimated $11 billion.
Given substantial healthcare and mortality burden of HF, rising healthcare costs, and the aging US population, continued improvements in HF prevention, management, and surveillance are important.
Higher levels of sodium and lower levels of potassium intake are associated with higher blood pressure. However, the shape and magnitude of these associations can vary by study participant ...characteristics or intake assessment method. Twenty-four-hour urinary excretion of sodium and potassium are unaffected by recall errors and represent all sources of intake, and were collected for the first time in a nationally representative US survey. Our objective was to assess the associations of blood pressure and hypertension with 24-hour urinary excretion of sodium and potassium among US adults.
Cross-sectional data were obtained from 766 participants age 20 to 69 years with complete blood pressure and 24-hour urine collections in the 2014 National Health and Nutrition Examination Survey, a nationally representative survey of the US noninstitutionalized population. Usual 24-hour urinary electrolyte excretion (sodium, potassium, and their ratio) was estimated from ≤2 collections on nonconsecutive days, adjusting for day-to-day variability in excretion. Outcomes included systolic and diastolic blood pressure from the average of 3 measures and hypertension status, based on average blood pressure ≥140/90 and antihypertensive medication use.
After multivariable adjustment, each 1000-mg difference in usual 24-hour sodium excretion was directly associated with systolic (4.58 mm Hg; 95% confidence interval CI, 2.64-6.51) and diastolic (2.25 mm Hg; 95% CI, 0.83-3.67) blood pressures. Each 1000-mg difference in potassium excretion was inversely associated with systolic blood pressure (-3.72 mm Hg; 95% CI, -6.01 to -1.42). Each 0.5 U difference in sodium-to-potassium ratio was directly associated with systolic blood pressure (1.72 mm Hg; 95% CI, 0.76-2.68). Hypertension was linearly associated with progressively higher sodium and lower potassium excretion; in comparison with the lowest quartile of excretion, the adjusted odds of hypertension for the highest quartile was 4.22 (95% CI, 1.36-13.15) for sodium, and 0.38 (95% CI, 0.17-0.87) for potassium (
<0.01 for trends).
These cross-sectional results show a strong dose-response association between urinary sodium excretion and blood pressure, and an inverse association between urinary potassium excretion and blood pressure, in a nationally representative sample of US adults.
The Xpert MTB/RIF assay is an automated molecular test that has improved the detection of tuberculosis and rifampicin resistance, but its sensitivity is inadequate in patients with paucibacillary ...disease or HIV. Xpert MTB/RIF Ultra (Xpert Ultra) was developed to overcome this limitation. We compared the diagnostic performance of Xpert Ultra with that of Xpert for detection of tuberculosis and rifampicin resistance.
In this prospective, multicentre, diagnostic accuracy study, we recruited adults with pulmonary tuberculosis symptoms presenting at primary health-care centres and hospitals in eight countries (South Africa, Uganda, Kenya, India, China, Georgia, Belarus, and Brazil). Participants were allocated to the case detection group if no drugs had been taken for tuberculosis in the past 6 months or to the multidrug-resistance risk group if drugs for tuberculosis had been taken in the past 6 months, but drug resistance was suspected. Demographic information, medical history, chest imaging results, and HIV test results were recorded at enrolment, and each participant gave at least three sputum specimen on 2 separate days. Xpert and Xpert Ultra diagnostic performance in the same sputum specimen was compared with culture tests and drug susceptibility testing as reference standards. The primary objectives were to estimate and compare the sensitivity of Xpert Ultra test with that of Xpert for detection of smear-negative tuberculosis and rifampicin resistance and to estimate and compare Xpert Ultra and Xpert specificities for detection of rifampicin resistance. Study participants in the case detection group were included in all analyses, whereas participants in the multidrug-resistance risk group were only included in analyses of rifampicin-resistance detection.
Between Feb 18, and Dec 24, 2016, we enrolled 2368 participants for sputum sampling. 248 participants were excluded from the analysis, and 1753 participants were distributed to the case detection group (n=1439) and the multidrug-resistance risk group (n=314). Sensitivities of Xpert Ultra and Xpert were 63% and 46%, respectively, for the 137 participants with smear-negative and culture-positive sputum (difference of 17%, 95% CI 10 to 24); 90% and 77%, respectively, for the 115 HIV-positive participants with culture-positive sputum (13%, 6·4 to 21); and 88% and 83%, respectively, across all 462 participants with culture-positive sputum (5·4%, 3·3 to 8·0). Specificities of Xpert Ultra and Xpert for case detection were 96% and 98% (−2·7%, −3·9 to −1·7) overall, and 93% and 98% for patients with a history of tuberculosis. Xpert Ultra and Xpert performed similarly in detecting rifampicin resistance.
For tuberculosis case detection, sensitivity of Xpert Ultra was superior to that of Xpert in patients with paucibacillary disease and in patients with HIV. However, this increase in sensitivity came at the expense of a decrease in specificity.
Government of Netherlands, Government of Australia, Bill & Melinda Gates Foundation, Government of the UK, and the National Institute of Allergy and Infectious Diseases.
Cancer cells often display altered cell-surface glycans compared to their nontransformed counterparts. However, functional contributions of glycans to cancer initiation and progression remain poorly ...understood. Here, from expression-based analyses across cancer lineages, we found that melanomas exhibit significant transcriptional changes in glycosylation-related genes. This gene signature revealed that, compared to normal melanocytes, melanomas downregulate I-branching glycosyltransferase, GCNT2, leading to a loss of cell-surface I-branched glycans. We found that GCNT2 inversely correlated with clinical progression and that loss of GCNT2 increased melanoma xenograft growth, promoted colony formation, and enhanced cell survival. Conversely, overexpression of GCNT2 decreased melanoma xenograft growth, inhibited colony formation, and increased cell death. More focused analyses revealed reduced signaling responses of two representative glycoprotein families modified by GCNT2, insulin-like growth factor receptor and integrins. Overall, these studies reveal how subtle changes in glycan structure can regulate several malignancy-associated pathways and alter melanoma signaling, growth, and survival.
Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor ...surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
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•Immune phagocytes share a conserved program during differentiation and tissue entry•IFNγ is a critical instructive cue in the steady state•IFNγ and tissue programming are co-opted across cancers and include SOCS2•SOCS2 is a critical determinant of tumor-immune surveillance in dendritic cells
Tumors exploit physiological mechanisms that are in place to keep tissue homeostasis in order to escape the surveillance of the immune system.
Our objective was to compare outcomes of a restrictive to a liberal red cell transfusion strategy in 20% or more total body surface area (TBSA) burn patients. We hypothesized that the restrictive ...group would have less blood stream infection (BSI), organ dysfunction, and mortality.
Patients with major burns have major (>1 blood volume) transfusion requirements. Studies suggest that a restrictive blood transfusion strategy is equivalent to a liberal strategy. However, major burn injury is precluded from these studies. The optimal transfusion strategy in major burn injury is thus needed but remains unknown.
This prospective randomized multicenter trial block randomized patients to a restrictive (hemoglobin 7-8 g/dL) or liberal (hemoglobin 10-11 g/dL) transfusion strategy throughout hospitalization. Data collected included demographics, infections, transfusions, and outcomes.
Eighteen burn centers enrolled 345 patients with 20% or more TBSA burn similar in age, TBSA burn, and inhalation injury. A total of 7054 units blood were transfused. The restrictive group received fewer blood transfusions: mean 20.3 ± 32.7 units, median = 8 (interquartile range: 3, 24) versus mean 31.8 ± 44.3 units, median = 16 (interquartile range: 7, 40) in the liberal group (P < 0.0001, Wilcoxon rank sum). BSI incidence, organ dysfunction, ventilator days, and time to wound healing (P > 0.05) were similar. In addition, there was no 30-day mortality difference: 9.5% restrictive versus 8.5% liberal (P = 0.892, χ test).
A restrictive transfusion strategy halved blood product utilization. Although the restrictive strategy did not decrease BSI, mortality, or organ dysfunction in major burn injury, these outcomes were no worse than the liberal strategy (Clinicaltrials.gov identifier NCT01079247).
Ferroportin is the primary means of cellular iron efflux and a key component of iron metabolism. Hepcidin regulates Fpn activity by inducing its internalization and degradation. The mechanism of ...internalization is reported to require JAK2 activation, phosphorylation of Fpn tyrosine residues 302 and 303, and initiation of transcription through STAT3 phosphorylation. These findings suggest Fpn may be a target for therapeutic intervention through JAK2 modulation. To evaluate the proposed mechanism, Fpn internalization was assessed using several techniques combined with reagents that specifically recognized cell-surface Fpn. In vitro results demonstrated that Hepc-induced Fpn internalization did not require JAK2 or phosphorylation of Fpn residues 302 and 303, nor did it induce JAK-STAT signaling. In vivo, inhibition of JAK2 had no effect on Hepc-induced hypoferremia. However, internalization was delayed by mutation of two Fpn lysine residues that may be targets of ubiquitination.
► Ferroportin internalization does not require phosphorylation of tyrosines 302 or 303 ► Ferroportin internalization does not require JAK2 expression or activity ► Ferroportin internalization does not induce JAK-STAT signaling ► Ferroportin internalization is delayed by mutation of lysines 240 and 258
Ly6G is a glycosylphosphatidylinositol (GPI)–anchored protein of unknown function that is commonly targeted to induce experimental neutrophil depletion in mice. In the present study, we found that ...doses of anti-Ly6G Abs too low to produce sustained neutropenia remained capable of inhibiting experimental arthritis, leaving joint tissues free of infiltrating neutrophils. Thioglycollate-stimulated peritonitis was also attenuated. No alteration in neutrophil apoptosis was observed, implicating impaired recruitment. Indeed, Ly6G ligation abrogated neutrophil migration toward LTB4 and other chemoattractants in a transwell system. Exploring the basis for this blockade, we identified colocalization of Ly6G and β2-integrins by confocal microscopy and confirmed close association by both coimmunoprecipitation and fluorescence lifetime imaging microscopy. Anti-Ly6G Ab impaired surface expression of β2-integrins in LTB4-stimulated neutrophils and mimicked CD11a blockade in inhibiting both ICAM-1 binding and firm adhesion to activated endothelium under flow conditions. Correspondingly, migration of β2-integrin–deficient neutrophils was no longer inhibited by anti-Ly6G. These results demonstrate that experimental targeting of Ly6G has functional effects on the neutrophil population and identify a previously unappreciated role for Ly6G as a modulator of neutrophil migration to sites of inflammation via a β2-integrin–dependent mechanism.
Humoral immunity is reliant on efficient recruitment of circulating naïve B cells from blood into peripheral lymph nodes (LN) and timely transition of naive B cells to high affinity antibody ...(Ab)-producing cells. Current understanding of factor(s) coordinating B cell adhesion, activation and differentiation within LN, however, is incomplete. Prior studies on naïve B cells reveal remarkably strong binding to putative immunoregulator, galectin (Gal)-9, that attenuates BCR activation and signaling, implicating Gal-9 as a negative regulator in B cell biology. Here, we investigated Gal-9 localization in human tonsils and LNs and unearthed conspicuously high expression of Gal-9 on high endothelial and post-capillary venules. Adhesion analyses showed that Gal-9 can bridge human circulating and naïve B cells to vascular endothelial cells (EC), while decelerating transendothelial migration. Moreover, Gal-9 interactions with naïve B cells induced global transcription of gene families related to regulation of cell signaling and membrane/cytoskeletal dynamics. Signaling lymphocytic activation molecule F7 (SLAMF7) was among key immunoregulators elevated by Gal-9-binding, while SLAMF7's cytosolic adapter EAT-2, which is required for cell activation, was eliminated. Gal-9 also activated phosphorylation of pro-survival factor, ERK. Together, these data suggest that Gal-9 promotes B cell – EC interactions while delivering anergic signals to control B cell reactivity.
•Human naïve B cells use galectin-9 to bind vascular endothelium and restrict TEM.•Galectin-9-binding triggers global immunoregulatory pathways in human naïve B cells.•Galectin-9-binding globally restricts cellular dynamics pathways in human naïve B cells.•Galectin-9-binding promotes human naïve B cell survival.•Galectin-9-binding engages a SLAMF7-inhibitory pathway in human naïve B cells.
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