Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS.

Lipoproteins isolated from normal human plasma can bind and neutralize bacterial lipopolysaccharide (LPS) and may represent an important mechanism in host defense against gram-negative septic shock. Recent studies have shown that experimentally elevating the levels of circulating high-density lipoproteins (HDL) provides protection against death in animal models of endotoxic shock. We sought to define the components of HDL that are required for neutralization of LPS. To accomplish this we have studied the functional neutralization of LPS by native and reconstituted HDL using a rapid assay that measures the CD14-dependent activation of leukocyte integrins on human neutrophils. We report here that reconstituted HDL particles (R-HDL), prepared from purified apolipoprotein A-I (apoA-I) combined with phospholipid and free cholesterol, are not sufficient to neutralize the biologic activity of LPS. However, addition of recombinant LPS binding protein (LBP), a protein known to transfer LPS to CD14 and enhance responses of cells to LPS, enabled prompt binding and neutralization of LPS by R-HDL. Thus, LBP appears capable of transferring LPS not only to CD14 but also to lipoprotein particles. In contrast with R-HDL, apoA-I containing lipoproteins (LpA-I) isolated from plasma by selected affinity immunosorption (SAIS) on an anti-apoA-I column, neutralized LPS without addition of exogenous LBP. Several lines of evidence demonstrated that LBP is a constituent of LpA-I in plasma. Passage of plasma over an anti-apoA-I column removed more than 99% of the LBP detectable by ELISA, whereas 31% of the LBP was recovered by elution of the column. Similarly, the ability of plasma to enable activation of neutrophils by LPS (LBP/Septin activity) was depleted and recovered by the same process. Furthermore, an immobilized anti-LBP monoclonal antibody coprecipitated apoA-I. The results described here suggest that in addition to its ability to transfer LPS to CD14, LBP may also transfer LPS to lipoproteins. Since LBP appears to be physically associated with lipoproteins in plasma, it is positioned to play an important role in the neutralization of LPS

Correspondence of F(R) gravity singularities in Jordan and Einstein frames

We study the finite time singularity correspondence between the Jordan and Einstein frames for various F(R) gravity theories. Particularly we investigate the ordinary pure F(R) gravity case and the unimodular F(R) gravity cases, in the absence of any matter fluids. In the ordinary F(R) gravity cases, by using specific illustrative examples, we show that it is possible to have various correspondences of finite time singularities, and in some cases it is possible a singular cosmology in one frame might be non-singular in the other frame. In the unimodular F(R) gravity case, the unimodular constraint is affected by the conformal transformation, so this has an effect on the metric we choose. Moreover, we study the Einstein frame counterpart theory of the unimodular F(R) gravity case, and we investigate the correspondences of the singularities in the two theories by considering specific illustrative examples. Finally, a brief dynamical system analysis is performed for the vacuum unimodular F(R) gravity and we demonstrate how the dynamical system behaves near the future Big Rip singularity

Xpert MTB/RIF - why the lack of morbidity and mortality impact in intervention trials?

: Compared with smear microscopy, the Xpert MTB/RIF assay (Xpert), with superior accuracy and capacity to diagnose rifampicin resistance, has advanced TB diagnostic capability. However, recent trials of Xpert impact have not demonstrated reductions in patient morbidity and mortality. We conducted a narrative review of Xpert impact trials to summarize which patient-relevant outcomes Xpert has improved and explore reasons for no observed morbidity or mortality reductions. We searched PubMed, Google Scholar, Cochrane Library and Embase and identified eight trials meeting inclusion criteria: three individually randomized, three cluster-randomized, and two pre-post trials. In six trials Xpert increased diagnostic yield of bacteriologically-confirmed TB from sputa and in four trials Xpert shortened time to TB treatment. However, all-cause mortality was similar between arms in all six trials reporting this outcome, and the only trial to assess Xpert impact on morbidity reported no impact. Trial characteristics that might explain lack of observed impact on morbidity and mortality include: higher rates of empiric TB treatment in microscopy compared with Xpert arms, enrollment of study populations not comprised exclusively of populations most likely to benefit from Xpert, and health system weaknesses. So far as equipoise exists, future trials that address past limitations are needed to inform Xpert use in resource-limited settings.<br/

Skin-derived dendritic cells acquire and degrade the scrapie agent following in vitro exposure

The accumulation of the scrapie agent in lymphoid tissues following inoculation via the skin is critical for efficient neuroinvasion, but how the agent is initially transported from the skin to the draining lymph node is not known. Langerhans cells (LCs) are specialized antigen-presenting cells that continually sample their microenvironment within the epidermis and transport captured antigens to draining lymph nodes. We considered LCs probable candidates to acquire and transport the scrapie agent after inoculation via the skin. XS106 cells are dendritic cells (DCs) isolated from mouse epidermis with characteristics of mature LC cells. To investigate the potential interaction of LCs with the scrapie agent XS106 cells were exposed to the scrapie agent in vitro. We show that XS106 cells rapidly acquire the scrapie agent following in vitro exposure. In addition, XS106 cells partially degrade the scrapie agent following extended cultivation. These data suggest that LCs might acquire and degrade the scrapie agent after inoculation via the skin, but data from additional experiments demonstrate that this ability could be lost in the presence of lipopolysaccharide or other immunostimulatory molecules. Our studies also imply that LCs would not undergo maturation following uptake of the scrapie agent in the skin, as the expression of surface antigens associated with LC maturation were unaltered following exposure. In conclusion, although LCs or DCs have the potential to acquire the scrapie agent within the epidermis our data suggest it is unlikely that they become activated and stimulated to transport the agent to the draining lymph node

Factors Affecting Blood Pressure Variability: Lessons Learned from Two Systematic Reviews of Randomized Controlled Trials

Systematic reviews can often reveal much more than the original objective of the work. The objectives of this retrospective analysis were to answer three basic questions about blood pressure variability: 1) Does blood pressure entry criterion have an effect on baseline blood pressure variability? 2) Do thiazide diuretics have a significant effect on blood pressure variability? and 3) Does systolic blood pressure vary to the same degree as diastolic blood pressure? This analysis of blood pressure variability is based on resting standardized research setting BP readings from two systematic reviews evaluating blood pressure lowering efficacy of thiazide diuretics from double blind randomized controlled trials in 33,611 patients with primary hypertension. The standard deviation reported in trials was the focus of the research and the unit of analysis. When a threshold systolic or diastolic blood pressure value is used to determine entry into a trial, baseline variability is significantly decreased, systolic from 14.0 to 9.3 mmHg and diastolic from 8.4 to 5.3 mmHg. Thiazides do not change BP variability as the standard deviation and coefficient of variation of systolic blood pressure and diastolic blood pressure did not differ between thiazide and placebo groups at end of treatment. The coefficient of variation of systolic blood pressure was significantly greater than the coefficient of variation of diastolic blood pressure. Entry criterion decreases the baseline blood pressure variability. Treatment with a thiazide diuretic does not affect blood pressure variability. Systolic blood pressure varies to a greater degree than diastolic blood pressure

Targeted Albumin Therapy Does Not Improve Short-Term Outcome in Hyponatremic Patients Hospitalized With Complications of Cirrhosis: Data From the ATTIRE Trial

INTRODUCTION: Patients with decompensated cirrhosis and hyponatremia have a poor prognosis. We investigated Albumin to Prevent Infection in Chronic Liver Failure trial data to determine whether targeted albumin infusions improved outcome in patients with hyponatremia at baseline. METHODS: We examined the interaction between targeted albumin and standard care for the composite primary end point, stratifying by baseline sodium ≥ and <130 mmol/L. RESULTS: Randomization to albumin was associated with a significant increase in sodium; however, there was no interaction between sodium category and treatment for the trial primary end point. DISCUSSION: Targeted intravenous albumin infusions increased serum sodium level in hospitalized hyponatremic patients with cirrhosis, but this did not improve outcome

Use of non-selective B-blockers is safe in hospitalised decompensated cirrhosis patients and exerts a potential anti-inflammatory effect: Data from the ATTIRE trial

Background: Nonselective B-blockers (NSBBs) are believed to have pleiotropic effects beyond reducing portal pressure. However, studies also report potential harm in patients hospitalized with cirrhosis and ascites. We therefore investigated whether NSBB use at ATTIRE trial entry (Albumin to prevent infection in chronic liver failure, 2016-19) was associated with increased renal or cardiovascular dysfunction, compared the incidence of infection and plasma markers of systemic inflammation, and examined mortality at 28-days, 3 and 6-months. Methods: In ATTIRE patients grouped by NSBB use at trial entry, we studied infection at baseline, hospital acquired infection and organ dysfunction during trial treatment period and mortality, with propensity score matching to account for differences in disease severity. Findings: There were no differences in renal or cardiovascular dysfunction between patients treated with NSBBs or not, during days 3–15 of hospitalization, despite elevated serum creatinine in NSBB patients at hospitalisation. Use of NSBBs was associated with a significant reduction in infection at hospitalization (p = 0.006), lower white cell counts throughout hospital stay (p < 0.001) and reduced plasma procalcitonin (p = 0.009) and interlukin-8 levels (p = 0.04) at baseline, but markers of bacterial translocation and systemic inflammation were the same in treatment groups. There was no reduction in hospital acquired infections in patients taking NSBBs and no beneficial impact on mortality at 28-days, 3 and 6-months. Interpretations: Our real-world data from a completed randomised trial show that use of NSBBs in decompensated cirrhosis patients is safe during hospitalisation. We also show a potential anti-inflammatory role for NSBBs which may be mediated by a downregulation of IL-8 induced leucocytosis, that was associated with reduced infection at baseline but not a survival benefit. Funding: Wellcome Trust and Department of Health and Social Care

Investigating potential confounding by indication when considering the association between proton pump inhibitor use, infection, hepatic encephalopathy and mortality in hospitalised decompensated cirrhosis: a post-hoc analysis of the ATTIRE trial

BACKGROUND: Proton pump inhibitors (PPIs) are commonly prescribed to prevent and treat upper gastrointestinal ulceration and bleeding. Studies have identified increased incidence of spontaneous bacterial peritonitis and hepatic encephalopathy (HE) in cirrhosis patients taking PPIs. However, results are conflicting, and as PPIs are prescribed for variceal bleeding, a major risk factor for infection and HE, it is challenging to discern whether these associations are causal. METHODS: In this post-hoc analysis of the ATTIRE trial, we pooled all patient data to investigate the effects of PPI use on clinical outcomes. ATTIRE was a multicentre, open-label, randomised trial of targeted 20% human albumin solution (HAS) daily infusions versus standard care involving 777 adults with decompensated cirrhosis hospitalised with acute complications and albumin <30 g/L. Study recruitment was between Jan 25, 2016, and June 28, 2019, at 35 hospitals across England, Scotland, and Wales. Key exclusion criteria were advanced hepatocellular carcinoma with life expectancy <8 weeks and patients receiving palliative care. In ATTIRE, patients were grouped by PPI use at trial entry. We studied infection and HE at baseline and incidence of hospital acquired infection, new onset HE, renal dysfunction and mortality. We attempted with propensity score matching to account for differences in disease severity. FINDINGS: Overall PPI use at baseline was not associated with increased incidence of infection, renal dysfunction or mortality, but was associated with significantly increased incidence of grade III/IV HE during hospital stay (P = 0.011). This was only significant for those taking intravenous PPIs and these patients had >10 times the incidence of variceal bleeding and near double the 28-day mortality compared to non-PPI patients. However, propensity score matching was not possible as there was such a strong selection of patients for PPI use, that we could not find sufficient non-PPI patients to match to. We found no impact of PPI use on plasma markers of bacterial translocation, infection or systemic inflammation. INTERPRETATIONS: Our real-world data from a completed randomised trial show that PPIs are widely prescribed in the UK and judicious use appears safe in patients hospitalised with decompensated cirrhosis. However, patients prescribed PPIs had fundamentally different phenotypes to those not prescribed PPIs, a form of confounding by indication, which should be strongly considered when interpreting studies and making recommendations about their use. FUNDING: Wellcome Trust and Department of Health and Social Care