Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.

NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.

Assessment of circulating insulin using liquid chromatography-mass spectrometry during insulin glargine treatment in type 2 diabetes: Implications for estimating insulin sensitivity and ß-cell function.

AIM: To determine the potential impact of the cross-reactivity of insulin glargine U-100 and its metabolites on insulin sensitivity and ß-cell measures in people with type 2 diabetes. MATERIALS AND METHODS: Using liquid chromatography-mass spectrometry (LC-MS), we measured concentrations of endogenous insulin, glargine and its two metabolites (M1 and M2) in fasting and oral glucose tolerance test-stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 PM the night before testing. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (Homeostatic Model Assessment 2 [HOMA2]-S%; QUICKI index; PREDIM index) and ß-cell function (HOMA2-B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and ß-cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] insulin/glucose). RESULTS: In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC-MS; however, the analogue and its metabolites cross-reacted by less than 100% in the insulin immunoassay. This incomplete cross-reactivity resulted in a systematic bias of fasting-based measures. By contrast, because M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin/glucose. CONCLUSIONS: Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess ß-cell responsiveness. However, given the cross-reactivity of the glargine metabolites in the insulin immunoassay, fasting-based measures of insulin sensitivity and ß-cell function are biased.

Interleukin-1α Is a Central Regulator of Leukocyte-Endothelial Adhesion in Myocardial Infarction and in Chronic Kidney Disease.

BACKGROUND: Cardiovascular diseases and chronic kidney disease (CKD) are highly prevalent, aggravate each other, and account for substantial mortality. Both conditions are characterized by activation of the innate immune system. The alarmin interleukin-1α (IL-1α) is expressed in a variety of cell types promoting (sterile) systemic inflammation. The aim of the present study was to examine the role of IL-1α in mediating inflammation in the setting of acute myocardial infarction (AMI) and CKD. METHODS: We assessed the expression of IL-1α on the surface of monocytes from patients with AMI and patients with CKD and determined its association with atherosclerotic cardiovascular disease events during follow-up in an explorative clinical study. Furthermore, we assessed the inflammatory effects of IL-1α in several organ injury models in Il1a-/- and Il1b-/- mice and investigated the underlying mechanisms in vitro in monocytes and endothelial cells. RESULTS: IL-1α is strongly expressed on the surface of monocytes from patients with AMI and CKD compared with healthy controls. Higher IL-1α surface expression on monocytes from patients with AMI and CKD was associated with a higher risk for atherosclerotic cardiovascular disease events, which underlines the clinical relevance of IL-1α. In mice, IL-1α, but not IL-1ß, mediates leukocyte-endothelial adhesion as determined by intravital microscopy. IL-1α promotes accumulation of macrophages and neutrophils in inflamed tissue in vivo. Furthermore, IL-1α on monocytes stimulates their homing at sites of vascular injury. A variety of stimuli such as free fatty acids or oxalate crystals induce IL-1α surface expression and release by monocytes, which then mediates their adhesion to the endothelium via IL-1 receptor-1. IL-1α also promotes expression of the VCAM-1 (vascular cell adhesion molecule-1) on endothelial cells, thereby fostering the adhesion of circulating leukocytes. IL-1α induces inflammatory injury after experimental AMI, and abrogation of IL-1α prevents the development of CKD in oxalate or adenine-fed mice. CONCLUSIONS: IL-1α represents a key mediator of leukocyte-endothelial adhesion and inflammation in AMI and CKD. Inhibition of IL-1α may serve as a novel anti-inflammatory treatment strategy.

Guanidinylated Apolipoprotein C3 (ApoC3) Associates with Kidney and Vascular Injury.

BACKGROUND: Coexistent CKD and cardiovascular diseases are highly prevalent in Western populations and account for substantial mortality. We recently found that apolipoprotein C-3 (ApoC3), a major constituent of triglyceride-rich lipoproteins, induces sterile systemic inflammation by activating the NOD-like receptor protein-3 (NLRP3) inflammasome in human monocytes via an alternative pathway. METHODS: To identify posttranslational modifications of ApoC3 in patients with CKD, we used mass spectrometry to analyze ApoC3 from such patients and from healthy individuals. We determined the effects of posttranslationally modified ApoC3 on monocyte inflammatory response in vitro, as well as in humanized mice subjected to unilateral ureter ligation (a kidney fibrosis model) and in a humanized mouse model for vascular injury and regeneration. Finally, we conducted a prospective observational trial of 543 patients with CKD to explore the association of posttranslationally modified ApoC3 with renal and cardiovascular events in such patients. RESULTS: We identified significant posttranslational guanidinylation of ApoC3 (gApoC3) in patients with CKD. We also found that mechanistically, guanidine and urea induce guanidinylation of ApoC3. A 2D-proteomic analysis revealed that gApoC3 accumulated in kidneys and plasma in a CKD mouse model (mice fed an adenine-rich diet). In addition, gApoC3 augmented the proinflammatory effects of ApoC3 in monocytes in vitro . In humanized mice, gApoC3 promoted kidney tissue fibrosis and impeded vascular regeneration. In CKD patients, higher gApoC3 plasma levels (as determined by mass spectrometry) were associated with increased mortality as well as with renal and cardiovascular events. CONCLUSIONS: Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, pointing to gApoC3 as a potential therapeutic target.

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

AIMS: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1ß can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. METHODS AND RESULTS: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. CONCLUSION: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

Measurement of urinary Dickkopf-3 uncovered silent progressive kidney injury in patients with chronic obstructive pulmonary disease.

Chronic kidney disease (CKD) represents a global public health problem with high disease related morbidity and mortality. Since CKD etiology is heterogeneous, early recognition of patients at risk for progressive kidney injury is important. Here, we evaluated the tubular epithelial derived glycoprotein dickkopf-3 (DKK3) as a urinary marker for the identification of progressive kidney injury in a non-CKD cohort of patients with chronic obstructive pulmonary disease (COPD) and in an experimental model. In COSYCONET, a prospective multicenter trial comprising 2,314 patients with stable COPD (follow-up 37.1 months), baseline urinary DKK3, proteinuria and estimated glomerular filtration rate (eGFR) were tested for their association with the risk of declining eGFR and the COPD marker, forced expiratory volume in one second. Baseline urinary DKK3 but not proteinuria or eGFR identified patients with a significantly higher risk for over a 10% (odds ratio: 1.54, 95% confidence interval: 1.13-2.08) and over a 20% (2.59: 1.28-5.25) decline of eGFR during follow-up. In particular, DKK3 was associated with a significantly higher risk for declining eGFR in patients with eGFR over 90 ml/min/1.73m2 and proteinuria under 30 mg/g. DKK3 was also associated with declining COPD marker (2.90: 1.70-4.68). The impact of DKK3 was further explored in wild-type and Dkk3-/- mice subjected to cigarette smoke-induced lung injury combined with a CKD model. In this model, genetic abrogation of DKK3 resulted in reduced pulmonary inflammation and preserved kidney function. Thus, our data highlight urinary DKK3 as a possible marker for early identification of patients with silent progressive CKD and for adverse outcomes in patients with COPD.

Association between urinary dickkopf-3, acute kidney injury, and subsequent loss of kidney function in patients undergoing cardiac surgery: an observational cohort study.

BACKGROUND: Cardiac surgery is associated with a high risk of postoperative acute kidney injury (AKI) and subsequent loss of kidney function. We explored the clinical utility of urinary dickkopf-3 (DKK3), a renal tubular stress marker, for preoperative identification of patients at risk for AKI and subsequent kidney function loss. METHODS: This observational cohort study included patients who had cardiac surgery in a derivation cohort and those who had cardiac surgery in a validation cohort (RenalRIP trial). The study comprised consecutive patients who had elective cardiac surgery at the Saarland University Medical Centre (Homburg, Germany; derivation cohort) and those undergoing elective cardiac surgery (selected on the basis of a Cleveland Clinical Foundation score of 6 or higher) who were enrolled in the prospective RenalRIP multicentre trial (validation cohort) and who were randomly assigned to remote ischaemic preconditioning or a sham procedure. The association between the ratio of preoperative urinary concentrations of DKK3 to creatinine (DKK3:creatinine) and postoperative AKI, defined according to the Kidney Disease Improving Global Outcomes criteria, and subsequent kidney function loss, as determined by estimated glomerular filtration rate, was assessed. FINDINGS: In the 733 patient in the derivation cohort, urinary concentrations of DKK3 to creatinine that were higher than 471 pg/mg were associated with significantly increased risk for AKI (odds ratio [OR] 1·65, 95% CI 1·10-2·47, p=0·015), independent of baseline kidney function. Compared with clinical and other laboratory measurements, urinary concentrations of DKK3:creatinine significantly improved AKI prediction (net reclassification improvement 0·32, 95% CI 0·23-0·42, p<0·0001). High urinary DKK3:creatinine concentrations were independently associated with significantly lower kidney function at hospital discharge and after a median follow-up of 820 days (IQR 733-910). In the RenalRIP trial, preoperative urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with a significantly higher risk for AKI (OR 1·94, 95% CI 1·08-3·47, p=0·026), persistent renal dysfunction (OR 6·67, 1·67-26·61, p=0·0072), and dialysis dependency (OR 13·57, 1·50-122·77, p=0·020) after 90 days compared with DKK3:creatinine concentrations of 471 pg/mg or less. Urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with significantly higher risk for AKI (OR 2·79, 95% CI 1·45-5·37) and persistent renal dysfunction (OR 3·82, 1·32-11·05) only in patients having a sham procedure, but not remote ischaemic preconditioning (AKI OR 1·35, 0·76-2·39 and persistent renal dysfunction OR 1·05, 0·12-9·45). INTERPRETATION: Preoperative urinary DKK3 is an independent predictor for postoperative AKI and for subsequent loss of kidney function. Urinary DKK3 might aid in the identification of patients in whom preventive treatment strategies are effective. FUNDING: No study funding.

Triaging Inpatient Admissions: an Opportunity for Resident Education.

In the context of internal medicine, "triage" is a newly popularized term that refers to constellation of activities related to determining the most appropriate disposition plans for patients, including assessing patients for admissions into the inpatient medicine service. The physician or "triagist" plays a critical role in the transition of care from the outpatient to the inpatient settings, yet little literature exists addressing this particular transition. The importance of this set of responsibilities has evolved over time as health systems become increasingly complex to navigate for physicians and patients. With the emphasis on hospital efficiency metrics such as emergency department throughput and appropriateness of admissions, this type of systems-based thinking is a necessary skill for practicing contemporary inpatient medicine. We believe that triaging admissions is a critical transition in the care continuum and represents an entrustable professional activity that integrates skills across multiple Accreditation Council for Graduate Medical Education (ACGME) competencies that internal medicine residents must master. Specific curricular competencies that address the domains of provider, system, and patient will deliver a solid foundation to fill a gap in skills and knowledge for the triagist role in IM residency training.

Proprotein convertase subtilisin/kexin type 9 in kidney disease.

Chronic kidney disease (CKD) is associated with a substantially increased risk for the development of atherosclerotic cardiovascular (CV) disease. Accordingly, CV mortality is increased even in the earliest stages of CKD. In the general population and in CKD patients, high plasma levels of low-density lipoprotein cholesterol (LDL-C) are crucially involved in the initiation and progression of atherosclerotic vascular lesions. Lowering LDL-C by use of statins and/or ezetimibe represents the gold standard of lipid-lowering therapy, with a great body of evidence from several large clinical trials. Statin therapy reduces CV events in patients with normal and impaired kidney function alike, while the evidence for patients on maintenance haemodialysis is weaker. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease represents a novel lipid-lowering tool. Currently the monoclonal antibodies evolocumab and alirocumab are the approved PCSK9 inhibitors. Despite maximum-tolerated statin therapy, they efficiently further reduce LDL-C plasma levels without any major adverse effects. Moreover, in large clinical outcome trials, both antibodies have been proven to lower CV events. Notably, the LDL-lowering capacity was independent of baseline kidney function and also efficient in patients with moderate CKD. However, patients with severely impaired kidney function, that is, the population at the highest CV risk, have been excluded from those trials. The relevance of the LDL-independent effects of PCSK9 inhibitors, such as lowering lipoprotein(a) or ameliorating dyslipidaemia in patients with nephrotic syndrome, has to be determined. Therefore further specific studies assessing the effects and outcomes of PCSK9-inhibiting treatment in CKD patients are warranted.

Dickkopf-3 (DKK3) in Urine Identifies Patients with Short-Term Risk of eGFR Loss.

BACKGROUND: The individual course of CKD may vary, and improved methods for identifying which patients will experience short-term eGFR loss are needed. Assessing urinary Dickkopf-3 (DKK3), a stress-induced tubular epithelia-derived profibrotic glycoprotein, may provide information about ongoing tubulointerstitial fibrosis and short-term eGFR loss. METHODS: To investigate urinary DKK3's potential as a biomarker of short-term eGFR loss (over 12 months), we prospectively assessed eGFR and urinary DKK3 levels in patients with CKD of various etiologies at baseline and annual follow-ups. We also measured urinary DKK3 in a general population sample and patients with diagnostic kidney biopsies or IgA nephropathy under treatment. RESULTS: Median urinary DKK3-to-creatinine concentration at baseline was significantly higher in patients with CKD than the general population sample (431 versus 33 pg/mg). In the CKD cohort, having a urinary DKK3-to-creatinine level >4000 pg/mg was independently and significantly associated after multiple adjustments with mean annual decline in eGFR of 7.6% over 12 months. Urinary DKK3 significantly improved prediction of kidney function decline compared with eGFR or albuminuria alone. Urinary DKK3-to-creatinine levels were related to the extent of tubulointerstitial fibrosis in kidney biopsies. In patients with IgA nephropathy, a rise in urinary DKK3 was associated with significant eGFR decline within 6 months, whereas stable or decreasing urinary DKK3 indicated a more favorable course. CONCLUSIONS: Urinary DKK3 levels identify patients at high risk for eGFR decline over the next 12 months regardless of the cause of kidney injury and beyond established biomarkers, potentially providing a tool to monitor CKD progression and assess effects of interventions.

Allergic airway inflammation induces migration of mast cell populations into the mouse airway.

Mast cells (MCs) and airway nerves play an important role in allergic asthma. However, little is known about the MCs and their interaction with airway nerves during allergic airway inflammation. This study aims to investigate the distribution and proliferation of MC populations in different lung compartments, along with the association of mast cells with nerve endings, using a house dust mite (HDM) model for allergic airway inflammation. BALB/c mice were exposed to HDM extract intranasally (25 µg/50 µl) for 5 consecutive days a week over 7 weeks. Immunofluorescence and Edu stains were used to examine the colocalisation of MCs and nerves and the proliferation of MCs, respectively. HDM treatment caused an increased migration of MCs into bronchi, alveolar parenchyma and airway vessels. The proportions of tryptase-chymase expressing MC (MCTC) increased significantly in the bronchi and the alveolar parenchyma but not in the vascular tissues, by allergic airway inflammation. The association of MCs with nerves was found only in the bronchi and there were no changes in comparison of controls to HDM-treated animals. The present study shows a strong migration of tryptase expressing MC (MCT) and MCTC into the bronchi and the alveolar parenchyma, as well as of MCT in the vascular compartment under HDM treatment. This supports the hypothesis that these mast cell populations may contribute to allergic airway inflammation.

Increase of Mast Cell-Nerve Association and Neuropeptide Receptor Expression on Mast Cells in Perennial Allergic Rhinitis.

OBJECTIVES: Mast cells (MCs) and nerves play an important role in allergic rhinitis (AR), but little is known about their crosstalk in AR. The aim of this study was to investigate MC-nerve interaction in the human nasal mucosa during AR. METHODS: The association between MCs and nerves, the expression of neuropeptide receptors (neurokinin 1 receptor [NK1R], neurokinin 2 receptor [NK2R], calcitonin gene-related peptide receptor [CGRPR], and MrgX2) on MCs, and protease-activated receptor 2 (PAR2) and tyrosine receptor kinase A (TrkA) on nerve fibres in the human nasal mucosa were investigated with immunofluorescence and real-time PCR. RESULTS: The association between MCs and nerves was found to be significantly increased, although the numbers of MCs and nerve fibres were unchanged during AR. MCs expressing tryptase-chymase (MCtc) were frequently associated with nerve fibres and these contacts increased significantly in AR. Neuropeptide receptors NK1R, NK2R, and CGRPR were firstly found to be largely localised on MCs. The number of MCs expressing NK1R and NK2R, but not CGRPR, was significantly increased in AR. Interestingly, MCtc mostly expressed these neuropeptide receptors. The newly discovered tachykinin receptor MrgX2 was not expressed on nasal MCs, but was expressed on gland cells and increased in AR. Additionally, tachykinergic nerve fibres were found to express PAR2 or TrkA as receptors for MCs. CONCLUSIONS: This study revealed for the first time an increase of MC-nerve association and neuropeptide receptor expression on MCs during AR as well as nerve fibres containing receptors for MCs. These results suggest that targeting or controlling airway sensory nerve function as a modulator of MCs may prevent allergic airway inflammation such as AR.

Breaking barriers, building faculty: A qualitative analysis to exploring faculty development in academic hospital medicine.

BACKGROUND: Hospital medicine (HM) continues to be primarily composed of junior hospitalists and research has highlighted a paucity of mentors and academic output. Faculty advancement programs have been identified as a means to support junior hospitalists in their career trajectories and to advance the field. The optimal approach to supporting faculty development (FD) efforts is not known. OBJECTIVE: To understand hospitalist groups' approaches to FD, including efforts that were perceived to be effective, and to identify barriers as well as potential future directions for FD. DESIGN: Rapid qualitative methods were utilized including templated summaries and matrix analysis to identify major themes. SETTING AND PARTICIPANTS: Virtual focus groups with hospitalists in the Hospital Medicine Reengineering Network (HOMERuN). MAIN OUTCOME AND MEASURES: Qualitative themes RESULTS: Nineteen individuals from 17 unique institutions from across the United States in May 2022 participated in seven focus groups. Four key themes emerged from the study and included (1) academic hospitalist programs face multifaceted challenges and barriers to FD in HM, (2) groups have embraced a diversity of structures and frameworks, (3) due to clinical volumes, FD programs have had to adapt and evolve to meet FD needs, and (4) participants identified multiple areas for improvement, including defining tangible outcomes of FD programs and creating a repository of FD material which can be shared widely.

Urinary DKK3 as a biomarker for short-term kidney function decline in children with chronic kidney disease: an observational cohort study.

BACKGROUND: Childhood-onset chronic kidney disease is a progressive condition that can have a major effect on life expectancy and quality. We evaluated the usefulness of the kidney tubular cell stress marker urinary Dickkopf-related protein 3 (DKK3) in determining the short-term risk of chronic kidney disease progression in children and identifying those who will benefit from specific nephroprotective interventions. METHODS: In this observational cohort study, we assessed the association between urinary DKK3 and the combined kidney endpoint (ie, the composite of 50% reduction of the estimated glomerular filtration rate [eGFR] or progression to end-stage kidney disease) or the risk of kidney replacement therapy (ie, dialysis or transplantation), and the interaction of the combined kidney endpoint with intensified blood pressure reduction in the randomised controlled ESCAPE trial. Moreover, urinary DKK3 and eGFR were quantified in children aged 3-18 years with chronic kidney disease and urine samples available enrolled in the prospective multicentre ESCAPE (NCT00221845; derivation cohort) and 4C (NCT01046448; validation cohort) studies at baseline and at 6-monthly follow-up visits. Analyses were adjusted for age, sex, hypertension, systolic blood pressure SD score (SDS), BMI SDS, albuminuria, and eGFR. FINDINGS: 659 children were included in the analysis (231 from ESCAPE and 428 from 4C), with 1173 half-year blocks in ESCAPE and 2762 in 4C. In both cohorts, urinary DKK3 above the median (ie, >1689 pg/mg creatinine) was associated with significantly greater 6-month eGFR decline than with urinary DKK3 at or below the median (-5·6% [95% CI -8·6 to -2·7] vs 1·0% [-1·9 to 3·9], p<0·0001, in ESCAPE; -6·2% [-7·3 to -5·0] vs -1·5% [-2·9 to -0·1], p<0·0001, in 4C), independently of diagnosis, eGFR, and albuminuria. In ESCAPE, the beneficial effect of intensified blood pressure control was limited to children with urinary DKK3 higher than 1689 pg/mg creatinine, in terms of the combined kidney endpoint (HR 0·27 [95% CI 0·14 to 0·55], p=0·0003, number needed to treat 4·0 [95% CI 3·7 to 4·4] vs 250·0 [66·9 to ∞]) and the need for kidney replacement therapy (HR 0·33 [0·13 to 0·85], p=0·021, number needed to treat 6·7 [6·1 to 7·2] vs 31·0 [27·4 to 35·9]). In 4C, inhibition of the renin-angiotensin-aldosterone system resulted in significantly lower urinary DKK3 concentrations (least-squares mean 12 235 pg/mg creatinine [95% CI 10 036 to 14 433] in patients not on angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers vs 6861 pg/mg creatinine [5616 to 8106] in those taking angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers, p<0·0001). INTERPRETATION: Urinary DKK3 indicates short-term risk of declining kidney function in children with chronic kidney disease and might allow a personalised medicine approach by identifying those who benefit from pharmacological nephroprotection, such as intensified blood pressure lowering. FUNDING: None.

The mesmerists inquire about "Oriental mind powers": West meets East in the search for the universal trance.

Contemporary interest in Asian meditation raises questions about when Westerners began investigating these practices. A synopsis of Western-originating scientific meditation research is followed by a brief introduction to mesmerism. Next, the unappreciated ways the mesmerists explored Oriental mind powers is recounted. How the mesmerists' cultural positioning, philosophy, and interest in mind-body practices facilitated their inquiries of Oriental medicine and Hindu contemplative practices is explored, followed by a consideration of why these investigations were unique for the era. The way this work subverted Western cultural imperialism is examined. A consideration of the historical continuities and discontinuities between the mesmerists' inquiries and twentieth-century meditation research concludes the article.

Verification of separate measurement procedures where analytical determinations influence the clinical interpretation of GFR: Iohexol quantitation by HPLC and LC-MS/MS.

BACKGROUND: The glomerular filtration rate (GFR) is monitored clinically to follow renal function of a patient. This is commonly performed using endogenous compounds, which estimate GFR (eGFR). However, several conditions exists which may confound or render the eGFR inaccurate. In such cases, it is appropriate to perform a procedure to directly measure GFR (mGFR). Iohexol plasma disappearance is a procedure to determine mGFR and is typically performed using bolus injection of contrast media followed by timed plasma collections. The iohexol plasma concentrations are referenced to the dose given and the elimination rate of iohexol is reflective of the mGFR. Therefore, analytical bias or interference in the iohexol analytical measurement procedure will directly impact the mGFR result. METHODS: Plasma sample iohexol concentrations were measured using both high performance liquid chromatography-ultraviolet detection (HPLC-UV) and liquid chromatography tandem mass spectrometry (LC-MS/MS) measurement procedures. Results were compared on 50 patients where the mGFR was calculated from the iohexol plasma disappearance on two collection time points. RESULTS: Bland-Altman analysis illustrated <1% mean bias when comparing iohexol concentration determinations from the measurement procedures. Passing-Bablok regression revealed y = 1.028x - 0.9420 (slope 95% CI: 1.011, 1.041; Y-intercept 95% CI: -1.606, -0.1638) when comparing LC-MS/MS to HPLC-UV. CONCLUSIONS: Comparison studies of the LC-MS/MS and HPLC-UV measurement procedures displayed a mean bias of <1% by Bland Altman analysis. Measurement of iohexol by LC-MS/MS and HPLC-UV produced similar results and suggests there should be minimal bias in concentration or computed mGFR solely due to the measurement procedure employed.

Warren Felt Evans: 19th-century mystic, wounded healer, and seminal theorist-practitioner of mind cure.

The Methodist-Episcopalian minister-turned-physician and philosopher of healing Warren Felt Evans (1817-1889) was one of the earliest practitioners of mental healing, also known as "mind cure." Originating in New England in the second half of the 19th century, mind cure spread through the country in the 1880s. Drawing from Evans's unpublished journals, I recount his struggles with chronic ill health and his turn to the Quietist mystics and Swedenborg, and then to the mesmerist-turned-mental-healer P. P. Quimby to procure both healing for his ills and philosophical sanctification for his soul. The transformational route Evans traveled reflects the mythico-religious journey of the wounded healer who suffers through a creative illness on the way to becoming a healer himself. The article places Evans and the mind cure movement within late-19th-century Boston's medical and cultural milieu. Evans's approach to psychological healing is explored by focusing on his mind-body healing philosophy and mental therapeutics as described in his first 2 mind cure books The Mental Cure (1869) and Mental Medicine (1872). (PsycINFO Database Record

Evaluation of white blood cell count, neutrophil percentage, and elevated temperature as predictors of bloodstream infection in burn patients.

OBJECTIVE: To investigate whether specific values of or changes in temperature, white blood cell count, or neutrophil percentage were predictive of bloodstream infection in burn patients. DESIGN: Retrospective review of electronic records. SETTING: Intensive care center at the US Army Institute of Surgical Research Burn Center. PATIENTS: Burn patients with blood cultures obtained from 2001 to 2004. MAIN OUTCOME MEASURES: Temperature recorded at the time blood cultures were obtained; highest temperature in each 6-hour interval during the 24 hours prior to this; white blood cell count and neutrophil percentage at the time of obtaining the blood culture and during the 24 hours preceding the blood culture; demographic data; and total body surface area burned. RESULTS: A total of 1063 blood cultures were obtained from 223 patients. Seventy-three people had 140 blood cultures from which microorganisms were recovered. Organisms that were recovered from blood cultures included 80 that were gram negative, 54 that were gram positive, 3 that were mixed gram positive/gram negative, and 3 yeasts. Although white blood cell count and neutrophil percentage at the time of the culture were statistically different between patients with and patients without bloodstream infection, receiver operating characteristic curve analysis revealed these values to be poor discriminators (receiver operating characteristic curve area = 0.624). Temperature or alterations in temperature in the preceding 24-hour period did not predict presence, absence, or type of bloodstream infection. CONCLUSIONS: Temperature, white blood cell count, neutrophil percentage, or changes in these values were not clinically reliable in predicting bloodstream infection. Further work is needed to identify alternative clinical parameters, which should prompt blood culture evaluations in this population.

Re-visioning antebellum American psychology: the dissemination of mesmerism, 1836-1854.

Mesmerism, the French method of treating illness and inducing trance, was introduced to the United States in 1836. A cohort of Americans took to the practice enthusiastically, publishing materials, presenting lectures attended by thousands, conducting empirical investigations, and treating untold numbers of ill people. These practitioners understood their profession addressed the mind, and they often referred to their work as "psychology." The mesmerists speculated about mind-brain links and investigated "interior states," "mental healing," and the controversial "higher mind powers" such as clairvoyance. Antebellum culture is the backdrop for this study of the rise, fall, and dispersion of mesmerism in the United States. Evidence provided warrants a reappraisal of mesmerism's significance for 19th-century psychology.