Nicotinamide restores tissue NAD+ and improves survival in rodent models of cardiac arrest.

Metabolic suppression in the ischemic heart is characterized by reduced levels of NAD+ and ATP. Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts, and enhances survival in a mouse model of cardiac arrest. Mouse cardiomyocytes were exposed to 30 min simulated ischemia and 90 min reperfusion. NAD+ content dropped 40% by the end of ischemia compared to pre-ischemia. Treatment with 100 µM nicotinamide (NAM) at the start of reperfusion completely restored the cellular level of NAD+ at 15 min of reperfusion. This rescue of NAD+ depletion was associated with improved contractile recovery as early as 10 min post-reperfusion. In a mouse model of cardiac arrest, 100 mg/kg NAM administered IV immediately after cardiopulmonary resuscitation resulted in 100% survival at 4 h as compared to 50% in the saline group. In an isolated rat heart model, the effect of NAM on cardiac function was measured for 20 min following 18 min global ischemia. Rate pressure product was reduced by 26% in the control group following arrest. Cardiac contractile function was completely recovered with NAM treatment given at the start of reperfusion. NAM restored tissue NAD+ and enhanced production of lactate and ATP, while reducing glucose diversion to sorbitol in the heart. We conclude that NAM can rapidly restore cardiac NAD+ following ischemia and enhance glycolysis and contractile recovery, with improved survival in a mouse model of cardiac arrest.

Intra-ischemic hypothermia cardioprotection involves modulation of PTEN/Akt/ERK signaling and fatty acid oxidation.

Therapeutic hypothermia (TH) provides cardioprotection from ischemia/reperfusion (I/R) injury. However, it remains unknown how TH regulates metabolic recovery. We tested the hypothesis that TH modulates PTEN, Akt, and ERK1/2, and improves metabolic recovery through mitigation of fatty acid oxidation and taurine release. Left ventricular function was monitored continuously in isolated rat hearts subjected to 20 min of global, no-flow ischemia. Moderate cooling (30°C) was applied at the start of ischemia and hearts were rewarmed after 10 min of reperfusion. The effect of TH on protein phosphorylation and expression at 0 and 30 min of reperfusion was investigated by western blot analysis. Post-ischemic cardiac metabolism was investigated by 13 C-NMR. TH enhanced recovery of cardiac function, reduced taurine release, and enhanced PTEN phosphorylation and expression. Phosphorylation of Akt and ERK1/2 was increased at the end of ischemia but decreased at the end of reperfusion. On NMR analysis, TH-treated hearts displayed decreased fatty acid oxidation. Direct cardioprotection by moderate intra-ischemic TH is associated with decreased fatty acid oxidation, reduced taurine release, enhanced PTEN phosphorylation and expression, and enhanced activation of both Akt and ERK1/2 prior to reperfusion.

The accuracy of breast MRI radiomic methodologies in predicting pathological complete response to neoadjuvant chemotherapy: A systematic review and network meta-analysis.

BACKGROUND: Achieving pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) improves survival outcomes for breast cancer patients. Currently, conventional histopathological biomarkers predicting such responses are inconsistent. Studies investigating radiomic texture analysis from breast magnetic resonance imaging (MRI) to predict pCR have varied radiomic protocols introducing heterogeneity between results. Thus, the efficacy of radiomic profiles compared to conventional strategies to predict pCR are inconclusive. PURPOSE: Comparing the predictive accuracy of different breast MRI radiomic protocols to identify the optimal strategy in predicting pCR to NAC. MATERIAL AND METHODS: A systematic review and network meta-analysis was performed according to PRISMA guidelines. Four databases were searched up to October 4th, 2021. Nine predictive strategies were compared, including conventional biomarker parameters, MRI radiomic analysis conducted before, during, or after NAC, combination strategies and nomographic methodology. RESULTS: 14 studies included radiomic data from 2,722 breast cancers, of which 994 were used in validation cohorts. All MRI derived radiomic features improved predictive accuracy when compared to biomarkers, except for pre-NAC MRI radiomics (odds ratio [OR]: 0.00; 95 % CI: -0.07-0.08). During-NAC and post-NAC MRI improved predictive accuracy compared to Pre-NAC MRI (OR: 0.14, 95 % CI: 0.02-0.26) and (OR: 0.26, 95 % CI: 0.07-0.45) respectively. Combining multiple MRIs did not improve predictive performance compared to Mid- or Post-NAC MRIs individually. CONCLUSION: Radiomic analysis of breast MRIs improve identification of patients likely to achieve a pCR to NAC. Post-NAC MRI are the most accurate imaging method to extrapolate radiomic data to predict pCR.

Optimal reconstructive strategies in the setting of post-mastectomy radiotherapy - A systematic review and network meta-analysis.

BACKGROUND: A third of breast cancer patients require mastectomy. In some high-risk cases postmastectomy radiotherapy (PMRT) is indicated, threatening reconstructive complications. Several PMRT and reconstruction combinations are used. Autologous flap (AF) reconstruction may be immediate (AF→PMRT), delayed-immediate with tissue expander (TE [TE→PMRT→AF]) or delayed (PMRT→AF). Implant-based breast reconstruction (IBBR) includes immediate TE followed by PMRT and conversion to permanent implant (PI [TE→PMRT→PI]), delayed TE insertion (PMRT→TE→PI), and prosthetic implant conversion prior to PMRT (TE→PI→PMRT). AIM: Perform a network metanalysis (NMA) assessing optimal sequencing of PMRT and reconstructive type. METHODS: A systematic review and NMA was performed according to PRISMA-NMA guidelines. NMA was conducted using R packages netmeta and Shiny. RESULTS: 16 studies from 4182 identified, involving 2322 reconstructions over three decades, met predefined inclusion criteria. Studies demonstrated moderate heterogeneity. Multiple comparisons combining direct and indirect evidence established AF-PMRT as the optimal approach to avoid reconstructive failure, compared with IBBR strategies (versus PMRT→TE→PI; OR [odds ratio] 0.10, CrI [95% credible interval] 0.02 to 0.55; versus TE→PMRT→PI; OR 0.13, CrI 0.02 to 0.75; versus TE→PI→PMRT OR 0.24, CrI 0.05 to 1.05). PMRT→AF best avoided infection, demonstrating significant improvement versus PMRT→TE→PI alone (OR 0.12, CrI 0.02 to 0.88). Subgroup analysis of IBBR found TE→PI→PMRT reduced failure rates (OR 0.35, CrI 0.15-0.81) compared to other IBBR strategies but increased capsular contracture. CONCLUSION: Immediate AF reconstruction is associated with reduced failure in the setting of PMRT. However, optimal reconstructive strategy depends on patient, surgeon and institutional factors. If IBBR is chosen, complication rates decrease if performed prior to PMRT. PROSPERO REGISTRATION: CRD 42020157077.

TAT delivery of a PTEN peptide inhibitor has direct cardioprotective effects and improves outcomes in rodent models of cardiac arrest.

We have recently shown that pharmacologic inhibition of PTEN significantly increases cardiac arrest survival in a mouse model, however, this protection required pretreatment 30 min before the arrest. To improve the onset of PTEN inhibition during cardiac arrest treatment, we have designed a TAT fused cell-permeable peptide (TAT-PTEN9c) based on the C-terminal PDZ binding motif of PTEN for rapid tissue delivery and protection. Western blot analysis demonstrated that TAT-PTEN9c peptide significantly enhanced Akt activation in mouse cardiomyocytes in a concentration- and time-dependent manner. Mice were subjected to 8 min asystolic arrest followed by CPR, and 30 mice with successful CPR were then randomly assigned to receive either saline or TAT-PTEN9c treatment. Survival was significantly increased in TAT-PTEN9c-treated mice compared with that of saline control at 4 h after CPR. The treated mice had increased Akt phosphorylation at 30 min resuscitation with significantly decreased sorbitol content in heart or brain tissues and reduced release of taurine and glutamate in blood, suggesting improved glucose metabolism. In an isolated rat heart Langendorff model, direct effects of TAT-PTEN9c on cardiac function were measured for 20 min following 20 min global ischemia. Rate pressure product was reduced by >20% for both TAT vehicle and nontreatment groups following arrest. Cardiac contractile function was completely recovered with TAT-PTEN9c treatment given at the start of reperfusion. We conclude that TAT-PTEN9c enhances Akt activation and decreases glucose shunting to the polyol pathway in critical organs, thereby preventing osmotic injury and early cardiovascular collapse and death.NEW & NOTEWORTHY We have designed a cell-permeable peptide, TAT-PTEN9c, to improve cardiac arrest survival. It blocked endogenous PTEN binding to its adaptor and enhanced Akt signaling in mouse cardiomyocytes. It improved mouse survival after cardiac arrest, which is related to improved glucose metabolism and reduced glucose shunting to sorbitol in critical organs.

Effect of oral vancomycin dose on outcomes in patients with Clostridioides difficile infection.

Clostridioides difficile infection (CDI) is a significant cause of morbidity and mortality. Oral vancomycin is a cornerstone of CDI treatment, but dosing strategies in clinical practice may differ from guideline recommendations. This study aimed to determine differences in outcomes between patients treated with standard (125 mg QID) and high-dose (≥250 mg QID) oral vancomycin. This dual-centre study evaluated adult patients admitted between January 2013 and July 2017. Patients were included in the study if they had a positive C. difficile toxin PCR, symptomatic infection and received ≥48 h of oral vancomycin. Disease severity was characterised using a variety of classifiers, including guideline definitions. The primary outcome was 90-day CDI recurrence; secondary outcomes included clinical failure, in-hospital mortality and 90-day re-admission. Inverse probability of treatment weighting (IPTW) was conducted to balance differences between groups. A total of 535 patients were included; 261 received standard and 274 received high-dose vancomycin. Baseline demographics were similar between groups, except that patients receiving high-dose vancomycin were more likely to have more severe disease and to be admitted to the ICU. Few patients had fulminant disease (14.4%). No significant differences in recurrence (OR, 1.52, 95% CI 0.82-2.84), clinical failure (OR, 0.64, 95% CI 0.328-1.26), mortality (OR, 1.44, 95% CI 0.78-2.66) or re-admission (OR, 1.03, 95% CI 0.70-1.51) were identified between patients receiving standard and high-dose vancomycin in the IPTW analyses. No differences in recurrence, mortality or re-admission were identified between standard and high-dose vancomycin for the treatment of CDI not requiring surgery.

Vaccine-induced thrombosis and thrombocytopenia (VITT) in Ireland: A review of cases and current practices.

Since the beginning of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) virus pandemic, several highly effective and safe vaccines have been produced at remarkable speed. Following global implementation of vaccination programmes, cases of thrombosis with thrombocytopenia following administration of adenoviral vector-based vaccines started being reported. In this review we discuss the known pathogenesis and epidemiology of so-called vaccine induced thrombocytopenia and thrombosis (VITT). We consider the available guidelines, diagnostic laboratory tests and management options for these patients. Finally, we discuss important unanswered questions and areas for future research in this novel pathoclinical entity.

Approach to the Treatment of Patients with Serious Multidrug-Resistant Pseudomonas aeruginosa Infections.

Multidrug resistance(MDR) among Pseudomonas aeruginosa (PSA) isolates presents a significant clinical challenge and can substantially complicate the approach to selection of optimal antibiotic therapy. This review addresses major considerations in antibiotic selection for patients with suspected or documented serious MDR-PSA infections. Common mechanisms contributing to MDR among clinical PSA isolates are summarized. Empiric and definitive therapy considerations are addressed including the potential role of combination therapy. Newer agents with in vitro activity against MDR-PSA (e.g., ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, and cefiderocol) and their potential roles in clinical settings are discussed. Although these newer agents are promising options for the treatment of MDR-PSA, clinical data remain generally limited. Future studies are needed to determine optimal agents for the empiric and definitive treatment of MDR-PSA.

Ligamentum teres reconstruction: indications, technique and minimum 1-year results in nine patients.

Ligamentum teres (LT) tear is a recognized cause of hip pain. Debridement of tears and capsule plication has shown satisfactory results. However, a group of patients with complete tears do not improve after debridement and physiotherapy. The purpose of this work was to describe the senior author's technique and clinical results for the early series of LT reconstructions. Retrospective analysis of prospectively collected data. Patients who underwent isolated LT reconstruction between 2013 and 2018. All the patients had previous debridement of a completely torn LT, capsule plication and rehabilitation. Patients who had any other associated procedure during LT reconstruction surgery and dysplastic acetabular features were excluded. Demographic and clinical data was reviewed. Complications, type of graft and modified Harris hip scores (mHHSs) were recorded preoperatively and at 1-year follow-up. Fifteen LT reconstructions were performed during the study period. Six were excluded (as they had additional procedures performed during surgery) and nine patients aged a mean 30 (range: 22-48) years old were included. The patients had a mean of 2 (range: 1-4) prior surgeries. At minimum 12 months (range: 12-24) 9/9 patients reported reduction of pain and instability symptoms with mHHSs of 84.2 (73.7-100) versus 51.7 (36.3-70.4) preoperatively (P = 0.00094). Three patients (of the total cohort of 15) underwent second-look arthroscopy (11-22 months after reconstruction). None of these patients underwent total hip replacement at a mean of 4 (range: 1-6) years. Arthroscopic LT reconstruction improved function and pain in patients with persistent pain and instability after resection of the LT.

Comparative Performance of Urinary Biomarkers for Vancomycin-Induced Kidney Injury According to Timeline of Injury.

Urinary biomarkers are superior to serum creatinine for defining onset and extent of kidney injury. This study classifies the temporal predictive ability of biomarkers for vancomycin-induced kidney injury (VIKI) as defined by histopathologic damage. Male Sprague-Dawley rats (n = 125) were randomized to receive 150 to 400 mg/kg of body weight/day vancomycin via once or twice daily intraperitoneal injection over 1, 3, or 6 days. Urine was collected once during the 24 h prior to euthanasia or twice for rats treated for 6 days. Receiver operating characteristic (ROC) curves were employed to assess the urinary biomarker performances of kidney injury molecule 1 (KIM-1), clusterin, osteopontin (OPN), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) to predict histopathologically defined VIKI (using a national standard pathological assessment scheme from hematoxylin and eosin stained kidneys). Urinary KIM-1, clusterin, and OPN outperformed cystatin C and NGAL with regard to sensitivity and specificity. For the earliest injury, urinary KIM-1 (area under the receiver operating characteristic curve [AUC], 0.662; P < 0.001) and clusterin (AUC, 0.706; P < 0.001) were the most sensitive for predicting even low-level histopathologic damage at 24 h compared to NGAL. KIM-1 and clusterin are the earliest and most sensitive predictors of VIKI. As injury progresses, KIM-1, clusterin, and OPN best define the extent of damage.

Enhanced Redox State and Efficiency of Glucose Oxidation With miR Based Suppression of Maladaptive NADPH-Dependent Malic Enzyme 1 Expression in Hypertrophied Hearts.

RATIONALE: Metabolic remodeling in hypertrophic hearts includes inefficient glucose oxidation via increased anaplerosis fueled by pyruvate carboxylation. Pyruvate carboxylation to malate through elevated ME1 (malic enzyme 1) consumes NADPH necessary for reduction of glutathione and maintenance of intracellular redox state. OBJECTIVE: To elucidate upregulated ME1 as a potential maladaptive mechanism for inefficient glucose oxidation and compromised redox state in hypertrophied hearts. METHODS AND RESULTS: ME1 expression was selectively inhibited, in vivo, via non-native miR-ME1 (miRNA specific to ME1) in pressure-overloaded rat hearts. Rats subjected to transverse aortic constriction (TAC) or Sham surgery received either miR-ME1 or PBS. Effects of ME1 suppression on anaplerosis and reduced glutathione (GSH) content were studied in isolated hearts supplied 13C-enriched substrate: palmitate, glucose, and lactate. Human myocardium collected from failing and nonfailing hearts during surgery enabled RT-qPCR confirmation of elevated ME1 gene expression in clinical heart failure versus nonfailing human hearts (P<0.04). TAC induced elevated ME1 content, but ME1 was lowered in hearts infused with miR-ME1 versus PBS. Although Sham miR-ME1 hearts showed no further reduction of inherently low anaplerosis in normal heart, miR-ME1 reduced anaplerosis in TAC to baseline: TAC miR-ME1=0.034±0.004; TAC PBS=0.081±0.005 (P<0.01). Countering elevated anaplerosis in TAC shifted pyruvate toward oxidation in the tricarboxylic acid cycle. Importantly, via the link to NADPH consumption by pyruvate carboxylation, ME1 suppression in TAC restored GSH content, reduced lactate production, and ultimately improved contractility. CONCLUSIONS: A maladaptive increase in anaplerosis via ME1 in TAC is associated with reduced GSH content. Suppressing increased ME1 expression in hypertrophied rat hearts, which is also elevated in failing human hearts, reduced pyruvate carboxylation thereby normalizing anaplerosis, restoring GSH content, and reducing lactate accumulation. Reducing ME1 induced favorable metabolic shifts for carbohydrate oxidation, improving intracellular redox state and enhanced cardiac performance in pathological hypertrophy.

A novel protein C-factor VII chimera provides new insights into the structural requirements for cytoprotective protease-activated receptor 1 signaling.

Essentials The basis of cytoprotective protease-activated receptor 1 (PAR1) signaling is not fully understood. Activated protein C chimera (APCFVII-82 ) was used to identify requirements for PAR1 signaling. APCFVII-82 did not initiate PAR1 signaling, but conferred monocyte anti-inflammatory activity. APC-specific light chain residues are required for cytoprotective PAR1 signaling. SUMMARY: Background Activated protein C (APC) cell signaling is largely reliant upon its ability to mediate protease-activated receptor (PAR) 1 proteolysis when bound to the endothelial cell (EC) protein C (PC) receptor (EPCR). Furthermore, EPCR-bound PC modulates PAR1 signaling by thrombin to induce APC-like EC cytoprotection. Objective The molecular determinants of EPCR-dependent cytoprotective PAR1 signaling remain poorly defined. To address this, a PC-factor VII chimera (PCFVII-82 ) possessing FVII N-terminal domains and conserved EPCR binding was characterized. Methods Activated PC-FVII chimera (APCFVII-82 ) anticoagulant activity was measured with calibrated automated thrombography and activated FV degradation assays. APCFVII-82 signaling activity was characterized by the use of reporter assays of PAR1 proteolysis and EC barrier integrity. APCFVII-82 anti-inflammatory activity was assessed according to its inhibition of nuclear factor-κB (NF-κB) activation and cytokine secretion from monocytes. Results PCFVII-82 was activated normally by thrombin on ECs, but was unable to inhibit plasma thrombin generation. Surprisingly, APCFVII-82 did not mediate EPCR-dependent PAR1 proteolysis, confer PAR1-dependent protection of thrombin-induced EC barrier disruption, or limit PAR1-dependent attenuation of interleukin-6 release from lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, EPCR occupation by active site-blocked APCFVII-82 was, like FVII, unable to mimic EC barrier stabilization induced by PC upon PAR1 proteolysis by thrombin. APCFVII-82 did, however, diminish LPS-induced NF-κB activation and tumor necrosis factor-α release from monocytes in an apolipoprotein E receptor 2-dependent manner, with similar efficacy as wild-type APC. Conclusions These findings identify a novel role for APC light chain amino acid residues outside the EPCR-binding site in enabling cytoprotective PAR1 signaling.

24-Hour Pharmacokinetic Relationships for Vancomycin and Novel Urinary Biomarkers of Acute Kidney Injury.

Vancomycin has been associated with acute kidney injury in preclinical and clinical settings; however, the precise exposure profiles associated with vancomycin-induced acute kidney injury have not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers. Male Sprague-Dawley rats received clinical-grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg of body weight were administered as a single dose or 2 divided doses over a 24-h period. At least five rats were utilized for each dosing protocol. A maximum of 8 plasma samples per rat were obtained, and urine was collected over the 24-h period. Kidney injury molecule-1 (KIM-1), clusterin, osteopontin, cystatin C, and neutrophil gelatinase-associated lipocalin levels were determined using Milliplex multianalyte profiling rat kidney panels. Vancomycin plasma concentrations were determined via a validated high-performance liquid chromatography methodology. Pharmacokinetic analyses were conducted using the Pmetrics package for R. Bayesian maximal a posteriori concentrations were generated and utilized to calculate the 24-h area under the concentration-time curve (AUC), the maximum concentration (Cmax), and the minimum concentration. Spearman's rank correlation coefficient (rs ) was used to assess the correlations between exposure parameters, biomarkers, and histopathological damage. Forty-seven rats contributed pharmacokinetic and toxicodynamic data. KIM-1 was the only urinary biomarker that correlated with both composite histopathological damage (rs = 0.348, P = 0.017) and proximal tubule damage (rs = 0.342, P = 0.019). The vancomycin AUC and Cmax were most predictive of increases in KIM-1 levels (rs = 0.438 and P = 0.002 for AUC and rs = 0.451 and P = 0.002 for Cmax). Novel urinary biomarkers demonstrate that kidney injury can occur within 24 h of vancomycin exposure as a function of either AUC or Cmax.

Profile of von Willebrand factor antigen and von Willebrand factor propeptide in an overall TIA and ischaemic stroke population and amongst subtypes.

INTRODUCTION: Von Willebrand factor propeptide (VWF:Ag II) is proposed to be a more sensitive marker of acute endothelial activation than von Willebrand factor antigen (VWF:Ag). Simultaneous data on VWF:Ag and VWF:Ag II profiles are very limited following TIA and ischaemic stroke. METHODS: In this prospective, observational, case-control study, plasma VWF:Ag and VWF:Ag II levels were quantified in 164 patients≤4weeks of TIA or ischaemic stroke (baseline), and then ≥14days (14d) and ≥90days (90d) later, and compared with those from 27 healthy controls. TIA and stroke subtyping was performed according to the TOAST classification. The relationship between VWF:Ag and VWF:Ag II levels and platelet activation status was assessed. RESULTS: 'Unadjusted' VWF:Ag and VWF:Ag II levels were higher in patients at baseline, 14d and 90d than in controls (p≤0.03). VWF:Ag levels remained higher in patients than controls at baseline (p≤0.03), but not at 14d or 90d after controlling for differences in age or hypertension, and were higher in patients at baseline and 90d after controlling for smoking status (p≤0.04). 'Adjusted' VWF:Ag II levels were not higher in patients than controls after controlling for age, hypertension or smoking (p≥0.1). Patients with symptomatic carotid stenosis (N=46) had higher VWF:Ag and VWF:Ag II levels than controls at all time-points (p≤0.002). There was no significant correlation between platelet activation status and VWF:Ag or VWF:Ag II levels. CONCLUSIONS: VWF:Ag and VWF:Ag II levels are increased in an overall TIA and ischaemic stroke population, especially in patients with recently symptomatic carotid stenosis. VWF:Ag II was not superior to VWF:Ag at detecting acute endothelial activation in this cohort and might reflect timing of blood sampling in our study.

N-linked glycan truncation causes enhanced clearance of plasma-derived von Willebrand factor.

Essentials von Willebrands factor (VWF) glycosylation plays a key role in modulating in vivo clearance. VWF glycoforms were used to examine the role of specific glycan moieties in regulating clearance. Reduction in sialylation resulted in enhanced VWF clearance through asialoglycoprotein receptor. Progressive VWF N-linked glycan trimming resulted in increased macrophage-mediated clearance. Click to hear Dr Denis discuss clearance of von Willebrand factor in a free presentation from the ISTH Academy SUMMARY: Background Enhanced von Willebrand factor (VWF) clearance is important in the etiology of both type 1 and type 2 von Willebrand disease (VWD). In addition, previous studies have demonstrated that VWF glycans play a key role in regulating in vivo clearance. However, the molecular mechanisms underlying VWF clearance remain poorly understood. Objective To define the molecular mechanisms through which VWF N-linked glycan structures influence in vivo clearance. Methods By use of a series of exoglycosidases, different plasma-derived VWF (pd-VWF) glycoforms were generated. In vivo clearance of these glycoforms was then assessed in VWF-/- mice in the presence or absence of inhibitors of asialoglycoprotein receptor (ASGPR), or following clodronate-induced macrophage depletion. Results Reduced amounts of N-linked and O-linked sialylation resulted in enhanced pd-VWF clearance modulated via ASGPR. In addition to this role of terminal sialylation, we further observed that progressive N-linked glycan trimming also resulted in markedly enhanced VWF clearance. Furthermore, these additional N-linked glycan effects on clearance were ASGPR-independent, and instead involved enhanced macrophage clearance that was mediated, at least in part, through LDL receptor-related protein 1. Conclusion The carbohydrate determinants expressed on VWF regulate susceptibility to proteolysis by ADAMTS-13. In addition, our findings now further demonstrate that non-sialic acid carbohydrate determinants expressed on VWF also play an unexpectedly important role in modulating in vivo clearance through both hepatic ASGPR-dependent and macrophage-dependent pathways. In addition, these data further support the hypothesis that variation in VWF glycosylation may be important in the pathophysiology underlying type 1C VWD.

The Warwick Agreement on femoroacetabular impingement syndrome (FAI syndrome): an international consensus statement.

The 2016 Warwick Agreement on femoroacetabular impingement (FAI) syndrome was convened to build an international, multidisciplinary consensus on the diagnosis and management of patients with FAI syndrome. 22 panel members and 1 patient from 9 countries and 5 different specialties participated in a 1-day consensus meeting on 29 June 2016. Prior to the meeting, 6 questions were agreed on, and recent relevant systematic reviews and seminal literature were circulated. Panel members gave presentations on the topics of the agreed questions at Sports Hip 2016, an open meeting held in the UK on 27-29 June. Presentations were followed by open discussion. At the 1-day consensus meeting, panel members developed statements in response to each question through open discussion; members then scored their level of agreement with each response on a scale of 0-10. Substantial agreement (range 9.5-10) was reached for each of the 6 consensus questions, and the associated terminology was agreed on. The term 'femoroacetabular impingement syndrome' was introduced to reflect the central role of patients' symptoms in the disorder. To reach a diagnosis, patients should have appropriate symptoms, positive clinical signs and imaging findings. Suitable treatments are conservative care, rehabilitation, and arthroscopic or open surgery. Current understanding of prognosis and topics for future research were discussed. The 2016 Warwick Agreement on FAI syndrome is an international multidisciplinary agreement on the diagnosis, treatment principles and key terminology relating to FAI syndrome.Author note The Warwick Agreement on femoroacetabular impingement syndrome has been endorsed by the following 25 clinical societies: American Medical Society for Sports Medicine (AMSSM), Association of Chartered Physiotherapists in Sports and Exercise Medicine (ACPSEM), Australasian College of Sports and Exercise Physicians (ACSEP), Austian Sports Physiotherapists, British Association of Sports and Exercise Medicine (BASEM), British Association of Sport Rehabilitators and Trainers (BASRaT), Canadian Academy of Sport and Exercise Medicine (CASEM), Danish Society of Sports Physical Therapy (DSSF), European College of Sports and Exercise Physicians (ECOSEP), European Society of Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA), Finnish Sports Physiotherapist Association (SUFT), German-Austrian-Swiss Society for Orthopaedic Traumatologic Sports Medicine (GOTS), International Federation of Sports Physical Therapy (IFSPT), International Society for Hip Arthroscopy (ISHA), Groupo di Interesse Specialistico dell'A.I.F.I., Norwegian Association of Sports Medicine and Physical Activity (NIMF), Norwegian Sports Physiotherapy Association (FFI), Society of Sports Therapists (SST), South African Sports Medicine Association (SASMA), Sports Medicine Australia (SMA), Sports Doctors Australia (SDrA), Sports Physiotherapy New Zealand (SPNZ), Swedish Society of Exercise and Sports Medicine (SFAIM), Swiss Society of Sports Medicine (SGMS/SGSM), Swiss Sports Physiotherapy Association (SSPA).

Pharmacokinetics of Cefepime in Patients with Cancer and Febrile Neutropenia in the Setting of Hematologic Malignancies or Hematopoeitic Cell Transplantation.

STUDY OBJECTIVE: To evaluate the steady-state pharmacokinetic parameters of standard cefepime dosing regimens in a hematologic malignancy and hematopoietic cell transplant patient population with febrile neutropenia. DESIGN: Open-label, single-center, prospective pharmacokinetic study. SETTING: National Cancer Institute-designated cancer center. PATIENTS: Nine adults with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia and were admitted to a hematology-oncology service between January and July 2014. INTERVENTION: Patients received empirical cefepime 2 g every 8 hours, administered as a 30-minute intravenous infusion, for febrile neutropenia. MEASUREMENTS AND MAIN RESULTS: Steady-state cefepime serum concentrations were measured after at least 2 days of continuous therapy. Venous blood samples were intensively sampled between 0 and 8 hours after the start of the 30-minute infusion at steady state. Seven of the nine patients had a hematologic malignancy diagnosis of acute leukemia, lymphoma, or myeloma, and two patients had a germ cell tumor diagnosis. Noncompartmental analysis revealed mean ± SD parameters as follows at steady state: area under the plasma concentration-time curve from 0-8 hours 222.9 ± 72.9 mg hour/L, maximum concentration 120.9 ± 21.8 mg/L, clearance 9.7 ± 3.7 L/hour, apparent volume of distribution 19.2 ± 4.65 L, and elimination half-life 1.4 ± 0.3 hours. A one-compartment pharmacokinetic model identified a mean ± SD volume of distribution of 20.9 ± 1.3 L and an elimination rate constant of 0.39 ± 0.03 hour(-1) . The mean estimated percentage of time that drug concentration remains above the pathogen minimum inhibitory concentration (fT>MIC) in serum was 55%, 77%, and 99% at MICs of 16, 8, and 4 mg/L, respectively. CONCLUSION: Patients with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia demonstrated homogeneous calculated cefepime volumes and clearances. The population parameters presented in this study may aid in the calculation of patient-specific fT>MIC for similar patients.

Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats.

Vancomycin has been associated with acute kidney injury (AKI). However, the pharmacokinetic/toxicodynamic relationship for AKI is not well defined. Allometrically scaled vancomycin exposures were used to assess the relationship between vancomycin exposure and AKI. Male Sprague-Dawley rats received clinical-grade vancomycin in normal saline (NS) as intraperitoneal (i.p.) injections for 24- to 72-h durations with doses ranging 0 to 200 mg/kg of body weight divided once or twice daily. Urine was collected over the protocol's final 24 h. Renal histopathology was qualitatively scored. Urinary biomarkers (e.g., cystatin C, clusterin, kidney injury molecule 1 [KIM-1], osteopontin, lipocalin 2/neutrophil gelatinase-associated lipocalin 2) were assayed using a Luminex xMAP system. Plasma vancomycin concentrations were assayed by high-performance liquid chromatography with UV detection. A three-compartment vancomycin pharmacokinetic model was fit to the data with the Pmetrics package for R. The exposure-response in the first 24 h was evaluated using Spearman's nonparametric correlation coefficient (rs) values for the area under the concentration-time curve during the first 24 h (AUC0-24), the maximum concentration in plasma during the first 24 h (Cmax0-24 ), and the lowest (minimum) concentration in plasma after the dose closest to 24 h (Cmin0-24 ). A total of 52 rats received vancomycin (n = 42) or NS (n = 10). The strongest exposure-response correlations were observed between AUC0-24 and Cmax0-24 and urinary AKI biomarkers. Exposure-response correlations (rs values) for AUC0-24, Cmax0-24 , and Cmin0-24 were 0.37, 0.39, and 0.22, respectively, for clusterin; 0.42, 0.45, and 0.26, respectively, for KIM-1; and 0.52, 0.55, and 0.42, respectively, for osteopontin. However, no differences in histopathological scores were observed. Optimal sampling times after administration of the i.p. dose were 0.25, 0.75, 2.75, and 8 h for the once-daily dosing schemes and 0.25, 1.25, 14.5, and 17.25 h for the twice-daily dosing schemes. Our observations suggest that AUC0-24 or Cmax0-24 correlates with increases in urinary AKI biomarkers.

FDG-PET imaging in hematological malignancies.

The majority of aggressive lymphomas is characterized by an up regulated glycolytic activity, which enables the visualization by F-18 FDG-PET/CT. One-stop hybrid FDG-PET/CT combines the functional and morphologic information, outperforming both, CT and FDG-PET as separate imaging modalities. This has resulted in several recommendations using FDG-PET/CT for staging, restaging, monitoring during therapy, and assessment of treatment response as well as identification of malignant transformation. FDG-PET/CT may obviate the need for a bone marrow biopsy in patients with Hodgkin's lymphoma and diffuse large B cell lymphoma. FDG-PET/CT response assessment is recommended for FDG-avid lymphomas, whereas CT-based response evaluation remains important in lymphomas with low or variable FDG avidity. The treatment induced change in metabolic activity allows for assessment of response after completion of therapy as well as prediction of outcome early during therapy. The five-point scale Deauville Criteria allows the assessment of treatment response based on visual FDG-PET analysis. Although the use of FDG-PET/CT for prediction of therapeutic response is promising it should only be conducted in the context of clinical trials. Surveillance FDG-PET/CT after complete remission is discouraged due to the relative high number of false-positive findings, which in turn may result in further unnecessary investigations. Future directions include the use of new PET tracers such as F-18 fluorothymidine (FLT), a surrogate biomarker of cellular proliferation and Ga-68 CXCR4, a chemokine receptor imaging biomarker as well as innovative digital PET/CT and PET/MRI techniques.

Lenalidomide as a novel treatment for refractory acquired von Willebrand syndrome associated with monoclonal gammopathy.

UNLABELLED: Essentials Treatment options are limited for refractory bleeding in acquired von Willebrand Syndrome (AVWS). Lenalidomide therapy was studied in two patients with AVWS due to monoclonal gammopathy (MG). Lenalidomide increased von Willebrand factor (VWF), lowered VWF clearance and resolved bleeding. Lenalidomide is a potential treatment option for refractory bleeding in AVWS secondary to MG. SUMMARY: Background Acquired von Willebrand syndrome (AVWS) is associated with lymphoproliferative disorders, including monoclonal gammopathy (MG) of undetermined significance (MGUS) and multiple myeloma. Patients commonly present with significant bleeding complications that are difficult to manage, owing to a markedly reduced von Willebrand factor (VWF) half-life. Objectives To investigate the use of the immunomodulatory drug lenalidomide in two patients with severe refractory bleeding caused by AVWS associated with MGs. Results In both patients, lenalidomide treatment resulted in significant clinical improvement, and marked increases in plasma VWF antigen (VWF:Ag) and VWF ristocetin cofactor levels. This normalization in plasma VWF levels was sustained for > 2 years in both patients. Furthermore, in one patient, plasma VWF levels remain normal for at least 14 months following discontinuation of lenalidomide treatment. To investigate the molecular mechanisms underlying these observations, VWF propeptide (VWFpp)/VWF:Ag ratios were analyzed to assess VWF clearance. At enrolment, plasma VWFpp/VWF:Ag ratios were significantly elevated in both patients. Importantly, lenalidomide treatment resulted in normalization of VWFpp/VWF:Ag ratios in both patients. These novel data suggest that lenalidomide functions to attenuate enhanced VWF clearance in AVWS. Interestingly, in a patient with MGUS, lenalidomide treatment was associated with a significant increase in plasma VWF levels, despite no major change in paraprotein level. Conclusions Collectively, our findings suggest that lenalidomide constitutes a novel therapeutic option for the management of AVWS associated with MG. The biological mechanism(s) through which lenalidomide causes a sustained increase in plasma VWF levels in AVWS independently of paraprotein level requires further study, but is in part modulated through inhibition of enhanced VWF clearance.