Newly Recognized Spotted Fever Group Rickettsia as Cause of Severe Rocky Mountain Spotted Fever-Like Illness, Northern California, USA.

The incidence of spotted fever group (SFG) rickettsioses in the United States has tripled since 2010. Rocky Mountain spotted fever, the most severe SFG rickettsiosis, is caused by Rickettsia rickettsii. The lack of species-specific confirmatory testing obfuscates the relative contribution of R. rickettsii and other SFG Rickettsia to this increase. We report a newly recognized rickettsial pathogen, Rickettsia sp. CA6269, as the cause of severe Rocky Mountain spotted fever-like illness in 2 case-patients residing in northern California. Multilocus sequence typing supported the recognition of this pathogen as a novel Rickettsia genotype most closely related to R. rickettsii. Cross-reactivity observed for an established molecular diagnostic test indicated that Rickettsia sp. CA6269 might be misidentified as R. rickettsii. We developed a Rickettsia sp. CA6269-specific real-time PCR to help resolve this diagnostic challenge and better characterize the spectrum of clinical disease and ecologic epidemiology of this pathogen.

The efficacy of albumin-globulin ratio to predict prognosis in cancer patients.

The goal of this systematic review was to identify all of the research within the last 10 years that investigated both the Albumin-Globulin Ratio (AGR) and outcomes of solid tumor cancer patients via quantitative prognostic variables. Multiple scientific databases were researched for journal articles that included keywords relating AGR to prognosis. Once isolated from the databases, the articles were de-duplicated and manually screened based on standardized inclusion/exclusion criteria in a blind format via Rayyan. The collective data were sorted by cancer type, corrected for population size, and used to calculate the average cut-off values for the most popular prognostic variables. In total, 18 independent types of cancer have been evaluated to see if AGR is a prognostic indicator based on multivariate analyses. The average cut-off value for AGR in overall survival was 1.356, while the average cut-off value for AGR in progression free survival was 1.292. AGR was found to be significantly associated with at least one prognostic variable in every type of cancer evaluated based on multivariate analyses. The ease of access and affordability of AGR makes it an invaluable tool applicable to nearly all patients. Overall, AGR is a proven prognostic variable that should always be considered in the evaluation of a solid tumor cancer patient's prognosis. Further research needs to be conducted studying the potential prognostic effect in more types of solid tumors.

Reductions in Reimbursement and Relative Value Units for Interventional Radiology Procedures: Trends from 2011 to 2021 Compared with Those for Other Physician Specialties.

PURPOSE: To compare recent trends in Medicare reimbursement and relative value units (RVUs) for interventional radiology (IR) procedures similar to those performed by non-IR specialties. MATERIALS AND METHODS: Data from the Centers for Medicare and Medicaid Services Physician Fee Schedule for facility reimbursement and RVU component values for 23 commonly performed single Current Procedural Terminology IR procedures were compared with similar procedures or procedures for similar indications performed by non-IR specialties between 2011 and 2021. RESULTS: The work RVU component decreased in 18 of 23 (78.3%) IR procedures compared with 6 of 23 (26.1%) similar procedures performed by non-IR specialties. The largest change in single RVU component was a 19.2% reduction in practice expense RVU for IR compared with a 16.5% reduction for similar procedures performed by non-IR specialties. CONCLUSIONS: As a specialty, IR experienced a disproportionately greater reduction in reimbursement and RVU valuation for a range of comparable procedures performed by non-IR specialties.

Incursions of divergent genotypes, evolution of virulence and host jumps shape a continental clonal population of the stripe rust pathogen Puccinia striiformis.

Long-distance migration and host adaptation by transboundary plant pathogens often brings detrimental effects to important agroecosystems. Efficient surveillance as a basis for responding to the dynamics of such pathogens is often hampered by a lack of information on incursion origin, evolutionary pathways and the genetic basis of rapidly evolving virulence across larger timescales. Here, we studied these genetic features by using historical isolates of the obligate biotrophic pathogen Puccinia striiformis f. sp. tritici (Pst), which causes one of the most widespread and devastating diseases, stripe (yellow) rust, of wheat. Through a combination of genotypic, phenotypic and genomic analyses, we assigned eight Pst isolates representing putative exotic Pst incursions into Australia to four previously defined genetic groups, PstS0, PstS1, PstS10 and PstS13. We showed that isolates of an additional incursion of P. striiformis, known locally as P. striiformis f. sp. pseudo-hordei, had a new and unique multilocus SSR genotype (MLG). We provide results of overall genomic variation of representative Pst isolates from each genetic group by comparative genomic analyses. We showed that isolates within the PstS1 and PstS13 genetic groups are most distinct at the whole-genome variant level from isolates belonging to genetic group PstS0, whereas the isolate from the PstS10 genetic group is intermediate. We further explored variable gene content, including putative effectors, representing both shared but also unique genetic changes that have occurred following introduction, some of which may additionally account for local adaptation of these isolates to triticale. Our genotypic and genomic data revealed new genetic insights into the evolution of diverse phenotypes of rust pathogens following incursion into a geographically isolated continental region.

Sources of non-methane hydrocarbons in surface air in Delhi, India.

Rapid economic growth and development have exacerbated air quality problems across India, driven by many poorly understood pollution sources and understanding their relative importance remains critical to characterising the key drivers of air pollution. A comprehensive suite of measurements of 90 non-methane hydrocarbons (NMHCs) (C2-C14), including 12 speciated monoterpenes and higher molecular weight monoaromatics, were made at an urban site in Old Delhi during the pre-monsoon (28-May to 05-Jun 2018) and post-monsoon (11 to 27-Oct 2018) seasons using dual-channel gas chromatography (DC-GC-FID) and two-dimensional gas chromatography (GC×GC-FID). Significantly higher mixing ratios of NMHCs were measured during the post-monsoon campaign, with a mean night-time enhancement of around 6. Like with NOx and CO, strong diurnal profiles were observed for all NMHCs, except isoprene, with very high NMHC mixing ratios between 35-1485 ppbv. The sum of mixing ratios of benzene, toluene, ethylbenzene and xylenes (BTEX) routinely exceeded 100 ppbv at night during the post-monsoon period, with a maximum measured mixing ratio of monoaromatic species of 370 ppbv. The mixing ratio of highly reactive monoterpenes peaked at around 6 ppbv in the post-monsoon campaign and correlated strongly with anthropogenic NMHCs, suggesting a strong non-biogenic source in Delhi. A detailed source apportionment study was conducted which included regression analysis to CO, acetylene and other NMHCs, hierarchical cluster analysis, EPA UNMIX 6.0, principal component analysis/absolute principal component scores (PCA/APCS) and comparison with NMHC ratios (benzene/toluene and i-/n-pentane) in ambient samples to liquid and solid fuels. These analyses suggested the primary source of anthropogenic NMHCs in Delhi was from traffic emissions (petrol and diesel), with average mixing ratio contributions from Unmix and PCA/APCS models of 38% from petrol, 14% from diesel and 32% from liquified petroleum gas (LPG) with a smaller contribution (16%) from solid fuel combustion. Detailed consideration of the underlying meteorology during the campaigns showed that the extreme night-time mixing ratios of NMHCs during the post-monsoon campaign were the result of emissions into a very shallow and stagnant boundary layer. The results of this study suggest that despite widespread open burning in India, traffic-related petrol and diesel emissions remain the key drivers of gas-phase urban air pollution in Delhi.

Effects of the MAGIC Guidelines on PICC Placement Volume: Advanced Practice Provider and Physician Trends Among Medicare Beneficiaries From 2010 to 2018.

BACKGROUND. The Michigan Appropriateness Guide for Intravenous Catheters (MAGIC) was published in 2015, recommending more restricted indications for peripherally inserted central catheter (PICC) placement, particularly for those placed by physicians. Changes in PICC placement volume since the publication of MAGIC is largely unknown. OBJECTIVE. The purpose of this article was to study the trends in volume and reimbursement for PICC placement by physicians and advanced practice providers (APPs) for Medicare enrollees from 2010 to 2018 with specific attention to the changes in volume after the publication of MAGIC in 2015. METHODS. Claims from the Medicare Part B Physician/Supplier Procedure Summary Master File for the years 2010-2018 were extracted using the Current Procedural Terminology code for PICC placement. Total volume and payment amounts (for the professional component) were analyzed. Trendline slopes for volume per 100,000 Medicare beneficiaries before and after the 2015 publication of MAGIC were compared. RESULTS. Volume for PICC placement by physicians and APPs steadily declined from 243,837 in 2010 to 130,361 in 2018 (46.5%). The PICC placement volume decreased sharply after the 2015 publication of the MAGIC guidelines. The slope of the trendline for all providers from 2010 to 2015 was -3.4 compared with -7.3 from 2015 to 2018. The change in slope was more pronounced for radiologists (-3.1 to -5.6) than for APPs (0.0 to -1.1). Professional payment per procedure for radiologists decreased from $78.04 in 2010 to $70.17 in 2018, and reimbursement for APPs proportionally decreased from $65.76 to $60.66 during this time. The relative share of PICC placement by radiologists declined from 77.0% in 2010 to 70.6% in 2018, with a corresponding increase in relative share by APPs from 13.5% to 18.4%. The percentage placed in outpatient procedures increased from 15.1% to 18.2%. CONCLUSION. The volume of PICC placements has steadily decreased since 2010, with a sharper decline between 2015 and 2016 corresponding with the publication of the MAGIC evidence-based guidelines. The role of APPs in PICC placement has increased over this time period. CLINICAL IMPACT. The findings of this study suggest that evidence-based guidelines impact clinical practice on a national level.

Exact design of complex amplitude holograms for producing arbitrary scalar fields.

Typical methods to holographically encode arbitrary wavefronts assume the hologram medium only applies either phase shifts or amplitude attenuation to the wavefront. In many cases, phase cannot be introduced to the wavefront without also affecting the amplitude. Here we show how to encode an arbitrary wavefront into an off-axis transmission hologram that returns the exact desired arbitrary wavefunction in a diffracted beam for phase-only, amplitude-only, or mixed phase and amplitude holograms with any periodic groove profile. We apply this to design thin holograms for electrons in a TEM, but our results are generally applicable to light and X-ray optics. We employ a phase reconstruction from a series of focal plane images to qualitatively show the accuracy of this method to impart the expected amplitude and phase to a specific diffraction order.

Diesel Exhaust Induces Mitochondrial Dysfunction, Hyperlipidemia, and Liver Steatosis.

OBJECTIVE: Air pollution is associated with increased cardiovascular morbidity and mortality, as well as dyslipidemia and metabolic syndrome. Our goal was to dissect the mechanisms involved. Approach and Results: We assessed the effects of exposure to air pollution on lipid metabolism in mice through assessment of plasma lipids and lipoproteins, oxidized fatty acids 9-HODE (9-hydroxyoctadecadienoic) and 13-HODE (13-hydroxyoctadecadienoic), lipid, and carbohydrate metabolism. Findings were corroborated, and mechanisms were further assessed in HepG2 hepatocytes in culture. ApoE knockout mice exposed to inhaled diesel exhaust (DE, 6 h/d, 5 days/wk for 16 weeks) exhibited elevated plasma cholesterol and triglyceride levels, increased hepatic triglyceride content, and higher hepatic levels of 9-HODE and 13-HODE, as compared to control mice exposed to filtered air. A direct effect of DE exposure on hepatocytes was demonstrated by treatment of HepG2 cells with a methanol extract of DE particles followed by loading with oleic acid. As observed in vivo, this led to increased triglyceride content and significant downregulation of ACAD9 mRNA expression. Treatment of HepG2 cells with DE particles and oleic acid did not alter de novo lipogenesis but inhibited total, mitochondrial, and ATP-linked oxygen consumption rate, indicative of mitochondrial dysfunction. Treatment of isolated mitochondria, prepared from mouse liver, with DE particles and oleic acid also inhibited mitochondrial complex activity and ß-oxidation. CONCLUSIONS: DE exposure leads to dyslipidemia and liver steatosis in ApoE knockout mice, likely due to mitochondrial dysfunction and decreased lipid catabolism.

Bundled Medicare Payments: Trends in Utilization and Physician Payments for Dialysis Arteriovenous Fistula and Graft Maintenance Procedures From 2010 to 2018.

OBJECTIVE. The purposes of this study were to evaluate the volume of and payments for dialysis arteriovenous fistula and arteriovenous graft maintenance procedures among Medicare beneficiaries from 2010 to 2018 and analyze trends by physician specialty and practice setting after the introduction of bundled Current Procedural Terminology (CPT) codes in 2017. MATERIALS AND METHODS. Claims from the Medicare Part B Physician/Supplier Procedure Summary Master File for the years 2010 through 2018 were extracted by use of the CPT codes for arteriovenous fistula and arteriovenous graft maintenance procedures. Total volumes, payment amounts (professional component), and trends were analyzed by physician specialty and practice setting. RESULTS. From 2010 to 2018, the volume of dialysis circuit maintenance procedures increased 25%, from 308,140 to 385,440 procedures. This increase was driven by increased volumes among nephrologists (30.0%) and surgeons (30.5%) with only a modest increase for interventional radiologists (1.5%). Total physician payments increased 20%, from $333.8 million to $399.5 million. After the introduction of bundled CPT codes in 2017, per-procedure physician payment decreased from $1073 in 2016 to $1025 in 2017 (4.5%). The true decrease in per-procedure payment was underestimated owing to inclusion of higher-cost stenting and embolization procedures in the dialysis-specific codes beginning in 2017. CONCLUSION. The volume of dialysis access maintenance procedures and total physician payments increased from 2010 to 2018 in keeping with the Centers for Medicare & Medicaid Services Fistula First Breakthrough Initiative. Introduction of bundled CPT codes in 2017, designed to reduce redundant payments, correlated with a decrease in average per-procedure physician payment.

Percutaneous thermal ablation for treatment of osteoid osteoma: a systematic review and analysis.

OBJECTIVE: Although radiofrequency ablation is well validated for treatment of osteoid osteoma, newer technologies, namely cryoablation, have been less thoroughly studied. The purpose is to perform a systematic review and pooled analysis of percutaneous ablation technologies for treatment of osteoid osteoma with subset analysis of intra-articular and spinal tumors. MATERIAL AND METHODS: A total of 36 of 79 identified manuscripts met inclusion criteria, comprising 1863 ablations in 1798 patients. Inclusion criteria were (1) retrospective or prospective analysis of thermal ablation of osteoid osteomas in any location, (2) at least 6 months of clinical follow-up, (3) 10 or more patients, (4) patients not included in a second study included in this review, and (5) English language or English translation available. Success rate was defined as all ablations minus technical failures, clinical failures, and recurrences. Subset analysis of intra-articular and spinal tumors was performed. RESULTS: Overall success rate was 91.9% (95% CI 91-93%). Technical failure, clinical failure, and recurrence rates were 0.3%, 2.1%, and 5.6% respectively. Complications were seen in 2.5% (95% CI 1.9-3.3%) patients. There was no significant difference when comparing radiofrequency ablation and cryoablation (p = 0.92). Success rates for intra-articular (radiofrequency ablation) and spinal tumors (radiofrequency and cryoablation) were 97% and 91.6% respectively. CONCLUSION: Percutaneous ablation of osteoid osteomas was highly successful with low complication rates. Efficacy of radiofrequency ablation and cryoablation is similar, which is consequential because cryoablation is associated with decreased pain, predictable nerve regeneration, and theoretical immunotherapy benefits. Treatment of more challenging intra-articular and spinal lesions demonstrated similarly high success and low complication rates.

Hepatic Venous Pressure Gradient Measurements in Children: Correlation With Hepatic Histology and Clinical Indicators of Portal Hypertension.

OBJECTIVES: In adults, elevated hepatic venous pressure gradients (HVPGs) are correlated with the degree of liver fibrosis on histopathology and predict worse outcomes including variceal bleeding and death. We aimed to examine the association between HVPG measurements, histopathologic findings, and clinical indicators of portal hypertension in children. METHODS: Utilizing retrospective data from 2 pediatric centers between 2006 and 2015, we identified children who underwent simultaneous HVPG measurement and transjugular liver biopsy. Medical charts were reviewed for histopathology, imaging, endoscopic, and clinical data. RESULTS: Forty-one children (median age 11 years) were included in the analysis with diagnoses of acute hepatitis (n = 15), chronic liver disease (n = 12), hepatic noncirrhotic portal hypertension (n = 4), acute liver failure (n = 3), and nonhepatic causes of portal hypertension (n = 7). Elevated mean HVPG measurements were found in children with acute liver failure (10 mmHg, range 4-12) and chronic liver disease (7 mmHg, range 1-12). HVPG measurements did not correlate with the histological severity of fibrosis (ρ = 0.23, P = 0.14) or portal inflammation (ρ = 0.24, P = 0.29), and no difference was found in HVPG when comparing children with and without a history of variceal bleeding (P = 0.43). CONCLUSIONS: HVPG measurements do not correlate significantly with the degree of hepatic fibrosis on biopsy. Furthermore, HVPG measurements are not associated with the presence of varices or history of variceal bleeding, suggesting the possibility of intrahepatic shunting in children with advanced liver disease. Therefore, unlike in adults, HVPG measurements may not accurately predict children who are at risk of complications from portal hypertension.

Structured Protocol for Benign Biliary Anastomotic Strictures: Impact on Long-Term Clinical Effectiveness.

OBJECTIVE: The purpose of this study is to compare long-term clinical effectiveness before and after implementation of a structured protocol for percutaneous drainage of benign anastomotic biliary strictures. MATERIALS AND METHODS: Three hundred five adult patients undergoing percutaneous biliary drainage for biliary anastomotic strictures between 1994 and 2015 were identified using Current Procedural Terminology billing codes, with 234 undergoing intervention before implementation of a structured protocol and 71 undergoing intervention after implementation of the protocol. The frequency of surgical anastomotic revision was compared between patients treated before and after the implementation of the structured protocol. Patient characteristics and treatment variables were also analyzed with respect to the frequency of surgical revision. A Kaplan-Meier analysis was performed to determine the long-term probabilities of avoiding surgical revision and patency rates. RESULTS: Overall, 72.8% of patients avoided surgical revision, with 71.1% before and 81.7% after the protocol was implemented (p = 0.1052). A larger maximum drain size was significantly associated with a lower frequency of surgical revision (p = 0.0006). The rates of surgical avoidance 5 years after treatment before and after protocol implementation were 69.1% and 80.8%, respectively. Patency rates 5 years after treatment before and after protocol implementation were 73.8% and 76.8%, respectively. CONCLUSION: Percutaneous drainage and management of benign biliary anastomotic strictures is an effective treatment regardless of the presence of a structured protocol. Although there was no significant benefit in terms of avoidance of surgical revision, the time until surgical revision and patency rates were increased with the protocol. In addition, a larger maximum drain size was associated with a better outcome.

Raman microspectroscopy and multivariate data analysis: optical differentiation of aqueous d- and l-tryptophan solutions.

The combination of Raman spectroscopy as a sensitive and selective optical measurement technique and multivariate data analysis forms a powerful tool for probing intermolecular interactions between enantiomers. In this study we demonstrate that the optical differentiation of aqueous d- and l-tryptophan solutions is possible using Raman spectroscopy and principal component analysis (PCA). The loadings of the PCA allow identifying these functional groups most relevant for enantiospecific interactions. Through a partial least squares regression (PLSR) a calibration line can be established for the mixing ratio of ternary aqueous d- and l-tryptophan solutions.

The effects of expanding outpatient and inpatient evaluation and management services in a pediatric interventional radiology practice.

BACKGROUND: Despite a continuing emphasis on evaluation and management clinical services in adult interventional radiology (IR) practice, the peer-reviewed literature addressing these services - and their potential economic benefits - is lacking in pediatric IR practice. OBJECTIVE: To measure the effects of expanding evaluation and management (E&M) services through the establishment of a dedicated pediatric interventional radiology outpatient clinic and inpatient E&M reporting system. MATERIALS AND METHODS: We collected and analyzed E&M current procedural terminology (CPT) codes from all patients seen in a pediatric interventional radiology outpatient clinic between November 2014 and August 2015. We also calculated the number of new patients seen in the clinic who had a subsequent procedure (procedural conversion rate). For comparison, we used historical data comprising pediatric patients seen in a general interventional radiology (IR) clinic for the 2 years immediately prior. An inpatient E&M reporting system was implemented and all inpatient E&M (and subsequent procedural) services between July 2015 and September 2015 were collected and analyzed. We estimated revenue for both outpatient and inpatient services using the Medicare Physician Fee Schedule global non-facility price as a surrogate. RESULTS: Following inception of a pediatric IR clinic, the number of new outpatients (5.5/month; +112%), procedural conversion rate (74.5%; +19%), estimated E&M revenue (+158%), and estimated procedural revenue from new outpatients (+228%) all increased. Following implementation of an inpatient clinic reporting system, there were 8.3 consults and 7.3 subsequent hospital encounters per month, with a procedural conversion rate of 88%. CONCLUSION: Growth was observed in all meaningful metrics following expansion of outpatient and inpatient pediatric IR E&M services.

Single-stick tunneled central venous access using the jugular veins in infants weighing less than 5 kg.

BACKGROUND: Despite the demonstrated feasibility of the single-stick technique in the femoral vein, its use in neonates and infants for placing central lines in internal and external jugular veins has not been reported. OBJECTIVE: Describe and assess the safety and efficacy of tunneled jugular central venous catheter placement performed under ultrasound (US) and fluoroscopic guidance in neonates and infants weighing <5 kg using the single-stick technique at three tertiary pediatric hospitals. MATERIALS AND METHODS: Thirty-three children weighing less than 5 kg received tunneled central venous access in either internal or external jugular veins using the single-stick technique. Patient history, procedural records and clinical follow-up documents were retrospectively reviewed. Complication rates were compared to those of 41 patients receiving single-stick femoral central lines. RESULTS: Technical complications occurred during one (3.0%) jugular placement with the patient having a failed right-side attempt with subsequent successful left-side placement. The catheters did not last the entire course of treatment in three (9.1%) patients with jugular lines. One patient had the catheter removed due to concern for infection, one catheter was accidentally removed during dressing changes, and one catheter was displaced and subsequently exchanged. Of patients receiving femoral central lines, 1 (2.4%) had a technical complication and 5 catheters (12.2%) did not last the entire course of treatment. CONCLUSION: The placement of tunneled central venous catheters in neonates/infants <5 kg is safe and technically feasible using the internal/external jugular vein via the single-stick technique. By theoretically reducing the risks of catheter infection by avoiding the diaper area and thrombosis by using larger veins, it may be preferable in certain patient populations.

Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates.

AIMS: To characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon-like peptide-1 (GLP-1) and glucagon receptors. MATERIALS AND METHODS: MEDI0382 was evaluated in vitro for its ability to stimulate cAMP accumulation in cell lines expressing transfected recombinant or endogenous GLP-1 or glucagon receptors, to potentiate glucose-stimulated insulin secretion (GSIS) in pancreatic ß-cell lines and stimulate hepatic glucose output (HGO) by primary hepatocytes. The ability of MEDI0382 to reduce body weight and improve energy balance (i.e. food intake and energy expenditure), as well as control blood glucose, was evaluated in mouse models of obesity and healthy cynomolgus monkeys following single and repeated daily subcutaneous administration for up to 2 months. RESULTS: MEDI0382 potently activated rodent, cynomolgus and human GLP-1 and glucagon receptors and exhibited a fivefold bias for activation of GLP-1 receptor versus the glucagon receptor. MEDI0382 produced superior weight loss and comparable glucose lowering to the GLP-1 peptide analogue liraglutide when administered daily at comparable doses in DIO mice. The additional fat mass reduction elicited by MEDI0382 probably results from a glucagon receptor-mediated increase in energy expenditure, whereas food intake suppression results from activation of the GLP-1 receptor. Notably, the significant weight loss elicited by MEDI0382 in DIO mice was recapitulated in cynomolgus monkeys. CONCLUSIONS: Repeated administration of MEDI0382 elicits profound weight loss in DIO mice and non-human primates, produces robust glucose control and reduces hepatic fat content and fasting insulin and glucose levels. The balance of activities at the GLP-1 and glucagon receptors is considered to be optimal for achieving weight and glucose control in overweight or obese Type 2 diabetic patients.

Ultrasound-Guided Liver Biopsy With Gelatin Sponge Pledget Tract Embolization in Infants Weighing Less Than 10 kg.

OBJECTIVES: The aim of the study was to describe and assess the technical success and safety of ultrasound-guided liver biopsy with gelatin sponge pledget tract embolization technique in infants <10 kg across 3 tertiary pediatric hospitals. MATERIALS AND METHODS: There were 67 pediatric patients weighing <10 kg (36 boys; 31 girls; average age 202 days; average weight 6 kg, range 1.5-9.9 kg) referred for liver biopsy performed with ultrasound guidance and gelatin sponge pledget tract embolization during a 2-year period. Patient history, procedural records, and clinical follow-up documents were retrospectively reviewed. RESULTS: A total of 67 procedures were included. There was 100% technical success rate and all samples obtained provided adequate tissue for histological assessment. Average number of 18 G biopsy passes was 3 (range 1-6). There were no procedure-related deaths. There was 1 complication (1%) in a 5-kg infant who was readmitted 36 hours after biopsy with a fever and fully recovered after antibiotics were administered. Biliary atresia was the most common underlying diagnosis (20%), whereas others included acute rejection (16%) and biliary obstruction (7%). CONCLUSIONS: Ultrasound-guided percutaneous liver biopsy with gelatin sponge pledget tract embolization technique in children weighing <10 kg is safe, effective, and use of this technique may lead to a reduction in rates of adverse events reported in other pediatric series.

Raman excess spectroscopy vs. principal component analysis: probing the intermolecular interactions between chiral molecules and imidazolium-based ionic liquids.

Raman spectroscopy is a very sensitive and specific measurement tool for probing intermolecular interaction structures. As imidazolium-based ionic liquids can favorably be used for enantioseparation, in this work two approaches for Raman signal analysis, namely by means of excess spectra and principal component analysis (PCA), are compared to extract detailed information about the interaction structure of the enantiomers d- and l-glucose in an aqueous solution of the ionic liquid [EMIM][EtSO4]. In contrast to the excess calculations, the loadings obtained from PCA lead to significant results since the interactions are weighted by their strength and significance. Moreover, the analysis of the weighted vibrations in the loadings indicate that hydrogen bonds are particularly formed between the ethyl sulphate anion of [EMIM][EtSO4] and the hydrogen atom of the OH-group at the C6-atom of glucose.

Macrophage ADAM17 deficiency augments CD36-dependent apoptotic cell uptake and the linked anti-inflammatory phenotype.

RATIONALE: Apoptotic cell phagocytosis (efferocytosis) is mediated by specific receptors and is essential for resolution of inflammation. In chronic inflammation, apoptotic cell clearance is dysfunctional and soluble levels of several apoptotic cell receptors are elevated. Reports have identified proteolytic cleavage as a mechanism capable of releasing soluble apoptotic cell receptors, but the functional implications of their proteolysis are unclear. OBJECTIVE: To test the hypothesis that ADAM17-mediated cleavage of apoptotic cell receptors limits efferocytosis in vivo. METHODS AND RESULTS: In vivo comparison of macrophage efferocytosis in wild-type and Adam17-null hematopoietic chimeras demonstrates that ADAM17 deficiency leads to a 60% increase in efferocytosis and an enhanced anti-inflammatory phenotype in a model of peritonitis. In vitro uptake of phosphatidylserine liposomes identifies the dual-pass apoptotic cell receptor CD36 as a major contributor to enhanced efferocytosis, and CD36 surface levels are elevated on macrophages from Adam17-null mice. Further, temporal elevation of CD36 expression with inflammation may also contribute to its impact. Soluble CD36 from macrophage-conditioned media comprises 2 species based on Western blotting, and mass spectrometry identifies 3 N-terminal peptides that represent probable cleavage sites. Levels of soluble CD36 are decreased in Adam17-null conditioned media, providing evidence for involvement of ADAM17 in CD36 cleavage. Importantly, enhanced efferocytosis in vivo by macrophages lacking ADAM17 is CD36 dependent and accelerates macrophage clearance from the peritoneum, thus promoting resolution of inflammation and highlighting the impact of increased apoptotic cell uptake. CONCLUSIONS: Our studies demonstrate the importance of ADAM17-mediated proteolysis for in vivo efferocytosis regulation and suggest a possible mechanistic link between chronic inflammation and defective efferocytosis.

Inclusion of Safety Pharmacology Endpoints in Repeat-Dose Toxicity Studies.

Whereas pharmacological responses tend to be fairly rapid in onset and are therefore detectable after a single dose, some diminish on repeated dosing, and others increase in magnitude and therefore can be missed or underestimated in single-dose safety pharmacology studies. Safety pharmacology measurements can be incorporated into repeat-dose toxicity studies, either routinely or on an ad hoc basis. Drivers for this are both scientific (see above) and regulatory (e.g. ICH S6, S7, S9). There are inherent challenges in achieving this: the availability of suitable technical and scientific expertise in the test facility, unsuitable laboratory conditions, use of simultaneous (as opposed to staggered) dosing, requirement for toxicokinetic sampling, unsuitability of certain techniques (e.g. use of anaesthesia, surgical implantation, food restriction), equipment availability at close proximity and sensitivity of the methods to detect small, clinically relevant, changes. Nonetheless, 'fit-for-purpose' data can still be acquired without requiring additional animals. Examples include assessment of behaviour, sensorimotor, visual and autonomic functions, ambulatory ECG and blood pressure, echocardiography, respiratory, gastrointestinal, renal and hepatic function. This is entirely achievable if the safety pharmacology measurements are relatively unobtrusive, both with respect to the animals and to the toxicology study itself. Careful pharmacological validation of any methods used, and establishing their detection sensitivity, is vital to ensure the credibility of generated data.