Choosing wisely in burn care.

BACKGROUND: The Choosing Wisely Campaign was launched in 2012 and has been applied to a broad spectrum of disciplines in almost thirty countries, with the objective of reducing unnecessary or potentially harmful investigations and procedures, thus limiting costs and improving outcomes. In Canada, patients with burn injuries are usually initially assessed by primary care and emergency providers, while plastic or general surgeons provide ongoing management. We sought to develop a series of Choosing Wisely statements for burn care to guide these practitioners and inform suitable, cost-effective investigations and treatment choices. METHODS: The Choosing Wisely Canada list for Burns was developed by members of the Canadian Special Interest Group of the American Burn Association. Eleven recommendations were generated from an initial list of 29 statements using a modified Delphi process and SurveyMonkey™. RESULTS: Recommendations included statements on avoidance of prophylactic antibiotics, restriction of blood products, use of adjunctive analgesic medications, monitoring and titration of opioid analgesics, and minimizing 'routine' bloodwork, microbiology or radiological investigations. CONCLUSIONS: The Choosing Wisely recommendations aim to encourage greater discussion between those involved in burn care, other health care professionals, and their patients, with a view to reduce the cost and adverse effects associated with unnecessary therapeutic and diagnostic procedures, while still maintaining high standards of evidence-based burn care.

A third of referrals are unnecessary: Critical review of burn outpatient clinic data.

OBJECTIVES: The purpose of this study was to establish patterns in types of burns referred to the Outpatient Clinic (OP) at Vancouver General Hospital (VGH). METHODS: A 2-year retrospective chart review was conducted of patients presenting to the OP Clinic from June 1, 2016 - June 1, 2018. Data collected included: patient demographics, depth of burn, Total Body Surface Area (TBSA), anatomical location of burn, geographical location of referral, and operative versus non-operative management. RESULTS: The OP Clinic served 470 patients for burn injuries with a total of 1852 visits. Of these, 20% were follow-up visits post-admission, and 73.6% were primary referrals from the emergency department (ED) or elsewhere. The vast majority (69.6%) of burns were less than 5% TBSA. Half involved the hands (50.9%), and half were superficial dermal in depth (45.1%). A third of patients attended only one appointment with the OP Clinic before discharge and 15% did not receive any treatment. CONCLUSIONS: The results of our study demonstrate gaps in current provincial referral guidelines leading to a significant number of "unnecessary referrals." Further research could correlate the results to current provincial referral guidelines to estimate their current efficacy in practical use.

Radiological criteria for atypical features of femur fractures: what we can learn when applied in a clinical study setting.

The paper focuses on the identification of atypical fractures (AFFs). This paper examines the concordance between objective classification and expert subjective review. We believe the paper adds critical information about how to apply the American Society of Bone and Mineral Research (ASBMR) criteria to diagnose AFFs and is of high interest to the field. INTRODUCTION: Assess American Society of Bone and Mineral Research (ASBMR) criteria for identifying atypical femoral fractures (AFFs). METHODS: Two orthopedic surgeons independently evaluated radiographs of 372 fractures, applying ASBMR criteria. We assessed ease of applying ASBMR criteria and whether criteria-based assessment matched qualitative expert assessment. RESULTS: There was up to 27% uncertainty about how to classify specific features. 84% of films were classified similarly for the presence of AFF according to ASBMR criteria; agreement increased to 94% after consensus meeting. Of 37 fractures categorized as AFFs based on ASBMR criteria, 23 (62.2%) were considered AFFs according to expert assessment (not relying on criteria). Only one (0.5%) femoral shaft fracture that did not meet ASBMR criteria was considered an AFF per expert assessment. The number of major ASBMR features present (four vs five) and whether there was periosteal or endosteal thickening ("beaking" or "flaring") played major roles in the discrepancies between ASBMR criteria-based and expert-based determinations. CONCLUSIONS: ASBMR AFF criteria were useful for reviewers but several features were difficult to interpret. Expert assessments did not agree with the ASBMR classification in almost one-third of cases, but rarely identified an AFF when a femoral shaft fracture did not meet ASBMR AFF criteria. Experts identified lateral cortical transverse fracture line and associated new-bone formation along with no or minimal comminution as crucial features necessary for the definition of atypical femoral fractures.

Multiple vertebral fractures following osteoporosis treatment discontinuation: a case-report after long-term Odanacatib.

INTRODUCTION: Case reports of women sustaining multiple vertebral fractures (VF) soon afterdenosumab discontinuation are accumulating. METHODS: We report a woman with five new vertebral fractures in ~8 months following discontinuation of long-term odanacatib (ODN), an experimental cathepsin K inhibitor. RESULTS: DXA examination demonstrated an ~12% decline in bone mineral density (BMD) and ~9% decline in trabecular bone score (TBS) since ODN discontinuation. Laboratory evaluation did not reveal a secondary cause of bone loss. CONCLUSIONS: This case mimics observations following denosumab discontinuation, but, to our knowledge, is the first reported with ODN and the first documenting substantial decline in TBS. While not directly clinically relevant as ODN is no longer being developed, this case raises the possibility that a syndrome of multiple vertebral fractures could follow discontinuation of various potent osteoporosis therapies that produce major BMD increases but do not have persisting bone effects (i.e., all non-bisphosphonates). Use of antiresorptive therapies to prevent rapid bone loss following discontinuation of potent bone active agents seems appropriate. Identification of those patients who could be at risk for the multiple VF syndrome is needed.

Transcriptomic variation of pharmacogenes in multiple human tissues and lymphoblastoid cell lines.

Variation in the expression level and activity of genes involved in drug disposition and action ('pharmacogenes') can affect drug response and toxicity, especially when in tissues of pharmacological importance. Previous studies have relied primarily on microarrays to understand gene expression differences, or have focused on a single tissue or small number of samples. The goal of this study was to use RNA-sequencing (RNA-seq) to determine the expression levels and alternative splicing of 389 Pharmacogenomics Research Network pharmacogenes across four tissues (liver, kidney, heart and adipose) and lymphoblastoid cell lines, which are used widely in pharmacogenomics studies. Analysis of RNA-seq data from 139 different individuals across the 5 tissues (20-45 individuals per tissue type) revealed substantial variation in both expression levels and splicing across samples and tissue types. Comparison with GTEx data yielded a consistent picture. This in-depth exploration also revealed 183 splicing events in pharmacogenes that were previously not annotated. Overall, this study serves as a rich resource for the research community to inform biomarker and drug discovery and use.

Retrospective study on the distribution of Dirofilaria immitis in dogs in Hungary.

Europe has experienced the spreading of vector-borne helminths including heartworms (Dirofilaria immitis) from the Mediterranean countries towards the northern ones in the past decades. Recently, the establishment of D. immitis was confirmed in Hungary on the basis of period prevalence studies involving dogs, red foxes (Vulpes vulpes) and golden jackals (Canis aureus). The aim of our retrospective study was to describe the spatial distribution of the parasite and the time course of spreading of D. immitis in Hungary. Necropsy records of 2622 dogs received at our laboratories from 2001 to 2015 were reviewed for heartworm infections. The locality of origin of animals was recorded in a geographic information system database and compared to the results of the period prevalence study involving wild canids. Autochthonous heartworm infection was detected in 27 dogs. The time course analysis indicates that the parasite established in Hungary in 2007. As temperature is one of the most important determinants of the distribution of D. immitis, the climate of the Great Hungarian Plain is the most suitable region for the establishment of D. immitis in Hungary. Our studies revealed that the Great Hungarian Plain became a D. immitis endemic region for 2015. Nevertheless, sporadic cases in wild canids and dogs also occur in other regions of the country.

Nanopatterning reconfigurable magnetic landscapes via thermally assisted scanning probe lithography.

The search for novel tools to control magnetism at the nanoscale is crucial for the development of new paradigms in optics, electronics and spintronics. So far, the fabrication of magnetic nanostructures has been achieved mainly through irreversible structural or chemical modifications. Here, we propose a new concept for creating reconfigurable magnetic nanopatterns by crafting, at the nanoscale, the magnetic anisotropy landscape of a ferromagnetic layer exchange-coupled to an antiferromagnetic layer. By performing localized field cooling with the hot tip of a scanning probe microscope, magnetic structures, with arbitrarily oriented magnetization and tunable unidirectional anisotropy, are reversibly patterned without modifying the film chemistry and topography. This opens unforeseen possibilities for the development of novel metamaterials with finely tuned magnetic properties, such as reconfigurable magneto-plasmonic and magnonic crystals. In this context, we experimentally demonstrate spatially controlled spin wave excitation and propagation in magnetic structures patterned with the proposed method.

Disparities in osteoporosis treatments.

UNLABELLED: Osteoporosis treatment rates within 2 years following an index event (fragility fracture, osteoporotic bone mineral density (BMD) T-score, or osteoporosis ICD-9 codes) were determined from 2005 to 2011. Most patients were not treated. Fracture patients had the lowest treatment rate. Low treatment rates also occurred in patients that were male, black, or had non-commercial insurance. INTRODUCTION: Clinical recognition of osteoporosis (osteoporotic BMD, assignment of an ICD-9 code, or the occurrence of fragility fractures) provides opportunities to treat patients at risk for future fracture. METHODS: A cohort of 36,965 patients was identified from 2005 to 2011 in the Indiana Health Information Exchange, with index events after age 50 of either non-traumatic fractures, an osteoporosis ICD-9 code, or a BMD T-score ≤ -2.5. Patients with osteoporosis treatment in the preceding year were excluded. Medication records during the ensuing 2 years were extracted to identify osteoporosis treatments, demographics, comorbidities, and co-medications. Predictors of treatment were evaluated in a multivariable logistic regression model. RESULTS: The cohort was 78 % female, 11 % black, 91 % urban-dwelling, and 53 % commercially insured. The index events were as follows: osteoporosis diagnosis (47 % of patients), fragility fracture (44 %), and osteoporotic T-scores (9 %). Within 2 years after the index event, 23.3 % received osteoporosis medications (of which, 82.2 % were oral bisphosphonates). Treatment rates were higher after osteoporosis diagnosis codes (29.3 %) or osteoporotic T-score (53.9 %) than after fracture index events (10.5 %) (p < 0.001). Age had an inverted U-shaped effect for women with highest odds around 60-65 years. Women (OR 1.86) and non-black patients (OR 1.52) were more likely to be treated (p < 0.001). Patients with public (versus commercial) insurance (OR 0.86, p < 0.001) or chronic comorbidities (ORs about 0.7-0.9, p < 0.001) were less likely to be treated. CONCLUSION: Most osteoporosis treatment candidates remained untreated. Men, black patients, and patients with fracture or chronic comorbidities were less likely to receive treatment, representing disparity in the recognition and treatment of osteoporosis.

[Accuracy and relevance of CT volumetry in open ocular injuries with intraocular foreign bodies]. / Genauigkeit und Relevanz der CT-Volumetrie bei offenen Bulbusverletzungen mit intraokularen Fremdkörpern.

BACKGROUND/OBJECTIVES: The aim of the study was to evaluate the volume of intraocular foreign bodies (IOFB) using computed tomography (CT) volumetry as a prognostic factor for clinical outcome in open ocular injuries. PATIENTS AND METHODS: This study compared the volume of 11 IOFBs more than 5 mm(3) in size based on CT volumetry with the real size determined by in vitro measurement. A retrospective evaluation of clinical data, visual acuity, complications and relation of size of IOFBs with clinical outcome in 33 patients (mean age 41.0 ± 13.5 years) with open ocular injuries treated at our department between January 2005 and December 2010 was carried out. RESULTS: No significant differences were found between pairwise in vitro measurement and CT volumetric size (p = 0.07). All patients were surgically treated by pars plana vitrectomy. The mean follow-up time was 7.6± 6.2 months and the mean preoperative best corrected visual acuity (BCVA) was 0.063 ± 0.16 (logMAR 1.2 ± 0.79). Postoperatively, a mean BCVA of 0.25 ± 0.2 (logMAR 0.6 ± 0.69) could be achieved. Clinical outcomes were significantly better in injuries with small IOFBs measuring < 15 mm(3) (p = 0.0098). CONCLUSIONS: The use of CT volumetry is an accurate method for measurement of IOFBs. Exact data about the size and measurement of volume are also an important factor for the prognosis of clinical outcome in open ocular injuries with IOFBs and CT volumetry can also provide important information about the localization of IOFBs.

Erlotinib in African Americans with advanced non-small cell lung cancer: a prospective randomized study with genetic and pharmacokinetic analyses.

Prospective studies on epidermal growth factor receptor (EGFR) inhibitors in African Americans with non-small cell lung cancer (NSCLC) have not previously been performed. In this phase II randomized study, 55 African Americans with NSCLC received 150 mg/day erlotinib or a body weight-adjusted dose with subsequent escalations to the maximum-allowable dose, 200 mg/day, to achieve rash. Erlotinib and OSI-420 exposures were lower than those observed in previous studies, consistent with CYP3A pharmacogenetics implying higher metabolic activity. Tumor genetics showed only two EGFR mutations, EGFR amplification in 17/47 samples, eight KRAS mutations, and five EML4-ALK translocations. Although absence of rash was associated with shorter time to progression (TTP), disease-control rate, TTP, and 1-year survival were not different between the two dose groups, indicating the dose-to-rash strategy failed to increase clinical benefit. Low incidence of toxicity and low erlotinib exposure suggest standardized and maximum-allowable dosing may be suboptimal in African Americans.

Cholesteryl ester transfer protein polymorphisms, statin use, and their impact on cholesterol levels and cardiovascular events.

The association of nonfunctional variants of the cholesteryl ester transfer protein (CETP) with efficacy of statins has been a subject of debate. We evaluated whether three functional CETP variants influence statin efficacy. The effect of CETP genotype on achieved levels of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), and total cholesterol during statin treatment was estimated by meta-analysis of the linear regression outcomes of three studies (11,021 individuals). The effect of these single-nucleotide polymorphisms (SNPs) on statin response in protecting against myocardial infarction (MI) was estimated by meta-analysis of statin × SNP interaction terms from logistic regression in five studies (16,570 individuals). The enhancer SNP rs3764261 significantly increased HDLc by 0.02 mmol/l per T allele (P = 6 × 10(-5)) and reduced protection against MI by statins (interaction odds ratio (OR) = 1.19 per T allele; P = 0.04). Focusing on functional CETP variants, we showed that in carriers of the rs3764261 T variant, HDLc increased more during statin treatment, and protection against MI by statins appeared to be reduced as compared with those in noncarriers.

Profiling solute carrier transporters in the human blood-brain barrier.

The neuroprotective function of the blood-brain barrier (BBB) presents a major challenge for drug delivery to the central nervous system (CNS). Critical to this function, BBB membrane transporters include the ATP-binding cassette (ABC) transporters, which limit drug penetration across the BBB, and the less-well-studied solute carrier (SLC) transporters. In this work, expression profiling of 359 SLC transporters, comparative expression analysis with kidney and liver, and immunoassays in brain microvessels (BMVs) identified previously unknown transporters at the human BBB.

Studies on the detection of concealed objects using the neutron reflection method.

The increment of reflected thermal and 1.45 eV resonance neutrons vs. the thickness of the reflector has been measured and described by an analytical expression. Macroscopic, Σß, and microscopic, σß, reflection cross sections averaged over the bulk reflector substances were deduced for some elements and compounds. It was found that the σß values are additive even for bulk samples and so the σßmol could be given for some illicit drugs, explosives and hiding materials.

Allelic mRNA expression imbalance in C-type lectins reveals a frequent regulatory SNP in the human surfactant protein A (SP-A) gene.

Genetic variation in C-type lectins influences infectious disease susceptibility but remains poorly understood. We used allelic mRNA expression imbalance (AEI) technology for surfactant protein (SP)-A1, SP-A2, SP-D, dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN), macrophage mannose receptor (MRC1) and Dectin-1, expressed in human macrophages and/or lung tissues. Frequent AEI, an indicator of regulatory polymorphisms, was observed in SP-A2, SP-D and DC-SIGN. AEI was measured for SP-A2 in 38 lung tissues using four marker single-nucleotide polymorphisms (SNPs) and was confirmed by next-generation sequencing of one lung RNA sample. Genomic DNA at the SP-A2 DNA locus was sequenced by Ion Torrent technology in 16 samples. Correlation analysis of genotypes with AEI identified a haplotype block, and, specifically, the intronic SNP rs1650232 (30% minor allele frequency); the only variant consistently associated with an approximately twofold change in mRNA allelic expression. Previously shown to alter a NAGNAG splice acceptor site with likely effects on SP-A2 expression, rs1650232 generates an alternative splice variant with three additional bases at the start of exon 3. Validated as a regulatory variant, rs1650232 is in partial linkage disequilibrium with known SP-A2 marker SNPs previously associated with risk for respiratory diseases including tuberculosis. Applying functional DNA variants in clinical association studies, rather than marker SNPs, will advance our understanding of genetic susceptibility to infectious diseases.

Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene-environment interaction.

Epistatic gene-gene interactions could contribute to the heritability of complex multigenic disorders, but few examples have been reported. Here, we focus on the role of aberrant dopaminergic signaling, involving the dopamine transporter DAT, a cocaine target, and the dopamine D2 receptor, which physically interacts with DAT. Splicing polymorphism rs2283265 of DRD2, encoding D2 receptors, were shown to confer risk of cocaine overdose/death (odds ratio ∼3) in subjects and controls from the Miami Dade County Brain Bank.(1) Risk of cocaine-related death attributable to the minor allele of rs2283265 was significantly enhanced to OR=7.5 (P=0.0008) in homozygous carriers of the main 6-repeat allele of DAT rs3836790, a regulatory VNTR in intron8 lacking significant effect itself. In contrast, carriers of the minor 5-repeat DAT allele showed no significant risk (OR=1.1, P=0.84). DAT rs3836790 and DRD2 rs2283265 also interacted by modulating DAT protein activity in the ventral putamen of cocaine abusers. In high-linkage disequilibrium with the VNTR, DAT rs6347 in exon9 yielded similar results. Assessing the impact of DAT alone, a rare DAT haplotype formed by the minor alleles of rs3836790 and rs27072, a regulatory DAT variant in the 3'-UTR, occurred in nearly one-third of the cocaine abusers but was absent in African American controls, apparently conferring strong risk. These results demonstrate gene-gene-drug interaction affecting risk of fatal cocaine intoxication.

Repeated simultaneous cortical electrophysiological and behavioral recording in rats exposed to manganese-containing nanoparticles.

Male Wistar rats wearing chronically implanted cortical electrodes were exposed to Mn-containing nanoparticles via the airways for 8 weeks following a 2-week pre-exposure period. The rats' cortical electrical activity and open field motility was recorded simultaneously, in weekly repetitions. It was supposed that this technique can provide better insight in the development of Mn-induced CNS damage. Decreased motility (less distance covered, longer periods of immobility) and increased total power of cortical electrical activity developed in parallel in the first 4-5 weeks of treatment but showed little change afterwards. Both the behavioral and the electrophysiological effect were in fair correlation with the rats' internal Mn exposure determined from brain samples. The results confirmed the non-linear dose- and time-dependence of Mn effects suggested by previous studies. Repeated simultaneous behavioral and electrophysiological recording during a longer treatment with neurotoxic metals (or other xenobiotics) seems to be a promising method.

A new experimental method for hiatal reinforcement using connective tissue patch transfer.

The closure of a large hiatal hernia still represents a challenge for the surgeon. Mesh reinforcement of a hiatoplasty generally decreases recurrence rate. An artificial mesh is cheaper compared with a biologic one, but has a higher complication rate. Our aim was to introduce a new biologic reinforcement method with less expenses. During organ donation for transplantation, tissue islets from pericardium and fascia lata were cryopreserved in a tissue bank. Later, the grafts were transplanted on the diaphragm of mongrel dogs. After 1, 3, and 6 months, the animals were sacrificed, and the transplanted patches were macroscopically and microscopically examined. There were no macroscopic signs of inflammation, abcedation, or significant adhesion formation. The grafts were well recognizable, with palpable thickening and moderate shrinkage. Microscopically, an organization process with fibrosis, neovascularization, and peritoneal integration could be observed. Reinforcement of a hiatoplasty with connective tissue transfer either with cryopreserved or autologous tissue is a good option. This is a cheap and easy method, which should also be tested in human interventions.

Alendronate and atrial fibrillation: a meta-analysis of randomized placebo-controlled clinical trials.

UNLABELLED: In this meta-analysis of all Merck-conducted, placebo-controlled clinical trials of alendronate, the occurrence of AF was uncommon, with most studies reporting two or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious AF was observed. INTRODUCTION: To explore the incidence of atrial fibrillation (AF) and other cardiovascular endpoints in clinical trials of alendronate. METHODS: All double-blind, placebo-controlled studies of alendronate 5, 10, or 20 mg daily, 35 mg once-weekly, 35 mg twice-weekly, and 70 mg once-weekly of at least 3 months duration conducted by Merck were included in this meta-analysis. The primary method of analysis was exact Poisson regression. Estimated relative risk (RR) of alendronate versus placebo and the associated 95% confidence interval was derived from a model that included number of episodes with factors for treatment group and study and an offset parameter for number of person-years on study. RESULTS: Of 41 studies considered, 32 met all criteria for inclusion in the analysis (participants-9,518 alendronate, 7,773 placebo). Estimated RR for all AF events was 1.16 (95% CI = 0.87, 1.55; p = 0.33). Most trials had two or fewer AF events. The RR of AF classified as a serious adverse event was 1.25 (95% CI = 0.82, 1.93; p = 0.33), but became 0.97 (95% CI = 0.51, 1.85) when the clinical fracture cohort of the Fracture Intervention Trial was excluded, indicating that results were driven by events in that study. Estimated RRs for other cardiovascular endpoints were less than 1. CONCLUSIONS: The incidence of atrial fibrillation was low in Merck clinical trials of alendronate and was not significantly increased in any single trial nor in the meta-analysis. Based on this analysis, alendronate use does not appear to be associated with an increased risk of atrial fibrillation.

Short-term in vivo precision of BMD and parameters of trabecular architecture at the distal forearm and tibia.

UNLABELLED: In vivo hr-pQCT precision was determined in 42 postmenopausal women using double baseline measurements from a multicenter trial of odanacatib. Errors, e.g., at the radius below 1.3% for BMD and below 6.3% for trabecular structure, were comparable to single-center results. Motion artifacts remain a challenge, particularly at the forearm. INTRODUCTION: The short-term in vivo precision of BMD, trabecular bone structure, cortical thickness and porosity of the forearm and tibia was measured by hr-pQCT. Also the effect of image quality on precision was evaluated. METHODS: In 42 postmenopausal women (age 64.4 ± 6.8 years) out of 214 subjects enrolled in a multi center advanced imaging phase III study of odanacatib (DXA spine or hip T-scores between -1.5 and -3.5), double baseline hr-pQCT (XtremeCT) measurements with repositioning were performed. The standard ultradistal location and a second, more proximally located VOI were measured at the radius and tibia to better assess cortical thickness and porosity. Image analysis and quality grading (grades: perfect, slight artifacts, pronounced artifacts, unacceptable) were performed centrally. RESULTS: At the radius RMS%CV values varied from 0.7% to 1.3% for BMD and BV/TV and from 5.6% to 6.3% for Tb.Sp, Tb.Th, Tb.N, and cortical porosity. Numerically at the tibia, precision errors were approx. 0.5% lower for BMD and 1% to 2% lower for structural parameters although most differences were insignificant. In the radius but not in the tibia, precision errors for cortical thickness were smaller at the distal compared to the ultradistal location (1% versus 2%). CONCLUSIONS: BMD precision errors were lower than those for trabecular architecture and cortical porosity. Motion artifacts remain a challenge, particularly at the forearm. Quality grading remains subjective, and more objective evaluation methods are needed. Precision in the context of a multicenter clinical trial, with centralized training and scan analysis, was comparable to single-center results previously reported.