Experimental and numerical investigations on the impact behaviour of pristine and patch-repaired composite laminates.

The present paper investigates the impact behaviour of both pristine carbon-fibre-reinforced-plastic (CFRP) composite laminates and repaired CFRP laminates. For the patch-repaired CFRP specimen, the pristine CFRP panel specimen has been damaged by cutting out a central disc of the CFRP material and then repaired using an adhesively bonded patch of CFRP to cover the hole. Drop-weight, impact tests are performed on these two types of specimens and a numerical elastic-plastic, three-dimensional damage model is developed and employed to simulate the impact behaviour of both types of specimen. This numerical model is meso-scale in nature and assumes that cracks initiate in the CFRP at a nano-scale, in the matrix around fibres, and trigger sub-micrometre intralaminar matrix cracks during the impact event. These localized regions of intralaminar cracking then lead to interlaminar, i.e. delamination, cracking between the neighbouring plies which possess different fibre orientations. These meso-scale, intralaminar and interlaminar, damage processes are modelled using the numerical finite-element analysis model with each individual ply treated as a continuum. Good agreement is found between the results from the experimental studies and the predictions from the numerical simulations. This article is part of the theme issue 'Nanocracks in nature and industry'.

Sensitivity and specificity of microRNA-122 for liver disease in dogs.

BACKGROUND: Current tests for diagnosing liver disease in dogs are sub-optimal. MicroRNA-122 (miR-122) is a sensitive and specific biomarker of liver injury in humans and rodents. Circulating miR-122 could have utility in identifying dogs with liver disease. OBJECTIVE: Establish the reference interval for miR-122 in healthy dogs and determine performance in a range of dog breeds with liver disease and control animals with non-liver disease. ANIMALS: Stored serum from 120 healthy dogs, 100 dogs with non-liver diseases, and 30 dogs with histologically confirmed liver disease was analyzed. METHODS: Retrospective study. Medical records of dogs with liver disease, non-liver disease and healthy dogs were reviewed. Serum miR-122 concentrations were measured by PCR and compared with the characteristics of the dogs and their conventional clinical measurements. RESULTS: In healthy dogs the 2.5th, 50th, and 97.5th quartiles of miR-122 were 110 (90% CI 80-114), 594 (505-682), and 3312 (2925-5144) copies/µL, respectively. There was no difference between healthy dogs and dogs with non-liver disease (median ± IQR: healthy dogs 609 [327-1014] copies/µL; non-liver disease 607 [300-1351] copies/µL). miR-122 was higher in dogs with liver disease (11 332 [4418-20 520] copies/µL, P < .001 compared to healthy dogs). miR-122 identified dogs with liver disease with high accuracy (receiver operating characteristic area under curve for comparison with healthy dogs: 0.93 [95% CI 0.86-0.99]). The upper limit of normal for healthy dogs (3312 copies/µL) had a sensitivity of 77% and specificity of 97% for identifying liver disease. CONCLUSION AND CLINICAL IMPORTANCE: Liver disease can be sensitively and specifically diagnosed in dogs by measurement of miR-122.

Attending a social event and consuming alcohol is associated with changes in serum microRNA: a before and after study in healthy adults.

PURPOSE: Circulating microRNAs represent a reservoir for biomarker discovery. Our objective was to profile the change in human circulating microRNA associated with recreational use of alcohol at a social event. MATERIAL AND METHODS: Blood was collected from healthy volunteers (N = 16) before and after recreational consumption of alcohol (ethanol). Biochemistry, hematology and ethanol measurements were performed. The change in the serum small RNA fraction was quantified by RNA sequencing. RESULTS: Blood ethanol was undetectable at study entry in all subjects [<10 mg/dL]. After consuming alcohol the median concentration was 89 mg/dL [IQR: 71-138. Min-max 20-175]. There were no changes in biochemistry and hematology parameters. Serum RNA sequencing identified 1371 small RNA species (1305 microRNAs). There were significant increases [adjusted p-value <0.05, fold increase 2 or more] in 265 microRNAs, around a fifth of the total [median fold increase 2.3 [IQR: 2.1-2.5; Max: 3.7]]. miR-185-5p decreased following alcohol exposure [adjusted p-value <0.05, fold decrease 2 or more]. CONCLUSIONS: The microRNA composition of human serum is dynamic and environmental factors may have a significant impact. Within its context of use the fold change 'signal' of a microRNA must be large enough to negate the risk of false results due to background 'noise'.

Long-term adverse effects of paracetamol - a review.

Paracetamol (acetaminophen) is the most commonly used drug in the world, with a long record of use in acute and chronic pain. In recent years, the benefits of paracetamol use in chronic conditions has been questioned, notably in the areas of osteoarthritis and lower back pain. Over the same period, concerns over the long-term adverse effects of paracetamol use have increased, initially in the field of hypertension, but more recently in other areas as well. The evidence base for the adverse effects of chronic paracetamol use consists of many cohort and observational studies, with few randomized controlled trials, many of which contradict each other, so these studies must be interpreted with caution. Nevertheless, there are some areas where the evidence for harm is more robust, and if a clinician is starting paracetamol with the expectation of chronic use it might be advisable to discuss these side effects with patients beforehand. In particular, an increased risk of gastrointestinal bleeding and a small (~4 mmHg) increase in systolic blood pressure are adverse effects for which the evidence is particularly strong, and which show a degree of dose dependence. As our estimation of the benefits decreases, an accurate assessment of the harms is ever more important. The present review summarizes the current evidence on the harms associated with chronic paracetamol use, focusing on cardiovascular disease, asthma and renal injury, and the effects of in utero exposure.

Association of Hypercalcemia Before Treatment With Hypocalcemia After Treatment in Dogs With Primary Hyperparathyroidism.

BACKGROUND: Development of hypocalcemia after treatment of hyperparathyroidism results in increased costs and risk of poorer outcomes. Previous studies have shown conflicting data about predictors of hypocalcemia after these procedures. HYPOTHESIS/OBJECTIVES: The objective of this study was to investigate whether ionized calcium (iCa) concentrations before treatment are predictive of hypocalcemia or its clinical signs after surgical removal or heat ablation in dogs with primary hyperparathyroidism. ANIMALS: Fifty-four dogs with primary hyperparathyroidism (29 female, 25 male; 49 retrospective, 5 prospective). METHODS: Dogs were enrolled if they met the inclusion criteria: persistent hypercalcemia (iCa >1.41 mmol/L) due to primary hyperparathyroidism and absence of preemptive calcitriol treatment. All dogs were treated with parathyroidectomy (n = 37) or percutaneous ultrasound-guided heat ablation (n = 17). After treatment, iCa was monitored twice daily until plateau or intervention. RESULTS: There was a moderate correlation between before-treatment hypercalcemia and after-treatment hypocalcemia. The prospective study was terminated due to ethical concerns given findings in the retrospective section. All dogs were placed into groups according to their pretreatment iCa: 1.46-1.61 mmol/L, 1.62-1.71 mmol/L, iCa 1.72-1.81 mmol/L, or >1.81 mmol/L. After treatment, the mean lowest iCa for each group, respectively, was 1.19, 1.18, 1.13, and 1.01 mmol/L. There was a significant association between higher group and proportion of dogs with iCa <1.00 mmol/L (P = .014). CONCLUSIONS AND CLINICAL IMPORTANCE: This study demonstrates a moderate correlation between iCa concentration before treatment and hypocalcemia after treatment. Dogs with higher initial iCa concentrations should be treated to prevent rapid decline and development of clinical hypocalcemia.

Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.

Acetaminophen (paracetamol-APAP) is the most common cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery (n = 116) and validation (n = 150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that at hospital presentation CYP-metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP-metabolite receiver operating characteristic area under the curve (ROC-AUC): 0.91 (95% confidence interval (CI) 0.83-0.98); ALT ROC-AUC: 0.67 (0.50-0.84); APAP ROC-AUC: 0.50 (0.33-0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP-metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision-making.

Renal extracellular vesicles: from physiology to clinical application.

Urinary extracellular vesicles (uEVs) are released from all regions of the kidney's nephron and from other cells that line the urinary tract. Extracellular vesicles retain proteomic and transcriptomic markers specific to their cell of origin and so represent a potential reservoir for kidney disease biomarker discovery. Exosomes, a subtype of uEVs, are distinguished from other vesicles by features related to their biogenesis within cells: mature multi-vesicular bodies fuse with the cellular membrane to liberate exosomes into the extracellular space. uEVs represent a novel cell signalling mechanism because they can be shuttled to a recipient cell and, through a number of proposed mechanisms, affect the recipient cell's proteome and function. Here we review the current evidence for uEV signalling along the nephron, their role in health and disease of the kidney, and their potential for clinical translation as biomarkers and therapeutics.

Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury.

Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.

Exosome isolation: a microfluidic road-map.

Exosomes, first isolated 30 years ago, are nanoscale vesicles shed by most types of cells. The nucleic acid rich content of these nanoparticles, floating in virtually all bodily fluids, has great potential for non-invasive molecular diagnostics and may represent a novel therapeutic delivery system. However, current isolation techniques such as ultracentrifugation are not convenient and do not result in high purity isolation. This represents an interesting challenge for microfluidic technologies, from a cost-effective perspective as well as for enhanced purity capabilities, and point-of-care acquisition and diagnosis. In this frontier review, we present the current challenges, comment the first microfluidic advances in this new field and propose a roadmap for future developments. This review enables biologists and clinicians familiar with exosome enrichment to assess the performance of novel microfluidic devices and, equally, enables microfluidic engineers to educate themselves about this new class of promising biomarker-rich particles and the challenges arising from their clinical use.

Impact of reducing the threshold for acetylcysteine treatment in acute paracetamol poisoning: the recent United Kingdom experience.

BACKGROUND: On 3 September 2012, the licensed indication for acetylcysteine was changed in the United Kingdom (UK) so that all patients with a plasma paracetamol concentration above a "100 mg/L" (4 h post ingestion) nomogram treatment line after an acute paracetamol (acetaminophen) overdose should be treated. This is a lower threshold than that used in the United States, Canada, Australia, and New Zealand. Here we report the impact of this change in the UK on the management of patients with acute overdose in different paracetamol concentration ranges. METHODS: This is a cohort study, consisting of a retrospective analysis conducted on prospectively collected audit data in three UK hospitals. Following appropriate ethical and data protection authority approval, data for patients presenting within 24 h of an acute timed single paracetamol overdose were extracted. Numbers of admissions and use of antidote in relation to different paracetamol concentration bands (< 100 mg/L; 100-149 mg/L; 150-199 mg/L; and ≥ 200 mg/L at 4 h) were analyzed for one-year periods before and after the change. RESULTS: Comparing the year before with the year after the change, there was no change in the numbers of patients presenting to hospital within 24 h of acute timed paracetamol overdose (1246 before and 1251 after), but more patients were admitted (759 before and 849 after) and treated with acetylcysteine (389 before and 539 after). Of the 150 additional patients treated with acetylcysteine in the year following the change, 114 (76%, 95% CI: 68.4-82.6) were in the 100-149 group and 9 (6.0%, 95% CI: 2.8-11.1) in the 150-199 group. CONCLUSIONS: Changes to national guidelines for managing paracetamol poisoning in the UK have increased the numbers of patients with acute overdose treated with acetylcysteine, with most additional treatments occurring in patients in the 100-149 mg/L dose range, a group at low risk of hepatotoxicity and higher risk of adverse reactions.

Compressive strength after blast of sandwich composite materials.

Composite sandwich materials have yet to be widely adopted in the construction of naval vessels despite their excellent strength-to-weight ratio and low radar return. One barrier to their wider use is our limited understanding of their performance when subjected to air blast. This paper focuses on this problem and specifically the strength remaining after damage caused during an explosion. Carbon-fibre-reinforced polymer (CFRP) composite skins on a styrene-acrylonitrile (SAN) polymer closed-cell foam core are the primary composite system evaluated. Glass-fibre-reinforced polymer (GFRP) composite skins were also included for comparison in a comparable sandwich configuration. Full-scale blast experiments were conducted, where 1.6×1.3 m sized panels were subjected to blast of a Hopkinson-Cranz scaled distance of 3.02 m kg(-1/3), 100 kg TNT equivalent at a stand-off distance of 14 m. This explosive blast represents a surface blast threat, where the shockwave propagates in air towards the naval vessel. Hopkinson was the first to investigate the characteristics of this explosive air-blast pulse (Hopkinson 1948 Proc. R. Soc. Lond. A 89, 411-413 (doi:10.1098/rspa.1914.0008)). Further analysis is provided on the performance of the CFRP sandwich panel relative to the GFRP sandwich panel when subjected to blast loading through use of high-speed speckle strain mapping. After the blast events, the residual compressive load-bearing capacity is investigated experimentally, using appropriate loading conditions that an in-service vessel may have to sustain. Residual strength testing is well established for post-impact ballistic assessment, but there has been less research performed on the residual strength of sandwich composites after blast.

The predictive value of hospital admission serum alanine transaminase activity in patients treated for paracetamol overdose.

BACKGROUND: Paracetamol is a major cause of poisoning. Treatment decisions are predominately based on the dose ingested and a timed blood paracetamol concentration because most patients present to hospital soon after overdose, before hepatotoxicity can be confirmed/excluded using serum alanine transaminase (ALT). Nonetheless, ALT is measured at hospital presentation; we investigated its value in predicting hepatotoxicity. METHODS: From March 2011 to May 2012, patients admitted to the Royal Infirmary of Edinburgh for paracetamol overdose treatment were identified. We determined the value of admission ALT (below or above our upper limit of normal-50 IU/l) at predicting three endpoints: 1-doubling of ALT; 2-peak ALT >1000 IU/l; 3-peak international normalized ratio (INR) >2. RESULTS: From 500 patients, 410 met the entry criteria; 264 presented within 8 h of overdose, 54 between 8 and 24 h, 53 after 24 h and 39 were staggered ingestions. Admission ALT was increased in 71. For endpoint 1 (ALT doubling), the positive predictive value (PPV) of admission ALT was 19% [95% confidence interval (CI) 12-30] with a negative predictive value (NPV) of 98% (95% CI 96-99); endpoint 2 (ALT >1000 IU/l: PPV 23% (95% CI 14-34) and NPV 100% (95% CI 99-100) and for endpoint 3 (INR >2): PPV 14% (95% CI 7-25) and NPV of 100% (95% CI 99-100). The NPV remained high when only late presenters were included. CONCLUSION: Admission ALT within the normal range has a high NPV and could be used, alone or in combination with newer biomarkers, to identify lower risk patients at hospital presentation.

Serum microRNA biomarkers for drug-induced liver injury.

New biomarkers of drug-induced liver injury (DILI) are required in the clinic and in preclinical pharmaceutical evaluation. Liver-enriched microRNAs are promising serum biomarkers of acetaminophen-induced acute liver injury in mice. The utility of circulating microRNAs as biomarkers of human acute DILI is discussed in the context of correlation with existing biomarkers of liver injury and patient outcomes in acetaminophen toxicity, mechanisms of cellular microRNA release, and their potential advantages over current clinical biomarkers of DILI.

Pediatric cervical kyphosis: a comparison of arthrodesis techniques.

STUDY DESIGN: Retrospective study. OBJECTIVE: To compare arthrodesis techniques for pediatric cervical kyphosis. SUMMARY OF BACKGROUND DATA: Cervical kyphosis is rare in the pediatric population. The most common etiologies are acquired instabilities or an underlying syndrome. The largest pediatric case series in the literature describes the treatment of nine patients. METHODS: A retrospective review was performed of pediatric patients treated for cervical kyphosis with posterior spinal fusion (PSF), anterior spinal fusion (ASF) with strut graft, or anteroposterior fusion with strut graft (A/PSF). Patients were divided into groups on the basis of the etiology of the kyphosis. Group 1 was composed of patients with acquired instability, either traumatic or postlaminectomy. Group 2 was composed of patients with syndromic deformity. RESULTS: Twenty-four patients were identified: 9 in group 1 and 15 in group 2. Arthrodesis techniques performed in group 1 were 2 PSF, 2 ASF, and 5 A/PSF and in group 2 were 11 PSF, 0 ASF, and 4 A/PSF. Primary union was achieved in all group 1 patients with no major complications. Pseudarthrosis and other major complications were frequent in group 2. Among syndromic patients (group 2) treated with primary PSF (11 patients), the mean immediate postoperative kyphosis was 32° in seven patients who achieved primary union and 77° in four patients with pseudarthrosis who required reoperation (P = 0.022); two of these four patients with pseudarthrosis developed late myelopathy with an episode of transient quadriparesis. Primary union was achieved in three of four syndromic patients with A/PSF; pseudarthrosis occurred in the patient with Gorham's disease. CONCLUSION: Arthrodesis was effective without major complications in nonsyndromic kyphosis. Complications were frequent in syndromic kyphosis. There was a significant association of greater residual kyphosis with pseudarthrosis in syndromic patients treated with PSF alone. Circumferential arthrodesis with strut grafting may decrease pseudarthrosis risk in syndromic patients with severe, rigid kyphosis. PSF alone may be sufficient in syndromic patients with flexible kyphosis when adequate postoperative correction is achieved.

Setting the stage for acute-on-chronic kidney injury.

Acute-on-chronic kidney disease will be familiar to many nephrologists. Hsu et al. quantify the risk of acute-on-chronic disease across the stages of preexisting chronic kidney disease. Their study demonstrates the valuable insights that large epidemiological studies can bring to the field of acute kidney injury.