Long-Term Safety and Efficacy of Transcatheter Microwave and Radiofrequency Denervation in a Chronic Ovine Model.

BACKGROUND: Transcatheter renal denervation (RDN) has had inconsistent efficacy and concerns for durability of denervation. We aimed to investigate long-term safety and efficacy of transcatheter microwave RDN in vivo in normotensive sheep in comparison to conventional radiofrequency ablation. METHODS AND RESULTS: Sheep underwent bilateral RDN, receiving 1 to 2 microwave ablations (maximum power of 80-120 W for 240 s-480 s) and 12 to 16 radiofrequency ablations (180 s-240 s) in the main renal artery in a paired fashion, alternating the side of treatment, euthanized at 2 weeks (acute N=15) or 5.5 months (chronic N=15), and compared with undenervated controls (N=4). Microwave RDN produced substantial circumferential perivascular injury compared with radiofrequency at both 2 weeks [area 239.8 (interquartile range [IQR] 152.0-343.4) mm2 versus 50.1 (IQR, 32.0-74.6) mm2, P <0.001; depth 16.4 (IQR, 13.9-18.9) mm versus 7.5 (IQR, 6.0-8.9) mm P <0.001] and 5.5 months [area 20.0 (IQR, 3.4-31.8) mm2 versus 5.0 (IQR, 1.4-7.3) mm2, P=0.025; depth 5.9 (IQR, 1.9-8.8) mm versus 3.1 (IQR, 1.2-4.1) mm, P=0.005] using mixed models. Renal denervation resulted in significant long-term reductions in viability of renal sympathetic nerves [58.9% reduction with microwave (P=0.01) and 45% reduction with radiofrequency (P=0.017)] and median cortical norepinephrine levels [71% reduction with microwave (P <0.001) and 72.9% reduction with radiofrequency (P <0.001)] at 5.5 months compared with undenervated controls. CONCLUSIONS: Transcatheter microwave RDN produces deep circumferential perivascular ablations without significant arterial injury to provide effective and durable RDN at 5.5 months compared with radiofrequency RDN.

Comparison of different methods used in drugs of abuse for sample validity testing including pH methods, specific gravity methods, TECO™ Drug Adulteration Test Strip and oxidant assay.

Objectives: In the absence of sample validity testing, a healthcare provider may fail to identify a patient's adulteration of their urine sample. This study compared different methods for specific gravity (SG), pH, TECO™ Drug Adulteration Test Strip (dipstick) and oxidant assay to explain the differences and also make an informative decision on method selection. Methods: Creatinine, SG and pH measurements are essential in sample validity testing. SG and pH automated chemical methods are compared against pH meter method, SG refractometer and dipstick method. Also, oxidant assay was compared against dipstick method. Results: SG chemical method agreement with refractometer is 81.9% and with dipstick method is 64.7%. The refractometer method agreement with dipstick method is 66.1%. pH chemical method agreement with pH Meter method is 74.3% and with dipstick method is 81.4%. pH meter method agreement is 85.7% with dipstick method. Results were analysed using Deming regression analysis and F-test. SG chemical method correlated better with refractometer than the dipstick method. Oxidant assay correlated well with dipstick method in detecting adulterants such as pyridinium chlorochromate, nitrite and bleach. Conclusions: Varying degrees of differences were seen in the SG and pH measurements. These differences were both method and instrument dependent. The automated chemical methods are recommended alongside oxidant assay for consistency, accuracy and faster turn-around time as part of sample validity testing for drugs of abuse.

Big data and artificial intelligence in future patient management. How is it all started? Where are we at now? Quo tendimus?

Background: This article is focused on the understanding of the key points and their importance and impact on the future of early disease predictive models, accurate and fast diagnosis, patient management, optimise treatment, precision medicine, and allocation of resources through the applications of Big Data (BD) and Artificial Intelligence (AI) in healthcare. Content: BD and AI processes include learning which is the acquisition of information and rules for using the information, reasoning which is using rules to reach approximate or definite conclusions and self-correction. This can help improve the detection of diseases, rare diseases, toxicity, identifying health system barriers causing under-diagnosis. BD combined with AI, Machine Learning (ML), computing and predictive-modelling, and combinatorics are used to interrogate structured and unstructured data computationally to reveal patterns, trends, potential correlations and relationships between disparate data sources and associations. Summary: Diagnosis-assisted systems and wearable devices will be part and parcel not only of patient management but also in the prevention and early detection of diseases. Also, Big Data will have an impact on payers, devise makers and pharmaceutical companies. BD and AI, which is the simulation of human intelligence processes, are more diverse and their application in monitoring and diagnosis will only grow bigger, wider and smarter. Outlook: BD connectivity and AI of diagnosis-assisted systems, wearable devices and smartphones are poised to transform patient and to change the traditional methods for patient management, especially in an era where is an explosion in medical data.

Comparison of several immunoassays used in drugs of abuse screening: Assessment against gold standard methods and calculation of measurement uncertainty.

BACKGROUND: Immunoassays provide simple, powerful and inexpensive screening methods for urine drug screening. Other substances and/or factors may interfere with the test and cause false or positive results. It is essential to understand the differences between methods to be able to evaluate their impact on the results. All evaluated immunoassays were assessed in comparison with GC-MS or LC-MS/MS, which are generally accepted as vigorous confirmation gold standard techniques. METHODS: CEDIA, DRI, EIA and EMIT II Plus screening immunoassays were evaluated on Beckman-Coulter AU5810 analyser. All results were confirmed using GC-MS or LC-MS/MS methods. Measurement Uncertainty for immunoassays was calculated by using standard deviation multiplied by 1.96 to cover 95% confidence interval of tested samples. RESULTS: No discrepancy was found between CEDIA and EMIT II Plus for cocaine, methadone, heroin, and benzodiazepines assays. No discrepancy was found between oxycodone DRI assay and Immunalysis enzyme immunoassay (EIA). Cannabinoids EMIT II Plus assay performed better than DRI assay. EMIT II Plus assays for amphetamine and ecstasy performed better than CEDIA amphetamine/ecstasy combined assay. Opiates EMIT II Plus assay performed better than CEDIA assay. Fentanyl Ark EIA method performed slightly better than the DRI method. Buprenorphine CEDIA second-generation assay performed better than CEDIA first-generation assay, EMIT II Plus assay and EMIT II Plus with added Beta-Glucuronidase assay. Measurement Uncertainty for immunoassays was calculated and tabulated. CONCLUSIONS: This study covered a fundamental gap in available knowledge by evaluating the performance of screening the current new generation of immunoassays methods for drugs of abuse in urine against gold standard methods.

Transvascular Pacing of Aorticorenal Ganglia Provides a Testable Procedural Endpoint for Renal Artery Denervation.

OBJECTIVES: This study sought to develop a method to assess renal sympathetic nerve function through localization and pacing of aorticorenal ganglia (ARG). BACKGROUND: Transcatheter renal denervation procedures often fail to produce complete renal denervation because of the lack of a physiological procedural endpoint. METHODS: High-frequency pacing was performed in the inferior vena cava and aorta in sheep (n = 19) to identify ARG pace-capture sites. Group A (n = 5) underwent injection at the ARG pace-capture site for histological verification, group B (n = 6) underwent unilateral irrigated radiofrequency ablation of ARG pace-capture sites and assessment of renal innervation at 1 week post-procedure; and group C (n = 8) underwent ARG pacing before and 2 to 3 weeks after unilateral microwave renal denervation. RESULTS: ARG pace-capture responses were observed at paired discrete sites above the ipsilateral renal artery eliciting a change in mean arterial blood pressure of 22.2 (interquartile range [IQR]: 15.5 to 34.3 mm Hg; p < 0.001) with concurrent ipsilateral renal arterial vasoconstriction, change in main renal artery diameter of -0.42 mm (IQR: -0.64 to -0.24 mm; p < 0.0001), and without consistent contralateral renal vasoconstriction. Sympathetic ganglionic tissue was observed at ARG pace-capture sites, and ganglion ablation led to significant ipsilateral renal denervation. Circumferential renal denervation resulted in immediate and sustained abolition of ARP pacing-induced renal vasoconstriction and significant ipsilateral renal denervation. CONCLUSIONS: Transvascular ARG pace-capture is feasible and recognized by concurrent hypertensive and ipsilateral renal arterial vasoconstrictive responses. Abolition of ARG pacing-induced vasoconstriction may indicate successful renal sympathetic denervation and serve as a physiological procedural endpoint to guide transcatheter renal denervation.

Transcatheter microwave ablation can deliver deep and circumferential perivascular nerve injury without significant arterial injury to provide effective renal denervation.

BACKGROUND: Clinical studies of transcatheter radiofrequency renal denervation for treating hypertension have been hampered by the lack of consistent denervation efficacy. We aimed to demonstrate the short-term efficacy and safety of transcatheter microwave renal denervation. METHODS: A novel 7F microwave system was validated in a sheep model of unilateral renal denervation. Up to two microwave ablations were delivered to each artery with maximum power at 100-110 W for 480 s. RESULTS: Catheter deployment and ablation was successful in all 19 targeted vessel segments, and ablation produced substantial circumferential perivascular injury; median ablation lesion area greater than 395 [interquartile range (IQR) 251-437] mm, depth 17.1 (IQR 15.8-18.4) mm, length 16 (IQR 12-20) mm, without collateral visceral injury. Limiting power to 100 W minimized arterial injury, while maintaining a deep circumferential perivascular ablation. Microwave denervation reduced median functional sympathetic nerve surface area at the renal hilum on antityrosine hydroxylase staining by 100% (IQR 87-100%, P = 0.0039), and median renal cortical norepinephrine content by 83% (IQR 76-92%, P = 0.0078), compared to the paired control kidney at 2-3 weeks postprocedure. CONCLUSION: Transcatheter microwave ablation can produce deep circumferential perivascular ablations over a long segment of the renal artery without significant arterial or collateral visceral injury to provide effective renal denervation.

Iodine deficiency in women of childbearing age: not bread alone?

BACKGROUND AND OBJECTIVES: Iodine deficiency remains a public health concern, particularly in pregnant women and those planning pregnancy because of the risk of impaired fetal neurological development. Following implementation of strategies to improve iodine intake in Australia, there has been minimal investigation into current iodine status. We aimed to characterise iodine status in a population of women of childbearing-age in Australia. METHODS AND STUDY DESIGN: A cross-sectional study was performed in 97 women of childbearing-age attending outpatient clinics at a tertiary hospital in Sydney. Pregnant and postmenopausal women were excluded. Iodine intake was surveyed via questionnaire. Spot urinary iodine (UI) was concurrently measured. The relationships between UI, dietary intake and use of iodine-containing multivitamins/medications were examined. RESULTS: Median UI was 117 ug/L. Forty women (41%) were iodine deficient (UI <100 ug/L). The most commonly consumed source of dietary iodine was bread (29/97, 30% daily). Forty-three women took iodine-containing multivitamins but 18/43 (41.2%) remained deficient. There were no significant associations between UI and diet. There was a smaller proportion of deficient people than in our previous study (125/180 non-pregnant subjects, 69%, vs 41% in this study, p<0.001). CONCLUSION: The overall population median is now sufficient, however, a significant proportion of this multicultural group are iodine deficient. There are similar proportions of deficiency in those using iodine supplements versus not. Contributors may include ethnicity-related dietary practices, limited awareness or poor adherence to iodine supplements. Despite public health strategies, a significant proportion of women of child-bearing age remained iodine deficient. Further research involving a larger population and contributors to iodine deficiency is warranted.

A novel flow cytometry single tube bead assay for quantitation of von Willebrand factor antigen and collagen-binding.

Deficiency of or defects in the plasma protein von Willebrand factor (VWF) lead to bleeding and von Willebrand disease (VWD), which may be congenital or acquired. VWD is considered the most common inherited bleeding disorder and laboratory testing for VWF level and activity is critical for appropriate diagnosis and management. We have designed and established a novel Flow Cytometry (FC) based method for measuring VWF antigen (VWF:Ag) and collagen binding (VWF:CB), together in the same tube and at the same time. The results of the novel FC method have been compared against existing reference methods using a range of normal and pathological material. Methods correlated well (VWF:Ag, r=0.866; VWF:CB, r=0.888) and generally permitted similar discrimination of quantitative versus qualitative VWD types (e.g. type 1 vs type 2A or 2B VWD). The novel procedure is expected to permit future streamlined performance of VWD screening, either using stand-alone FC systems or potentially incorporated into FC-capable automated blood cell and particle counters to allow for improved, automated and faster identification or exclusion of VWD.

Relationship between short activated partial thromboplastin times, thrombin generation, procoagulant factors and procoagulant phospholipid activity.

Short activated partial thromboplastin times (APTTs) are associated with thrombosis. However, what short APTTs actually represent in terms of possible mechanistic pathways is not well characterized. We have assessed thrombin generation as compared with levels of procoagulant factor (fibrinogen, V, VIII, IX, XI and XII) activities, von Willebrand factor level and activity using collagen binding, as well as procoagulant phospholipid activity, in 113 consecutive samples exhibiting a short APTT compared with an equal number of age-matched and sex-matched samples yielding a normal APTT. We found a significant difference in peak thrombin generation, velocity index and area under the curve between the two groups, and that thrombin generation markers correlated with the APTT, procoagulant phospholipid activity and several procoagulant clotting factors. We conclude that short APTTs represent a procoagulant milieu, as represented by heightened thrombin generation and several other heightened procoagulant activities, which may help explain the association with thrombosis.

A robust method for testing urinary iodine using a microtitre robotic system.

PROJECT: Iodine deficiency disorders are due to inadequate thyroid hormone production and 2 billion individuals worldwide are estimated to have insufficient iodine intake. Laboratory assessment methods include urinary iodine (UI) concentration, blood FT3, FT4, TSH and Thyroglobulin. The aim of this study was to set up a robust method for testing urinary iodine using a microtitre robotic system. PROCEDURE: The UI method described is based on the Sandell-Kolthoff reaction, which utilizes the catalytic role of iodine in the reduction of ceric ammonium sulphate in the presence of arsenious acid. This method was automated for use on microtitre robotic system. RESULTS: The method was compared with the currently employed manual Sandell-Kolthoff reaction method in our laboratory as reference. The two methods correlated well using weighted Deming regression analysis (slope=1.066, intercept=6.5, r=0.994; n=211). Interassay and intraassay variations were similar to the reference method, but cost analysis indicated a large reduction in costs related to increased throughput, and reduced consumables and labour. CONCLUSIONS: We have successfully adapted UI testing to an automated method, permitting cheaper, faster and robust screening of large numbers of patients and populations. The described protocol can be used on different microtitre robotic systems permitting up to 372 patient samples per run for 4 microtitre plate systems.

A laboratory evaluation into the short activated partial thromboplastin time.

Although short activated partial thromboplastin times (APTTs) are generally considered to be laboratory artefacts of problematic blood collections, there is mounting evidence that in some cases a short APTT may reflect a hypercoagulable state, potentially associated with increased thrombotic risk and adverse cardiovascular events. We prospectively evaluated the phenomenon of short APTTs in 113 consecutive samples compared with an equal number of age and sex-matched normal APTT samples. We found a significant difference in various test parameters including prothrombin time (PT), Factor (F) V, FVIII, FXI, FXII, von Willebrand factor (VWF) antigen and collagen-binding activity, and in the level of procoagulant phospholipids, as assessed using a novel assay procedure (XACT). Interestingly, there was a significant negative association for fibrinogen, and although elevated, there was no significant association for FIX. On the basis of identified consecutive samples having multiple low APTTs on several sequential days, a proportion of laboratory-defined short APTTs appear to represent in-vivo hypercoagulability. In conclusion, plasma from patients presenting with short APTTs is reflective of a complex hypercoagulant milieu that could feasibly contribute to thrombotic risk, and 20% or more of laboratory definable short APTTs appear to reflect in-vivo phenomenon.

A practical approach to instrument selection, evaluation, basic financial management and implementation in pathology and research.

In response to increasingly complex demands in terms of productivity and budgets, there is a critical need to avoid mistakes during instrument selection that will be financially costly, and adversely affect customers, staff, productivity and test turnaround time. As there is no "one size fits all", guidelines must be appropriate to permit informed decision making. A Medline search was conducted to assess background knowledge in this area, using the terms "laboratory instrument selection" and "laboratory instrument evaluation". Searches returned over 800 articles, of which only seven were directly related to the topic of the search, with most outdated, and suggesting a paucity of appropriate information. Additional resources used included the American Association of Clinical Chemistry (AACC) website and the Internet. Appropriate criteria for instrument selection were established in the current report based on subjective and objective (technical) evaluations. Additionally, a sound and simple financial approach is also suggested to help in making informed decisions and avoid costly mistakes. We propose that such a process as outlined in our report will protect laboratories from making costly and avoidable mistakes in the acquisition of major equipment.

Hemostatic dysfunction associated with endocrine disorders as a major risk factor and cause of human morbidity and mortality: a comprehensive meta-review.

We review the association between disorders of endocrine function and hemostasis. The content of more than 570 review articles were appraised to provide the core of 81 key articles referenced in this chapter. The search method used MEDLINE and EMBASE electronic databases and the key words e NDOCRINE DYSFUNCTION, DIABETES, GRAVES' DISEASE, HYPOTHYROIDISM, HYPERTHYROIDISM, THYROTOXICOSIS, VON WILLEBRAND DISEASE, VON WILLEBRAND FACTOR, BLEEDING DISORDERS, PLATELETS DYSFUNCTION, HEMOSTASIS DYSFUNCTION, and REVIEW. Abnormalities of hemostasis, platelets, and endothelium and the presence of microparticles, abnormal expression of adhesion molecules, and elevated von Willebrand factor are all associated with cardiovascular disease and are also features of various endocrine disorders, including diabetes and its complications, insulin resistance, polycystic ovary syndrome, and various thyroid disorders. Related causes and associated factors, including obesity, alcohol, hyperlipidemia, omega fatty acids, vitamin D, serotonin, insulin-like growth factors, angiotensin-converting enzyme, and C-reactive protein, are also discussed in this review.

A new quality control model using performance goals based on biological variation in External Quality Assurance Schemes.

A new quality control model using performance goals based on biological variation in External Quality Assurance Schemes (EQAS) is described. The proposed model aims to use assay (analytical) CV(A), bias and total error available from participation in EQAS to describe assay performance using minimum, desirable and optimum quality specifications based on biological variation. The model provides further analysis of EQAS data and should be useful in better management of laboratory quality control, as it provides further information that can facilitate trouble-shooting. Additionally, it can help in evaluating the performance of current and proposed new laboratory methods by applying a unifying system if different EQAS are used to cover a range of analytes.