Achieving optimal adherence to medical therapy by telehealth: Findings from the ORBITA medication adherence sub-study

INTRODUCTION: The ORBITA trial of percutaneous coronary intervention (PCI) versus a placebo procedure for patients with stable angina was conducted across six sites in the United Kingdom via home monitoring and telephone consultations. Patients underwent detailed assessment of medication adherence which allowed us to measure the efficacy of the implementation of the optimization protocol and interpretation of the main trial endpoints. METHODS: Prescribing data were collected throughout the trial. Self-reported adherence was assessed, and urine samples collected at pre-randomization and at follow-up for direct assessment of adherence using high-performance liquid chromatography with tandem mass spectrometry (HPLC MS/MS). RESULTS: Self-reported adherence was >96% for all drugs in both treatment groups at both stages. The percentage of samples in which drug was detected at pre-randomization and at follow-up in the PCI versus placebo groups respectively was: clopidogrel, 96% versus 90% and 98% versus 94%; atorvastatin, 95% versus 92% and 92% versus 91%; perindopril, 95% versus 97% and 85% versus 100%; bisoprolol, 98% versus 99% and 96% versus 97%; amlodipine, 99% versus 99% and 94% versus 96%; nicorandil, 98% versus 96% and 94% versus 92%; ivabradine, 100% versus 100% and 100% versus 100%; and ranolazine, 100% versus 100% and 100% versus 100%. CONCLUSIONS: Adherence levels were high throughout the study when quantified by self-reporting methods and similarly high proportions of drug were detected by urinary assay. The results indicate successful implementation of the optimization protocol delivered by telephone, an approach that could serve as a model for treatment of chronic conditions, particularly as consultations are increasingly conducted online

Prevention of lithium-ion battery thermal runaway using polymer-substrate current collectors

Isolating electronically conducting material from internal short circuits is a promising way to prevent the onset of thermal runaway within lithium-ion cells. Here, a metal-coated polymer current collector, which is designed to disconnect internal short circuits by withdrawing from the heating region, is tested in 18650 cells. In addition to having lower mass and manufacturing costs, cells with metal-coated polymer current collectors demonstrate a reduced risk of thermal runaway during nail penetration. High-speed synchrotron X-ray radiography of 18650 cells during nail-penetration testing, in tandem with pre- and post-mortem X-ray computed tomography, provides insights into the function of the current collectors. The results are compared with those of 18650 cells with standard commercial aluminum and copper current collectors. Cells with aluminum-coated polymer current collectors demonstrated 100% success in thermal runaway prevention during nail penetration, retaining a cell voltage >4.00 V, while standard cells consistently experienced thermal runaway

Killing the umpire: cooperative defects in mitotic checkpoint and BRCA2 genes on the road to transformation

Recent findings from mouse models of BRCA2 genetic lesions have provided intriguing insights and important questions concerning modes of tumor development in familial breast and ovarian cancers. Fibroblasts from mice homozygous for the BRCA2(Tr) allele grow poorly and display an array of chromosomal abnormalities that are consistent with a role for BRCA2 in DNA repair. This growth defect can be overcome and cellular transformation promoted by the expression of defective, dominant negative alleles of p53 and of the mitotic checkpoint gene Bub1, both of which are known to induce chromosome instability. These findings are mirrored in the genetic lesions sustained in tumors found in the rare BRCA2(Tr/Tr)mice that survive to adulthood, which include defects in p53 as well as the mitotic checkpoint proteins Bub1 and Mad3L. Together, these data hint that tumors in these mice evolve from an unusually intense selective pressure to remove DNA damage checkpoints, which in turn might be facilitated by chromosomal abolition of mitotic checkpoints and the consequent increase in shuffling of genetic information. How these genetic lesions co-operate to yield transformed cells and how these data relate to BRCA1 and BRCA2 defects in the human population are important questions raised by this work

Sixteen-year follow-up of hyperopic laser in situ keratomileusis

PURPOSE: To assess the long-term efficacy and safety of hyperopic laser in situ keratomileusis (LASIK). SETTING: Department of Ophthalmology, St. Thomas' Hospital, London, United Kingdom. DESIGN: Prospective cohort study. METHODS: Hyperopic LASIK was performed using a mechanical microkeratome, an optical zone of 6.5 mm, and a blend zone of 1.5 mm. Simple hyperopia was treated. RESULTS: The mean patient age was 51.6 years (range 34 to 60 years). Preoperatively, the mean spherical equivalent (SE) was +3.74 diopters (D) (range +1.25 to +6.50 D). The mean attempted correction was +3.64 D (range +1.5 to +6.0 D). The mean follow-up was 16.5 years. The mean SE was +0.28 D (range -1.0 to +1.5 D) at 12 months, +0.84 D (range -0.75 to +3.35 D) at 5 years, and +1.74 D (range -0.75 to +4.13 D) at 16 years, representing an increase in hyperopia of +1.47 D ± 1.43 (SD) between 1 year and 16 years (P < .0001) and of +1.13 ± 0.8 D between 5 years and 16 years (P < .03). The uncorrected distance visual acuity improved at 16 years (P < .0001); corrected distance visual acuity (CDVA) was unchanged (P < .2). The efficacy index was 0.5 and the safety index, 1.09. One eye (3%) lost 2 lines of CDVA. Keratometry remained stable between 1 year and 16 years (P < 1.0). Four eyes (12%) had cataract surgery, and 2 (6%) had laser iridotomy. There was no ectasia. CONCLUSIONS: After hyperopic LASIK, an increase in hyperopia occurred between 1 and 5 years and 16 years. At 16 years, efficacy was limited but with no sight-threatening complications. FINANCIAL DISCLOSURES: Dr. Marshall was a consultant to Summit Technology, Inc. Dr. O'Brart holds a noncommercial research grant from Alcon Laboratories, Inc. None of the other authors has a financial or proprietary interest in any material or method mentioned

Differences in the signaling pathways of α1A- and α1B-adrenoceptors are related to different endosomal targeting

Aims: To compare the constitutive and agonist-dependent endosomal trafficking of α1A- and α1B-adrenoceptors (ARs) and to establish if the internalization pattern determines the signaling pathways of each subtype. Methods: Using CypHer5 technology and VSV-G epitope tagged α1A- and α1B-ARs stably and transiently expressed in HEK 293 cells, we analyzed by confocal microscopy the constitutive and agonist-induced internalization of each subtype, and the temporal relationship between agonist induced internalization and the increase in intracellular calcium (determined by FLUO-3 flouorescence), or the phosphorylation of ERK1/2 and p38 MAP kinases (determined by Western blot). Results and Conclusions: Constitutive as well as agonist-induced trafficking of α1A and α1B ARs maintain two different endosomal pools of receptors: one located close to the plasma membrane and the other deeper into the cytosol. Each subtype exhibited specific characteristics of internalization and distribution between these pools that determines their signaling pathways: α1A-ARs, when located in the plasma membrane, signal through calcium and ERK1/2 pathways but, when translocated to deeper endosomes, through a mechanism sensitive to β-arrestin and concanavalin A, continue signaling through ERK1/2 and also activate the p38 pathway. α1B-ARs signal through calcium and ERK1/2 only when located in the membrane and the signals disappear after endocytosis and by disruption of the membrane lipid rafts by methyl-β-cyclodextrin

An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial

Background: Cardiovascular diseases (CVD) are responsible for significant morbidity, premature mortality, and economic burden. Despite established evidence that supports the use of preventive medications among patients at high CVD risk, treatment gaps remain. Building on prior evidence and a theoretical framework, a complex intervention has been designed to address these gaps among high-risk, under-treated patients in the Australian primary care setting. This intervention comprises a general practice quality improvement tool incorporating clinical decision support and audit/feedback capabilities; availability of a range of CVD polypills (fixed-dose combinations of two blood pressure lowering agents, a statin ± aspirin) for prescription when appropriate; and access to a pharmacy-based program to support long-term medication adherence and lifestyle modification. Methods: Following a systematic development process, the intervention will be evaluated in a pragmatic cluster randomized controlled trial including 70 general practices for a median period of 18 months. The 35 general practices in the intervention group will work with a nominated partner pharmacy, whereas those in the control group will provide usual care without access to the intervention tools. The primary outcome is the proportion of patients at high CVD risk who were inadequately treated at baseline who achieve target blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels at the study end. The outcomes will be analyzed using data from electronic medical records, utilizing a validated extraction tool. Detailed process and economic evaluations will also be performed. Discussion: The study intends to establish evidence about an intervention that combines technological innovation with team collaboration between patients, pharmacists, and general practitioners (GPs) for CVD prevention. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN1261600023342

Spontaneous intracranial arterial dissection in the young: diagnosis by CT angiography

BACKGROUND: Spontaneous carotid artery dissections have been rarely reported in children. Diagnosis has traditionally been confirmed by catheter arteriography. More recently diagnosis has been made by magnetic resonance imaging and magnetic resonance angiography; however the sensitivity of these techniques has yet to be determined. The authors are unaware of reports of carotid dissection confirmed by dynamic computed tomography (computerized tomographic arteriography) in the young. CASE PRESENTATION: We recently evaluated a fourteen year-old male following the development of transient neurologic symptoms. There was no antecedent illness or trauma. Dynamic computed tomography revealed an intracranial dissection involving the supraclinoid segment of the left internal carotid artery (confirmed by catheter arteriography). Studies for vasculitis, pro-thrombotic states, and defects of collagen were negative. CONCLUSION: Spontaneous carotid artery dissection is a potential cause of transient neurological symptoms and ischemic stroke in the pediatric population. Dynamic computed tomography appears to be a reliable diagnostic tool which can lead to early diagnosis

Haemoglobin mass and running time trial performance after recombinant human erythropoietin administration in trained men

&lt;p&gt;Recombinant human erythropoietin (rHuEpo) increases haemoglobin mass (Hbmass) and maximal oxygen uptake (v˙ O2 max).&lt;/p&gt; &lt;p&gt;Purpose: This study defined the time course of changes in Hbmass, v˙ O2 max as well as running time trial performance following 4 weeks of rHuEpo administration to determine whether the laboratory observations would translate into actual improvements in running performance in the field.&lt;/p&gt; &lt;p&gt;Methods: 19 trained men received rHuEpo injections of 50 IUNkg21 body mass every two days for 4 weeks. Hbmass was determined weekly using the optimized carbon monoxide rebreathing method until 4 weeks after administration. v˙ O2 max and 3,000 m time trial performance were measured pre, post administration and at the end of the study.&lt;/p&gt; &lt;p&gt;Results: Relative to baseline, running performance significantly improved by ,6% after administration (10:3061:07 min:sec vs. 11:0861:15 min:sec, p,0.001) and remained significantly enhanced by ,3% 4 weeks after administration (10:4661:13 min:sec, p,0.001), while v˙ O2 max was also significantly increased post administration (60.765.8 mLNmin21Nkg21 vs. 56.066.2 mLNmin21Nkg21, p,0.001) and remained significantly increased 4 weeks after rHuEpo (58.065.6 mLNmin21Nkg21, p = 0.021). Hbmass was significantly increased at the end of administration compared to baseline (15.261.5 gNkg21 vs. 12.761.2 gNkg21, p,0.001). The rate of decrease in Hbmass toward baseline values post rHuEpo was similar to that of the increase during administration (20.53 gNkg21Nwk21, 95% confidence interval (CI) (20.68, 20.38) vs. 0.54 gNkg21Nwk21, CI (0.46, 0.63)) but Hbmass was still significantly elevated 4 weeks after administration compared to baseline (13.761.1 gNkg21, p&#60;0.001).&lt;/p&gt; &lt;p&gt;Conclusion: Running performance was improved following 4 weeks of rHuEpo and remained elevated 4 weeks after administration compared to baseline. These field performance effects coincided with rHuEpo-induced elevated v˙ O2 max and Hbmass.&lt;/p&gt