Search

Background:The human organic cation transporter-1 (OCT-1) is the primary active protein for imatinib uptake into target BCR-ABL-positive cells. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used by chronic myeloid leukaemia (CML) patients on imatinib to manage musculoskeletal complaints.Methods:Here we investigated the impact of NSAIDs on functional activity of the OCT-1 (OCT-1 activity; OA) in CML cells.Results:Although ten of twelve NSAIDs tested had no significant impact on OA (P>0.05), we observed increased OA (27% increase in K562; 22% increase in KU812 cells, P<0.05) and reduced IC50imatinib when treated with diclofenac. Co-incubation with imatinib and diclofenac resulted in a significantly lower viable cell number compared with imatinib alone. In contrast, ibuprofen led to a significant decrease in OA, an increase in IC50imatinib and thus reduced the cytotoxicity of imatinib. In primary CML samples, diclofenac significantly increased OA, particularly in patients with low OA (<4 ng per 200 000 cells), and significantly decreased IC50imatinib. Ibuprofen induced significant decreases in OA in CML samples and healthy donors.Conclusion:On the basis of the expected impact of these two drugs on OA, ibuprofen should be avoided in combination with imatinib. Further studies are warranted regarding the potential benefit of diclofenac to improve OA in a clinical setting. [ABSTRACT FROM AUTHOR]

Abstract: Symmetrical supercapacitors and their serially connected two-cell stacks via a bipolar electrode were constructed with nanocomposites of manganese oxides and carbon nanotubes (MnO x /CNTs) as the electrode materials. Nanocomposites with different contents of MnO x were synthesised through the redox reaction between KMnO4 and CNTs in aqueous solutions. The nanocomposites were characterised by scanning and transmission electron microscopy, BET nitrogen adsorption and X-ray diffraction before being examined in a three-electrode cell with a novel trenched graphite disc electrode by electrochemical means, including cyclic voltammetry, galvanostatic charging–discharging, and electrochemical impedance spectroscopy. The nanocomposites demonstrated capacitive behaviour in the potential range of 0–0.85V (vs Ag/AgCl) in aqueous KCl electrolytes with less than 9% capacitance decrease after 9000 charging–discharging cycles. Symmetrical supercapacitors of identical positive and negative MnO x /CNTs electrodes showed capacitive performance in good agreement with the individual electrodes (e.g. 0.90V, 0.53F, 1.3cm2). The bipolarly connected two-cell stacks of the symmetrical cells exhibited characteristics in accordance with expectation, including a doubled stack voltage and reduced internal resistance per cell. [Copyright &y& Elsevier]

The current work aimed to study the effect of heat treatment duration on mechanical and tribological performances of Ni-P-PTFE coating on low carbon high tensile steel (EH-36) substrate in dry environment under pin-on-disk sliding contact. The effect of normal load on scratch behaviors of Ni-P-PTFE coating with different heat treatment durations was studied under a single pass scratch action. It was found that heat treatment enhances the friction (10%) and wear (30%) behavior of Ni-P-PTFE coating. Heat treatment duration was found to have significant role in strengthening the Ni-P-PTFE coating tribological performances under varying load applications. The best tribological performances and scratch behaviors were observed on HT 80. [ABSTRACT FROM AUTHOR]

Summary: Sunlight exposure by improving vitamin D status could be a simple public health strategy in reducing falls among frail elder people. In a randomised controlled trial, adherence to sunlight exposure was low (median adherence, 26%) and no effect of increased UV exposure on falls risk was observed (incidence rate ratio (IRR) 1.06, P = 0.73). Introduction: This study aimed to determine whether increased sunlight exposure was effective to improve vitamin D status and reduce falls in the elderly. Methods: In a cluster randomised controlled trial (NCT00322166 at ClinicalTrials.gov), 602 residents aged 70 or more (mean age, 86.4 years; 71% female) were recruited from 51 aged care facilities in Northern Sydney, Australia. Participants were randomised by facility to receive either increased sunlight exposure (additional 30-40 min/day in the early morning) with (UV+) or without (UV) calcium supplementation (600 mg/day) or neither (control) for a year. The co-primary endpoints were change in serum 25 hydroxy vitamin D (25OHD) and falls incidence after 12 months. Results: Adherence to sunlight exposure was low (median adherence, 26%; IQR, 7%-45%). Serum 25OHD levels were low at baseline (median, 32.9 nmol/L) and increased only slightly depending on the number of sunlight sessions attended over 12 months ( P = 0.04). During the study, 327 falls occurred in 111 (54%) subjects in the control group, 326 falls in 111 (58%) subjects in the UV only group and 335 falls in 108 (52%) subjects in the UV+ group. By intention-to-treat analysis, there was no significant effect of increased UV exposure on falls risk (IRR, 1.06; 95% CI, 0.76-1.48; P = 0.73). However, in 66 participants who attended ≥130 sessions per year (adherence, ≥50% of 260 sessions-five per week), falls were significantly reduced (IRR, 0.52; 95% CI, 0.31-0.88; P = 0.01) compared with the control group. Conclusions: Increased sunlight exposure did not reduce vitamin D deficiency or falls risk in frail older people. This public health strategy was not effective most likely due to poor adherence to the intervention. [ABSTRACT FROM AUTHOR]

Background: Heat-inactivated probiotics (HPs) may provide an effective alternative to live probiotics (P) by avoiding their risks (eg, probiotic sepsis) while retaining the benefits. We assessed the safety and efficacy of a HP in very preterm (VP: gestation <32 weeks) infants., Methods: VP infants were randomly allocated to receive a HP or P mixture ( Bifidobacterium breve M-16V, Bifidobacterium longum subsp. infantis M-63, Bifidobacterium longum subsp. longum BB536, total 3×10 9  CFU/day) assuring blinding. Primary outcome was faecal calprotectin (FCP) levels were compared after 3 weeks of supplementation. Secondary outcomes included faecal microbiota and short chain fatty acid (SCFA) levels., Results: 86 VP infants were randomised to HP or P group (n=43 each). Total FCP and SCFA were comparable between HP and P groups within 7 days (T1) and between day 21 and 28 (T2) after supplementation. At T2, median (range) FCP was 75 (8-563) in the HP group and 80 (21-277) in the P group (p=0.71). Propionate was significantly raised in both groups, while butyrate was significantly raised in the HP group (all p<0.01). Bacterial richness and diversity increased but was comparable between HP and P (p>0.05). Beta diversity showed similar community structures in both groups (all p>0.05). Changes in faecal Actinobacteria, Bacteroidetes and Bifidobacteriacae levels were comparable in both groups at T1 and T2. There was no probiotic sepsis., Conclusions: HP was safe and showed no significant difference in FCP as compared with a live probiotic. Adequately powered trials are needed to assess the effects of HP on clinically significant outcomes in preterm infants., Trial Registration Number: ACTRN12618000489291., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The Internet has become the primary information source for patients, with most turning to online resources before seeking medical advice., Objective: The aim of this study is to evaluate the quality of online information on hidradenitis suppurativa available to patients., Methods: The authors performed an Internet search using the search terms "hidradenitis suppurativa," "hidradenitis suppurativa treatment," "hidradenitis suppurativa surgery," and "acne inversa." They identified the initial 100 websites from Google, Yahoo, and Bing. Websites were evaluated based on the modified Ensuring Quality Information for Patients instrument., Results: Of the 300 websites, 95 (31.7%) were incorporated after accounting for the exclusion criteria: duplicate entries, websites not pertinent to the subject matter, websites inaccessible due to location restrictions or necessitating user accounts for access, websites in languages other than English, and websites originating from scientific publications directed at a scientific audience rather than the general population. Ensuring Quality Information for Patients scores ranged from 5 to 30/36, with a median of 17., Conclusion: This analysis unveils a diverse array of websites that could confound patients navigating toward high-caliber resources. These barriers may hinder the access to top-tier online patient information and magnify disparities in referral rates, patient engagement, treatment satisfaction, and quality of life., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Patient experience is positively associated with clinical effectiveness, quality care, and patient safety. This study examines the experience of care of adolescents and young adult (AYA) cancer patients from Australia and the United States, allowing a comparison of patient experiences in the context of different national models of cancer care delivery. Participants ( n  = 190) were aged 15-29 years and received cancer treatment from 2014 to 2019. Australians ( n  = 118) were recruited nationally by health care professionals. U.S. participants ( n  = 72) were recruited nationally via social media. The survey included demographic and disease variables, and questions regarding medical treatment, information and support provision, care coordination, and satisfaction across the treatment pathway. Sensitivity analyses examined the possible contribution of age and gender. Most patients from both countries were satisfied or very satisfied with their medical treatment (chemotherapy, radiotherapy, and surgery). There were significant differences between countries in the provision of fertility preservation services, age-appropriate communication, and psychosocial support. Our findings suggest when a national system of oversight with both state and federal funding is implemented, as is the case in Australia but not in the United States, significantly more AYAs with cancer receive age-appropriate information and support services, and improved access to specialist services such as fertility care. A national approach with government funding and centralized accountability appears to be associated with substantial benefits for the well-being of AYAs undergoing cancer treatment.

Introduction: Arsenic methylation converts inorganic arsenic (iAs) to monomethyl (MMA) and dimethyl (DMA) arsenic compounds. Body mass index (BMI) has been positively associated with arsenic methylation efficiency (higher DMA%) in adults, but evidence in pregnancy is inconsistent. We estimated associations between anthropometric measures and arsenic methylation among pregnant women in rural northern Bangladesh., Methods: We enrolled pregnant women (n = 784) (median [IQR] gestational week: 14 [13, 15]) in Gaibandha District, Bangladesh from 2018 to 2019. Anthropometric measures were BMI, subscapular and triceps skinfold thicknesses, and mid-upper arm circumference (MUAC), fat area (MUAFA), and muscle area (MUAMA). Arsenic methylation measures were urinary iAs, MMA, and DMA divided by their sum and multiplied by 100 (iAs%, MMA%, and DMA%), primary methylation index (MMA/iAs; PMI), and secondary methylation index (DMA/MMA; SMI). In complete cases (n = 765 [97.6%]), we fitted linear, beta, and Dirichlet regression models to estimate cross-sectional differences in iAs%, MMA%, DMA%, PMI, and SMI per IQR-unit difference in each anthropometric measure, adjusting for drinking water arsenic, age, gestational age, education, living standards index, and plasma folate, vitamin B12, and homocysteine., Results: Median (IQR) BMI, subscapular skinfold thickness, triceps skinfold thickness, MUAC, MUAFA, and MUAMA were 21.5 (19.4, 23.8) kg/m 2 , 17.9 (13.2, 24.2) mm, 14.2 (10.2, 18.7) mm, 25.9 (23.8, 28.0) cm, 15.3 (10.5, 20.3) cm 2 , and 29.9 (25.6, 34.2) cm 2 , respectively. Median (IQR) iAs%, MMA%, DMA%, PMI, and SMI were 12.0 (9.3, 15.2)%, 6.6 (5.3, 8.3)%, 81.0 (77.1, 84.6)%, 0.6 (0.4, 0.7), and 12.2 (9.3, 15.7), respectively. In both unadjusted and adjusted linear models, all anthropometric measures were negatively associated with iAs%, MMA%, and PMI and positively associated with DMA% and SMI. For example, fully adjusted mean differences (95% CI) in DMA% per IQR-unit difference in BMI, subscapular skinfolds thickness, triceps skinfold thickness, MUAC, MUAFA, and MUAMA were 1.72 (1.16, 2.28), 1.58 (0.95, 2.21), 1.74 (1.11, 2.37), 1.45 (0.85, 2.06), 1.70 (1.08, 2.31), and 0.70 (0.13, 1.27) pp, respectively., Conclusions: Anthropometric measures were positively associated with arsenic methylation efficiency among pregnant women in the early second trimester., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cannabidiol (CBD), one major nonintoxicating phytocannabinoid from Cannabis sativa demonstrated anti-inflammatory effects in animal models of several inflammatory conditions, including arthritis. However, it is still unknown which cell types mediate these anti-inflammatory effects of CBD, and, since CBD binds to a plethora of receptors and enzymes, it is complicated to pinpoint its mechanism of action. In this study, we elucidate the effects of CBD on B cells and peripheral blood mononuclear cells (PBMCs) in respect to survival, calcium mobilization, drug uptake, and cytokine (IL-6, IL-10, and TNF) and immunoglobulin production. Methods: Modulation of intracellular calcium and drug uptake in B cells was determined by using the fluorescent dyes Cal-520 and PoPo3, respectively. Cytokine and immunoglobulin production was evaluated by enzyme-linked immunosorbent assay. PBMC composition and B cell survival after CBD treatment was assessed by flow cytometry. Results: B cells express two major target receptors for CBD, TRPV2 (transient receptor potential vanilloid 2) and TRPA1 (transient receptor potential ankyrin 1), which are not regulated by B cell activation. CBD increased intracellular calcium levels in mouse and human B cells, which was accompanied by enhanced uptake of PoPo3. These effects were not dependent on transient receptor potential channel activation. CBD increased the number of early apoptotic B cells at the expense of viable cells and diminished interleukin (IL)-10 and tumor necrosis factor (TNF) production when activated T cell independently. In PBMCs, CBD increased IL-10 production when B cells were activated T cell dependent, while decreasing TNF levels when activated T cell independently. In PBMC/rheumatoid synovial fibroblast cocultures, CBD reduced IL-10 production when B cells were activated T cell independently. Immunoglobulin M production was augmented by CBD when B cells were activated with CpG. Conclusion: CBD is able to provide pro- and anti-inflammatory effects in isolated B cells and PBMCs. This is dependent on the activating stimulus (T cell dependent or independent) and concentration of CBD. Therefore, CBD might be used to dampen B cell activity in autoimmune conditions such as rheumatoid arthritis, in which B cells are activated by specific autoantigens.

Our pilot RCT found that probiotic supplementation with the three-strain bifidobacterial product (B. breve M-16V, B. longum subsp. infantis M-63 and B. longum subsp. longum BB536) attenuates gut dysbiosis, increases stool short-chain fatty acid (SCFA) levels and improves the growth of head circumference in neonates with congenital gastrointestinal surgical conditions (CGISC). In this article, we have provided guidelines for designing future multicentre RCTs based on the experience gained from our pilot RCT. The recommendations include advice about sample size, potential confounders, outcomes of interest, probiotic strain selection, storage, dose, duration and microbial quality assurance, collection of stool samples, storage and analysis and reporting. Following these guidelines will increase the validity of future RCTs in this area and hence confidence in their results. IMPACT: Probiotic supplementation attenuates gut dysbiosis, increases stool short-chain fatty acid (SCFA) levels and improves the growth of head circumference in neonates with congenital gastrointestinal surgical conditions. The current review provides evidence-based guidelines to conduct adequately powered RCTs in this field., (© 2022. Crown.)

Objective: Most adolescents and young adults (AYA) can expect to survive a cancer diagnosis and treatment, but all will be left with the potential of long-term negative effects that can impact their ability to reach their full potential in life. Understanding aspects of psychological, functional, and social health and well-being outcomes, is pivotal for optimising long-term well-being., Methods: We completed a systematic review of longitudinal studies reporting outcomes after anti-cancer treatment for Adolescents and Young Adults diagnosed between the age of 12-29 years according to established systematic review processes. The protocol was registered with PROSPERO (ID: CRD 42020203116)., Results: Thirteen reports from 10 studies met eligibility criteria representing 17,645 individuals (50.3% female, mean age at diagnosis 22 years, and 26 years at last, follow up). Eleven reports were from eight quantitative studies that relied on self-report surveys and two were qualitative studies. Psychological outcomes were reported to improve over time, as were functional health outcomes, although reported health behaviours were inconsistent between studies. Neurocognitive deficits were reported to affect the ability to return to work and impacts on fertility and sexuality were sustained over time., Conclusions: While some outcomes for AYA are reported to improve over time, particularly for physical functioning, and anxiety and depression, the long-term impact of cancer on many important domains remains largely unknown. Specifically, the evidence to understand what changes occur over time, and when, remains underdeveloped., (© 2022 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)

Sinoatrial node dysfunction can manifest as bradycardia, leading to symptoms of syncope and sudden cardiac death. Electronic pacemakers are the current standard of care but are limited due to a lack of biological chronotropic control, cost of revision surgeries, and risk of lead- and device-related complications. We therefore aimed to develop a biological alternative to electronic devices by using a clinically relevant gene therapy vector to demonstrate conversion of cardiomyocytes into sinoatrial node-like cells in an in vitro context. Neonatal rat ventricular myocytes were transduced with recombinant adeno-associated virus vector 6 encoding either hTBX18 or green fluorescent protein and maintained for 3 weeks. At the endpoint, qPCR, Western blot analysis and immunocytochemistry were used to assess for reprogramming into pacemaker cells. Cell morphology and Arclight action potentials were imaged via confocal microscopy. Compared to GFP , hTBX18 -transduced cells showed that hTBX18 , HCN4 and Cx45 were upregulated. Cx43 was significantly downregulated, while sarcomeric α-actinin remained unchanged. Cardiomyocytes transduced with hTBX18 acquired the tapering morphology of native pacemaker cells, as compared to the block-like, striated appearance of ventricular cardiomyocytes. Analysis of the action potentials showed phase 4 depolarization and a significant decrease in the APD50 of the hTBX18 -transduced cells. We have demonstrated that rAAV- hTBX18 gene transfer to ventricular myocytes results in morphological, molecular, physiological, and functional changes, recapitulating the pacemaker phenotype in an in vitro setting. The generation of these induced pacemaker-like cells using a clinically relevant vector opens new prospects for biological pacemaker development.

δ9-Tetrahydrocannabinol (THC) has demonstrated anti-inflammatory effects in animal models of arthritis, but its mechanism of action and cellular targets are still unclear. The purpose of this study is to elucidate the effects of THC (0.1-25 µM) on synovial fibroblasts from patients with rheumatoid arthritis (RASF) and peripheral blood mononuclear cells (PBMC) from healthy donors in respect to proliferation, calcium mobilization, drug uptake, cytokine and immunoglobulin production. Intracellular calcium and drug uptake were determined by fluorescent dyes Cal-520 and PoPo3, respectively. Cytokine and immunoglobulin production were evaluated by ELISA. Cannabinoid receptors 1 and 2 (CB 1 and CB 2 ) were detected by flow cytometry. RASF express CB 1 and CB 2 and the latter was increased by tumor necrosis factor (TNF). In RASF, THC (≥5 µM) increased intracellular calcium levels/PoPo3 uptake in a TRPA1-dependent manner and reduced interleukin-8 (IL-8) and matrix metalloprotease 3 (MMP-3) production at high concentrations (25 µM). Proliferation was slightly enhanced at intermediate THC concentrations (1-10 µM) but was completely abrogated at 25 µM. In PBMC alone, THC decreased interleukin-10 (IL-10) production and increased immunoglobulin G (IgG). In PBMC/RASF co-culture, THC decreased TNF production when cells were stimulated with interferon-γ (IFN-γ) or CpG. THC provides pro- and anti-inflammatory effects in RASF and PBMC. This is dependent on the activating stimulus and concentration of THC. Therefore, THC might be used to treat inflammation in RA but it might need titrating to determine the effective concentration.

Objective: Evidence indicates that multistrain probiotics benefit preterm infants more than single-strain (SS) probiotics. We assessed the effects of SS versus triple-strain (TS) probiotic supplementation (PS) in extremely preterm (EP) infants., Design: EP infants (gestational age (GA) <28 weeks) were randomly allocated to TS or SS probiotic, assuring blinding. Reference (REF) group was EP infants in the placebo arm of our previous probiotic trial. PS was commenced with feeds and continued until 37 weeks' corrected GA. Primary outcome was time to full feed (TFF: 150 mL/kg/day). Secondary outcomes included short-chain fatty acids and faecal microbiota collected at T1 (first week) and T2 (after 3 weeks of PS) using 16S ribosomal RNA gene sequencing., Results: 173 EP (SS: 86, TS: 87) neonates with similar GA and birth weight (BW) were randomised. Median TFF was comparable (11 (IQR 8-16) vs 10 (IQR 8-16) days, p=0.92). Faecal propionate (SS, p<0.001, and TS, p=0.0009) and butyrate levels (TS, p=0.029) were significantly raised in T2 versus T1 samples. Secondary clinical outcomes were comparable. At T2, alpha diversity was comparable (p>0.05) between groups, whereas beta-diversity analysis revealed significant differences between PS and REF groups (both p=0.001). Actinobacteria were higher (both p<0.01), and Proteobacteria, Firmicutes and Bacteroidetes were lower in PS versus REF. Gammaproteobacteria, Clostridia and Negativicutes were lower in both PS versus REF., Conclusion: TFF in EP infants was similar between SS and TS probiotics. Both probiotics were effective in reducing dysbiosis (higher bifidobacteria and lower Gammaproteobacteria). Long-term significance of increased propionate and butyrate needs further studies., Trial Registration Number: ACTRN 12615000940572., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cardiac arrhythmias are a leading cause of death. The mainstay method for diagnosing arrhythmias (eg, atrial fibrillation) and cardiac conduction disorders (eg, prolonged corrected QT interval [QTc]) is by using 12-lead electrocardiography (ECG). Handheld 12-lead ECG devices are emerging in the market. In tandem with emerging technology options, evaluations of device usability should go beyond validation of the device in a controlled laboratory setting and assess user perceptions and experiences, which are crucial for successful implementation in clinical practice., Objective: This study aimed to evaluate clinician and patient perceptions and experiences, regarding the usability of a handheld 12-lead ECG device compared to a conventional 12-lead ECG machine, and generalizability of this user-centered approach., Methods: International Organization for Standardization Guidelines on Usability and the Technology Acceptance Model were integrated to form the framework for this study, which was conducted in outpatient clinics and cardiology wards at Westmead Hospital, New South Wales, Australia. Each patient underwent 2 ECGs (1 by each device) in 2 postures (supine and standing) acquired in random sequence. The times taken by clinicians to acquire the first ECG (efficiency) using the devices were analyzed using linear regression. Electrocardiographic parameters (QT interval, QTc interval, heart rate, PR interval, QRS interval) and participant satisfaction surveys were collected. Device reliability was assessed by evaluating the mean difference of QTc measurements within ±15 ms, intraclass correlation coefficient, and level of agreement of the devices in detecting atrial fibrillation and prolonged QTc. Clinicians' perceptions and feedback were assessed with semistructured interviews based on the Technology Acceptance Model., Results: A total of 100 patients (age: mean 57.9 years, SD 15.2; sex: male: n=64, female n=36) and 11 clinicians (experience acquiring ECGs daily or weekly 10/11, 91%) participated, and 783 ECGs were acquired. Mean differences in QTc measurements of both handheld and conventional devices were within ±15 ms with high intraclass correlation coefficients (range 0.90-0.96), and the devices had a good level of agreement in diagnosing atrial fibrillation and prolonged QTc (κ=0.68-0.93). Regardless of device, QTc measurements when patients were standing were longer duration than QTc measurements when patients were supine. Clinicians' ECG acquisition times improved with usage (P<.001). Clinicians reported that device characteristics (small size, light weight, portability, and wireless ECG transmission) were highly desired features. Most clinicians agreed that the handheld device could be used for clinician-led mass screening with enhancement in efficiency by increasing user training. Regardless of device, patients reported that they felt comfortable when they were connected to the ECG devices., Conclusions: Reliability and usability of the handheld 12-lead ECG device were comparable to those of a conventional ECG machine. The user-centered evaluation approach helped us identify remediable action to improve the efficiency in using the device and identified highly desirable device features that could potentially help mass screening and remote assessment of patients. The approach could be applied to evaluate and better understand the acceptability and usability of new medical devices., (©Kam Cheong Wong, Aravinda Thiagalingam, Saurabh Kumar, Simone Marschner, Ritu Kunwar, Jannine Bailey, Cindy Kok, Tim Usherwood, Clara K Chow. Originally published in JMIR Cardio (https://cardio.jmir.org), 26.08.2021.)

Multiple organ failure is the trademark of sepsis. Sepsis occurs when the body's reaction to infection causes injury to its tissues and organs. As a consequence, fluid builds up in the tissues causing organ failure and leading to septic shock eventually. Some symptoms of sepsis include fever, arrhythmias, blood vessel leaks, impaired clotting, and generalised inflammation. In order to address the limitations in current diagnosis, we have proposed a cost-effective automated diagnostic tool in this study. A deep temporal convolution network has been developed for the prediction of sepsis. Septic data was fed to the model and a high accuracy and area under ROC curve (AUROC) of 98.8% and 98.0% were achieved respectively, for per time-step metrics. A relatively high accuracy and AUROC of 95.5% and 91.0% were also achieved respectively, for per-patient metrics. This is a novel study in that it has investigated per time-step metrics, compared to other studies which investigated per-patient metrics. Our model has also been evaluated by three validation methods. Thus, the recommended model is robust with high accuracy and precision and has the potential to be used as a tool for the prediction of sepsis in hospitals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To compare the efficacy of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on upper limb function recovery among patients who recently had stroke., Methods: Subjects with recent stroke (within 1 month) were randomized to rTMS (n=25) and tDCS (n=26) applied over the non-lesioned hemisphere for three sessions per week, followed by tailored upper limb rehabilitation training for a total of 2 weeks. The primary outcomes were changes in the Motor Assessment Scale (MAS), Fugl-Meyer arm score test, Nine-Hole Peg Test (9HPT), hand grip strength, and modified Barthel Index at weeks 2 and 4. Both therapists responsible for training and assessment were blinded to the intervention allocated., Results: There was an improvement in all the motor performance scales among both groups (p<0.001). These improvements persisted at discharge. However, there was no significant difference in any of the assessment scales between the two groups. The rTMS group showed a statistically non-significant greater improvement in MAS, 9HPT, and handgrip strength than the tDCS group., Conclusion: Both interventions produce a statistically significant improvement in upper limb function. There was no statistically significant difference between the two intervention methods with respect to motor performance. It is suggested that a larger study may help to clarify the superiority of either methods.

Purpose: In the last decade, interest in gene therapy as a therapeutic technology has increased, largely driven by an exciting yet modest number of successful applications for monogenic diseases. Setbacks in the use of gene therapy for cardiac disease have motivated efforts to develop vectors with enhanced tropism for the heart and more efficient delivery methods. Although monogenic diseases are the logical target, cardiac arrhythmias represent a group of conditions amenable to gene therapy because of focal targets (biological pacemakers, nodal conduction, or stem cell-related arrhythmias) or bystander effects on cells not directly transduced because of electrical coupling., Methods: This review provides a contemporary narrative of the field of gene therapy for experimental cardiac arrhythmias, including those associated with stem cell transplant. Recent articles published in the English language and available through the PubMed database and other prominent literature are discussed., Findings: The promise of gene therapy has been realized for a handful of monogenic diseases and is actively being pursued for cardiac applications in preclinical models. With improved vectors, it is likely that cardiac disease will also benefit from this technology. Cardiac arrhythmias, whether inherited or acquired, are a group of conditions with a potentially lower threshold for phenotypic correction and as such hold unique potential as targets for cardiac gene therapy., Implications: There has been a proliferation of research on the potential of gene therapy for cardiac arrhythmias. This body of investigation forms a strong basis on which further developments, particularly with viral vectors, are likely to help this technology progress along its translational trajectory., (Copyright © 2020 Elsevier Inc. All rights reserved.)

With the purpose of obtaining white emission from single layer organic light emitting diodes (OLEDs), fluorene benzotriazole based polymers with double bond subunits (namely TP2 and SP3 with and without thiophene linker, respectively) were synthesized by a Suzuki cross-coupling polymerization reaction. SP3 and TP2 were used as an emissive layer of the OLED devices due to their outstanding solubility in organic solvents, photoluminescence intensity and morphological suitability for fine thin film-forming capability. The optical, electrochemical, light emission and electroluminescence characteristics, Density Functional Theory (DFT) calculations and admittance spectroscopic analysis of OLEDs based on SP3 and TP2 were realized in detail to understand the effects of thiophene linker addition as a donor unit to the main chain of fluorene benzotriazole based polymers. As a result, TP2 emitted a bright yellow emission with a maximum brightness of 243 cd m -2 at 40 mA cm -2 , and a maximum current efficiency of 1.38 cd A -1 with more broad electroluminescence characteristics than SP3 polymer without the thiophene linker. SP3 emitted a greenish yellow emission with a maximum brightness of 1001 cd m -2 at 845 mA cm -2 , and a maximum current efficiency of 0.33 cd A -1 . Carrier transport properties, charge carrier transit time and the equivalent circuit modelling studies were obtained through admittance spectroscopy. An equivalent circuit model with a combination of two resistors and one capacitor explained the charge conduction mechanism of SP3 and TP2 based OLEDs. SP3 and TP2 OLED devices represented typical p-type transporting characteristics with mobilities of 0.073 and 0.017 cm 2 V -1 s -1 , respectively with simplified device configuration. All the results indicate that thiophene addition to the main chain of fluorene benzotriazole based polymers with double bond subunits lead to a promising candidate for white emissive materials used in single layer white OLEDs., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Atrial fibrillation (AF) and other arrhythmias are prevalent and often encountered by general practitioners (GPs). In response to the growing prevalence and to assist practitioners in the diagnosis and management of AF, the Cardiac Society of Australia & New Zealand and Heart Foundation of Australia published the first Australian AF Guidelines in 2018. We aimed to examine (a) the proportion of GPs who performed any form of AF screening and identify the methods they applied, (b) GPs' awareness of the AF Guidelines and approaches to arrhythmia screening, (c) the roles of conventional 12-lead ECG and mobile health devices, and (d) GPs' confidence in ECG interpretation and need for training., Methods: A cross-sectional online survey titled "GPs Screen their patients for Atrial Fibrillation and othEr aRrhythmia (GPSAFER)" was conducted from October 2018 to March 2019. The participants were recruited via various GP networks across Australia. Ethics approval was granted by The University of Sydney., Results: A total of 463 surveys were completed. Many GPs (394/463, 85.1%, 95% CI 81.5-88.2%) performed some forms of AF screening and applied at least one AF screening method, most frequently pulse palpation (389/463, 84.0%). Some (299/463, 64.6%) GPs considered assessing their patients for other arrhythmias (237/299, 79.3% for complete heart block and 236/299, 78.9% for long-QT). Most GPs (424/463, 91.6%) were not using mobile ECG devices in their practice but some (147/463, 31.7%) were contemplating it. One third (175/463, 37.8%) of GPs were aware of the Australian AF Guidelines; those aware were more likely to perform AF screening (98.9% vs 76.7%, p <  0.001). Factors significantly and positively associated with AF screening were "awareness of the AF Guidelines" (p <  0.001), "number of years working in general practice" (p <  0.001), and "confidence in ECG interpretation of AF" (p = 0.003). Most GPs reported that they were very or extremely confident in interpreting AF (381/463, 82.3%) and complete heart block (266/463, 57.5%). Many GPs (349/463, 75.4%) would like to receive online ECG interpretation training., Conclusions: Assessment of arrhythmias is common in general practice and GPs are open to further training in ECG interpretation and using mobile ECG devices to aid their clinical practice. Increasing awareness of AF Guidelines and improving confidence in ECG interpretation may increase AF screening.

Differences between mouse and human hearts pose a significant limitation to the value of small animal models when predicting vector behavior following recombinant adeno-associated viral (rAAV) vector-mediated cardiac gene therapy. Hence, sheep have been adopted as a preclinical animal, as they better model the anatomy and cardiac physiological processes of humans. There is, however, no comprehensive data on the shedding profile of rAAV in sheep following intracoronary delivery, so as to understand biosafety risks in future preclinical and clinical applications. In this study, sheep received intracoronary delivery of rAAV serotypes 2/6 (2 × 10 12  vg), 2/8, and 2/9 (1 × 10 13  vg) at doses previously administered in preclinical and clinical trials. This was followed by assessment over 96 h to examine vector shedding in urine, feces, nasal mucus, and saliva samples. Vector genomes were detected via real-time quantitative PCR in urine and feces up to 48 and 72 h post vector delivery, respectively. Of these results, functional vector particles were only detected via a highly sensitive infectious replication assay in feces samples up to 48 h following vector delivery. We conclude that rAAV-mediated gene transfer into sheep hearts results in low-grade shedding of non-functional vector particles for all excreta samples, except in the case of feces, where functional vector particles are present up to 48 h following vector delivery. These results may be used to inform containment and decontamination guidelines for large animal dealings, and to understand the biosafety risks associated with future preclinical and clinical uses of rAAV.

Nonalcoholic steatohepatitis (NASH) is a metabolic liver disease that progresses from simple steatosis to the disease state of inflammation and fibrosis. Previous studies suggest that apoptosis and necroptosis may contribute to the pathogenesis of NASH, based on several murine models. However, the mechanisms underlying the transition of simple steatosis to steatohepatitis remain unclear, because it is difficult to identify when and where such cell deaths begin to occur in the pathophysiological process of NASH. In the present study, our aim is to investigate which type of cell death plays a role as the trigger for initiating inflammation in fatty liver. By establishing a simple method of discriminating between apoptosis and necrosis in the liver, we found that necrosis occurred prior to apoptosis at the onset of steatohepatitis in the choline-deficient, ethionine-supplemented (CDE) diet model. To further investigate what type of necrosis is involved in the initial necrotic cell death, we examined the effect of necroptosis and ferroptosis inhibition by administering inhibitors to wild-type mice in the CDE diet model. In addition, necroptosis was evaluated using mixed lineage kinase domain-like protein (MLKL) knockout mice, which is lacking in a terminal executor of necroptosis. Consequently, necroptosis inhibition failed to block the onset of necrotic cell death, while ferroptosis inhibition protected hepatocytes from necrotic death almost completely, and suppressed the subsequent infiltration of immune cells and inflammatory reaction. Furthermore, the amount of oxidized phosphatidylethanolamine, which is involved in ferroptosis pathway, was increased in the liver sample of the CDE diet-fed mice. These findings suggest that hepatic ferroptosis plays an important role as the trigger for initiating inflammation in steatohepatitis and may be a therapeutic target for preventing the onset of steatohepatitis.

Introduction: Simple and scalable strategies are needed to improve 'out-of-hospital' support and management for people living with cardiovascular disease (CVD) and respiratory disease. Text messaging via mobile phones has been shown to be effective in helping promote lifestyle change and is supported by quantitative and qualitative evidence. The aim of this study is to test the effectiveness and implementation of a 6-month text messaging support programme for people with CVD and respiratory disease as an addition to cardiac and pulmonary outpatient rehabilitation., Methods and Analysis: Pragmatic randomised controlled trial (n=310) to test the effectiveness of a 6-month text message support programme on clinical outcomes in people with CVD and chronic respiratory disease who are attending outpatient cardiac and pulmonary rehabilitation. The study includes a nested process evaluation to inform scalability and implementation across settings. The intervention group will receive a text message support programme comprising five messages per week for 26 weeks and the control group will continue with standard care. The primary outcome is exercise capacity (6 min walk distance). Secondary outcomes include clinical measures (proportion of people meeting the Australian guideline-recommended blood pressure and cholesterol targets), lifestyle outcomes (smoking rates, achievement of national guidelines for nutrition and physical activity), quality of life, mood (Hospital Anxiety and Depression Scale), medication adherence and attendance at and completion of rehabilitation., Ethics and Dissemination: Primary ethics approval was received from the Sydney Local Health District Hospital Human Research Ethics Committee and associated Governance committees at sites. Results will be disseminated via the usual scientific forums including peer-reviewed publications and presentations at international conferences. At its conclusion, the study will determine the effectiveness and implementation of a simple programme that aims to improve health outcomes and attendance at rehabilitation for people with CVD and chronic respiratory disease., Trial Registration Number: ACTRN12616001167459., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We aimed to evaluate the effects on depression scores of a lifestyle-focused cardiac support programme delivered via mobile phone text messaging among patients with coronary heart disease (CHD)., Design: Substudy and secondary analysis of a parallel-group, single-blind randomised controlled trial of patients with CHD., Setting: A tertiary hospital in Sydney, Australia., Intervention: The Tobacco, Exercise and dieT MEssages programme comprised four text messages per week for 6 months that provided education, motivation and support on diet, physical activity, general cardiac education and smoking, if relevant. The programme did not have any specific mental health component., Outcomes: Depression scores at 6 months measured using the Patient Health Questionnaire-9 (PHQ-9). Treatment effect across subgroups was measured using log-binomial regression model for the binary outcome (depressed/not depressed, where depressed is any score of PHQ-9 ≥5) with treatment, subgroup and treatment by subgroup interaction as fixed effects., Results: Depression scores at 6 months were lower in the intervention group compared with the control group, mean difference 1.9 (95% CI 1.5 to 2.4, p<0.0001). The frequency of mild or greater depressive symptoms (PHQ-9 scores≥5) at 6 months was 21/333 (6.3%) in the intervention group and 86/350 (24.6%) in the control group (relative risk (RR) 0.26, 95% CI 0.16 to 0.40, p<0.001). This proportional reduction in depressive symptoms was similar across groups defined by age, sex, education, body mass index, physical activity, current smoking, current drinking and history of depression, diabetes and hypertension. In particular, the rates of PHQ-9 ≥5 among people with a history of depression were 4/44 (9.1%) vs 29/62 (46.8%) in intervention vs control (RR 0.19, 95% CI 0.07 to 0.51, p<0.001), and were 17/289 (5.9%) vs 57/288 (19.8%) among others (RR 0.30, 95% CI 0.18 to 0.50, p<0.001)., Conclusions: Among people with CHD, a cardiac support programme delivered via mobile phone text messaging was associated with fewer symptoms of mild-to-moderate depression at 6 months in the treatment group compared with controls., Trial Registration Number: ACTRN12611000161921., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The synovial fluid motion in an artificial hip joint is important in understanding the thermo-fluids effects that can affect the reliability of the joint, although it is difficult to be studied theoretically, as the modelling involves the viscous fluid interacting with a moving surface. A new analytical solution has been derived for the maximum induced fluid motion within a spherical gap with an oscillating lower surface and a stationary upper surface, assuming one-dimensional incompressible laminar Newtonian flow with constant properties, and using the Navier-Stokes equation. The resulting time-dependent motion is analysed in terms of two dimensionless parameters R and β , which are functions of geometry, fluid properties and the oscillation rate. The model is then applied to the conditions of the synovial fluid enclosed in the artificial hip joint and it is found that the motion may be described by a simpler velocity variation, whereby laying the foundation to thermal studies in the joint.

Tribbles pseudokinase 1 ( Trib1 ) is a negative regulator of CCAAT/enhancer binding protein α (C/EBPα) and is known to induce granulopoiesis while suppressing monocyte differentiation. Loss of Trib1 was previously shown to increase the neutrophil population in the spleen but lead to M2-like macrophage reduction. Because M2 macrophages are anti-inflammatory and promote tissue repair by producing fibrogenic factors, we investigated liver fibrosis in Trib1 -deficient mice. Interestingly, loss of Trib1 suppressed fibrosis in the CCl 4 -induced chronic liver injury model. Trib1 knockout increased neutrophils but had a minimal effect on the macrophage population in the liver. Hepatic expressions of neutrophil matrix metalloproteinases ( Mmp ) 8 and Mmp9 were increased, but the production of fibrogenic factors, including transforming growth factor β1, was not affected by loss of Trib1 . These results suggest that neutrophils are responsible for the suppression of fibrosis in Trib1 -deficient liver. Consistently, transplantation of Trib1 -deficient bone marrow cells into wild-type mice alleviated CCl 4 -induced fibrosis. Furthermore, expression of chemokine (C-X-C motif) ligand 1 ( Cxcl1 ) by adeno-associated viral vector in the normal liver recruited neutrophils and suppressed CCl 4 -induced fibrosis; infusion of wild-type neutrophils in CCl 4 -treated mice also ameliorated fibrosis. Using recombinant adeno-associated virus-mediated expression of Mmp8 and Mmp9 alleviated liver fibrosis. Finally, neutrophil depletion by infusion of Ly6G antibody significantly enhanced CCl 4 -induced fibrosis. Conclusion : While neutrophils are well known to exacerbate acute liver injury, our results demonstrate a beneficial role of neutrophils in chronic liver injury by promoting fibrolysis. ( Hepatology Communications 2018;2:703-717).

The goal for preterm infants is to achieve full oral feeds quickly and ultimately progress to full breastfeeding. Supplementary oral feeds are often given when the mother is not available to breastfeed. Bottles typically deliver milk in a different fashion compared to breastfeeding, which is thought to hamper transition to full breastfeeding. The aim of this study was to compare the sucking dynamics of preterm infants fed at the breast to feeding with an experimental novel teat (NT) designed to release milk only upon the application of vacuum. Simultaneous ultrasound imaging of the infant oral cavity and measurement of intra-oral vacuum was performed during a breastfeed and a feed with the NT. Test weighs were used to measure milk intake. Linear mixed effects models were performed to investigate differences by feed type, and simultaneous linear regression was performed to investigate individual patterns. Tongue movement was not different between breastfeeding and the NT. Intra-oral vacuums (median (interquartile range: IQR)) were significantly lower with the NT (Baseline vacuum: -5.8 mmHg (-11.0, 0.1); Peak: 40.0 mmHg (-54.6, -27.1)) compared to breastfeeding (Baseline: -31.1 mmHg (-60.0, -12.7); Peak: -106.2 mmHg (-153.0, -65.5)). Milk intake was significantly higher with the NT (33 mL (22.5, 42.5)) compared to the breastfeed (12 mL (3, 15.5)). The novel teat encouraged a similar tongue action to breastfeeding, and infants transferred a greater volume of milk with the novel teat. Intra-oral vacuums were lower in strength with the novel teat compared to the breast. Use of the novel teat for the training of sucking dynamics in preterm infants has the potential to improve breastfeeding success and requires further investigation., Competing Interests: The authors declare no conflict of interest and that Medela AG (Switzerland) provides an unrestricted research grant to Donna Geddes from which salaries to Donna Geddes and Anna Hepworth are paid. Medela AG provided a Top-up Scholarship for Zoya Gridneva and has provided speaker’s fees to Donna Geddes for educational lectures. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Background: Identifying simple, low-cost and scalable means of supporting lifestyle change and medication adherence for patients following a cardiovascular (CV) event is important., Objective: The TEXTMEDS (TEXT messages to improve MEDication adherence and Secondary prevention) study aims to investigate whether a cardiac education and support programme sent via mobile phone text message improves medication adherence and risk factor levels in patients following an acute coronary syndrome (ACS)., Study Design: A single-blind, multicentre, randomised clinical trial of 1400 patients after an ACS with 12 months follow-up. The intervention group will receive multiple weekly text messages that provide information, motivation, support to adhere to medications, quit smoking (if relevant) and recommendations for healthy diet and exercise. The primary endpoint is the percentage of patients who are adherent to cardioprotective medications and the key secondary outcomes are mean systolic blood pressure (BP) and low-density lipoprotein cholesterol. Secondary outcomes will also include total cholesterol, mean diastolic BP, the percentage of participants who are adherent to each cardioprotective medication class, the percentage of participants who achieve target levels of CV risk factors, major vascular events, hospital readmissions and all-cause mortality. The study will be augmented by formal economic and process evaluations to assess acceptability, utility and cost-effectiveness., Summary: The study will provide multicentre randomised trial evidence of the effects of a text message-based programme on cardioprotective medication adherence and levels of CV risk factors., Ethics and Dissemination: Primary ethics approval was received from Western Sydney Local Health District Human Research Ethics Committee (HREC2012/12/4.1 (3648) AU RED HREC/13/WMEAD/15). Results will be disseminated via peer-reviewed publications and presentations at international conferences., Trial Registration Number: ACTRN12613000793718; Pre-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The novel synthetic triterpenoid, bardoxolone methyl, has the ability to upregulate cytoprotective proteins via induction of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. This makes it a promising therapeutic agent in disease states characterized by dysregulated oxidative signalling. We have examined the effect of a Nrf2 activator, dihydro-CDDO-trifluoroethyl amide (DH404), a derivative of bardoxolone methyl, on post-infarct cardiac remodeling in rats., Methods/results: DH404, administered from day 2 post myocardial infarction (MI: 30min transient ischemia followed by reperfusion) resulted in almost complete protection against adverse ventricular remodeling as assessed at day 28 (left ventricular end-systolic area: sham 0.14±0.01cm 2 , MI vehicle 0.29±0.04cm 2 vs. MI DH404 0.18±0.02cm 2 , P<0.05); infarct size (21.3±3.4% MI vehicle vs. 10.9±2.3% MI DH404, P<0.05) with associated benefits on systolic function (fractional shortening: sham 71.9±2.6%, MI vehicle 36.2±1.9% vs. MI DH404 58.6±4.0%, P<0.05). These structural and functional benefits were associated with lower myocardial expression of atrial natriuretic peptide (ANP, P<0.01 vs. MI vehicle), and decreased fibronectin (P<0.01 vs. MI vehicle) in DH404-treated MI rats at 28 days. MI increased glutathionylation of endothelial nitric oxide synthase (eNOS) in vitro - a molecular switch that uncouples the enzyme, increasing superoxide production and decreasing nitric oxide (NO) bioavailability. MI-induced eNOS glutathionylation was substantially ameliorated by DH404. An associated increase in glutaredoxin 1 (Grx1) co-immunoprecipitation with eNOS without a change in expression was mechanistically intriguing. Indeed, in parallel in vitro experiments, silencing of Grx1 abolished the protective effect of DH404 against Angiotensin II-induced eNOS uncoupling., Conclusion: The bardoxolone derivative DH404 significantly attenuated cardiac remodeling post MI, at least in part, by re-coupling of eNOS and increasing the functional interaction of Grx1 with eNOS. This agent may have clinical benefits protecting against post MI cardiomyopathy., (Copyright © 2017. Published by Elsevier Inc.)

We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2 V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFR C329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2 V617F -positive clone in this PV patient harbors EGFR C329R , thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN samples, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2 V617F disease clone in MPN.

Purpose of Review: Many cases of CVD may be avoidable through lowering behavioural risk factors such as smoking and physical inactivity. Mobile health (mHealth) provides a novel opportunity to deliver cardiovascular prevention programs in a format that is potentially scalable. Here, we provide an overview of text messaging-based mHealth interventions in cardiovascular prevention., Recent Findings: Text messaging-based interventions appear effective on a range of behavioural risk factors and can effect change on multiple risk factors-e.g. smoking, weight, blood pressure-simultaneously. For many texting studies, there are challenges in interpretation as many texting interventions are part of larger complex interventions making it difficult to determine the benefits of the separate components. Whilst there is evidence for text messaging improving cardiovascular risk factor levels in the short-term, future studies are needed to examine the durability of these effects and whether they can be translated to improvements in clinical care and outcomes.

COSMIC (http://cancer.sanger.ac.uk) is an expert-curated database of somatic mutations in human cancer. Broad and comprehensive in scope, recent releases in 2016 describe over 4 million coding mutations across all human cancer disease types. Mutations are annotated across the entire genome, but expert curation is focused on over 400 key cancer genes. Now encompassing the majority of molecular mutation mechanisms in oncogenetics, COSMIC additionally describes 10 million non-coding mutations, 1 million copy-number aberrations, 9 million gene-expression variants, and almost 8 million differentially methylated CpGs. This information combines a consistent interpretation of the data from the major cancer genome consortia and cancer genome literature with exhaustive hand curation of over 22,000 gene-specific literature publications. This unit describes the graphical Web site in detail; alternative protocols overview other ways the entire database can be accessed, analyzed, and downloaded. © 2016 by John Wiley & Sons, Inc., (Copyright © 2016 John Wiley & Sons, Inc.)

Early molecular response (EMR, BCR-ABL1 (IS)⩽10% at 3 months) is a strong predictor of outcome in imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients, but for patients who transform early, 3 months may be too late for effective therapeutic intervention. Here, we employed multiplex cytokine profiling of plasma samples to test newly diagnosed CP-CML patients who subsequently received imatinib treatment. A wide range of pro-inflammatory and angiogenesis-promoting cytokines, chemokines and growth factors were elevated in the plasma of CML patients compared with that of healthy donors. Most of these normalized after tyrosine kinase inhibitor treatment while others remained high in remission samples. Importantly, we identified TGF-α and IL-6 as novel biomarkers with high diagnostic plasma levels strongly predictive of subsequent failure to achieve EMR and deep molecular response, as well as transformation to blast crisis and event-free survival. Interestingly, high TGF-α alone can also delineate a poor response group raising the possibility of a pathogenic role. This suggests that the incorporation of these simple measurements to the diagnostic work-up of CP-CML patients may enable therapy intensity to be individualized early according to the cytokine-risk profile of the patient.

Aim: To investigate the prevalence and risk factors of delirium in an extended care unit, the persistence of delirium and 3-month outcome., Method: Patients aged >65 years were recruited. Basic demographic data, medical comorbidity using the Charlson Comorbidity Index, pre-existing cognitive impairment using the informant questionnaire on cognitive decline in the elderly, place of residence and physical function as measured by the modified Barthel Index were recorded. Delirium was assessed by the Confusion Assessment Method and Direct Observation Scale. Delirium status, physical function and placement were reassessed on discharge, and at 1 month and 3 months after discharge., Results: A total of 261 patients were recruited with a mean age of 81.9 years. Delirium was present in 89 participants (34.1%). Of these, 70 patients continued to be delirious on discharge. A total of 76 patients had persistent delirium at 1 month, and 49 remained to be delirious at 3 months. Pre-existing cognitive impairment (OR 9.12), use of psychoactive drugs (OR 3.61), presence of metabolic disturbances (OR 3.53), acute infection (OR 3.49) and old age home residents (OR 3.04) were associated with delirium on admission. A smaller number of delirium patients can return home on discharge, and they have poorer functional status on admission, at discharge, and at 1 month and 3 months after discharge. Unplanned hospital admission was significantly higher among the delirium group (42.9% vs 24.1%, P < 0.001)., Conclusion: Delirium in post-acute convalescence units is highly prevalent and persistent. It is associated with poor functional recovery, higher nursing home placement and unplanned hospital admission. These findings reinforce the necessity to implement a program to prevent, early detect and treat delirium in elderly patients admitted to post-acute care units. Geriatr Gerontol Int 2016; 16: 586-592., (© 2015 Japan Geriatrics Society.)

Objective: We aimed to determine if a novel feeding system where milk only flowed when the preterm infant created a vacuum would influence time to full oral feeds, the length of stay (LOS) in hospital and breastfeeding at discharge., Study Design: This was a randomized controlled trial in the tertiary neonatal intensive care unit at King Edward Memorial Hospital, Perth, Australia. Eligibility criteria were: preterm infants of gestational age 25 to 34 weeks receiving >75% human milk by gastric tube. Infants were randomly assigned to being fed with a novel teat (NT) or conventional teat (CT). Intention to treat analysis was performed., Result: Time to full suck feeds was not different between groups. LOS was shorter (mean: 2.5 days; P=0.026) and less formula was fed at discharge in the NT group (P=0.036)., Conclusion: Use of a NT that releases milk when the infant applies vacuum while establishing breastfeeding reduces duration of hospitalization of preterm infants.

Objective: The aim of the present study was to assess whether the outdoor areas of residential aged care facilities used for a sunlight intervention trial had the design features that encouraged participants' use of these spaces., Methods: The design principles recommended in the 'Vitamin D and the Built Environment in Victoria' guidelines were used to assess the outdoor spaces of residential aged care facilities that were used in a randomised controlled trial (RCT) of sunlight exposure. Attendance rates in the sunlight RCT were analysed in relation to global impression scores of the facilities using one-way analysis of variance., Results: Thirty-six outdoor areas of 31 facilities were assessed. The facilities met the guidelines for sun exposure, and were generally safe and accessible. However, many lacked privacy, security and aesthetic appeal. Most of the outdoor spaces were not used for regularly scheduled activities. Attendance rates were higher in those facilities with the highest global impression scores compared with those with the lowest scores (F(2,367) = 3.262, P = 0.039)., Conclusions: The physical environment of the outdoor areas of residential aged care facilities was associated with their use for sunlight exposure. Suitably designed or modified spaces have the potential to encourage their greater use, and residential aged care facilities should also plan regular activities in those areas. These measures can facilitate safe sun exposure, as well as physical activity and social interaction in older people.

Introduction: The Global Burden of Disease Study 2010 estimated the worldwide health burden of 291 diseases and injuries and 67 risk factors by calculating disability-adjusted life years (DALYs). Osteoporosis was not considered as a disease, and bone mineral density (BMD) was analysed as a risk factor for fractures, which formed part of the health burden due to falls., Objectives: To calculate (1) the global distribution of BMD, (2) its population attributable fraction (PAF) for fractures and subsequently for falls, and (3) the number of DALYs due to BMD., Methods: A systematic review was performed seeking population-based studies in which BMD was measured by dual-energy X-ray absorptiometry at the femoral neck in people aged 50 years and over. Age- and sex-specific mean ± SD BMD values (g/cm(2)) were extracted from eligible studies. Comparative risk assessment methodology was used to calculate PAFs of BMD for fractures. The theoretical minimum risk exposure distribution was estimated as the age- and sex-specific 90th centile from the Third National Health and Nutrition Examination Survey (NHANES III). Relative risks of fractures were obtained from a previous meta-analysis. Hospital data were used to calculate the fraction of the health burden of falls that was due to fractures., Results: Global deaths and DALYs attributable to low BMD increased from 103 000 and 3 125 000 in 1990 to 188 000 and 5 216 000 in 2010, respectively. The percentage of low BMD in the total global burden almost doubled from 1990 (0.12%) to 2010 (0.21%). Around one-third of falls-related deaths were attributable to low BMD., Conclusions: Low BMD is responsible for a growing global health burden, only partially representative of the real burden of osteoporosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Multiple myeloma (MM), a hematological malignancy characterized by the clonal growth of malignant plasma cells (PCs) in the bone marrow, is preceded by the benign asymptomatic condition, monoclonal gammopathy of undetermined significance (MGUS). Several genetic abnormalities have been identified as critical for the development of MM; however, a number of these abnormalities are also found in patients with MGUS, indicating that there are other, as yet unidentified, factors that contribute to the onset of MM disease. In this study, we identify a Samsn1 gene deletion in the 5TGM1/C57BL/KaLwRij murine model of myeloma. In addition, SAMSN1 expression is reduced in the malignant CD138+ PCs of patients with MM and this reduced expression correlates to total PC burden. We identify promoter methylation as a potential mechanism through which SAMSN1 expression is modulated in human myeloma cell lines. Notably, re-expression of Samsn1 in the 5TGM1 murine PC line resulted in complete inhibition of MM disease development in vivo and decreased proliferation in stromal cell-PC co-cultures in vitro. This is the first study to identify deletion of a key gene in the C57BL/KaLwRij mice that also displays reduced gene expression in patients with MM and is therefore likely to play an integral role in MM disease development., (Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Glutathionylation of endothelial nitric oxide synthase (eNOS) "uncouples" the enzyme, switching its function from nitric oxide (NO) to O2(•-) generation. We examined whether this reversible redox modification plays a role in angiotensin II (Ang II)-induced endothelial dysfunction., Methods and Results: Ang II increased eNOS glutathionylation in cultured human umbilical vein endothelial cells (HUVECs), rabbit aorta, and human arteries in vitro. This was associated with decreased NO bioavailability and eNOS activity as well as increased O2(•-) generation. Ang II-induced decrease in eNOS activity was mediated by glutathionylation, as shown by restoration of function by glutaredoxin-1. Moreover, Ang II-induced increase in O2(•-) and decrease in NO were abolished in HUVECs transiently transfected, with mutant eNOS rendered resistant to glutathionylation. Ang II effects were nicotinamide adenine dinucleotide phosphate (NADPH) oxidase dependent because preincubation with gp 91ds-tat, an inhibitor of NADPH oxidase, abolished the increase in eNOS glutathionylation and loss of eNOS activity. Functional significance of glutathionylation in intact vessels was supported by Ang II-induced impairment of endothelium-dependent vasorelaxation that was abolished by the disulfide reducing agent, dithiothreitol. Furthermore, attenuation of Ang II signaling in vivo by administration of an angiotensin converting enzyme (ACE) inhibitor reduced eNOS glutathionylation, increased NO, diminished O2(•-), improved endothelium-dependent vasorelaxation and reduced blood pressure., Conclusions: Uncoupling of eNOS by glutathionylation is a key mediator of Ang II-induced endothelial dysfunction, and its reversal is a mechanism for cardiovascular protection by ACE inhibition. We suggest that Ang II-induced O2(•-) generation in endothelial cells, although dependent on NADPH oxidase, is amplified by glutathionylation-dependent eNOS uncoupling.

Unlabelled: The aim of this study was to determine the vitamin D response to sunlight ultraviolet radiation in older people. Increases in vitamin D depended on the season of exposure, but the changes were small. Natural sun exposure is not a practical intervention for vitamin D deficiency in this population., Purpose: The purpose of this study is to measure the ultraviolet radiation (UVR) exposure of those in residential aged care in an earlier trial of sunlight exposure and to determine its effect on their vitamin D response., Methods: Attendance data, demographic, clinical and biochemical variables for 248 participants were used for a secondary analysis of a previous cluster randomized trial of sunlight exposure and falls. The ambient solar UV Index data were used to calculate the participants' UVR dose. Multiple linear regression was used to test if UVR exposure over 6 months, as measured by the standard erythemal dose (SED), was a predictor of vitamin D response, controlling for age, gender, BMI, calcium intake, baseline vitamin D and season of exposure., Results: The median 25-hydroxyvitamin D (25OHD) was 32.4 nmol/L at baseline and 34.6 nmol/L at 6 months (p = 0.35). The significant predictors of 25OHD at 6 months were UVR exposures in spring-summer (coefficient = 0.105, 95 % confidence interval (CI) 0.001-0.209, p = 0.05) and autumn-winter (coefficient = 0.056, 95 % CI 0.005-0.107, p = 0.03) and baseline vitamin D (adjusted coefficient = 0.594, 95 % CI 0.465-0.724, p = 0.00). In those starting sunlight sessions in spring, an increase of 1 unit in log SED was associated with 11 % increase in 25OHD., Conclusions: Natural UVR exposure can increase 25OHD levels in older people in residential care, but depends on the season of exposure. However, due to inadequate sun exposure, 25OHD did not reach optimal levels. Nevertheless, where sun exposure is encouraged in this group, the focus for the start of exposure should be in the months of spring or autumn, as this timing was associated with a vitamin D response.

Urea cycle defects presenting in the neonatal period with hyperammonaemia are associated with high morbidity and mortality, and necessitate liver transplantation for long-term management. Gene therapy is therefore an attractive possibility, with vectors based on adeno-associated virus (rAAV) currently showing exciting promise in liver-targeted clinical trials in adults. Successful use of rAAV vectors in infants, however, is more challenging as episomal rAAV genomes will be lost from proliferating hepatocytes during liver growth, leaving stable transgene expression dependent on the subset of vector genomes that undergo genomic integration. To explore this challenge, we exploited the partially ornithine transcarbamylase (OTC)-deficient spf(ash) mouse model and small hairpin RNA-mediated knockdown of residual endogenous OTC enzyme activity in adult mice that had received neonatal treatment with an OTC-encoding rAAV. This leaves mice reliant on vector-encoded OTC activity that has persisted from the newborn period. Despite stable transduction in approximately 8% of hepatocytes and residual vector-encoded OTC activity of up to 33% of wild-type, well above endogenous spf(ash) levels (5-7%), mice were not protected from hyperammonaemia. These data show that the distribution of OTC activity within the liver is critical and that rAAV vector re-delivery after early neonatal treatment is likely to be necessary for stable control of hyperammonaemia into adulthood.

Background: Increasing numbers of travelers using immunosuppressive drugs visit hepatitis A endemic countries. Data on protection rates after hepatitis A vaccination in this group are scarce., Methods: In this retrospective study, records of subjects with hepatitis A serology taken after vaccination were searched for in travel clinic databases. Relation between immunosuppressive drug use, age, gender, and time between vaccination and serology was evaluated., Results: Seroprotection rates within 4 weeks after primary vaccination (50%) are lower than after 4 weeks (64%). After the complete series of two vaccinations seroprotection rates reach 95% although success depends on the immunosuppressive drug being used. Subjects under anti-TNF alpha treatment have significantly lower seroprotection rates than subjects using classical immunosuppressive drugs after the second vaccination. There is no influence of age or gender on seroprotection rates., Conclusions: Last-minute vaccination in subjects using immunosuppressive medication is not reliable, only 60% of our subjects had a protective antibody level after a single vaccination. When serology was done within 4 weeks after a single vaccination, seroprotection rates were only 50%, after 4 weeks this number rose to 64%. When persons visit a travel clinic in time for a complete vaccination series, satisfactory seroprotection rates can be reached. Seroprotection rate depends on the drug being used, persons using anti-TNF alpha are less protected., (© 2013 International Society of Travel Medicine.)

Background: Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time., Methods: We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden., Findings: In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania., Interpretation: Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children., Funding: Bill & Melinda Gates Foundation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

This study aimed to explore whether recording of a prior adverse pregnancy outcome (postpartum hemorrhage) in a medical record increases the likelihood that recurrence of the same event is reported in hospital data. Using a sample of 588 pregnancies [2 consecutive pregnancies for 294 randomly selected women with at least one postpartum hemorrhage (PPH)], we compared 'coded' recurrence rates in hospital data with those obtained from medical record audit. 'Coded' recurrence in a second pregnancy was also compared for women with or without a documented history of prior PPH. We found a 'coded' recurrence rate of 18.5% and an 'audited' recurrence rate of 28.4%. The 'coded' rate of recurrence among women who had a documented history of PPH was 27.4% compared to 19.1% when the previous PPH was not noted in the second pregnancy medical record. Medical record reporting of uterine atony as the cause for postpartum hemorrhages in first and second births was 37.9 and 34.0% while 'coded' hospital data reporting attributed 79.8 and 73.9% respectively to atony. Our study results indicate that a history of postpartum hemorrhage may be a stronger risk factor for subsequent PPH than previously demonstrated. A recorded history of PPH was associated with an increased likelihood of reporting a subsequent PPH, and in such cases recurrence rates approximate true recurrence. The contribution of uterine atony as a cause of postpartum hemorrhage is over-estimated using hospital data.

Many metabolic diseases are compelling candidates for gene therapy, and are the subject of vigorous pre-clinical research. Successful phenotype correction in mouse models is now commonplace and research effort is increasingly being directed towards addressing the translational challenges inherent in human clinical trials. This paper places current efforts to develop gene therapy approaches to metabolic disease in historical context and describes contemporary research in the authors' laboratory on urea cycle defects, particularly ornithine transcarbamylase deficiency, in a manner that is illustrative of the general state of the field.

The prevalence of osteoporosis is expected to increase with the ageing of the world's population. This article reviews the epidemiology, risk factors and health burden of osteoporosis. In the Global Burden of Disease (GBD) Study 2005, osteoporosis is studied as a risk factor for fracture by considering the bone-mineral-density (BMD) measurement as the continuous exposure variable. We have performed a systematic review seeking population-based studies with BMD data measured by dual-X-ray absorptiometry (DXA). The femoral neck was selected as the unique location and all values were converted into Hologic(®) to enable inclusion of worldwide data for analysis. Provisional results on mean BMD values for different world regions are shown in age breakdowns for males and females 50 years or over, as well as mean T-scores using the young, white, female reference of National Health and Nutrition Examination Survey (NHANES) III. Results show remarkable geographical differences and a time trend towards improvement of the BMD values in Asian and European populations., (2010 Elsevier Ltd. All rights reserved.)