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Extending the charge cutoff voltage of LiCoO 2 (LCO) beyond 4.2 V is considered as a key parameter to obtain higher energy densities. Following gaps have been identified based on a thorough literature survey especially for higher cutoff voltage of nanoscale engineered LCO cathodes, (i) different metal oxides and metal fluoride surface coatings have been mostly done independently by different groups, (ii) room temperature performance was the focus with limited investigations at high temperature, (iii) nonexistence of low temperature cycling studies and (iv) no reports on high rate capability of LCO beyond 4.5 V (especially at 4.8 V) needs to be investigated. Herein, we report the effect of nanoscale engineering of LCO along with the role of coating chemistry and thickness to study its electrochemical performance at higher voltages and at wide operating temperatures. Surface coating was implemented with different metal oxides and a metal fluoride with tunable thickness. At 4.5 V, 5 wt% Al 2 O 3 coated LiCoO 2 (LCO@Al 2 O 3 -5) delivered a reversible capacity of 169 mAh g -1 at 100 mA g -1 and 151 mAh g -1 at high rate of 10 C (2 A g -1 ) and 72% retention at the end of 500 cycles. At 55 °C, it exhibited better stability over 500 cycles at 5 C and even at -12.5 °C it maintained 72% of its initial capacity after 100 cycles at 200 mA g -1 . At 4.8 V cut-off, LCO@Al 2 O 3 -5 rendered reversible capacity of 213 mAh g -1 at 100 mA g -1 , a high value compared to literatures reported for LCO. Also noted that it delivered a capacity of 126 mAh g -1 at a current density of 1 A g -1 , whereas bare could only exhibit 66 mAh g -1 under same testing conditions. Enhanced performance of LCO@Al 2 O 3 -5 can be ascribed to the lower charge transfer resistance derived from the stable solid solution formation on the interface. Ex situ XRD and ex situ Raman analysis at different stages of charge/discharge cycles correlates the enhanced performance of LCO@Al 2 O 3 -5 with its structural stability and minimal structural degradation., (© 2022 IOP Publishing Ltd.)

Background: Socioeconomic deprivation is associated with health inequality. Previous studies have described associations between primary care prescribing rates and deprivation for individual drugs or drug classes. We explore the correlation between socioeconomic deprivation and the rate of prescribing of individual pharmaceutical drugs, and drug classes, in primary care in England, to identify prescribing inequalities that would require further investigation., Methods: In this cross-sectional study, national primary care prescribing data, by primary care practice, were retrieved for the calendar year 2019 in England. Socioeconomic deprivation was quantified using the Index of Multiple Deprivation (IMD) score. Correlations were calculated using Spearman's rank correlation coefficient (ρ), adjusting for practice list size and demographics, with a Bonferroni-corrected p value threshold of 5×10 -5 ., Results: We included 1.05 billion prescription items dispensed from 6896 England practices. 142/206 (69%) drug classes and 505/774 (65%) drugs were significantly correlated with IMD score (p<5×10 -5 ). Of the 774 included drugs, 31 (4%) were moderately positively associated with IMD score (ρ>0.4). Only one was moderately negatively correlated with IMD score (ρ<-0.4), suggesting higher prescribing rates in more affluent areas. The drug classes most strongly associated with IMD score included opioid and non-opioid analgesics, antipsychotics and reflux medications. Drug classes most strongly associated with affluence included epinephrine, combined oral contraceptives and hormone replacement therapy., Conclusion: We identify novel associations of prescribing with deprivation. Further work is required to identify the underlying reasons for these associations so that appropriate interventions can be formulated to address drivers of inequality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

We conducted a scoping review of studies on health outcomes from electronic nicotine delivery systems (ENDS). The objective was to identify, narratively synthesize, assess the strength and quality of evidence and critically appraise studies that have reported disease end points associated with the use of ENDS. We included published literature on the health impact of ENDS from 01/01/2015 until 01/02/2020 following the PRISMA guidelines using PubMed, Embase, Scopus and Google Scholar. The database search identified 755 studies, and other sources 265; 37 studies met final eligibility criteria. Levels of evidence included 24(65%) cross-sectional, one (2.7%) case-control and six (16%) case studies, four (11%) cohort studies, one (2.7%) randomized controlled trial (RCT) and one (2.7%) meta-analysis; 27(73%) studies reported only on harms, eight (22%) reported on benefits, two (2%) on benefits and harms. Quality ratings were poor in 20 (54%), fair in 9(24%) and good in 8(22%) of studies. In our review, ENDS was not shown to be causative for harmful cardiovascular disease (CVD) outcomes and shown to be beneficial for hypertensive patients. Switching from cigarettes to e-cigarettes resulted in reduced exacerbations of chronic obstructive pulmonary disease (COPD), with no evidence of long-term deterioration in lung function. Mental Health, cancer and mortality were not adequately studied to form any consensus. Our review has not demonstrated ENDS to be causative of harmful CVD outcomes; furthermore switching from cigarettes to e-cigarettes was associated with improved hypertensive control and reduced exacerbations of COPD, with no evidence of increased asthma risk or long-term respiratory harm. Mental health, cancer and mortality outcomes have not been adequately studied to form a conclusion. Overall, the findings of our review did not provide evidence to counter the consensus held by many that ENDS use is safer than the risks posed from smoking cigarettes., (© 2021. The Author(s).)

In the present study, a protocol was developed for processing of human adipose derived mesenchymal stem cell secretome formulation of varying concentration. Its molecular composition was evaluated, and its effectiveness in vitro using breast cancer cell lines, and in vivo in a nude mice breast cancer model was studied to determine its role in suppressing triple negative breast cancer in a dose dependent manner. Because the secretome could have value as an add-on therapy along with a current drug, the effectiveness of the secretome both in monotherapy and in combination therapy along with paclitaxel was evaluated. The results showed significant cell kill when exposed to the secretome above 20 mg/ml at which concentration there was no toxicity to normal cells. 70 mg/ml of SF showed 90 ± 10% apoptosis and significant decrease in CD44 + /CD24 - , MDR1+ and PDL-1+ cancer cells. In vivo, the tumor showed no growth after daily intra tumor injections at 50 mg/ml and 100 mg/ml doses whereas substantial tumor growth occurred after saline intra tumor injection. The study concludes that SF is a potential biotherapeutic for breast cancer and could be used initially as an add-on therapy to other standard of care to provide improved efficacy without other adverse effects., (© 2021. The Author(s).)

Objectives: Review evidence is lacking about how contraception is affected by severe social disruption, such as that caused by the COVID-19 pandemic. The purpose of this scoping review was to explore the impact of natural and man-made disasters on contraception in OECD member countries., Methods: Manual searches and systematic searches in six electronic databases were conducted with no language restrictions. All articles were screened by at least two researchers. The data were analysed thematically., Results: 108 articles were included. Most focussed on the Zika virus outbreak ( n  = 50) and the COVID-19 pandemic ( n  = 28). Four key themes were identified: importance of contraception during disasters, impact of disasters on contraceptive behaviour, barriers to contraception during disasters and ways of improving use of contraception during disasters. Despite efforts to increase access to contraception including by transforming ways of delivery, barriers to use meant that unmet need persisted., Conclusions: To prevent adverse health outcomes and reduce health costs as a result of failure to have access to contraception during disasters, there is a need to intensify efforts to remove barriers to use. This should include increasing access and information on methods of contraception and their side effects (e.g., menstrual suppression) and making contraception freely available.

Early detection of liver tumors and cirrhotic lesions by magnetic resonance imaging (MRI) remains a great challenge. Here, we report a biomineral nanocontrast agent based on iron-doped nanocalcium phosphate (nCP:Fe-CA) for magnetic resonance imaging of early-stage liver cirrhotic and hepatocellular carcinoma nodules using rat models. We have optimized an intravenously injectable, aqueous suspension of nCP:Fe-CA having an average size of 137.6 nm, a spherical shape, magnetic relaxivity of 63 mM -1 S -1 , and colloidal stability for 48 h, post-resuspension in an aqueous phase. Compared to superparamagnetic iron oxide nanoparticles (SPIONs), the optimized nCP:Fe-CA could detect liver tumor lesions as small as ∼0.25 cm, whereas the current clinical detection limit is ∼1 cm. In addition, multiple cirrhotic nodules of size <0.2 cm could be detected by nCP:Fe-CA-assisted MRI. The number of nodules observed after injecting nCP:Fe-CA was ∼3 times higher than that without CA (5-10 nodules). A biocompatibility study on healthy rats injected with nCP:Fe-CA showed unaltered liver transaminases, blood urea nitrogen, serum creatinine, and insignificant hemolysis. Furthermore, hepatobiliary clearance of nCP:Fe-CA was observed in 72 h compared to prolonged retention of SPIONs for 30 days when tested under identical conditions. Overall, the nCP:Fe-CA nanoparticles showed promising results as a biocompatible, MR contrast (T2) agent for the early-stage imaging of liver cirrhosis and hepatocellular carcinoma.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been predominantly respiratory. This study aimed to evaluate the presence of virus in non-airborne body fluids as transmission vehicles. Medline, EMBASE, and Cochrane Library databases were searched from December 01, 2019, to July 01, 2020, using terms relating to SARS-CoV-2 and non-airborne clinical sample sources (feces, urine, blood, serum, serum, and peritoneum). Studies in humans, of any design, were included. Risk of bias assessment was performed using the Quality Assessment of Diagnostic Accuracy 2 tool. Preferred Reporting Items for Systematic Reviews & Meta-Analyses) guidelines were used for abstracting data. If ≥5 studies reported proportions for the same non-respiratory site, a meta-analysis was conducted using either a fixed or random-effects model, depending on the presence of heterogeneity. A total of 22 studies with 648 patients were included. Most were cross-sectional and cohort studies. The SARS-CoV-2 RNA was most frequently detected in feces. Detectable RNA was reported in 17% of the blood samples, 8% of the serum, 16% in the semen, but rarely in urine. Prevalence of SARS-CoV-2 in non-airborne sites varies widely with a third of non-airborne fluids. Patients with bowel and non-specific symptoms have persistence of virus in feces for upto 2 weeks after symptom resolution. Although there was a very low detection rate in urine, given the more frequent prevalence in blood samples, the presence of SARS-CoV-2 in patients with disrupted urothelium or undergoing urinary tract procedures, is likely to be higher. Healthcare providers need to consider non-airborne transmission and persistence of SARS-CoV-2 in body fluids to enable appropriate precautions to protect healthcare workers and carers.

Background: In March 2018, NHS England published guidance for clinical commissioning groups (CCGs) to encourage implementation of policy to reduce primary care prescriptions of over-the-counter medications, including simple analgesia., Aim: To investigate the impact of guidance publication on prescribing rates of simple analgesia (oral paracetamol, oral ibuprofen, and topical non-steroidal anti-inflammatory drugs) in primary care; CCG guidance implementation intentions; and whether the guidance has created health inequality based on socioeconomic status., Design and Setting: Interrupted time series analysis of primary care prescribing data in England., Method: Practice-level prescribing data from January 2015 to March 2019 were obtained from NHS Digital. Interrupted time series analyses were used to assess the association of guidance publication with prescribing rates. The association between practice-level prescribing rates and Index of Multiple Deprivation scores before and after publication was quantified using multivariable Poisson regression. Freedom of information requests were submitted to all CCGs., Results: There was a statistically significant 4.4% reduction in prescribing of simple analgesia following guidance publication (adjusted incidence rate ratio 0.96, 95% CI = 0.92 to 0.99, P = 0.027), adjusting for underlying time trend and seasonality. There was considerable diversity across CCGs in whether or how they chose to implement the guidance. Practice-level prescribing rates were greater in more deprived areas., Conclusion: Guidance publication was associated with a small reduction in the prescribing rates of simple analgesia across England, without evidence of creating additional health inequality. Careful implementation by CCGs would be required to optimise cost saving to the NHS., (© The Authors.)

Background : High levels of antimicrobial resistance (AMR) in Ghana require the exploration of new approaches to optimise antimicrobial prescribing. This study aims to establish the feasibility of implementation of different delayed/back-up prescribing models on antimicrobial prescribing for upper respiratory tract infections (URTIs). Methods : This study was part of a quality improvement project at LEKMA Hospital, Ghana, (Dec 2019-Feb 2020). Patients meeting inclusion criteria were assigned to one of four groups (Group 0: No prescription given; Group 1; Patient received post-dated antibiotic prescription; Group 2: Offer of a rapid reassessment of patient by a nurse practitioner after 3 days; and Group 3: Post-dated prescription forwarded to hospital pharmacy). Patients were contacted 10 days afterwards to ascertain wellbeing and actions taken, and patients were asked rate the service on a Likert scale. Post-study informal discussions were conducted with hospital staff. Results: In total, 142 patients met inclusion criteria. Groups 0, 1, 2 and 3 had 61, 16, 44 and 21 patients, respectively. Common diagnosis was sore throat (73%). Only one patient took antibiotics after 3 days. Nearly all (141/142) patients were successfully contacted on day 10, and of these, 102 (72%) rated their experiences as good or very good. Informal discussions with staff revealed improved knowledge of AMR. Conclusions: Delayed/back-up prescribing can reduce antibiotic consumption amongst outpatient department patients with suspected URTIs. Delayed/back-up prescribing can be implemented safely in low and middle-income countries (LMICs).

Introduction: Globally, a record number of people are affected by humanitarian crises caused by conflict and natural disasters. Many such populations live in settings where epidemiological transition is underway. Following the United Nations high level meeting on non-communicable diseases, the global commitment to Universal Health Coverage and needs expressed by humanitarian agencies, there is increasing effort to develop guidelines for the management of hypertension in humanitarian settings. The objective was to investigate the prevalence and incidence of hypertension in populations directly affected by humanitarian crises; the cascade of care in these populations and patient knowledge of and attitude to hypertension., Methods: A literature search was carried out in five databases. Grey literature was searched. The population of interest was adult, non-pregnant, civilians living in any country who were directly exposed to a crisis since 1999. Eligibility assessment, data extraction and quality appraisal were carried out in duplicate., Results: Sixty-one studies were included in the narrative synthesis. They reported on a range of crises including the wars in Syria and Iraq, the Great East Japan Earthquake, Hurricane Katrina and Palestinian refugees. There were few studies from Africa or Asia (excluding Japan). The studies predominantly assessed prevalence of hypertension. This varied with geography and age of the population. Access to care, patient understanding and patient views on hypertension were poorly examined. Most of the studies had a high risk of bias due to methods used in the diagnosis of hypertension and in the selection of study populations., Conclusion: Hypertension is seen in a range of humanitarian settings and the burden can be considerable. Further studies are needed to accurately estimate prevalence of hypertension in crisis-affected populations throughout the world. An appreciation of patient knowledge and understanding of hypertension as well as the cascade of care would be invaluable in informing service provision., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Concerns have been raised that women from deprived backgrounds are less likely to be receiving hormone replacement therapy (HRT) treatment and its benefits, although evidence in support of this is lacking., Aim: To investigate general practice HRT prescription trends and their association with markers of socioeconomic deprivation., Design and Setting: Cross-sectional study of primary care prescribing data in England in 2018., Method: Practice-level prescribing rate was defined as the number of items of HRT prescribed per 1000 registered female patients aged ≥40 years. The association between Index of Multiple Deprivation (IMD) score and HRT prescribing rate was tested using multivariate Poisson regression, adjusting for practice proportions of obesity, smoking, hypertension, diabetes, coronary heart disease and cerebrovascular disease, and practice list size., Results: The overall prescribing rate of HRT was 29% lower in practices from the most deprived quintile compared with the most affluent (incidence rate ratio [IRR] = 0.71; 95% confidence interval [CI] = 0.68 to 0.73). After adjusting for all cardiovascular disease outcomes and risk factors, the prescribing rate in the most deprived quintile was still 18% lower than in the least deprived quintile (adjusted IRR = 0.82; 95% CI = 0.77 to 0.86). In more deprived practices, there was a significantly higher tendency to prescribe oral HRT than transdermal preparations ( P <0.001)., Conclusion: This study highlights inequalities associated with HRT prescription. This may reflect a large unmet need in terms of menopause care in areas of deprivation. Further research is needed to identify the factors from patient and GP perspectives that may explain this., (© British Journal of General Practice 2020.)

Background: Benzodiazepines and Z-drugs (such as zopiclone) are widely prescribed in primary care. Given their association with addiction and dependence, understanding where and for whom these medications are being prescribed is a necessary step in addressing potentially harmful prescribing., Objective: To determine whether there is an association between primary care practice benzodiazepine and Z-drug prescribing and practice population socioeconomic status in England., Methods: This was a cross-sectional study. An aggregated data set was created to include primary care prescribing data for 2017, practice age and sex profiles and practice Index of Multiple Deprivation (IMD) scores-a marker of socioeconomic status. Drug doses were converted to their milligram-equivalent of diazepam to allow comparison. Multiple linear regression was used to examine the association between IMD and prescribing (for all benzodiazepines and Z-drugs in total, and individually), adjusting for practice sex (% male) and older age (>65 years) distribution (%)., Results: Benzodiazepine and Z-drug prescribing overall was positively associated with practice-level IMD score, with more prescribing in practices with more underserved patients, after adjusting for age and sex (P < 0.001), although the strength of the association varied by individual drug. Overall, however, IMD score, age and sex only explained a small proportion of the overall variation in prescribing across GP practices., Conclusion: Our findings may, in part, be a reflection of an underlying association between the indications for benzodiazepine and Z-drug prescribing and socioeconomic status. Further work is required to more accurately define the major contributors of prescribing variation., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Between 11-13 December 2018, local public health authorities in the West Midlands, England were alerted to 34 reports of diarrhoea with abdominal cramps. Symptom onset was ~10 h after diners ate Christmas meals at a restaurant between 7-9 December 2018. A retrospective case-control study, environmental and microbiological investigations were undertaken to determine the source and control the outbreak. An analytical study was undertaken with odds ratios (OR) and 95% confidence intervals (CI). Forty persons were recruited to the analytical study (28/40 cases). Multivariable analysis found that leeks in cheese sauce was the only item associated with illness (aOR 51.1; 95% CI 4.13-2492.1). Environmental investigations identified significant lapses in food safety, including lapses in temperature control during cooking and hot holding, likely cross-contamination between raw and cooked foods and the reuse of leftover cheese sauce for the next day's service. No food samples were taken during the exposure period. Two faecal samples were positive for Clostridium perfringens with one confirming the enterotoxigenic gene. Cheese sauce is an unusual vehicle for the organism and the first time this has been reported in England.

Materials with high-power charge-discharge capabilities are of interest to overcome the power limitations of conventional Li-ion batteries. In this study, a unique solvothermal synthesis of Li 4 Ti 5 O 12 nanoparticles is proposed by using an off-stoichiometric precursor ratio. A Li-deficient off-stoichiometry leads to the coexistence of phase-separated crystalline nanoparticles of Li 4 Ti 5 O 12 and TiO 2 exhibiting reasonable high-rate performances. However, after the solvothermal process, an extended aging of the hydrolyzed solution leads to the formation of a Li 4 Ti 5 O 12 nanoplate-like structure with a self-assembled disordered surface layer without crystalline TiO 2 . The Li 4 Ti 5 O 12 nanoplates with the disordered surface layer deliver ultrahigh-rate performances for both charging and discharging in the range of 50-300C and reversible capacities of 156 and 113 mAh g -1 at these two rates, respectively. Furthermore, the electrode exhibits an ultrahigh-charging-rate capability up to 1200C (60 mAh g -1 ; discharge limited to 100C). Unlike previously reported high-rate half cells, we demonstrate a high-power Li-ion battery by coupling Li 4 Ti 5 O 12 with a high-rate LiMn 2 O 4 cathode. The full cell exhibits ultrafast charging/discharging for 140 and 12 s while retaining 97 and 66% of the anode theoretical capacity, respectively. Room- (25 °C), low- (- 10 °C), and high- (55 °C) temperature cycling data show the wide temperature operation range of the cell at a high rate of 100C.

In vivo tracking of transplanted stem cells to monitor their migration, biodistribution, and engraftment in the host tissue is important for assessing the efficacy of stem cell therapeutics. Here, we report a biomineral nanocontrast agent, iron doped calcium phosphate nanoparticles (nCP:Fe), for the in vivo tracking of stem cells in brain using magnetic resonance imaging (MRI). We have synthesized ∼100 nm sized nCP nanoparticles doped with 9.81 wt % Fe 3+ . In vitro studies using mesenchymal stem cells (MSCs) showed excellent biocompatibility for nCP:Fe with ∼87% labeling efficiency under optimized conditions (100 μg/mL, 6 h). Most importantly, the labeling was not found to affect the neurogenic differentiation potential of MSCs. MRI of labeled cells (∼22.34 pg Fe/cell) showed significant reduction in T2 relaxation time from 195 to 89 ms, rendering dark contrast. In vivo transplantation of labeled cells (1 × 10 6 cells) in external capsule of healthy rat brain showed a clearly distinguishable hypointense (dark) region in T2 weighted MR images, which remained visible up to 30 days. Subsequently, MRI tracking of labeled MSCs transplanted intracerebrally, 3 mm near to the LPS induced inflammatory site in brain, showed successful migration of labeled MSCs toward the site of inflammation. The cell migration was confirmed ex vivo by Prussian-blue (Fe 3+ ) and Alizarin-red (Ca 2+ ) staining of tissue sections, where individual cells were found migrated to the site of inflammation over a period of 30 days. In summary, our results clearly show that, as a biocompatible mineral composition, nCP:Fe is a promising magnetic nanocontrast agent for MRI based cell tracking in vivo.

MicroRNA-15a (miR-15a) and miR-16, which are transcribed from the miR-15a/miR-16-1 cluster, inhibit post-ischemic angiogenesis. MicroRNA (miRNA) binding to mRNA coding sequences (CDSs) is a newly emerging mechanism of gene expression regulation. We aimed to (1) identify new mediators of the anti-angiogenic action of miR-15a and -16, (2) develop an adenovirus (Ad)-based miR-15a/16 decoy system carrying a luciferase reporter (Luc) to both sense and inhibit miR-15a/16 activity, and (3) investigate Ad.Luc-Decoy-15a/16 therapeutic potential in a mouse limb ischemia (LI) model. LI increased miR-15a and -16 expression in mouse muscular endothelial cells (ECs). The miRNAs also increased in cultured human umbilical vein ECs (HUVECs) exposed to serum starvation, but not hypoxia. Using bioinformatic tools and luciferase activity assays, we characterized miR-15a and -16 binding to Tie2 CDS. In HUVECs, miR-15a or -16 overexpression reduced Tie2 at the protein, but not the mRNA, level. Conversely, miR-15a or -16 inhibition improved angiogenesis in a Tie2-dependent manner. Local Ad.Luc-Decoy-15a/16 delivery increased Tie2 levels in ischemic skeletal muscle and improved post-LI angiogenesis and perfusion recovery, with reduced toe necrosis. Bioluminescent imaging (in vivo imaging system [IVIS]) provided evidence that the Ad.Luc-Decoy-15a/16 system responds to miR-15a/16 increases. In conclusion, we have provided novel mechanistic evidence of the therapeutic potential of local miR-15a/16 inhibition in LI., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Fabrication and testing of a novel nanostructured surface-enhanced Raman catheter device is reported for rapid detection, classification, and grading of normal, premalignant, and malignant tissues with high sensitivity and accuracy. The sensor part of catheter is formed by a surface-enhanced Raman scattering (SERS) substrate made up of leaf-like TiO 2 nanostructures decorated with 30 nm sized Ag nanoparticles. The device is tested using a total of 37 patient samples wherein SERS signatures of oral tissues consisting of malignant oral squamous cell carcinoma (OSCC), verrucous carcinoma, premalignant leukoplakia, and disease-free conditions are detected and classified with an accuracy of 97.24% within a short detection-cum-processing time of nearly 25-30 min per patient. Neoplastic grade changes detected using this device correlate strongly with conventional pathological data, enabling correct classification of tumors into three grades with an accuracy of 97.84% in OSCC. Thus, the potential of a SERS catheter device as a point-of-care pathological tool is shown for the rapid and accurate detection, classification, and grading of solid tumors., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: Although electronic cigarettes (e-cigarettes) and other tobacco-related products are becoming widely popular as alternatives to tobacco, little has been published on the knowledge of healthcare workers about their use. Thus, the aim of this study was to elicit the current knowledge and perceptions about e-cigarettes and tobacco harm reduction (THR) among medical residents in public health (MRPH)., Material and Methods: A Europe-wide cross-sectional study was carried out amongst MRPH from the countries associated with the European Network of MRPH from April to October 2018 using an online questionnaire., Results: 256 MRPHs agreed to participate in the survey. Approximately half the participants were women (57.4%), with a median age of 30 years, and were mainly Italian (26.7%), Spanish (16.9%) and Portuguese (16.5%). Smoking prevalence was 12.9%. Overall, risk scores significantly differed for each investigated smoking product when compared with e-cigarettes; with tobacco cigarettes and snus perceived as more risky, and nicotine replacement therapy (NRT) and non-NRT oral medications seen as less risky ( p < 0.01 for all). Regarding the effects of nicotine on health, the vast majority of MRPHs associated nicotine with all smoking-related diseases. Knowledge of THR was low throughout the whole sample., Conclusions: European MRPH showed a suboptimal level of knowledge about e-cigarettes and THR. Training programs for public health and preventive medicine trainees should address this gap.

This article was migrated. The article was marked as recommended. Introduction The People's Open Access Education Initiative (Peoples-uni) provides online education for health professionals in Public Health at the master's level. Although fees are low due to the use of volunteers and Open Educational Resources, a bursary scheme is provided to waive all or some of the fees. This study tests the hypothesis that student outcomes of completing and passing modules are higher among those given a bursary than others. Methods Data were retrieved for all students enrolling between 2009-2017, including demographics and module outcomes, where available. Multivariable logistic regression was used to identify factors associated with a successful bursary application, as well as to elicit whether a successful bursary application was associated with ever completing, or ever passing, a module. Results Data were obtained from 1499 students. Of these, 624 (42%) had ever completed a module, and 513 (34%) had ever passed a module. 503 students (34%) had applied for a bursary, of whom 285 (57%) were successful. After adjusting for demographic variables, employment status and education level, students who were given a bursary were more likely to ever pass a module (adjusted odds ratio [aOR] 2.3, 95% CI 1.7,3.3), as were those who applied for a bursary but were unsuccessful (aOR 1.9, 95% CI 1.3,2.8), compared with students who had not applied for a bursary. Similar results were obtained for the outcome of completing a module. Conclusions Students who were successful in gaining a bursary, as well as those who were not but still able to enroll, were more likely to complete or pass a module than those who did not apply. These results point to the success of the bursary scheme and give us confidence to continue to offer bursaries, in order to sustain the mission of improving population health through capacity building in low resource settings., (Copyright: © 2019 Machingura PI et al.)

Epidermal growth factor receptor variant III (EGFRvIII) is known to be specifically expressed in cancer cells and associated with tumor virulence. The receptor provides an opportunity for both specifically targeting the tumor cells as well as for potentially controlling and inhibiting tumor progression. In this study, humanized anti-EGFRvIII single-chain fragment variable (hscFv) was expressed in insect cell culture system to accommodate post-translational glycosylations crucial for the fragment stability and efficacy. Target specific binding of the developed fragment to EGFRvIII expressing cell lines and EGFRvIII positive glioblastoma patient samples was evaluated by immunocytochemistry and immunohistochemistry respectively. Downstream intracellular signaling mechanisms related to the action of the developed antibody fragment on growth/metabolism of the cell was evaluated in U87-EGFRvIII human glioblastoma cell lines. It was observed that the hscFv bound specifically to EGFRvIII in mutant expressing cells. Functionally, hscFv was found to confer anti-proliferative properties in EGFRvIII expressing cell lines by downregulating phosphorylation of EGFR/EGFRvIII, Lyn, PI3K and GLUT3 involved in proliferation and metabolism. This study demonstrated the significance of hscFv as a potential immunotherapeutic agent as well as a targeting agent for specific delivery of drugs to EGFRvIII expressing cancer cells., (Copyright © 2018. Published by Elsevier B.V.)

Background and Objectives: Chronic kidney disease (CKD) is a global health burden and is independently associated with increased cardiovascular disease risk. Assessment of cardiovascular risk in the general population using prognostic models based on routinely collected risk factors is embedded in clinical practice. In CKD, prognostic models may misrepresent risk due to the interplay of traditional atherosclerotic and non-traditional risk factors. This systematic review's aim was to identify routinely collected risk factors for inclusion in a CKD-specific cardiovascular prognostic model., Design, Setting, Participants and Measurements: Systematic review and meta-analysis of observational cohort studies and randomized controlled trials. Studies identified from MEDLINE and Embase searches using a pre-defined and registered protocol (PROSPERO ID-2016:CRD42016036187). The main inclusion criteria were individuals ≥18 years of age with non-endstage CKD. Routinely collected risk factors where multi-variable adjustment for established cardiovascular risk factors had occurred were extracted. The primary outcome was fatal and non-fatal cardiovascular events., Results: The review of 3,232, abstracts identified 29 routinely collected risk factors of which 20 were presented in more than 1 cohort. 21 cohorts were identified in relation to 27,465 individuals and 100,838 person-years. In addition to established traditional general population cardiovascular risk factors, left ventricular hypertrophy, serum albumin, phosphate, urate and hemoglobin were all found to be statistically significant in their association with future cardiovascular events., Conclusions: These non-traditional risk factors should be assessed in the development of future cardiovascular prognostic models for use in individuals with CKD.

Theranostic nanoparticles based on biocompatible mineral compositions can significantly improve the translational potential of image guided cancer nano-therapy. Here, we report development of a single-phase calcium phosphate biomineral nanoparticle (nCP) with dual-mode magnetic resonance contrast (T1-T2) together with radiofrequency (RF) mediated thermal response suitable for image-guided RF ablation of cancer. The nanoparticles (NP) are engineered to provide dual MR contrast by an optimized doping concentration (4.1 at%) of paramagnetic ion, Fe 3+ , which also renders lossy dielectric character for nCP leading to thermal response under RF exposure. In vivo compatibility and dual-mode MR contrast are demonstrated in healthy rat models. MRI and T2 mapping suggest hepatobiliary clearance by ~96 hours. MRI guided intratumoral injection in subcutaneous rat glioma and orthotopic liver tumor models provide clear visualization of NP in MRI which also helps in quantifying NP distribution within tumor. Furthermore, by utilising RF mediated thermal response, NP treated tumor could be ablated using clinically approved RF ablation system (10 W,13.3 GHz). Real-time in vivo thermal imaging exhibits 119 ± 10% increase in temperature change (ΔT) for NP treated orthotopic liver tumor (ΔT = 51.5 ± 2 °C), compared to untreated healthy liver control (ΔT = 21.5 ± 2 °C). In effect, we demonstrate a promising nano-biomineral theranostic agent for dual-mode MRI combined with radiofrequency ablation of solid tumors.

The pericardial fluid (PF) is contained in the pericardial sac surrounding the heart. MicroRNA (miRNA) exchange via exosomes (endogenous nanoparticles) contributes to cell-to-cell communication. We investigated the hypotheses that the PF is enriched with miRNAs secreted by the heart and that it mediates vascular responses through exosome exchange of miRNAs. The study was developed using leftover material from aortic valve surgery. We found that in comparison with peripheral plasma, the PF contains exosomes enriched with miRNAs co-expressed in patients' myocardium and vasculature. At a functional level, PF exosomes improved survival, proliferation, and networking of cultured endothelial cells (ECs) and restored the angiogenic capacity of ECs depleted (via Dicer silencing) of their endogenous miRNA content. Moreover, PF exosomes improved post-ischemic blood flow recovery and angiogenesis in mice. Mechanistically, (1) let-7b-5p is proangiogenic and inhibits its target gene, TGFBR1, in ECs; (2) PF exosomes transfer a functional let-7b-5p to ECs, thus reducing their TGFBR1 expression; and (3) let-7b-5p depletion in PF exosomes impairs the angiogenic response to these nanoparticles. Collectively, our data support the concept that PF exosomes orchestrate vascular repair via miRNA transfer., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors., Objective: To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin., Sources: MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions., Methods: Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers., Results: We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP)., Limitations: There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking., Conclusions: Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Boehringer Ingelheim, Bracknell, UK)., Funding: The National Institute for Health Research Health Technology Assessment programme.

This combinational therapy is mainly aimed for complete eradication of tumor by killing both cancer cells and cancer stem cells. Salinomycin (SLM) was targeted towards cancer stem cells whereas paclitaxel (PTX) was used to kill cancer cells. Drug loaded poly (lactic-co-glycolic acid) nanoparticles were prepared by emulsion solvent diffusion method using cationic stabilizer. Size of the nanoparticles (below 150nm) was determined by dynamic light scattering technique and transmission electron microscopy. In vitro release study confirmed the sustained release pattern of SLM and PTX from nanoparticles more than a month. Cytotoxicity studies on MCF-7 cells revealed the toxicity potential of nanoparticles over drug solutions. Hyaluronic acid (HA) was coated onto the surface of SLM nanoparticles for targeting CD44 receptors over expressed on cancer stem cells and they showed the highest cytotoxicity with minimum IC50 on breast cancer cells. Synergistic cytotoxic effect was also observed with combination of nanoparticles. Cell uptake studies were carried out using FITC loaded nanoparticles. These particles showed improved cellular uptake over FITC solution and HA coating further enhanced the effect by 1.5 folds. CD44 binding efficiency of nanoparticles was studied by staining MDA-MB-231 cells with anti CD44 human antibody and CD44(+) cells were enumerated using flow cytometry. CD44(+) cell count was drastically decreased when treated with HA coated SLM nanoparticles indicating their efficiency towards cancer stem cells. Combination of HA coated SLM nanoparticles and PTX nanoparticles showed the highest cytotoxicity against CD44(+) cells. Hence combinational therapy using conventional chemotherapeutic drug and cancer stem cell inhibitor could be a promising approach in overcoming cancer recurrence due to resistant cell population., (Copyright © 2016. Published by Elsevier B.V.)

Despite graphene being proposed for a multitude of biomedical applications, there is a dearth in the fundamental cellular and molecular level understanding of how few-layer graphene (FLG) interacts with human primary cells. Herein, using human primary umbilical vein endothelial cells as model of vascular transport, we investigated the basic mechanism underlying the biological behavior of graphene. Mechanistic toxicity studies using a battery of cell based assays revealed an organized oxidative stress paradigm involving cytosolic reactive oxygen stress, mitochondrial superoxide generation, lipid peroxidation, glutathione oxidation, mitochondrial membrane depolarization, enhanced calcium efflux, all leading to cell death by apoptosis/necrosis. We further investigated the effect of graphene interactions using cDNA microarray analysis and identified potential adverse effects by down regulating key genes involved in DNA damage response and repair mechanisms. Single cell gel electrophoresis assay/Comet assay confirmed the DNA damaging potential of graphene towards human primary cells., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Radiofrequency ablation (RFA) and doxorubicin (Dox) chemotherapy are separately approved for liver cancer therapy; however, both have limited success in the clinic due to suboptimal/nonuniform heating and systemic side effects, respectively. Here, we report a biodegradable nanoparticle (NP) system showing excellent RF hyperthermic response together with the ability to locally deliver Dox in the liver under RF trigger and control. The nanosystem was prepared by doping a clinically permissible dose (∼4.3 wt %, 0.03 ppm) of stannous ions in alginate nanoparticles (∼100 nm) coloaded with Dox at ∼13.4 wt % concentration and surface conjugated with galactose for targeting asialo-glycoprotein receptors in liver tumors. Targeted NP-uptake and increased cytotoxicity when combined with RF exposure was demonstrated in HEPG2 liver cancer cells. Following in vitro (chicken liver phantom) demonstration of locally augmented RF thermal response, in vivo scintigraphic imaging of 99 Tc-labeled NPs was performed to optimize liver localization in Sprague-Dawley (SD) rats. RF ablation was performed in vivo using a cooled-tip probe, and uniformly enhanced (∼44%) thermal ablation was demonstrated with magnetic resonance imaging along with RF-controlled Dox release. In orthotopic rat liver tumor models, real-time infrared imaging revealed significantly higher (∼20 °C) RF thermal response at the tumor site, resulting in uniform augmented ablation (∼80%) even at a low RF power exposure of 15 W for just 1 min duration. Being a clinically acceptable, biodegradable material, alginate nanoparticles hold strong translational potential for augmented RF hyperthermia combined with triggered drug release.

Introduction: Exosome nanoparticles carry a composite cargo, including microRNAs (miRs). Cultured cardiovascular cells release miR-containing exosomes. The exosomal trafficking of miRNAs from the heart is largely unexplored. Working on clinical samples from coronary-artery by-pass graft (CABG) surgery, we investigated if: 1) exosomes containing cardiac miRs and hence putatively released by cardiac cells increase in the circulation after surgery; 2) circulating exosomes and exosomal cardiac miRs correlate with cardiac troponin (cTn), the current "gold standard" surrogate biomarker of myocardial damage., Methods and Results: The concentration of exosome-sized nanoparticles was determined in serial plasma samples. Cardiac-expressed (miR-1, miR-24, miR-133a/b, miR-208a/b, miR-210), non-cardiovascular (miR-122) and quality control miRs were measured in whole plasma and in plasma exosomes. Linear regression analyses were employed to establish the extent to which the circulating individual miRs, exosomes and exosomal cardiac miR correlated with cTn-I. Cardiac-expressed miRs and the nanoparticle number increased in the plasma on completion of surgery for up to 48 hours. The exosomal concentration of cardiac miRs also increased after CABG. Cardiac miRs in the whole plasma did not correlate significantly with cTn-I. By contrast cTn-I was positively correlated with the plasma exosome level and the exosomal cardiac miRs., Conclusions: The plasma concentrations of exosomes and their cargo of cardiac miRs increased in patients undergoing CABG and were positively correlated with hs-cTnI. These data provide evidence that CABG induces the trafficking of exosomes from the heart to the peripheral circulation. Future studies are necessary to investigate the potential of circulating exosomes as clinical biomarkers in cardiac patients.

Objectives: The practice of open reporting and instituting a blame-free culture improves a system's ability to deal with risky processes, and the attitude of staff toward safety processes is a critical factor. We compared the attitudes and knowledge of incident reporting between junior physicians and nurses in a district general hospital., Methods: A questionnaire was designed to examine health care workers' attitudes toward reporting and errors. It also assessed knowledge of incident reporting and attitudes toward training in patient safety. Staff nurses (n = 50) and junior physicians (n = 50) were sampled on a voluntary basis and completed the survey online and anonymously., Results: Although similar proportions of each group knew a safety organization (70% of nurses versus 58% of physicians, P = 0.21), significantly more nurses had filled out an incident report (96% of nurses versus 52% of physicians, P < 0.001). The physicians felt that they did not have sufficient training in patient safety (66% of physicians versus 24% of nurses, P < 0.001), and consequently, fewer felt confident with patient safety issues (38% versus 72%, P < 0.001) The majority of all respondents agreed that incident reporting was beneficial (69%, P = 0.001), although a large proportion also felt that they would be blamed for errors (61%, P = 0.03)., Conclusions: This study suggests that junior physicians are lacking in confidence and disengaged with incident reporting. Nurses generally have a more positive and confident view toward patient safety issues and thus are more involved in reporting practices. Health care institutions should focus on promoting a safety culture in the organization through blame-free incident reporting systems. This should include ensuring that junior physicians obtain a comprehensive education in incident reporting and patient safety.

Background: Screening programmes can potentially identify people at high cardiovascular risk and reduce cardiovascular disease (CVD) morbidity and mortality. However, there is currently not enough evidence showing clear clinical or economic benefits of systematic screening-like programmes over the widely practised opportunistic risk assessment of CVD in primary care settings., Objectives: The primary objective of this review was to assess the effectiveness, costs and adverse effects of systematic risk assessment compared to opportunistic risk assessment for the primary prevention of CVD., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library, MEDLINE, EMBASE on 30 January 2015, and Web of Science Core Collection and additional databases on the Cochrane Library on 4 December 2014. We also searched two clinical trial registers and checked reference lists of relevant articles. We applied no language restrictions., Selection Criteria: We selected randomised controlled trials (RCTs) that assessed the effects of systematic risk assessment, defined as a screening-like programme involving a predetermined selection process of people, compared with opportunistic risk assessment which ranged from no risk assessment at all to incentivised case finding of CVD and related risk factors. Participants included healthy adults from the general population, including those who are at risk of CVD., Data Collection and Analysis: Two review authors independently selected studies. One review author extracted data and assessed them for risk of bias and a second checked them. We assessed evidence quality using the GRADE approach and present this in a 'Summary of findings' table., Main Results: Nine completed RCTs met the inclusion criteria, of which four were cluster-randomised. We also identified five ongoing trials. The included studies had a high or unclear risk of bias, and the GRADE ratings of overall quality were low or very low. The length of follow-up varied from one year in four studies, three years in one study, five or six years in two studies, and ten years in two studies. Eight studies recruited participants from the general population, although there were differences in the age ranges targeted. One study recruited family members of cardiac patients (high risk assessment). There were considerable differences between the studies in the interventions received by the intervention and control groups. There was insufficient evidence to stratify by the types of risk assessment approaches.Limited data were available on all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.92 to 1.02; 3 studies,103,571 participants, I² = 0%; low-quality evidence) and cardiovascular mortality (RR 1.00, 95% CI 0.90 to 1.11; 2 studies, 43,955 participants, I² = 0%), and suggest that screening has no effect on these outcomes. Data were also limited for combined non-fatal endpoints; overall, evidence indicates no difference in total coronary heart disease (RR 1.01, 95% CI 0.95 to 1.07; 4 studies, 5 comparisons, 110,168 participants, I² = 0%; low-quality evidence), non-fatal coronary heart disease (RR 0.98, 95% CI 0.89 to 1.09; 2 studies, 43,955 participants, I² = 39%), total stroke (RR 0.99, 95% CI 0.90 to 1.10; 2 studies, 79,631 participants, I² = 0%, low-quality evidence), and non-fatal stroke (RR 1.17, 95% CI 0.94 to 1.47; 1 study, 20,015 participants).Overall, systematic risk assessment appears to result in lower total cholesterol levels (mean difference (MD) -0.11 mmol/l, 95% CI -0.17 to -0.04, 6 studies, 7 comparisons, 12,591 participants, I² = 57%; very low-quality evidence), lower systolic blood pressure (MD -3.05 mmHg, 95% CI -4.84 to -1.25, 6 studies, 7 comparisons, 12,591 participants, I² = 82%; very low-quality evidence) and lower diastolic blood pressure (MD -1.34 mmHg, 95% CI -1.76 to -0.93, 6 studies, 7 comparisons, 12,591 participants, I² = 0%; low-quality evidence). One study assessed adverse effects and found no difference in psychological distress at five years (1126 participants)., Authors' Conclusions: The results are limited by the heterogeneity between trials in terms of participants recruited, interventions and duration of follow-up. Limited data suggest that systematic risk assessment for CVD has no statistically significant effects on clinical endpoints. There is limited evidence to suggest that CVD systematic risk assessment may have some favourable effects on cardiovascular risk factors. The completion of the five ongoing trials will add to the evidence base.

Radiofrequency ablation (RFA) is a clinically established therapy for hepatocellular carcinoma (HCC). However, because of poor radio-thermal conductivity of liver tissues, RFA is less efficient against relatively larger (>5 cm) liver tumors. Recently, nanoparticle-enabled RFA has emerged as a better strategy. On the basis of our recent understanding on biodegradability and novel electrothermal properties of graphene, herein, we report development of transferrin conjugated, biodegradable graphene (TfG) for RFA therapy. Cellular uptake studies using confocal microscopy and Raman imaging revealed significantly higher TfG uptake by HCC cells compared to bare graphene. TfG-treated cancer cells upon 5 min exposure to 100 W, 13.5 MHz RF showed >85% cell death, which was 4 times greater than bare graphene. Further evaluation in 3D (3 Dimensional) HCC culture system as well as in vivo rat models demonstrated uniform destruction of tumor cells throughout the 3D microenvironment. This study reveals the potential of molecularly targeted graphene for augmented RFA therapy of liver tumor.

The efficacy of protein-vorinostat nanomedicine (NV) is demonstrated in leukemic stem cells (LSC) isolated from refractory acute myeloid leukemia (AML) patient samples, where it successfully ablated both CD34 + CD38 - CD123 + LSC and non-LSC "leukemic blast" compartments, without inducing myelosuppression or hemotoxicity. Besides, NV also exerted excellent synergistic lethality against leukemic bone marrow cells (BMC) at lower concentrations (0.1 μM) in combination with DNA methyltransferase (DNMT) inhibitor, decitabine. Considering the extermination of resilient LSC and synergism with decitabine, NV shows promise for clinical translation in the setting of a more tolerable and effective epigenetic targeted therapy for leukemia.

Four organic donor-π-bridge-acceptor dyes containing phenothiazine as a spacer and cyanoacrylic acid as an acceptor were synthesized and tested as sensitizers in dye-sensitized solar cells (DSCs). The influence of iodide- and cobalt-based redox electrolytes on the photovoltaic device performance was investigated. In these new dyes, systematic π-conjugation was extended by inserting one or two phenothiazine moieties and investigated within the context of the resulting photoinduced charge-transfer properties. A detailed investigation, including transient absorption spectroscopy and quantum chemical methods, provided important information on the role of extended π-conjugation on the photophysical properties and photovoltaic device performance. Overall, the results showed that the extension of π-conjugation by one phenothiazine unit resulted in the best device performance owing to reduced recombination rates, whereas extension by two phenothiazine units reduced dye adsorption on TiO2 probably owing to the increase in molecular size. The performance of the dyes in DSCs was found to be a complex interaction between dye structure and size., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Porous nanohydroxyapatite (nanoHA) is a promising bone substitute, but it is brittle, which limits its utility for load bearing applications. To address this issue, herein, biodegradable electrospun microfibrous sheets of poly(L-lactic acid)-(PLLA)-polyvinyl alcohol (PVA) were incorporated into a gelatin-nanoHA matrix which was investigated for its mechanical properties, the physical integration of the fibers with the matrix, cell infiltration, osteogenic differentiation and bone regeneration. The inclusion of sacrificial fibers like PVA along with PLLA and leaching resulted in improved cellular infiltration towards the center of the scaffold. Furthermore, the treatment of PLLA fibers with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide enhanced their hydrophilicity, ensuring firm anchorage between the fibers and the gelatin-HA matrix. The incorporation of PLLA microfibers within the gelatin-nanoHA matrix reduced the brittleness of the scaffolds, the effect being proportional to the number of layers of fibrous sheets in the matrix. The proliferation and osteogenic differentiation of human adipose-derived mesenchymal stem cells was augmented on the fibrous scaffolds in comparison to those scaffolds devoid of fibers. Finally, the scaffold could promote cell infiltration, together with bone regeneration, upon implantation in a rabbit femoral cortical defect within 4 weeks. The bone regeneration potential was significantly higher when compared to commercially available HA (Surgiwear™). Thus, this biomimetic, porous, 3D composite scaffold could be offered as a promising candidate for bone regeneration in orthopedics.

Copper (Cu), an essential micronutrient, plays a fundamental role in inflammation and angiogenesis; however, its precise mechanism remains undefined. Here we uncover a novel role of Cu transport protein Antioxidant-1 (Atox1), which is originally appreciated as a Cu chaperone and recently discovered as a Cu-dependent transcription factor, in inflammatory neovascularization. Atox1 expression is upregulated in patients and mice with critical limb ischemia. Atox1-deficient mice show impaired limb perfusion recovery with reduced arteriogenesis, angiogenesis, and recruitment of inflammatory cells. In vivo intravital microscopy, bone marrow reconstitution, and Atox1 gene transfer in Atox1(-/-) mice show that Atox1 in endothelial cells (ECs) is essential for neovascularization and recruitment of inflammatory cells which release VEGF and TNFα. Mechanistically, Atox1-depleted ECs demonstrate that Cu chaperone function of Atox1 mediated through Cu transporter ATP7A is required for VEGF-induced angiogenesis via activation of Cu enzyme lysyl oxidase. Moreover, Atox1 functions as a Cu-dependent transcription factor for NADPH oxidase organizer p47phox, thereby increasing ROS-NFκB-VCAM-1/ICAM-1 expression and monocyte adhesion in ECs inflamed with TNFα in an ATP7A-independent manner. These findings demonstrate a novel linkage between Atox1 and NADPH oxidase involved in inflammatory neovascularization and suggest Atox1 as a potential therapeutic target for treatment of ischemic disease.

Obtaining functional capillaries through the bulk has been identified as a major challenge in tissue engineering, particularly for critical-sized defects. In the present study, a multilayered scaffold system was developed for bone tissue regeneration, designed for through-the-thickness vascularization of the construct. The basic principle of this approach was to alternately layer mesenchymal stem cell-seeded nanofibers (osteogenic layer) with microfibers or porous ceramics (osteoconductive layer), with an intercalating angiogenic zone between the two and with each individual layer in the microscale dimension (100-400 μm). Such a design can create a scaffold system potentially capable of spatially distributed vascularization in the overall bulk tissue. In the cellular approach, the angiogenic zone consisted of collagen/fibronectin gel with endothelial cells and pericytes, while in the acellular approach, cells were omitted from the zone without altering the gel composition. The cells incorporated into the construct were analyzed for viability, distribution, and organization of cells on the layers and vessel development in vitro. Furthermore, the layered constructs were implanted in the subcutaneous space of nude mice and the processes of vascularization and bone tissue regeneration were followed by histological and energy-dispersive X-ray spectroscopy (EDS) analysis. The results indicated that the microenvironment in the angiogenic zone, microscale size of the layers, and the continuously channeled architecture at the interface were adequate for infiltrating host vessels through the bulk and vascularizing the construct. Through-the-thickness vascularization and mineralization were accomplished in the construct, suggesting that a suitably bioengineered layered construct may be a useful design for regeneration of large bone defects.

Our previous in vivo study showed that multilayered scaffolds made of an angiogenic layer embedded between an osteogenic layer and an osteoconductive layer, with layer thickness in the 100-400 μm range, resulted in through-the-thickness vascularization of the construct even in the absence of exogenous endothelial cells. The angiogenic layer was a collagen-fibronectin gel, and the osteogenic layer was made from nanofibrous polycaprolactone while the osteoconductive layer was made either from microporous hydroxyapatite or microfibrous polycaprolactone. In this follow-up study, we implanted these acellular and cellular multilayered constructs in critical-sized rat calvarial defects and evaluated their vascularization and bone formation potential. Vascularization and bone formation at the defect were evaluated and quantified using microcomputed tomography (microCT) followed by perfusion of the animals with the radio opaque contrast agent, MICROFIL. The extent of bony bridging and union within the critical-sized defect was evaluated using a previously established scoring system from the microCT data set. Similarly the new bone formation in the defect was quantified from the microCT data set as previously reported. Histological evaluation at 4 and 12 weeks validated the microCT findings. Our experimental results showed that acellular multilayered scaffolds with microscale-thick nanofibers and porous ceramic discs with angiogenic zone at their interface can regenerate functional vasculature and bone similar to that of cellular constructs in critical-sized calvarial defects. This result suggests that suitably bioengineered acellular multilayered constructs can be an improved and more translational approach in functional in vivo bone regeneration.

The communication between vascular endothelial cells (ECs) and pericytes in the microvasculature is fundamental for vascular growth and homeostasis; however, these processes are disrupted by diabetes. Here we show that modulation of p75(NTR) expression in ECs exposed to high glucose activates transcription of miR-503, which negatively affects pericyte function. p75(NTR) activates NF-κB to bind the miR-503 promoter and upregulate miR-503 expression in ECs. NF-κB further induces activation of Rho kinase and shedding of endothelial microparticles carrying miR-503, which transfer miR-503 from ECs to vascular pericytes. The integrin-mediated uptake of miR-503 in the recipient pericytes reduces expression of EFNB2 and VEGFA, resulting in impaired migration and proliferation. We confirm operation of the above mechanisms in mouse models of diabetes, in which EC-derived miR-503 reduces pericyte coverage of capillaries, increased permeability and impaired post-ischaemic angiogenesis in limb muscles. Collectively, our data demonstrate that miR-503 regulates pericyte-endothelial crosstalk in microvascular diabetic complications.

Under ultralow radiofrequency (RF) power, transferrin-conjugated graphene nanoparticles can thermally ablate drug- or radiation-resistant cancer cells very effectively. The results suggest that graphene-based RF hyperthermia can be an efficient method to manage drug-/radiation-resistant cancers., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Development of parenteral nanoformulations is highly challenging due to the stringent demands on stability, reproducibility and high drug loading with minimal excipients. This study focuses on the development of a pharmaceutically acceptable nanomatrix system for parenteral delivery based on Hydroxyethyl Starch (HES), a FDA approved polymer that is relatively unexplored in drug delivery research. HES nanoparticles were prepared through a simple, two-step crosslinking-precipitation route, yielding 160±5 nm, nearly monodispersed spherical particles with high colloidal stability. The utility of this nanocarrier for parenteral delivery was verified by a panel of hemo/cytocompatibility assays at high concentrations (0.05-1 mg/ml) in vitro and in vivo. HES nanomatrix was found effective in encapsulating two chemically distinct drugs having varying hydrophobicities, with the release behavior being influenced by their chemical nature and drug-matrix interactions. Better in vitro efficacy was measured for the nanoencapsulated drug than its bare form, establishing the potential of HES nanocarriers for controlled drug delivery., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: Gestational diabetes mellitus (GDM) produces fetal hyperglycemia with increased lifelong risks for the exposed offspring of cardiovascular and other diseases. Epigenetic mechanisms induce long-term gene expression changes in response to in utero environmental perturbations. Moreover, microRNAs (miRs) control the function of endothelial cells (ECs) under physiological and pathological conditions and can target the epigenetic machinery. We investigated the functional and expressional effect of GDM on human fetal ECs of the umbilical cord vein (HUVECs). We focused on miR-101 and 1 of its targets, enhancer of zester homolog-2 (EZH2), which trimethylates the lysine 27 of histone 3, thus repressing gene transcription. EZH2 exists as isoforms α and β., Approach and Results: HUVECs were prepared from GDM or healthy pregnancies and tested in apoptosis, migration, and Matrigel assays. GDM-HUVECs demonstrated decreased functional capacities, increased miR-101 expression, and reduced EZH2- β and trimethylation of histone H3 on lysine 27 levels. MiR-101 inhibition increased EZH2 expression and improved GDM-HUVEC function. Healthy HUVECs were exposed to high or normal d-glucose concentration for 48 hours and then tested for miR-101 and EZH2 expression. Similar to GDM, high glucose increased miR-101 expression. Chromatin immunoprecipitation using an antibody for EZH2 followed by polymerase chain reaction analyses for miR-101 gene promoter regions showed that both GDM and high glucose concentration reduced EZH2 binding to the miR-101 locus in HUVECs. Moreover, EZH2-β overexpression inhibited miR-101 promoter activity in HUVECs., Conclusions: GDM impairs HUVEC function via miR-101 upregulation. EZH2 is both a transcriptional inhibitor and a target gene of miR-101 in HUVECs, and it contributes to some of the miR-101-induced defects of GDM-HUVECs., (© 2015 American Heart Association, Inc.)

Background: Endovascular aortic aneurysm repair (EVAR) has been associated with a reduction in early morbidity and mortality compared with open surgery, creating an opportunity for aneurysm repair in those previously considered unfit for intervention. We determine the published incidence of complications and survival after elective EVAR in nonagenarians., Methods: A systematic literature search was performed using the PubMed, EMBASE, and Cochrane databases up to December 2012. Two observers independently screened search results and extracted data., Results: Six retrospective reports were identified including 361 patients (81% men) with a mean age of 91.6 years. The mean aneurysm size was 69 mm. Comorbidities include hypertension (81%), ischemic heart disease (50%), peripheral vascular disease (30%), and chronic obstructive pulmonary disease (20%). There was no intraoperative mortality, 22% of patients had perioperative medical or surgical complications, and 24% had endoleaks. Mean duration of hospital stay was 4 days. Thirty-day mortality was 5%, and survival at 1, 3, and 5 years was 82%, 56%, and 17%, respectively., Conclusions: Although the complication rates and longer term survival after elective EVAR in carefully selected nonagenarians appear acceptable, they are higher than those reported in younger patients. Given the typical life expectancy, careful consideration should be given to individual cases before undertaking EVAR in the nonagenarian., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Guidance has been published on how best to report randomised controlled trials (Consolidated Standards of Reporting Trials - CONSORT) and systematic reviews (Preferred Reporting Items for Systematic Reviews and Meta-analysis - PRISMA). In 2011, we reported a low rate of enforcement by surgery journals for submitted manuscripts to conform to these guidelines. The aim of this follow-up study is to establish whether there has been any improvement., Methods: We studied the 134 surgery journals indexed in the Journal Citation Report. The 'Instructions to Authors' were scrutinised for inclusion of the following guidance: CONSORT, PRISMA, clinical trial registration and systematic review registration., Results: Compared to 2011, there has been an improvement in the endorsement of reporting guidance in journals' 'Instructions to Authors' in 2014, as follows: trial registration (42% vs 33%), CONSORT (42% vs 30%) and PRISMA (19% vs 10%, all p < 0.001). As in 2011, journals with a higher impact were more likely to adopt trial registration (p < 0.001), CONSORT (p < 0.001) and PRISMA (p = 0.002). Journals with editorial offices in the UK were more likely to endorse guidance compared to those outside the UK (p < 0.05). Only one journal mentioned registration for systematic reviews., Conclusions: Surgery journals are presently more likely to require submitted manuscripts to follow published reporting guidance compared to three years ago. However, overall concordance rates are still low, and an improvement is required to help enhance the quality of reporting - and ultimately the conduct - of randomised control trials and systematic reviews in surgery.

Introduction: Systematic reviews and meta-analyses are important in shaping clinical practice, but the underlying quality of these studies is critical. The PRISMA guidelines for the reporting of systematic reviews, published in 2009, aimed to improve the quality of reporting of these studies. We looked at whether the reporting of systematic reviews relevant to vascular surgery had improved since the introduction of these guidelines., Methods: All systematic reviews and meta-analyses published in the top five general and top five vascular surgery journals in the years 2008 (pre-PRIMSA) and 2012 (post-PRISMA) were included. We examined the proportion of concordance of each individual paper with the 27 PRISMA statements., Results: A total of 74 studies were found (n = 37 in 2008, n = 37 in 2012), most of which were found in the specific vascular surgery journals. The average proportion of concordance of systematic reviews to the PRISMA guidance increased between 2008 and 2012 (from 65% to 73%, p < 0.01), indicating some improvement in reporting quality., Discussion: Since the publication of the PRISMA guidance, there has been a marginal improvement in the quality of reporting of systematic reviews and meta-analyses in the field of vascular surgery. However, given the importance of these studies, this needs to be improved, especially as poor reporting may reflect poor methodology in conduct. Journals' instructions to authors should insist on submissions following the published guidance, and this intervention would likely improve both the methodology and quality of reporting of published systematic reviews., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Combinatorial drug delivery is an attractive, but challenging requirement of next generation cancer nanomedicines. Here, we report a transferrin-targeted core-shell nanomedicine formed by encapsulating two clinically used single-agent drugs, doxorubicin and sorafenib against liver cancer. Doxorubicin was loaded in poly(vinyl alcohol) nano-core and sorafenib in albumin nano-shell, both formed by a sequential freeze-thaw/coacervation method. While sorafenib from the nano-shell inhibited aberrant oncogenic signaling involved in cell proliferation, doxorubicin from the nano-core evoked DNA intercalation thereby killing >75% of cancer cells. Upon targeting using transferrin ligands, the nanoparticles showed enhanced cellular uptake and synergistic cytotoxicity in ~92% of cells, particularly in iron-deficient microenvironment. Studies using 3D spheroids of liver tumor indicated efficient penetration of targeted core-shell nanoparticles throughout the tissue causing uniform cell killing. Thus, we show that rationally designed core-shell nanoparticles can effectively combine clinically relevant single-agent drugs for exerting synergistic activity against liver cancer., From the Clinical Editor: Transferrin-targeted core-shell nanomedicine encapsulating doxorubicin and sorafenib was studied as a drug delivery system against hepatocellular carcinoma, resulting in enhanced and synergistic therapeutic effects, paving the way towards potential future clinical applications of similar techniques., (Copyright © 2014 Elsevier Inc. All rights reserved.)