Potential of Microneedles in Enhancing Delivery of Photosensitising Agents for Photodynamic Therapy

Photodynamic therapy can be used in the treatment of pre-malignant and malignant diseases. It offers advantages over other therapies currently used in the treatment of skin lesions including avoidance of damage to surrounding tissue and minimal or no scarring. Unfortunately, systemic delivery of photosensitising agents can result in adverse effects, such as prolonged cutaneous photosensitivity; while topical administration lacks efficacy in the clearance of deeper skin lesions and those with a thick overlying keratotic layer. Therefore, enhancement of conventional photosensitiser delivery is desired. However, the physicochemical properties of photosensitising agents, such as extreme hydrophilicity or lipophilicity and large molecular weights make this challenging. This paper reviews the potential of microneedles as a viable method to overcome these delivery-limiting physicochemical characteristics and discusses the current benefits and limitations of solid, dissolving and hydrogel-forming microneedles. Clinical studies in which microneedles have successfully improved photodynamic therapy are also discussed, along with benefits which microneedles offer, such as precise photosensitiser localisation, painless application and reduction in waiting times between photosensitiser administration and irradiation highlighted.

Supplementary feeding increases Common Buzzard Buteo buteo productivity but only in poor-quality habitat

Temporal heterogeneity in the effects of food supply during the breeding season on the productivity of the Common Buzzard Buteo buteo was investigated in a supplementary feeding experiment. Pairs were fed artificially (1) before egg-laying, (2) after chicks hatched and (3) continuously throughout the season, and compared with (4) unfed controls. Pairs fed before egg-laying had marginally larger clutches than those not fed, but lay date, egg volume and weight, brood size and hatching success were unaffected. Territorial quality had far greater effects, with pairs nesting in low-quality habitats (bog, scrub and semi-natural grassland) laying later and having lower hatching success, smaller broods and fewer fledglings than those in more productive agricultural landscapes. Supplementary feeding after egg hatching neutralized the negative effect of poor habitat, resulting in fed birds having significantly more fledglings. This study emphasizes the importance of food availability when provisioning chicks in suboptimal habitats and has implications for the success of diversionary feeding in reducing game losses to Buzzards.

Risk factor control is key in diabetic nephropathy

Prolonged duration of diabetes, poor glycaemic control and hypertension are major risk factors for both diabetic nephropathy and cardiovascular disease. Optimising blood sugar control together with excellent control of blood pressure can reduce the risk of developing diabetic nephropathy. Diabetic nephropathy should be considered in any patient with diabetes when persistent albuminuria develops. Microalbuminuria is the earliest clinically detectable indicator of diabetic nephropathy risk. The majority of patients with diabetic nephropathy are appropriately diagnosed based on elevated urinary albumin excretion and/or reduced 0032-6518 renal function. Patients with type 2 diabetes should have annual urinary ACR measurements from the time of diabetes diagnosis while those with type 1 diabetes should commence five years after diagnosis. Blood pressure lowering to 130/80mmHg and reduction of proteinuria to <1 g/day retards progression of diabetic nephropathy and reduces the number of cardiovascular events. Drugs that block the renin-angiotensin-aldosterone system (RAAS) are effective in reducing proteinuria, managing hypertension and reducing cardiovascular risk. Unless there are clear contraindications or intolerance all patients with diabetic nephropathy should be prescribed an ACEI or ARB. Stopping an ACEI or ARB during intercurrent illness or times of volume depletion is critically important. Patients with diabetic nephropathy should have at least yearly measurements of blood pressure, renal function and urinary ACR.

New SR drive with integrated charging capacity for plug-in hybrid electric vehicles (PHEVs)

Plug-in hybrid electric vehicles (PHEVs) provide much promise in reducing greenhouse gas emissions and, thus, are a focal point of research and development. Existing on-board charging capacity is effective but requires the use of several power conversion devices and power converters, which reduce reliability and cost efficiency. This paper presents a novel three-phase switched reluctance (SR) motor drive with integrated charging functions (including internal combustion engine and grid charging). The electrical energy flow within the drivetrain is controlled by a power electronic converter with less power switching devices and magnetic devices. It allows the desired energy conversion between the engine generator, the battery, and the SR motor under different operation modes. Battery-charging techniques are developed to operate under both motor-driving mode and standstill-charging mode. During the magnetization mode, the machine's phase windings are energized by the dc-link voltage. The power converter and the machine phase windings are controlled with a three-phase relay to enable the use of the ac-dc rectifier. The power converter can work as a buck-boost-type or a buck-type dc-dc converter for charging the battery. Simulation results in MATLAB/Simulink and experiments on a 3-kW SR motor validate the effectiveness of the proposed technologies, which may have significant economic implications and improve the PHEVs' market acceptance

Region-based Mixture of Gaussians Modelling for Foreground Detection in Dynamic Scenes

One of the most widely used techniques in computer vision for foreground detection is to model each background pixel as a Mixture of Gaussians (MoG). While this is effective for a static camera with a fixed or a slowly varying background, it fails to handle any fast, dynamic movement in the background. In this paper, we propose a generalised framework, called region-based MoG (RMoG), that takes into consideration neighbouring pixels while generating the model of the observed scene. The model equations are derived from Expectation Maximisation theory for batch mode, and stochastic approximation is used for online mode updates. We evaluate our region-based approach against ten sequences containing dynamic backgrounds, and show that the region-based approach provides a performance improvement over the traditional single pixel MoG. For feature and region sizes that are equal, the effect of increasing the learning rate is to reduce both true and false positives. Comparison with four state-of-the art approaches shows that RMoG outperforms the others in reducing false positives whilst still maintaining reasonable foreground definition. Lastly, using the ChangeDetection (CDNet 2014) benchmark, we evaluated RMoG against numerous surveillance scenes and found it to amongst the leading performers for dynamic background scenes, whilst providing comparable performance for other commonly occurring surveillance scenes.

Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation

Introduction
Despite excellent first year outcomes in kidney transplantation, there remain significant long-term complications related to new-onset diabetes after transplantation (NODAT). The purpose of this study was to validate the findings of previous investigations of candidate gene variants in patients undergoing a protocolised, contemporary immunosuppression regimen, using detailed serial biochemical testing to identify NODAT development.

Methods
One hundred twelve live and deceased donor renal transplant recipients were prospectively followed-up for NODAT onset, biochemical testing at days 7, 90, and 365 after transplantation. Sixty-eight patients were included after exclusion for non-white ethnicity and pre-transplant diabetes. Literature review to identify candidate gene variants was undertaken as described previously.

Results
Over 25% of patients developed NODAT. In an adjusted model for age, sex, BMI, and BMI change over 12 months, five out of the studied 37 single nucleotide polymorphisms (SNPs) were significantly associated with NODAT: rs16936667:PRDM14 OR 10.57;95% CI 1.8–63.0;p = 0.01, rs1801282:PPARG OR 8.5; 95% CI 1.4–52.7; p = 0.02, rs8192678:PPARGC1A OR 0.26; 95% CI 0.08–0.91; p = 0.03, rs2144908:HNF4A OR 7.0; 95% CI 1.1–45.0;p = 0.04 and rs2340721:ATF6 OR 0.21; 95%CI 0.04–1.0; p = 0.05.

Conclusion
This study represents a replication study of candidate SNPs associated with developing NODAT and implicates mTOR as the central regulator via altered insulin sensitivity, pancreatic β cell, and mitochondrial survival and dysfunction as evidenced by the five SNPs.

General significance
1) Highlights the importance of careful biochemical phenotyping with oral glucose tolerance tests to diagnose NODAT in reducing time to diagnosis and missed cases.
2)This alters potential genotype:phenotype association.
3)The replication study generates the hypothesis that mTOR signalling pathway may be involved in NODAT development.

Dose-response relationship in phase 1 clinical trials: a European Drug Development Network (EDDN) Collaboration Study

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.

Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.

Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).

Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD)

Effectiveness of a Multifaceted Intervention for Potentially Inappropriate Prescribing in Older Patients in Primary Care: A Cluster-Randomized Controlled Trial (OPTI-SCRIPT Study)

PURPOSE Potentially inappropriate prescribing (PIP) is common in older people and can result in increased morbidity, adverse drug events, and hospitalizations. The OPTI-SCRIPT study (Optimizing Prescribing for Older People in Primary Care, a cluster-randomized controlled trial) tested the effectiveness of a multifaceted intervention for reducing PIP in primary care.

METHODS We conducted a cluster-randomized controlled trial among 21 general practitioner practices and 196 patients with PIP. Intervention participants received a complex, multifaceted intervention incorporating academic detailing; review of medicines with web-based pharmaceutical treatment algorithms that provide recommended alternative-treatment options; and tailored patient information leaflets. Control practices delivered usual care and received simple, patient-level PIP feedback. Primary outcomes were the proportion of patients with PIP and the mean number of potentially inappropriate prescriptions. We performed intention-to-treat analysis using random-effects regression.

RESULTS All 21 practices and 190 patients were followed. At intervention completion, patients in the intervention group had significantly lower odds of having PIP than patients in the control group (adjusted odds ratio = 0.32; 95% CI, 0.15–0.70; P = .02). The mean number of PIP drugs in the intervention group was 0.70, compared with 1.18 in the control group (P = .02). The intervention group was almost one-third less likely than the control group to have PIP drugs at intervention completion, but this difference was not significant (incidence rate ratio = 0.71; 95% CI, 0.50–1.02; P = .49). The intervention was effective in reducing proton pump inhibitor prescribing (adjusted odds ratio = 0.30; 95% CI, 0.14–0.68; P = .04).

CONCLUSIONS The OPTI-SCRIPT intervention incorporating academic detailing with a pharmacist, and a review of medicines with web-based pharmaceutical treatment algorithms, was effective in reducing PIP, particularly in modifying prescribing of proton pump inhibitors, the most commonly occurring PIP drugs nationally.

The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell adhesion and induces apoptosis in acute lymphoblastic leukaemia cells

Although recent decades have seen an improved cure rate for newly diagnosed paediatric acute lymphoplastic leukaemia (ALL), the treatment options for adult ALL, T-cell ALL (T-ALL) and relapsed disease remain poor. We have developed a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds and established their anticancer efficacy in a variety of human tumour cell types. Here, we demonstrate that PBOX-15 inhibits cell growth, and induces G2/M cell cycle arrest and apoptosis in both T-ALL and B-cell ALL (B-ALL) cells. In addition, prior to PBOX-15-induced apoptosis, PBOX-15 decreases ALL cell adhesion, spreading and migration. Concurrently, PBOX-15 differentially down-regulates β1-, β2- and α4-integrin expression in ALL cells and significantly decreases integrin-mediated cell attachment. PBOX-15 interferes with the lateral mobility and clustering of integrins in both B-ALL and T-ALL cells. These data suggest that PBOX-15 is not only effective in inducing apoptosis in ALL cells, but also has the potential to disrupt integrin-mediated adhesion of malignant lymphocytes, which represents a novel avenue for regulating leukaemic cell homing and migration.

Sustained inhibition of deacetylases is required for the antitumor activity of the histone deactylase inhibitors panobinostat and vorinostat in models of colorectal cancer

Despite compelling preclinical data in colorectal cancer (CRC), the efficacy of HDACIs has been disappointing in the clinic. The goal of this study was to evaluate the effectiveness of vorinostat and panobinostat in a dose- and exposure-dependent manner in order to better understand the dynamics of drug action and antitumor efficacy. In a standard 72 h drug exposure MTS assay, notable concentration-dependent antiproliferative effects were observed in the IC50 range of 1.2-2.8 μmol/L for vorinostat and 5.1-17.5 nmol/L for panobinostat. However, shorter clinically relevant exposures of 3 or 6 h failed to elicit any significant growth inhibition and in most cases a >24 h exposure to vorinostat or panobinostat was required to induce a sigmoidal dose-response. Similar results were observed in colony formation assays where ≥ 24 h of exposure was required to effectively reduce colony formation. Induction of acetyl-H3, acetyl-H4 and p21 by vorinostat were transient and rapidly reversed within 12 h of drug removal. In contrast, panobinostat-induced acetyl-H3, acetyl-H4, and p21 persisted for 48 h after an initial 3 h exposure. Treatment of HCT116 xenografts with panobinostat induced significant increases in acetyl-H3 and downregulation of thymidylate synthase after treatment. Although HDACIs exert both potent growth inhibition and cytotoxic effects when CRC cells were exposed to drug for ≥ 24 h, these cells demonstrate an inherent ability to survive HDACI concentrations and exposure times that exceed those clinically achievable. Continued efforts to develop novel HDACIs with improved pharmacokinetics/phamacodynamics, enhanced intratumoral delivery and class/isoform-specificity are needed to improve the therapeutic potential of HDACIs and HDACI-based combination regimens in solid tumors.

Factors that impact on the use of mechanical ventilation weaning protocols in critically ill adults and children: a qualitative-evidence synthesis

Background:
Prolonged mechanical ventilation is associated with a longer intensive care unit (ICU) length of stay and higher mortality. Consequently, methods to improve ventilator weaning processes have been sought. Two recent Cochrane systematic reviews in ICU adult and paediatric populations concluded that protocols can be effective in reducing the duration of mechanical ventilation, but there was significant heterogeneity in study findings. Growing awareness of the benefits of understanding the contextual factors impacting on effectiveness has encouraged the integration of qualitative evidence syntheses with effectiveness reviews, which has delivered important insights into the reasons underpinning (differential) effectiveness of healthcare interventions.

Objectives:
1. To locate, appraise and synthesize qualitative evidence concerning the barriers and facilitators of the use of protocols for weaning critically-ill adults and children from mechanical ventilation;

2. To integrate this synthesis with two Cochrane effectiveness reviews of protocolized weaning to help explain observed heterogeneity by identifying contextual factors that impact on the use of protocols for weaning critically-ill adults and children from mechanical ventilation;

3. To use the integrated body of evidence to suggest the circumstances in which weaning protocols are most likely to be used.

Search methods:
We used a range of search terms identified with the help of the SPICE (Setting, Perspective, Intervention, Comparison, Evaluation) mnemonic. Where available, we used appropriate methodological filters for specific databases. We searched the following databases: Ovid MEDLINE, Embase, OVID, PsycINFO, CINAHL Plus, EBSCOHost, Web of Science Core Collection, ASSIA, IBSS, Sociological Abstracts, ProQuest and LILACS on the 26th February 2015. In addition, we searched: the grey literature; the websites of professional associations for relevant publications; and the reference lists of all publications reviewed. We also contacted authors of the trials included in the effectiveness reviews as well as of studies (potentially) included in the qualitative synthesis, conducted citation searches of the publications reporting these studies, and contacted content experts.

We reran the search on 3rd July 2016 and found three studies, which are awaiting classification.

Selection criteria:
We included qualitative studies that described: the circumstances in which protocols are designed, implemented or used, or both, and the views and experiences of healthcare professionals either involved in the design, implementation or use of weaning protocols or involved in the weaning of critically-ill adults and children from mechanical ventilation not using protocols. We included studies that: reflected on any aspect of the use of protocols, explored contextual factors relevant to the development, implementation or use of weaning protocols, and reported contextual phenomena and outcomes identified as relevant to the effectiveness of protocolized weaning from mechanical ventilation.

Data collection and analysis:
At each stage, two review authors undertook designated tasks, with the results shared amongst the wider team for discussion and final development. We independently reviewed all retrieved titles, abstracts and full papers for inclusion, and independently extracted selected data from included studies. We used the findings of the included studies to develop a new set of analytic themes focused on the barriers and facilitators to the use of protocols, and further refined them to produce a set of summary statements. We used the Confidence in the Evidence from Reviews of Qualitative Research (CERQual) framework to arrive at a final assessment of the overall confidence of the evidence used in the synthesis. We included all studies but undertook two sensitivity analyses to determine how the removal of certain bodies of evidence impacted on the content and confidence of the synthesis. We deployed a logic model to integrate the findings of the qualitative evidence synthesis with those of the Cochrane effectiveness reviews.

Main results:
We included 11 studies in our synthesis, involving 267 participants (one study did not report the number of participants). Five more studies are awaiting classification and will be dealt with when we update the review.

The quality of the evidence was mixed; of the 35 summary statements, we assessed 17 as ‘low’, 13 as ‘moderate’ and five as ‘high’ confidence. Our synthesis produced nine analytical themes, which report potential barriers and facilitators to the use of protocols. The themes are: the need for continual staff training and development; clinical experience as this promotes felt and perceived competence and confidence to wean; the vulnerability of weaning to disparate interprofessional working; an understanding of protocols as militating against a necessary proactivity in clinical practice; perceived nursing scope of practice and professional risk; ICU structure and processes of care; the ability of protocols to act as a prompt for shared care and consistency in weaning practice; maximizing the use of protocols through visibility and ease of implementation; and the ability of protocols to act as a framework for communication with parents.

Authors' conclusions:
There is a clear need for weaning protocols to take account of the social and cultural environment in which they are to be implemented. Irrespective of its inherent strengths, a protocol will not be used if it does not accommodate these complexities. In terms of protocol development, comprehensive interprofessional input will help to ensure broad-based understanding and a sense of ‘ownership’. In terms of implementation, all relevant ICU staff will benefit from general weaning as well as protocol-specific training; not only will this help secure a relevant clinical knowledge base and operational understanding, but will also demonstrate to others that this knowledge and understanding is in place. In order to maximize relevance and acceptability, protocols should be designed with the patient profile and requirements of the target ICU in mind. Predictably, an under-resourced ICU will impact adversely on protocol implementation, as staff will prioritize management of acutely deteriorating and critically-ill patients.

Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)

The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.

Protocol: A randomised controlled trial evaluation of Cancer Focus NI’s ‘Dead Cool’ smoking prevention programme in post-primary schools

This paper presents a research protocol for a randomised controlled efficacy trial of the ‘Dead Cool’ smoking prevention programme. Dead Cool is a three to four-hour programme designed to be used by teachers with Year 9 students in Northern Ireland. The main outcome of the programme is to prevent students from starting to smoke. The protocol reports a research design intended to test the efficacy of the programme in 20 post-primary school settings. Selected schools included those from secondary /grammar/integrated/single sex/coeducational, rural and urban schools from both the maintained and controlled state sector and independent sector schools. Outcome measures include self-reported behaviours, monitoring of carbon monoxide (CO) in exhaled breath and focus groups designed to assess implementation fidelity and opinions on efficacy in intervention schools and explore the ‘counterfactual’ potential treatments in control schools.

Determinants of pediatric cataract program outcomes and follow-up in a large series in Mexico.

PURPOSE:

To report determinants of outcomes and follow-up in a large Mexican pediatric cataract project.

SETTING:

Hospital Luis Sanchez Bulnes, Mexico City, Mexico.

METHODS:

Data were collected prospectively from a pediatric cataract surgery program at the Hospital Luis Sanchez Bulnes, implemented by Helen Keller International. Preoperative data included age, sex, baseline visual acuity, type of cataract, laterality, and presence of conditions such as amblyopia. Surgical data included vitrectomy, capsulotomy, complications, and use of intraocular lenses (IOLs). Postoperative data included final visual acuity, refraction, number of follow-up visits, and program support for follow-up.

RESULTS:

Of 574 eyes of 415 children (mean age 7.1 years +/- 4.7 [SD]), IOLs were placed in 416 (87%). At least 1 follow-up was attended by 408 patients (98.3%) (mean total follow-up 3.5 +/- 1.8 months); 40% of eyes achieved a final visual acuity of 6/18 or better. Children living farther from the hospital had fewer postoperative visits (P = .04), while children receiving program support had more visits (P = .001). Factors predictive of better acuity included receiving an IOL during surgery (P = .04) and provision of postoperative spectacles (P = .001). Predictive of worse acuity were amblyopia (P = .003), postoperative complications (P = .0001), unilateral surgery (P = .0075), and female sex (P = .045).

CONCLUSIONS:

The results underscore the importance of surgical training in reducing complications, early intervention before amblyopia (observed in 40% of patients) can develop, and vigorous treatment if amblyopia is present. The positive impact of program support on follow-up is encouraging, although direct financial support may pose a problem for sustainability. More work is needed to understand reasons for worse outcomes in girls.

Impact of non-pharmacological interventions on prevention and treatment of delirium in critically ill patients: protocol for a systematic review of quantitative and qualitative research

Background: Critically ill patients have an increased risk of developing delirium during their intensive care stay.To date, pharmacological interventions have not been shown to be effective for delirium management but non-pharmacological interventions have shown some promise. The aim of this systematic review is to identify effective non-pharmacological interventions for reducing the incidence or the duration of delirium in critically ill patients.

Methods: We will search MEDLINE, EMBASE, CINAHL, Web of Science, AMED, psycINFO and the Cochrane Library.We will include studies of critically ill adults and children. We will include randomised trials and controlled trials which measure the effectiveness of one or more non-pharmacological interventions in reducing incidence or duration ofdelirium in critically ill patients. We will also include qualitative studies that provide an insight into patients and their families’ experiences of delirium and non-pharmacological interventions. Two independent reviewers will assess studies for eligibility, extract data and appraise quality. We will conduct meta-analyses if possible or present results narratively.Qualitative studies will also be reviewed by two independent reviewers, and a specially designed quality assessment tool incorporating the CASP framework and the POPAY framework will be used to assess quality.

Discussion: Although non-pharmacological interventions have been studied in populations outside of intensive care units and multicomponent interventions have successfully reduced incidence and duration of delirium, no systematic review of non-pharmacological interventions specifically targeting delirium in critically ill patients have been undertaken to date. This systematic review will provide evidence for the development of a multicomponent intervention for delirium management of critically ill patients that can be tested in a subsequent multicentre randomised trial.