A core outcome set for the treatment of pregnant women with pregestational diabetes: an international consensus study.

OBJECTIVE: To develop a core outcome set (COS) for randomised controlled trials (RCTs) evaluating the effectiveness of interventions for the treatment of pregnant women with pregestational diabetes mellitus (PGDM). DESIGN: A consensus developmental study. SETTING: International. POPULATION: Two hundred and five stakeholders completed the first round. METHODS: The study consisted of three components. (1) A systematic review of the literature to produce a list of outcomes reported in RCTs assessing the effectiveness of interventions for the treatment of pregnant women with PGDM. (2) A three-round, online eDelphi survey to prioritise these outcomes by international stakeholders (including healthcare professionals, researchers and women with PGDM). (3) A consensus meeting where stakeholders from each group decided on the final COS. MAIN OUTCOME MEASURES: All outcomes were extracted from the literature. RESULTS: We extracted 131 unique outcomes from 67 records meeting the full inclusion criteria. Of the 205 stakeholders who completed the first round, 174/205 (85%) and 165/174 (95%) completed rounds 2 and 3, respectively. Participants at the subsequent consensus meeting chose 19 outcomes for inclusion into the COS: trimester-specific haemoglobin A1c, maternal weight gain during pregnancy, severe maternal hypoglycaemia, diabetic ketoacidosis, miscarriage, pregnancy-induced hypertension, pre-eclampsia, maternal death, birthweight, large for gestational age, small for gestational age, gestational age at birth, preterm birth, mode of birth, shoulder dystocia, neonatal hypoglycaemia, congenital malformations, stillbirth and neonatal death. CONCLUSIONS: This COS will enable better comparison between RCTs to produce robust evidence synthesis, improve trial reporting and optimise research efficiency in studies assessing treatment of pregnant women with PGDM. TWEETABLE ABSTRACT: 165 key stakeholders have developed #Treatment #CoreOutcomes in pregnant women with #diabetes existing before pregnancy.

A systematic review on outcome reporting in randomised controlled trials assessing treatment interventions in pregnant women with pregestational diabetes.

BACKGROUND: Pregestational diabetes mellitus (PGDM) is associated with adverse pregnancy outcomes. Studies assessing interventions to improve maternal and infant outcomes have increased exponentially over recent years. Several outcomes in this field of maternal diabetes are rare, making it difficult to synthesise evidence. OBJECTIVES: To collect outcomes reported in studies assessing treatment interventions in pregnant women with PGDM. SEARCH STRATEGY: CENTRAL, Web of Science, Medline, CINAHL, Embase and ClinicalTrials.gov from their inception until 27 January 2020. SELECTION CRITERIA: Any randomised controlled trial assessing treatment interventions in pregnant women with PGDM reported in English. DATA COLLECTION AND ANALYSIS: Two independent reviewers assessed the suitability of articles and retrieved the data. Outcomes extracted from the literature were broadly categorised into maternal, fetal/infant or other outcomes by the study advisory group. MAIN RESULTS: Sixty-seven of the 1475 studies identified fulfilled the inclusion criteria. The median number of outcomes reported per study was 15 (range 1-46). The majority of studies were from North America and Europe. Insulin and metformin were the most commonly investigated pharmacological interventions. Glucose monitoring was the most assessed technological intervention. In all, 131 unique outcomes were extracted: maternal (n = 69), fetal/infant (n = 61) and other (n = 1). CONCLUSIONS: Outcome reporting in treatment interventions trials of pregnant women with PGDM is varied, making it difficult to synthesise evidence, especially for rare outcomes. Systems are needed to standardise outcome reporting in future clinical trials and so facilitate evidence synthesis in this area of maternal diabetes. REGISTRATION: The systematic review was registered prospectively with the International Prospective Register of Systematic Reviews (PROSPERO) database (Registration number CRD42020173549). TWEETABLE ABSTRACT: Outcome reporting is heterogeneous in intervention trials of pregnant women with diabetes existing before pregnancy.

A progressive and severe rash.

A 73-year-old female attended the Emergency Department with a twenty four hour history of a progressive, diffuse macular rash, predominantly affecting limbs and trunk, with associated oral and ocular discharge.

A progressive and severe rash - Answers.

A 73-year-old female patient with epilepsy presented to hospital with a progressive, diffuse macular rash over the trunk and limbs with associated mucosal blistering and discharge. Ocular symptoms initially predominated and she was treated for presumed bacterial conjunctivitis by her General Practitioner the previous day. On the acute medical unit supportive management was initiated for suspected adverse drug reaction (ADR) to a recent lamotrigine dose increase. Skin biopsy confirmed a diagnosis of toxic epidermal necrolysis. We present this case to highlight the importance of medication history taking and raise awareness of indolent presentations of life-threatening ADRs. Caution should be applied following dose changes to anti-epileptics, even if previously stable.

Ultrasensitive microarray bioassays using cyanine5 dye-doped silica nanoparticles.

Herein we report the use of high brightness Cyanine5-doped silica nanoparticles (NPs) for the detection of antibodies or DNA in microarray bioassays. NP labels showed negligible non-specific binding, greater sensitivity and lower limits of detection when compared to free dye-labelled biomolecules. Moreover, the spotted microarrays used in this study required low NP and antibody concentrations to generate large data sets with improved statistical accuracy. These NPs have significant potential for use in biosensing for disease detection.

Multivalent linkers for improved covalent binding of oligonucleotides to dye-doped silica nanoparticles.

This paper describes the fabrication of oligonucleotide-coated Cy5-doped silica nanoparticles using a combination of multivalent linkers and their use in surface-based DNA sandwich hybridization assays. Dipodal silane is introduced as a means to fabricate amine-coated silica nanoparticles and its advantages compared to monopodal silanes are discussed. The use of dipodal silane in conjunction with three different polymer linkers (oxidized dextran, linear and 8-arm polyethylene glycol (PEG)) to immobilize single-stranded DNA to Cy5-doped nanoparticles is investigated and dynamic light scattering measurements and Fourier transform infrared spectroscopy are used to follow the progression of the functionalization of the nanoparticles. We observe a significant improvement in the binding stability of the single-stranded DNA when the dipodal silane and 8-arm PEG are used in combination, when compared to alternative conjugation strategies. Both 8mer and 22mer oligonucleotides are securely conjugated to the high-brightness nanoparticles and their availability to hybridize with a complementary strand is confirmed using solution-based DNA hybridization experiments. In addition, a full surface-based sandwich assay demonstrates the potential these nanoparticles have in the detection of less than 500 femtomolar of a DNA analogue of micro RNA, miR-451.

Model-Based Design of a Decision Tree for Treating HER2+ Cancers Based on Genetic and Protein Biomarkers.

Human cancers are incredibly diverse with regard to molecular aberrations, dependence on oncogenic signaling pathways, and responses to pharmacological intervention. We wished to assess how cellular dependence on the canonical PI3K vs. MAPK pathways within HER2+ cancers affects responses to combinations of targeted therapies, and biomarkers predictive of their activity. Through an integrative analysis of mechanistic model simulations and in vitro cell line profiling, we designed a six-arm decision tree to stratify treatment of HER2+ cancers using combinations of targeted agents. Activating mutations in the PI3K and MAPK pathways (PIK3CA and KRAS), and expression of the HER3 ligand heregulin determined sensitivity to combinations of inhibitors against HER2 (lapatinib), HER3 (MM-111), AKT (MK-2206), and MEK (GSK-1120212; trametinib), in addition to the standard of care trastuzumab (Herceptin). The strategy used to identify effective combinations and predictive biomarkers in HER2-expressing tumors may be more broadly extendable to other human cancers.

An integrated centrifugo-opto-microfluidic platform for arraying, analysis, identification and manipulation of individual cells.

In this work we present a centrifugal microfluidic system enabling highly efficient collective trapping and alignment of particles such as microbeads and cells, their multi-colour fluorescent detection and subsequent manipulation by optical tweezers. We demonstrate array-based capture and imaging followed by "cherry-picking" of individual particles, first for fluorescently labelled polystyrene (PS) beads and then for cells. Different cell lines are discriminated based on intracellular as well as surface-based markers.

Intracellular pH-sensing using core/shell silica nanoparticles.

An in-depth understanding of biochemical processes occurring within biological systems is key for early diagnosis of disease and identification of appropriate treatments. Nanobiophotonics offers huge potential benefits for intracellular diagnostics and therapeutics. Intracellular sensing using fluorescent nanoparticles is a potentially useful tool for real-time, in vivo monitoring of important cellular analytes. This work is focused on synthesis of optical chemical nanosensors for the quantitative analysis of pH inside living cells. The structure of the nanosensor comprises a biofriendly silica matrix with co-encapsulated Texas Red, acting as a reference dye, and pH-sensitive fluorescein isothiocyanate enabling ratiometric quantitative environmental detection. In order to obtain silica-based nanoparticles -70 nm in size, a modified sol-gel-based Stöber method was employed. The potential of these nanosensors for intracellular pH monitoring is demonstrated inside a live human embryonic kidney cell line whereby a significant change in fluorescence is observed when the cell pH is switched from acidic to basic. High loading efficiencies of nanoparticles into the cells is seen, with little effect on cell morphology even following extended nanoparticle exposure (up to 72 h). Nanoparticle incubation time and the fast response of the nanosensor (-2 s) make it a very powerful tool in monitoring the processes occurring within the cytosol.

Silica nanoparticles for cell imaging and intracellular sensing.

There is increasing interest in the use of nanoparticles (NPs) for biomedical applications. In particular, nanobiophotonic approaches using fluorescence offers the potential of high sensitivity and selectivity in applications such as cell imaging and intracellular sensing. In this review, we focus primarily on the use of fluorescent silica NPs for these applications and, in so doing, aim to enhance and complement the key recent review articles on these topics. We summarize the main synthetic approaches, namely the Stöber and microemulsion processes, and, in this context, we deal with issues in relation to both covalent and physical incorporation of different types of dyes in the particles. The important issue of NP functionalization for conjugation to biomolecules is discussed and strategies published in the recent literature are highlighted and evaluated. We cite recent examples of the use of fluorescent silica NPs for cell imaging in the areas of cancer, stem cell and infectious disease research, and we review the current literature on the use of silica NPs for intracellular sensing of oxygen, pH and ionic species. We include a short final section which seeks to identify the main challenges and obstacles in relation to the potential widespread use of these particles for in vivo diagnostics and therapeutics.

Synthesis, tailoring and characterization of silica nanoparticles containing a highly stable ruthenium complex.

This paper describes the synthesis and characterization of sol-gel silica nanoparticles (NPs) derived from tetraethoxysilane (TEOS) and from tetraethoxysilane and methyltriethoxysilane (TEOS-MTEOS) in which is encapsulated, an in-house synthesized, stable oxygen-sensitive ruthenium complex, ruthenium (II) (bis-2,2-bipyridyl)-2(4-carboxylphenyl) imidazo[4,5-f][1,10]phenanthroline. These NPs were characterized using dynamic light scattering, transmission electron microscopy, scanning electron microscopy, Fourier transform infrared spectroscopy and Brunauer-Emmett-Teller analysis. The spherical, stable and monodispersed NPs have been prepared using the Stöber method. It was found that the addition of prehydrolyzed MTEOS-based sol prepared in an acidic environment to the reaction mixture containing TEOS NPs synthesized for 6 h produced material with increased porosity when compared to pure silica NPs. Oxygen sensitivity, stability, photobleaching and leaching have been characterized. The hybrid NPs exhibit enhanced O2 sensitivity but a high degree of leaching when compared to pure silica NPs, which have minimum O2 sensitivity and no leaching.

A rapid, topographical platelet activation assay.

Platelets are central in maintaining normal haemostasis and are responsible for the cessation of blood loss following vascular injury. Platelet adhesion, leading to thrombus formation, involves rapid and distinct morphological changes culminating in cell aggregation. Rapid and highly specific platelet diagnostic tests are currently being developed to enable monitoring of drug response in patients with cardiovascular diseases. For a diagnostic device to be effective it needs to be rapid and simple, requiring minimal user interaction and providing results with minimal delay. This study describes the development of a rapid, label free platform for assay platelet function and demonstrates its use to monitor the influence of anti-thrombotic drugs. A rapid, single-step cell purification surface immobilises platelets from whole blood onto a protein array at specific locations used to define the assay site. Morphological changes and cell aggregation properties of activated platelets are exploited and combined within a label free, rapid, dye displacement chamber to determine cell morphology. Stimulation-dependent changes in cell morphology are described using both high resolution AFM imaging and a dye displacement platform.

From particle to platelet: optimization of a stable, high brightness fluorescent nanoparticle based cell detection platform.

Nanoparticles are increasingly used as diagnostic tools due to the ease with which their surface chemistry, optical and physical properties can be controlled. Molecules, drugs, enzymes and fluorophores can be protected within the particle core or conjugated externally conferring nanoparticle biocompatibility, target specificity or environmental sensitivity. This study details the development and characterisation of stable, bright, dye-doped silica nanoparticles which are surface functionalised with PAMAM dendrimers to enable efficient conjugation to platelet activation-specific antibodies. We present the physical and optical properties and demonstrate colloidal stability. We also provide the first evidence of how NPs can be employed to specifically label human platelets immobilised on a lab-on-a-chip platform. Using a single step protocol, we demonstrate highly specific platelet labelling with the distribution of antibody-conjugated NPs matching that expected for the platelet GPIIb/IIIa receptor. The work highlights the potential of functionalized fluorescent NPs as diagnostic tools for cardiovascular disease. FROM THE CLINICAL EDITOR: This study details the development and characterization of PAMAM dendrimer functionalized, stable, and bright dye-doped silica nanoparticles that enable efficient conjugation to platelet activation-specific antibodies. These fluorescent NPs may specifically label human platelets that can be used as diagnostic tools for cardiovascular disease.

The performance of a fluoroscopic electronic portal imaging device modified for portability.

Advances in external beam therapy technology have made routine, efficient conformal therapy a reality. With it comes the increasing need for online treatment verification, which is only achievable at present through the use of electronic portal imaging devices (EPIDs). For a large radiotherapy centre, the provision of one EPID per treatment machine proves extremely expensive. This paper details modifications to the design of a commercial fluoroscopic EPID (the SRI-100) to produce a portable system, capable of providing quick, high quality imaging on more than one treatment machine. We describe the necessary hardware and software changes made to the system, as well as the variety of mechanical and quality control checks performed for testing the stability and quality of the imaging. The modified system has been found to be both electronically and mechanically robust, with associated image quality, scaling, distortion and movement similar to other EPIDs in the department. Although the modification was designed specifically to allow for the acquisition of images from multiple treatment machines, it may also enable the operation of the EPID for other uses such as total body irradiation (TBI) treatment verification and a further range of quality control procedures on the linear accelerator itself.

Tailoring of sol-gel films for optical sensing of oxygen in gas and aqueous phase.

Sol-gel-based optical sensors for both gas-phase and dissolved oxygen have been developed. Both sensors operate on the principle of fluorescence quenching of a ruthenium complex which has been entrapped in a porous sol-gel silica film. A comprehensive investigation was carried out in order to establish optimal film-processing parameters for the two sensing environments. Both tetraethoxysilane and organically modified sol-gel precursors such as methyltriethoxysilane and ethyltriethoxysilane were used. Film hydrophobicity increases as a function of modified precursor content, and this was correlated with enhanced dissolved oxygen (DO) sensor performance. Extending the aliphatic group of the modified precursor further improved DO sensitivity. The influence of water/precursor molar ratio, R, on the sol-gel film microstructure was investigated. R value tailoring of the microstructure and film surface hydrophobicity tailoring were correlated with oxygen diffusion behavior in the films via the Stern-Volmer constants for both gas phase and DO sensing. Excellent performance characteristics were measured for both gas-phase and DO oxygen sensors. The long-term quenching stability of DO sensing films was established over a period of 6 months.

Apolipoprotein E and Alzheimer's disease: strength of association is related to age at onset.

Apolipoprotein E (apoE) epsilon 4 allele frequency among Alzheimer's disease (AD) patients is increased compared to control subjects and is influenced by the presence of other genetic factors and age at symptom onset. We examined the relationship between age at AD symptom onset and apoE by comparing the apoE epsilon 4 allele frequency of normal, elderly control subjects (n = 107) to that in AD patients (n = 123), divided into four age-at-onset periods. Additionally, the distribution of symptom onset ages of AD patients with and without apoE epsilon 4 alleles was determined. We observed increased apoE epsilon 4 allele frequencies between the AD onset ages of 55 and 75 years, but not at the extremes of onset ages (i.e. onset between 45 and 54 years of age and after age 75). Our data suggests that having an apoE epsilon 4 allele increases the likelihood that AD patients will develop symptoms in the middle range of onset ages. At the extremes of AD onset ages, non-apoE factors, including other genetic factors and age, are more important determinants of risk of developing AD.

Self-regulation in an undergraduate psychology course: results from a performance examination.

Forty-four undergraduate students enrolled in a psychology course entitled "Biofeedback and Self-Regulation" over a period of three semesters. Twenty percent of each student's grade in the course was derived from the level of self-regulation skills, as measured in an individual performance examination. Results show students can develop impressive self-regulation skills in a course format. Results also indicate that the performance examination measures abilities which are altogether different from those utilized in written examinations.