The Cheshire & Merseyside Collaborative trainee-led on-call service: a review of safety and efficiency.

AIM: To assess safety and efficiency of the Cheshire & Merseyside Collaborative, the largest trainee led on-call service in the UK, based on discrepancy rates and time taken to issue reports. MATERIALS & METHODS: All studies reported by the collaborative in a 4-week period were evaluated for discrepancy and the time taken to issue a report. These figures were compared against the Royal College of Radiologists (RCR) guidelines and a recent national audit of discrepancy rates. The time taken to report was measured against the National Institute of Health and Clinical Excellence (NICE) and Trauma Audit Research Network (TARN) guidelines. RESULTS: The overall discrepancy rates for the collaborative were 2.5% for minor discrepancies and 2% for major discrepancies, which is within the RCR standard. The median time taken to issue a report was 30 min, which is within the NICE and TARN 1-h targets. CONCLUSIONS: The Cheshire & Merseyside Collaborative can be deemed a safe and efficient way of delivering an out-of-hours radiology service.

Improving child weight management uptake through enhanced National Child Measurement Programme parental feedback letters: A randomised controlled trial.

This single-blind, pragmatic, cluster randomised controlled trial aims to investigate uptake of children's weight management services in response to enhanced National Child Measurement Programme (NCMP) letters providing weight status feedback to parents in three English counties in 2015. Parents of 2642 overweight or very overweight (obese) children aged 10-11 years received an intervention or control letter informing them of their child's weight status. Intervention letters included (i) a visual tool to help weight status recognition, (ii) a social norms statement, and for very overweight children, (iii) a prepopulated booking form for weight management services. The primary outcome was weight management service enrolment. Additional outcome measures included attendance at and contact made with weight management services, and a number of self-report variables. A small effect was observed, with intervention parents being significantly more likely to enrol their children in weight management services (4.33% of Intervention group) than control parents (2.19% of Control group) in both unadjusted (OR = 2.08, p = .008) and adjusted analyses (AOR = 2.48, p = .001). A similar picture emerged for contact with services (4.80% Intervention vs. 2.41% Control; OR = 2.10, p = .003; AOR = 2.46, p < .001) and attendance at services, although group differences in the latter measure were not significant after corrections for multiple comparisons (1.89% Intervention vs. 1.02% Control; AOR = 2.11, p = .047). No effects were found on self-report variables. Theoretically informed weight status feedback letters appear to be an effective strategy to improve enrolment in paediatric weight management services.

From cookies to carrots; the effect of inhibitory control training on children's snack selections.

Children consume too much sugar and not enough fruit and vegetables, increasing their risk of adverse health outcomes. Inhibitory control training (ICT) reduces children's and adults' intake of energy-dense foods in both laboratory and real-life settings. However, no studies have yet examined whether ICT can increase healthy food choice when energy-dense options are also available. We investigated whether a food-specific Go/No-Go task could influence the food choices of children aged 4-11, as measured by a hypothetical food choice task using healthy and unhealthy food images printed on cards. Participants played either an active game (healthy foods = 100% go, unhealthy foods = 100% no-go; Studies 1 & 2), a food control game (both healthy and unhealthy foods = 50% go, 50% no-go; Studies 1 & 2) or a non-food control game (sports equipment = 100% go, technology = 100% no-go; Study 2 only) followed by the choice task. In Study 2, food card choices were also measured before training to examine change in choices. A post-training real food choice task was added to check that choices made in the card-based task were representative of choices made when faced with real healthy and unhealthy foods. Overall, the active group chose the greatest number of healthy food cards. Study 2 confirmed that this was due to increases in healthy food card choice in this group only. Active group participants chose a greater number of healthy foods in the real food choice task compared to children in the non-food control group only. The results are discussed with reference to methodological issues and the development of future healthy eating interventions.

Parents' voices: "Our process of advocating for our child with autism." A meta-synthesis of parents' perspectives.

BACKGROUND: Advocacy has been described by parents of children with autism as an important coping strategy, enabling them to move forward by redirecting emotions into actions. A key factor in the development of collaborative and constructive partnerships between service providers and parents is having an understanding of how parents engage in advocacy and the support needed to do so. This meta-synthesis was undertaken to consolidate in-depth qualitative data from parents' perspectives of the process that they use to advocate for their children with autism. METHODS: A qualitative meta-synthesis was conducted, whereby 15 databases were systematically searched. Thirty-one studies were identified and appraised using an adapted version of the Critical Appraisal Skills Programme tool. Data were synthesized into themes through the steps of review, meta-aggregation, integration, and interpretation. RESULTS: The voices of 1,662 parents are presented describing the process of advocacy in the stages of seeking a diagnosis, seeking self-education, and taking action. Taking action includes 2 subthemes: seeking, access, and use of support services and community engagement and educating others. CONCLUSIONS: Results highlight the significant impact that positive experiences with first-line professionals have during the diagnosis process and how these experiences lay the foundation for all future relationships with other service providers. Important implications arise from this meta-synthesis for service providers in supporting parents' advocacy and hence building constructive relationships with families with a child with autism.

Hypoxia causes IL-8 secretion, Charcot Leyden crystal formation, and suppression of corticosteroid-induced apoptosis in human eosinophils.

BACKGROUND: Inflamed environments are typically hypercellular, rich in pro-inflammatory cytokines, and profoundly hypoxic. While the effects of hypoxia on neutrophil longevity and function have been widely studied, little is known about the consequences of this stimulus on eosinophils. OBJECTIVE: We sought to investigate the effects of hypoxia on several key aspects of eosinophil biology, namely secretion, survival, and their sensitivity to glucocorticosteroids (GCS), agents that normally induce eosinophil apoptosis. METHODS: Eosinophils derived from patients with asthma/atopy or healthy controls were incubated under normoxia and hypoxia, with or without glucocorticoids. Activation was measured by flow cytometry, ELISA of cultured supernatants, and F-actin staining; apoptosis and efferocytosis by morphology and flow cytometry; and GCS efficacy by apoptosis assays and qPCR. RESULTS: Hypoxic incubation (3 kPa) caused (i) stabilization of HIF-2α and up-regulation of hypoxia-regulated genes including BNIP3 (BCL2/adenovirus E1B 19-kDa protein-interacting protein 3) and GLUT1 (glucose transporter 1); (ii) secretion of pre-formed IL-8, and Charcot Leyden crystal (CLC) formation, which was most evident in eosinophils derived from atopic and asthmatic donors; (iii) enhanced F-actin formation; (iv) marked prolongation of eosinophil lifespan (via a NF-κB and Class I PI3-kinase-dependent mechanism); and (v) complete abrogation of the normal pro-apoptotic effect of dexamethasone and fluticasone furoate. This latter effect was evident despite preservation of GCS-mediated gene transactivation under hypoxia. CONCLUSION AND CLINICAL RELEVANCE: These data indicate that hypoxia promotes an eosinophil pro-inflammatory phenotype by enhancing eosinophil secretory function, delaying constitutive apoptosis, and importantly, antagonizing the normal pro-apoptotic effect of GCS. As eosinophils typically accumulate at sites that are relatively hypoxic, particularly during periods of inflammation, these findings may have important implications to understanding the behaviour of these cells in vivo.

Racial differences in the pain management of children recovering from anesthesia.

BACKGROUND: When pain management has been studied in settings such as pediatric emergency departments, racial disparities have been clearly identified. To our knowledge, this has not been studied in the pediatric perioperative setting. We sought to determine whether there are differences based on race in the administration of analgesia to children suffering from pain in the postanesthesia care unit. METHODS: This is a prospective, observational, study of 771 children aged 4-17 years who underwent elective outpatient surgery. Racial differences in probability of receiving analgesia for pain in the recovery room were assessed using bivariable and multivariable logistic regression analyses. RESULTS: A total of 294 children (38.2%) received at least one class of analgesia (opioid or nonopioid); while 210 (27.2%) received intravenous (i.v.) opioid analgesia in the recovery room. Overall postanesthesia care unit analgesia utilization was similar between white and minority children (white children 36.8% vs minority children 43.4%, OR 1.3; 95% CI=0.92-1.89; P=.134). We found no significant difference by racial/ethnic group in the likelihood of a child receiving i.v. opioid for severe postoperative pain (white children 76.0% vs 85.7%, OR 1.89; 95% CI=0.37-9.67; P=.437). However, minority children were more likely to receive i.v. opioid analgesia than their white peers (white children 24.5% vs minority children 34.2%, OR 1.5; 95% CI=1.04-2.2; P=.03). On multivariable analysis, minority children had a 63% higher adjusted odds of receiving i.v. opioids in the recovery room (OR=1.63; 95% CI, 1.05-2.62; P=.03). CONCLUSIONS: Receipt of analgesia for acute postoperative pain was not significantly associated with a child's race. Minority children were more likely to receive i.v. opioids for the management of mild pain.

Density-functional theory molecular dynamics simulations of a-HfO2/Ge(100)(2 × 1) and a-ZrO2/Ge(100)(2 × 1) interface passivation.

The structural properties of a-HfO2/Ge(2 × 1)-(001) and a-ZrO2/Ge(2 × 1)-(001) interfaces were investigated with and without a GeOx interface interlayer using density-functional theory (DFT) molecular dynamics (MD) simulations. Realistic a-HfO2 and a-ZrO2 samples were generated using a hybrid classical-DFT MD "melt-and-quench" approach and tested against experimental properties. The oxide/Ge stacks were annealed at 700 K, cooled to 0 K, and relaxed providing the system with enough freedom to form realistic interfaces. For each high-K/Ge stack type, two systems with single and double interfaces were investigated. All stacks were free of midgap states; however, stacks with a GeO(x) interlayer had band-edge states which decreased the band gaps by 0%-30%. These band-edge states were mainly produced by under-coordinated Ge atoms in GeO(x) layer or its vicinity due to deformation, intermixing, and bond-breaking. The DFT-MD simulations show that electronically passive interfaces can be formed either directly between high-K dielectrics and Ge or with a monolayer of GeO2 if the processing does not create or properly passivate under-coordinated Ge atoms and Ge's with significantly distorted bonding angles. Comparison to the charge states of the interfacial atoms from DFT to experimental x-ray photoelectron spectroscopy results shows that while most studies of gate oxide on Ge(001) have a GeO(x) interfacial layer, it is possible to form an oxide/Ge interface without a GeO(x) interfacial layer. Comparison to experiments is consistent with the dangling bonds in the suboxide being responsible for midgap state formation.

Tamarins: Insights into monogamous and non-monogamous single female social and breeding systems.

Tamarins are reported to live in small multimale-multifemale groups characterized by a single breeding female. Here we present information on the composition and genetic relatedness of individuals in 12 wild-trapped groups of Weddell's saddleback tamarins (Saguinus weddelli) from northern Bolivia to determine if groups are best described as nuclear or extended families suggesting social monogamy or whether groups contain several unrelated same sex adults indicative of social polyandry/polygyny. Mean group size was 6.25 including an average of 2.16 adult males (range 1-4) and 2.08 adult females (1-3). No group contained only one adult male and one adult female and 25% of groups contained two parous females. We estimated the genetic relatedness among individuals using 13 polymorphic microsatellite markers. Across the population, mean relatedness was low and not significantly different among adult males versus among adult females, suggesting that both sexes disperse from their natal groups. Adults of both sexes also tended to have close same-sex adult relatives within their groups; relatedness among adult females of the same group averaged 0.31 and among adult males was 0.26. This suggests that tamarins of one or both sexes sometimes delay dispersal and remain as adults in their natal group or that emigration of same-sexed relatives into the same group may be common. Finally, parentage analyses indicated that, whereas the parents of juveniles generally were present in the group, this was not always the case. Based on these data, published reports of the presence of multiple breeding males and occasionally multiple breeding females in the same group, and the fact that less than 10% of groups in the wild contain a single adult male-adult female pair, we argue that social polyandry best characterizes the composition of tamarin groups and that monogamy is not a common mating pattern in Saguinus weddelli or other tamarin species.

Parents' voices: 'why and how we advocate'. A meta-synthesis of parents' experiences of advocating for their child with autism spectrum disorder.

Parenting a child with autism spectrum disorder (ASD) can be stressful, and accessing services can add to this stress. Self-efficacy, agency and advocacy are important for parents when accessing and using services. To develop insight into parental advocacy, a meta-synthesis was undertaken to consolidate the literature focussing on parents' experiences of advocating for their child with ASD. A qualitative meta-synthesis was conducted. Fifteen databases were systematically searched by using key terms related to ASD, children, parents/carers, advocacy and qualitative studies. Twenty-four studies were identified and appraised using an adapted version of the Critical Appraisal Skills Programme tool. Data were synthesized into themes through the steps of review, meta-aggregation, integration and interpretation. Two overarching concepts emerged, illustrating both the challenging nature of advocacy and the associated personal and societal benefits. These two concepts are supported by eight themes: a life-long, all-encompassing challenge; advocacy as a parental coping strategy; advocacy involving working to create a future; balancing roles and needs; isolation versus support; personal impacts of advocacy; benefits of advocacy; and the barriers to advocacy. The experience of advocacy for parents with a child with ASD is complex and intensive, presenting both personal and societal benefits, as well as challenges for parents. In supporting individuals with ASD and family well-being, service providers need to have an understanding of the advocating role of parents and ensure that opportunities exist for their voices to be heard during service delivery.

Amblyomma americanum tick saliva insulin-like growth factor binding protein-related protein 1 binds insulin but not insulin-like growth factors.

Silencing Amblyomma americanum insulin-like growth factor binding protein-related protein 1 (AamIGFBP-rP1) mRNA prevented ticks from feeding to repletion. In this study, we used recombinant (r)AamIGFBP-rP1 in a series of assays to obtain further insight into the role(s) of this protein in tick feeding regulation. Our results suggest that AamIGFBP-1 is an antigenic protein that is apparently exclusively expressed in salivary glands. We found that both males and females secrete AamIGFBP-rP1 into the host during feeding and confirmed that female ticks secrete this protein from within 24-48 h after attachment. Our data suggest that native AamIGFBP-rP1 is a functional insulin binding protein in that both yeast- and insect cell-expressed rAamIGFBP-rP1 bound insulin, but not insulin-like growth factors. When subjected to anti-blood clotting and platelet aggregation assays, rAamIGFBP-rP1 did not have any effect. Unlike human IGFBP-rP1, which is controlled by trypsinization, rAamIGFBP-rP1 is resistant to digestion, suggesting that the tick protein may not be under mammalian host control at the tick feeding site. The majority of tick-borne pathogens are transmitted 48 h after the tick has attached. Thus, the demonstrated antigenicity and secretion into the host within 24-48 h of the tick starting to feed makes AamIGFBP-rP1 an attractive target for antitick vaccine development.

Personalized ophthalmology.

Ophthalmology has been an early adopter of personalized medicine. Drawing on genomic advances to improve molecular diagnosis, such as next-generation sequencing, and basic and translational research to develop novel therapies, application of genetic technologies in ophthalmology now heralds development of gene replacement therapies for some inherited monogenic eye diseases. It also promises to alter prediction, diagnosis and management of the complex disease age-related macular degeneration. Personalized ophthalmology is underpinned by an understanding of the molecular basis of eye disease. Two important areas of focus are required for adoption of personalized approaches: disease stratification and individualization. Disease stratification relies on phenotypic and genetic assessment leading to molecular diagnosis; individualization encompasses all aspects of patient management from optimized genetic counseling and conventional therapies to trials of novel DNA-based therapies. This review discusses the clinical implications of these twin strategies. Advantages and implications of genetic testing for patients with inherited eye diseases, choice of molecular diagnostic modality, drivers for adoption of personalized ophthalmology, service planning implications, ethical considerations and future challenges are considered. Indeed, whilst many difficulties remain, personalized ophthalmology truly has the potential to revolutionize the specialty.

Inferring outcrossing in the homothallic fungus Sclerotinia sclerotiorum using linkage disequilibrium decay.

The occurrence and frequency of outcrossing in homothallic fungal species in nature is an unresolved question. Here we report detection of frequent outcrossing in the homothallic fungus Sclerotinia sclerotiorum. In using multilocus linkage disequilibrium (LD) to infer recombination among microsatellite alleles, high mutation rates confound the estimates of recombination. To distinguish high mutation rates from recombination to infer outcrossing, 8 population samples comprising 268 S. sclerotiorum isolates from widely distributed agricultural fields were genotyped for 12 microsatellite markers, resulting in multiple polymorphic markers on three chromosomes. Each isolate was homokaryotic for the 12 loci. Pairwise LD was estimated using three methods: Fisher's exact test, index of association (IA) and Hedrick's D'. For most of the populations, pairwise LD decayed with increasing physical distance between loci in two of the three chromosomes. Therefore, the observed recombination of alleles cannot be simply attributed to mutation alone. Different recombination rates in various DNA regions (recombination hot/cold spots) and different evolutionary histories of the populations could explain the observed differences in rates of LD decay among the chromosomes and among populations. The majority of the isolates exhibited mycelial incompatibility, minimizing the possibility of heterokaryon formation and mitotic recombination. Thus, the observed high intrachromosomal recombination is due to meiotic recombination, suggesting frequent outcrossing in these populations, supporting the view that homothallism favors universal compatibility of gametes instead of traditionally believed haploid selfing in S. sclerotiorum. Frequent outcrossing facilitates emergence and spread of new traits such as fungicide resistance, increasing difficulties in managing Sclerotinia diseases.

Left out in the cold: Moving beyond hormonal therapy for the treatment of immunologically cold prostate cancer with CAR T cell immunotherapies.

Prostate cancer is primarily hormone-dependent, and medical treatments have focused on inhibiting androgen biosynthesis or signaling through various approaches. Despite significant advances with the introduction of androgen receptor signalling inhibitors (ARSIs), patients continue to progress to castration-resistant prostate cancer (CRPC), highlighting the need for targeted therapies that extend beyond hormonal blockade. Chimeric Antigen Receptor (CAR) T cells and other engineered immune cells represent a new generation of adoptive cellular therapies. While these therapies have significantly enhanced outcomes for patients with hematological malignancies, ongoing research is exploring the broader use of CAR T therapy in solid tumors, including advanced prostate cancer. In general, CAR T cell therapies are less effective against solid cancers with the immunosuppressive tumor microenvironment hindering T cell infiltration, activation and cytotoxicity following antigen recognition. In addition, inherent tumor heterogeneity exists in patients with advanced prostate cancer that may prevent durable therapeutic responses using single-target agents. These barriers must be overcome to inform clinical trial design and improve treatment efficacy. In this review, we discuss the innovative and rationally designed strategies under investigation to improve the clinical translation of cellular immunotherapy in prostate cancer and maximise therapeutic outcomes for these patients.

How long do nosocomial pathogens persist on inanimate surfaces? A scoping review.

Healthcare hygiene plays a crucial role in the prevention of healthcare-associated infections. Patients admitted to a room where the previous occupant had a multi-drug-resistant bacterial infection are at an increased risk of colonization and infection with the same organism. A 2006 systematic review by Kramer et al. found that certain pathogens can survive for months on dry surfaces. The aim of this review is to update Kramer et al.'s previous review and provide contemporary data on the survival of pathogens relevant to the healthcare environment. We systematically searched Ovid MEDLINE, CINAHL and Scopus databases for studies that described the survival time of common nosocomial pathogens in the environment. Pathogens included in the review were bacterial, viral, and fungal. Studies were independently screened against predetermined inclusion/exclusion criteria by two researchers. Conflicts were resolved by one of two senior researchers. A spreadsheet was developed for the data extraction. The search identified 1736 studies. Following removal of duplicates and application of the search criteria, the synthesis of results from 62 included studies were included. 117 organisms were reported. The longest surviving organism reported was Klebsiella pneumoniae which was found to have persisted for 600 days. Common pathogens of concern to infection prevention and control, can survive or persist on inanimate surfaces for months. This data supports the need for a risk-based approach to cleaning and disinfection practices, accompanied by appropriate training, audit and feedback which are proven to be effective when adopted in a 'bundle' approach.

Ventral tegmental area dopamine neural activity switches simultaneously with rule representations in the prefrontal cortex and hippocampus.

Multiple brain regions need to coordinate activity to support cognitive flexibility and behavioral adaptation. Neural activity in both the hippocampus (HPC) and prefrontal cortex (PFC) is known to represent spatial context and is sensitive to reward and rule alterations. Midbrain dopamine (DA) activity is key in reward seeking behavior and learning. There is abundant evidence that midbrain DA modulates HPC and PFC activity. However, it remains underexplored how these networks engage dynamically and coordinate temporally when animals must adjust their behavior according to changing reward contingencies. In particular, is there any relationship between DA reward prediction change during rule switching, and rule representation changes in PFC and CA1? We addressed these questions using simultaneous recording of neuronal population activity from the hippocampal area CA1, PFC and ventral tegmental area (VTA) in male TH-Cre rats performing two spatial working memory tasks with frequent rule switches in blocks of trials. CA1 and PFC ensembles showed rule-specific activity both during maze running and at reward locations, with PFC rule coding more consistent across animals compared to CA1. Optogenetically tagged VTA DA neuron firing activity responded to and predicted reward outcome. We found that the correct prediction in DA emerged gradually over trials after rule-switching in coordination with transitions in PFC and CA1 ensemble representations of the current rule after a rule switch, followed by behavioral adaptation to the correct rule sequence. Therefore, our study demonstrates a crucial temporal coordination between the rule representation in PFC/CA1, the dopamine reward signal and behavioral strategy.

Fewer invited talks by women in evolutionary biology symposia.

Lower visibility of female scientists, compared to male scientists, is a potential reason for the under-representation of women among senior academic ranks. Visibility in the scientific community stems partly from presenting research as an invited speaker at organized meetings. We analysed the sex ratio of presenters at the European Society for Evolutionary Biology (ESEB) Congress 2011, where all abstract submissions were accepted for presentation. Women were under-represented among invited speakers at symposia (15% women) compared to all presenters (46%), regular oral presenters (41%) and plenary speakers (25%). At the ESEB congresses in 2001-2011, 9-23% of invited speakers were women. This under-representation of women is partly attributable to a larger proportion of women, than men, declining invitations: in 2011, 50% of women declined an invitation to speak compared to 26% of men. We expect invited speakers to be scientists from top ranked institutions or authors of recent papers in high-impact journals. Considering all invited speakers (including declined invitations), 23% were women. This was lower than the baseline sex ratios of early-mid career stage scientists, but was similar to senior scientists and authors that have published in high-impact journals. High-quality science by women therefore has low exposure at international meetings, which will constrain Evolutionary Biology from reaching its full potential. We wish to highlight the wider implications of turning down invitations to speak, and encourage conference organizers to implement steps to increase acceptance rates of invited talks.

Psychosocial interventions for managing pain in older adults: outcomes and clinical implications.

Interest in the use of psychosocial interventions to help older adults manage pain is growing. In this article, we review this approach. The first section reviews the conceptual background for psychosocial interventions with a special emphasis on the biopsychosocial model of pain. The second section highlights three psychosocial interventions used with older adults: cognitive behavioural therapy, emotional disclosure, and mind-body interventions (specifically mindfulness-based stress reduction and yoga). The final section of the paper highlights important future directions for work in this area.

Low-dose carboplatin modifies the tumor microenvironment to augment CAR T cell efficacy in human prostate cancer models.

Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (LeY)-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, LeY CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although LeY CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.

Comparison of safety and tolerability with continuous (exenatide once weekly) or intermittent (exenatide twice daily) GLP-1 receptor agonism in patients with type 2 diabetes.

AIMS: Exenatide is a glucagon-like peptide-1 receptor agonist shown to improve glycaemic control in patients with type 2 diabetes (T2DM). Intermittent exenatide exposure is achieved with the twice-daily formulation (ExBID), while the once-weekly formulation (ExQW) provides continuous exenatide exposure. This integrated, retrospective analysis compared safety and tolerability of ExQW vs. ExBID in patients with T2DM. METHODS: Data were pooled from two open-label, randomized, comparator-controlled, trials directly comparing ExQW (N = 277) to ExBID (N = 268). Between-group differences in adverse event (AE) and hypoglycaemia incidences were calculated. Incidence over time and duration of selected AEs (nausea, vomiting, and injection-site-related AEs) were also summarized. RESULTS: The most common AEs were nausea, diarrhoea, injection-site pruritus, and vomiting. Nausea and vomiting occurred less frequently with ExQW vs. ExBID, peaking at initiation (ExQW) or at initiation and dose escalation (ExBID), and decreasing over time. Few patients discontinued because of gastrointestinal-related AEs. Injection-site AEs were more common with ExQW but decreased over time in both groups. No major hypoglycaemia occurred; minor hypoglycaemia occurred with low incidence in patients not using concomitant sulphonylurea, with no difference between ExQW and ExBID. Serious AEs and discontinuations because of AEs were reported with similar frequency in both groups. CONCLUSIONS: Both exenatide formulations were generally safe and well-tolerated, with ExQW associated with less nausea and vomiting but more injection-site AEs. Continuous vs. intermittent exposure did not impact the overall tolerability profile of exenatide, with no evidence of prolonged duration or worsened intensities of AEs with continuous exposure.

Techniques of assessing hypoxia at the bench and bedside.

Tissues require an adequate supply of oxygen in order to maintain normal cell function. Low oxygen tension (hypoxia) is characteristic of a number of conditions, including cancer, atherosclerosis, rheumatoid arthritis, critical limb ischaemia, peripheral vascular disease, and ischaemic heart disease. Tissue hypoxia is found in tumours, atherosclerotic plaque, and ischaemic myocardium. There is a growing interest in methods to detect and assess hypoxia, given that hypoxia is important in the progression of these diseases. Hypoxia can be assessed at the level of the whole organ, tissue, or cell, using both invasive and non-invasive methods, and by a range of immunohistochemical, biochemical, or imaging techniques. This review describes and critiques current methods of assessing hypoxia that are used at the bench and in clinical practice.