Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Role of Caustic Addition in Bitumen-Clay Interactions

Coating of bitumen by clays, known as slime coating, is detrimental to bitumen recovery from oil sands using the warm slurry extn. process. Sodium hydroxide (caustic) is added to the extn. process to balance many competing processing challenges, which include undesirable slime coating. The current research aims at understanding the role of caustic addn. in controlling interactions of bitumen with various types of model clays. The interaction potential was studied by quartz crystal microbalance with dissipation monitoring (QCM-D). After confirming the slime coating potential of montmorillonite clays on bitumen in the presence of calcium ions, the interaction of kaolinite and illite with bitumen was studied. To represent more closely the industrial applications, tailings water from bitumen extn. tests at different caustic dosage was used. At caustic dosage up to 0.5 wt % oil sands ore, a negligible coating of kaolinite on the bitumen was detd. However, at a lower level of caustic addn., illite was shown to attach to the bitumen, with the interaction potential decreasing with increasing caustic dosage. Increasing concn. of humic acids as a result of increasing caustic dosage was identified to limit the interaction potential of illite with bitumen. This fundamental study clearly shows that the crit. role of caustics in modulating interactions of clays with bitumen depends upon the type of clays. Thus, clay type was identified as a key operational variable

Quantitative assessment of the conjunctival microcirculation using a smartphone and slit-lamp biomicroscope

Purpose: The conjunctival microcirculation is a readily-accessible vascular bed for quantitative haemodynamic assessment and has been studied previously using a digital charge-coupled device (CCD). Smartphone video imaging of the conjunctiva, and haemodynamic parameter quantification, represents a novel approach. We report the feasibility of smartphone video acquisition and subsequent haemodynamic measure quantification via semi-automated means. Methods: Using an Apple iPhone 6 s and a Topcon SL-D4 slit-lamp biomicroscope, we obtained videos of the conjunctival microcirculation in 4 fields of view per patient, for 17 low cardiovascular risk patients. After image registration and processing, we quantified the diameter, mean axial velocity, mean blood volume flow, and wall shear rate for each vessel studied. Vessels were grouped into quartiles based on their diameter i.e. group 1 (&lt;11 μm), 2 (11–16 μm), 3 (16–22 μm) and 4 (&gt;22 μm). Results: From the 17 healthy controls (mean QRISK3 6.6%), we obtained quantifiable haemodynamics from 626 vessel segments. The mean diameter of microvessels, across all sites, was 21.1μm (range 5.8–58 μm). Mean axial velocity was 0.50mm/s (range 0.11–1mm/s) and there was a modestly positive correlation (r 0.322) seen with increasing diameter, best appreciated when comparing group 4 to the remaining groups (p &lt; .0001). Blood volume flow (mean 145.61pl/s, range 7.05–1178.81pl/s) was strongly correlated with increasing diameter (r 0.943, p &lt; .0001) and wall shear rate (mean 157.31 s − 1, range 37.37–841.66 s − 1) negatively correlated with increasing diameter (r − 0.703, p &lt; .0001). Conclusions: We, for the first time, report the successful assessment and quantification of the conjunctival microcirculatory haemodynamics using a smartphone-based system. </p

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Assessment of the conjunctival microcirculation for patients presenting with acute myocardial infarction compared to healthy controls

Microcirculatory dysfunction occurs early in cardiovascular disease (CVD) development. Acute myocardial infarction (MI) is a late consequence of CVD. The conjunctival microcirculation is readily-accessible for quantitative assessment and has not previously been studied in MI patients. We compared the conjunctival microcirculation of acute MI patients and age/sex-matched healthy controls to determine if there were differences in microcirculatory parameters. We acquired images using an iPhone 6s and slit-lamp biomicroscope. Parameters measured included diameter, axial velocity, wall shear rate and blood volume flow. Results are for all vessels as they were not sub-classified into arterioles or venules. The conjunctival microcirculation was assessed in 56 controls and 59 inpatients with a presenting diagnosis of MI. Mean vessel diameter for the controls was 21.41 ± 7.57 μm compared to 22.32 ± 7.66 μm for the MI patients (p &lt; 0.001). Axial velocity for the controls was 0.53 ± 0.15 mm/s compared to 0.49 ± 0.17 mm/s for the MI patients (p &lt; 0.001). Wall shear rate was higher for controls than MI patients (162 ± 93 s-1 vs 145 ± 88 s-1, p &lt; 0.001). Blood volume flow did not differ significantly for the controls and MI patients (153 ± 124 pl/s vs 154 ± 125 pl/s, p = 0.84). This pilot iPhone and slit-lamp assessment of the conjunctival microcirculation found lower axial velocity and wall shear rate in patients with acute MI. Further study is required to correlate these findings further and assess long-term outcomes in this patient group with a severe CVD phenotype.</p

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

How does online postal self-sampling (OPSS) shape access to testing for sexually transmitted infections (STIs)? A qualitative study of service users

Background: Sexually transmitted infections (STIs) are a serious public health issue in many countries. Online postal self-sampling (OPSS) is increasingly used to test for STIs, a trend accelerated by the COVID-19 pandemic. There remains limited understanding of how service users experience OPSS and what leads them to access it over clinic-based services, or vice versa. This research seeks to address these gaps, by undertaking a large qualitative study which sits within the ASSIST study, a mixed-methods, realist evaluation of OPSS. Methods: Participants were recruited via clinic-based and online sexual health services in three case study areas in England. Purposive sampling was used to over-represent populations disproportionately affected by poor sexual health: young people; people of colour; men who have sex with men; and trans and non-binary people. Semi-structured interviews were analysed using Levesque’s conceptual framework of access to healthcare. Results: We interviewed 100 service users. Participants typically became aware of OPSS from sexual health services, the internet or word of mouth. Acceptability of OPSS was facilitated by the perceived privacy it offered over clinic-based services, which some participants found embarrassing to access. OPSS also enabled participants to overcome barriers to reaching clinic-based services, such as a lack of appointment availability, although difficulty obtaining OPSS kits in some areas undermined this. As all services in our case study areas were free to use, affordability did not significantly shape access, although OPSS enabled some participants to avoid costs associated with travelling to clinic-based services. Participants were usually able to engage with OPSS, finding it easy to use and reliable, although blood self-sampling was challenging for most. Participants valued the support offered by clinic-based services beyond STI testing, including the opportunity to access contraception or ask staff questions, and felt this was more appropriate when they had specific concerns about their sexual health, such as STI symptoms. Conclusions: Our findings constitute one of the largest qualitative studies to have explored OPSS and offer valuable insights to providers. OPSS shapes access to STI testing in a number of ways, including facilitating access in many circumstances, but users also want to retain access to clinic-based services, particularly for when they believe they need support beyond STI testing

Citizen science versus professional data collection: Comparison of approaches to mosquito monitoring in Germany

Due to the recent emergence of invasive mosquito species and the outbreaks of mosquito-borne diseases in Europe, research on the ecology and diversity of the mosquito fauna has returned to scientific agendas. Through a nationwide surveillance programme in Germany, mosquitoes have been monitored actively by systematically operated traps since 2011, and passively by the 'Mückenatlas' (mosquito atlas) citizen science project launched in 2012. To assess the performance of both monitoring methods we compared the two respective datasets with regard to habitat coverage, species composition and the ability to detect invasive mosquitoes. The datasets include observations from the beginning of the project until the end of 2017. We found significant differences in species composition caused by land use types and the participants' recording activity. Active monitoring performed better in mapping mosquito diversity, whereas passive monitoring better detected invasive species, thereby using data from private premises scientists usually cannot access. Synthesis and applications. Active and passive monitoring is complementary. Combining them allows for the determination of mosquito diversity, efficient detection of emerging invasive species and the initiation of rapid-response actions against such invaders. The 'Mückenatlas' sets an example for the usefulness of citizen science when included in a national monitoring programme, an approach that may be worth copying for tackling the global spread of arthropod vectors of disease agents