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The ongoing, observational BICSTaR (BICtegravir Single Tablet Regimen) cohort study is evaluating real-world effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with HIV across 14 countries over 24 months. We present 12-month data from the BICSTaR Asia cohort.

Pineal masses commonly present with Parinaud syndrome, a triad consisting of upgaze restriction, convergence-retraction nystagmus, and pupillary light-near dissociation from compression of the quadrigeminal plate.

Oesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barrett's oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barrett's oesophagus.

Impaired neurocognitive function is an increasingly recognized morbidity in patients who have cancer. Cancer treatments, psychosocial stressors, and the malignancy itself can alter brain function. The mechanisms by which this occurs are under active investigation. Although there is a growing appreciation of its prevalence and causes, there remain limited therapeutic options for the treatment of neurocognitive dysfunction in this population. A persistent scientific and clinical effort to understand its mechanisms and impact is critical to the care of oncology patients.

Supplemental Digital Content is available in the text.Histomorphologic prognostic biomarkers that can be measured using only an hematoxylin and eosin stain are very attractive because they are simple and cheap. We conceived an entirely novel biomarker of this type, the Breslow density (BD), which measures invasive melanoma cell density at the site where Breslow thickness (BT) is measured. This study assessed BD’s prognostic value. In this study, BD was measured in 1329 melanoma patients. Measurement accuracy and precision was assessed using intraclass correlation coefficient (ICC). Survival was assessed with a primary end-point of melanoma-specific survival (MSS) and also overall survival and metastasis-free survival. We found that BD measurement was accurate compared with gold standard image analysis (ICC, 0.84). Precision was excellent for 3 observers with different experience (ICC, 0.93) and for an observer using only written instructions (ICC, 0.93). BD was a highly significant predictor in multivariable analysis for overall survival, MSS, and metastasis-free survival (each, P<0.001) and it explained MSS better than BT, but BT and BD together had best explanatory capability. A BD cut point of ≥65% was trained in 970 melanomas and validated in 359. This cut point showed promise as a novel way to upstage melanoma from T stage “a” to “b.” BD was combined with BT to create a targeted burden score. This was a validated as an adjunct to American Joint Committee on Cancer stage. In summary, BD can be measured accurately and precisely. It demonstrated independent prognostic value and explained MSS better than BT alone. Notably, we demonstrated ways that BD could be used with American Joint Committee on Cancer version 8 staging.

Movement connects otherwise isolated populations, influencing demographic persistence and promoting gene flow. We evaluated the effect of movement on the genetic and demographic viability of the red wolf (Canis rufus) and tested the application of metapopulation theory to management of this endangered predator. The establishment of a captive subpopulation in the 1970s allowed persistence of the species and facilitated a reintroduction program that supported 2 wild subpopulations, one of which persists today. We assessed the effect of historical and potential future movement between the wild and captive subpopulations on the genetic and demographic viability of the metapopulation. We analyzed approximately 30 years of individual‐level data to quantify the effects of historical movement among subpopulations and constructed an individual‐based metapopulation model to predict the effects of future potential movement (i.e., releases of captive wolves) on the species’ persistence and genetic diversity. Counter to theory, increased movement has had positive demographic effects, with higher per capitamovement rates leading to increased metapopulation growth and decreased subpopulation synchrony. These counter‐theoretical results are likely due to differences in reproduction and survival rates among subpopulations and the small size of the metapopulation. Furthermore, higher rates of movement did not increase retention of genetic diversity, likely because of the active pedigree‐based breeding management of the species already maximizing gene retention. Our model indicates that future releases of captive wolves are necessary, but not sufficient, for the survival of the species, and must be combined with changes to demographic rates in both the captive and northeastern North Carolina subpopulations. Our results highlight the need for models and field data that more adequately describe the viability of small metapopulations. © 2017 The Wildlife Society. Historical movement of red wolves between captive and wild subpopulations has promoted metapopulation viability and future releases of captive wolves to the wild subpopulation are necessary for the long‐term viability of the red wolf metapopulation but must be combined with reductions in wild wolf mortality rates to have maximum effect.

England and Wales have one of the highest frequencies of autopsy in the world. Implementation of post-mortem CT (PMCT), enhanced with targeted coronary angiography (PMCTA), in adults to avoid invasive autopsy would have cultural, religious, and potential economic benefits. We aimed to assess the diagnostic accuracy of PMCTA as a first-line technique in post-mortem investigations.

ObjectiveOesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA.DesignWe used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk.ResultsWe identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10−5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk.ConclusionsThis study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1influence disease susceptibility.

The use of electronic cigarettes (e-cigarettes) is a rapidly growing trend throughout the United States. E-cigarettes have been linked to the risk of causing explosion and fire.

Supplemental Digital Content is available in the text.

Infectious diseases pose a significant threat to global biodiversity and may contribute to extinction. As such, establishing baseline disease prevalence in vulnerable species where disease could affect persistence is important to conservation. We assessed potential disease threats to endangered red wolves (Canis rufus) by evaluating regional (southeastern United States) disease occurrences in mammals and parasite prevalence in red wolves and sympatric coyotes (Canis latrans) in North Carolina. Common viral pathogens in the southeast region, such as canine distemper and canine parvovirus, and numerous widespread endoparasites could pose a threat to the red wolf population. The most prevalent parasites in red wolves and sympatric coyotes were heartworm (Dirofilaria immitis), hookworm (Ancylostoma caninum), and Ehrlichiaspp.; several red wolves and coyotes were also positive for bacteria causing Lyme disease (Borrelia burgdorferi). Coyotes had a more species-rich parasite community than red wolves, suggesting they could harbor more parasites and act as a disease reservoir. Species identity and sex did not significantly affect parasite loads, but young canids were less likely to have heartworm and more likely to have high levels of endoparasites. Continued disease monitoring is important for red wolf recovery because low levels of genetic variability may compromise the wolves' abilities to combat novel pathogens from closely related species, such as domestic dogs and coyotes.

Aim:To ascertain the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066 and p-STAT3 target engagement within recurrent glioblastoma (GBM) patients. Patients & methods:In a first-in-human open-label, single-center, single-arm 3 + 3 design Phase I clinical trial, eight patients were treated with WP1066 until disease progression or unacceptable toxicities. Results:In the absence of significant toxicity, the MFD was identified to be 8 mg/kg. The most common adverse event was grade 1 nausea and diarrhea in 50% of patients. No treatment-related deaths occurred; 6 of 8 patients died from disease progression and one was lost to follow-up. Of 8 patients with radiographic follow-up, all had progressive disease. The longest response duration exceeded 3.25 months. The median progression-free survival (PFS) time was 2.3 months (95% CI: 1.7 months-NA months), and 6-month PFS (PFS6) rate was 0%. The median overall survival (OS) rate was 25 months (95% CI: 22.5 months-NA months), with an estimated 1-year OS rate of 100%. Pharmacokinetic (PK) data demonstrated that at 8 mg/kg, the T1/2was 2–3 h with a dose dependent increase in the Cmax. Immune monitoring of the peripheral blood demonstrated that there was p-STAT3 suppression starting at a dose of 1 mg/kg. Conclusion:Immune analyses indicated that WP1066 inhibited systemic immune p-STAT3. WP1066 had an MFD identified at 8 mg/kg which is the target allometric dose based on prior preclinical modeling in combination with radiation therapy and a Phase II study is being planned for newly diagnosed MGMT promoter unmethylated glioblastoma patients.

Aim:To ascertain the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066 and p-STAT3 target engagement within recurrent glioblastoma (GBM) patients. Patients & methods:In a first-in-human open-label, single-center, single-arm 3 + 3 design Phase I clinical trial, eight patients were treated with WP1066 until disease progression or unacceptable toxicities. Results:In the absence of significant toxicity, the MFD was identified to be 8 mg/kg. The most common adverse event was grade 1 nausea and diarrhea in 50% of patients. No treatment-related deaths occurred; 6 of 8 patients died from disease progression and one was lost to follow-up. Of 8 patients with radiographic follow-up, all had progressive disease. The longest response duration exceeded 3.25 months. The median progression-free survival (PFS) time was 2.3 months (95% CI: 1.7 months-NA months), and 6-month PFS (PFS6) rate was 0%. The median overall survival (OS) rate was 25 months (95% CI: 22.5 months-NA months), with an estimated 1-year OS rate of 100%. Pharmacokinetic (PK) data demonstrated that at 8 mg/kg, the T1/2was 2–3 h with a dose dependent increase in the Cmax. Immune monitoring of the peripheral blood demonstrated that there was p-STAT3 suppression starting at a dose of 1 mg/kg. Conclusion:Immune analyses indicated that WP1066 inhibited systemic immune p-STAT3. WP1066 had an MFD identified at 8 mg/kg which is the target allometric dose based on prior preclinical modeling in combination with radiation therapy and a Phase II study is being planned for newly diagnosed MGMT promoter unmethylated glioblastoma patients.

Organic pesticides are difficult compounds to extract from soils and sediments due to their strong affinity for soil particulates. Different pesticide compounds migrate to varying extents in the environment depending on their chemical structures, with effects ranging from strong adsorption to soil particles to rapid dissolution in water. Published methodologies report procedures for extracting and analysing discrete compounds or chemical classes but there is a lack of previous work concerned with methodologies for the simultaneous extraction and analysis of organic pesticides from different chemical classes. The soil environment is a complex matrix and farmers use a variety of compounds for pest control; with regular crop rotation a diverse mixture of chemicals is likely to be present in arable fields. Mindful of a legacy of pesticide contamination in water and the requirement for management of water resources at catchment scales there is a need to quantitatively assess the storage and transport of a variety of organic pesticides in different phases; soil, sediment and water. This paper describes a methodology for analysing seven different organic pesticides representative of five different classes of pesticide using a single methodology. Prior to use all glassware was deactivated using dimethyldichlorosilane to prevent adsorption effects. Soils then underwent a triple ultrasonication in acetone before being methylated with trimethylsilyldiazomethane. Final extracts were dissolved in hexane and analysed by GC/MS. Recoveries from the soil were determined to range between 70% and 114%.

Legal context On 30 April 2010, WIPO released a study on copyright in the public domain, authored by Séverine Dusollier, a Professor of Law at the University of Namur in Belgium. This very comprehensive report sought to examine the balance between exclusive intellectual property protection and public domain works. It also sought to establish the best means of shaping legislation to allow the public domain to flourish. Key points There is a balance between something being public domain in the sense that physically, it is accessible to the public, and the effort and investment in making something available in very convenient digital form, especially true in relation to artworks. Practical significance Any proposal for a new legislative framework for copyright and the public domain, or alteration to the status quo, is of key importance to those businesses providing or using significant quantities of digitised image data. It is useful to consider whether, in times where governments are under significant pressure to reduce investment in the arts; and philanthropic generosity is spread more thinly, commerce provides the means by which the public can have broadened access to otherwise public domain works, but with a price to pay.

Polyphosphate, a linear polymer of inorganic phosphate, is secreted by activated platelets and accumulates in many infectious microorganisms. We recently showed that polyphosphate modulates the blood coagulation cascade at 3 steps: it triggers the contact pathway, it accelerates factor V activation, and it enhances fibrin polymerization. We now report that polyphosphate exerts differential effects on blood clotting, depending on polymer length. Very long polymers (≥ 500mers, such as those present in microorganisms) were required for optimal activation of the contact pathway, while shorter polymers (∼ 100mers, similar to the polymer lengths released by platelets) were sufficient to accelerate factor V activation and abrogate the anticoagulant function of the tissue factor pathway inhibitor. Optimal enhancement of fibrin clot turbidity by polyphosphate required ≥ 250mers. Pyrophosphate, which is also secreted by activated platelets, potently blocked polyphosphate-mediated enhancement of fibrin clot structure, suggesting that pyrophosphate is a novel regulator of fibrin function. In conclusion, polyphosphate of the size secreted by platelets is very efficient at accelerating blood clotting reactions but is less efficient at initiating them or at modulating clot structure. Microbial polyphosphate, which is highly procoagulant, may function in host responses to pathogens.