Search

Introduction: Electronic cigarettes (e-cigarettes) lack regulatory status as therapeutic products in all jurisdictions worldwide. They are potentially unsafe consumer products, with significant evidence showing they pose a risk to human health. Therefore, developing rapid, economical test methods to assess the chemical composition of e-liquids in heated and unheated forms and the aerosols produced by e-cigarettes is crucial. Methods: Four different e-liquids were heated using two different methods: 1) “typical” vaping using an e-cigarette device, by cycling “on” for three seconds every minute for two hours (e-liquid obtained from the remainder in the tank and aerosol collected in an impinger) and, 2) “accelerated” heating, using an e-cigarette coil, submerged in e-liquid, and heating in short 20 second bursts “on” then 20 seconds “off” for two minutes only (liquid traps aerosol produced). All e-liquids were then analyzed to test for the presence and quantity of 13 chemicals by gas-chromatography mass-spectrometry and compared to an unheated sample. Results: E-liquids heated with the “accelerated” method showed a comparable trend to the “typical” heating method, of increase or decrease in chemical compound quantity, for greater than two-thirds of the detected compounds analyzed over all e-liquids. Six chemicals were detected as aerosol from the impinger fluid with the “typical” heating method, most at negligible levels. Conclusion: We propose this rapid method could form the basis of a standardized screening tool to test heated e-liquids (and e-cigarette aerosols) for harmful or banned substances to ensure only approved products reach the consumer, and the potential harms of e-cigarette use are reduced.

An approach to diverse cross-benzoin and α-siloxy ketone products which leverages a simple yet underutilized C-C bond disconnection strategy is reported. Acyl substitution of readily accessible α-siloxy Weinreb amides with organolithium compounds enables access to a broad scope of aryl, heteroaryl, alkyl, alkenyl, and alkynyl derivatives. Enantiopure benzoins can be accessed via a chiral pool approach, and the utility of accessible cross-benzoins and α-siloxy ketones is highlighted in a suite of downstream synthetic applications.

This integrative review explores the impact of borderline personality disorder (BPD) symptomology and behaviours on occupational capacity, participation, and sustainability. The disorder has also been associated with lower education levels, higher levels of attrition in tertiary education populations, and low occupational participation and employment rates. Personality traits and symptomology have been found to substantially detract from employability. Articles were identified from CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO/Ovid, ProQuest, and PubMed databases. The Joanna Briggs' Institute (JBI) critical appraisal tools were used to evaluate the quality of evidence, and inductive thematic analysis used to extract main themes. Four themes regarding 'barriers', 'enablers', 'treatment', and 'benefits' emerged amongst the 11 eligible articles. The negative symptomology was a barrier to occupational participation, and people with BPD engaged in self-stigmatizing and non-disclosure. However, the positive symptomology such as boldness and honesty were enablers. Treatment was found to be a key element, and occupational engagement was also found to have positive effectives. The evidence indicates that employment improved the symptoms, and a long-term treatment plan is a key element. Some upskilling of mental health workers may be required, including a focus on possible positive symptomology as a way of dealing with the stigmatization. Some awareness raising of the disorder, including for employers, may be needed, with education programmes that deal with the stigmatization. Future funding should focus on specialized programmes targeting unemployment for this group.

Excessive production, secretion, and retention of abnormal mucus is a pathological feature of many obstructive airways diseases including asthma. Azithromycin is an antibiotic that also possesses immunomodulatory and mucoregulatory activities, which may contribute to the clinical effectiveness of azithromycin in asthma. The current study investigated these nonantibiotic activities of azithromycin in mice exposed daily to intranasal house dust mite (HDM) extract for 10 days. HDM-exposed mice exhibited airways hyperresponsiveness to aerosolized methacholine, a pronounced mixed eosinophilic and neutrophilic inflammatory response, increased airway smooth muscle (ASM) thickness, and elevated levels of epithelial mucin staining. Azithromycin (50 mg/kg sc, 2 h before each HDM exposure) attenuated HDM-induced airways hyperresponsiveness to methacholine, airways inflammation (bronchoalveolar lavage eosinophil and neutrophils numbers, and IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, and RANTES levels), and epithelial mucin staining (mucous metaplasia) by at least 50% (compared with HDM-exposed mice, P < 0.05). Isolated tracheal segments of HDM-exposed mice secreted Muc5ac and Muc5b (above baseline levels) in response to exogenous ATP. Moreover, ATP-induced secretion of mucins was attenuated in segments obtained from azithromycin-treated, HDM-exposed mice ( P < 0.05). In additional ex vivo studies, ATP-induced secretion of Muc5ac (but not muc5b) from HDM-exposed tracheal segments was inhibited by in vitro exposure to azithromycin. In vitro azithromycin also inhibited ATP-induced secretion of Muc5ac and Muc5b in tracheal segments from IL-13-exposed mice. In summary, azithromycin inhibited ATP-induced mucin secretion and airways inflammation in HDM-exposed mice, both of which are likely to contribute to suppression of airways hyperresponsiveness.

Background Insect bite inflammation may mimic cellulitis and promote unnecessary antibiotic usage, contributing to antimicrobial resistance in primary care. We wondered how general practice clinicians assess and manage insect bites, diagnose cellulitis, and prescribe antibiotics. Method This is a Quality Improvement study in which 10 general practices in England and Wales investigated patients attending for the first time with insect bites between April and September 2021 to their practices. Mode of consultation, presentation, management plan, and reattendance or referral were noted. Total practice flucloxacillin prescribing was compared to that for insect bites. Results A combined list size of 161,346 yielded 355 insect bite consultations. Nearly two-thirds were female, ages 3–89 years old, with July as the peak month and a mean weekly incidence of 8 per 100,000. GPs still undertook most consultations; most were phone consultations, with photo support for over half. Over 40% presented between days 1 and 3 and common symptoms were redness, itchness, pain, and heat. Vital sign recording was not common, and only 22% of patients were already taking an antihistamine despite 45% complaining of itch. Antibiotics were prescribed to nearly three-quarters of the patients, mainly orally and mostly as flucloxacillin. Reattendance occurred for 12% and referral to hospital for 2%. Flucloxacillin for insect bites contributed a mean of 5.1% of total practice flucloxacillin prescriptions, with a peak of 10.7% in July. Conclusions Antibiotics are likely to be overused in our insect bite practice and patients could make more use of antihistamines for itch before consulting.

SummaryThe development ofTrypanosoma bruceiin its mammalian host is marked by a distinct morphological change as replicative “slender” forms differentiate into cell-cycle arrested “stumpy” forms in a quorum-sensing dependent manner. Although stumpy forms dominate chronic infections at the population level, the proportion of replicative parasites at the individual cell level and the irreversibility of arrest in the bloodstream is unclear. Here, we experimentally demonstrate that developmental cell cycle arrest is definitively irreversible in acute and chronic infections in mice. Furthermore, analysis of replicative capacity and single-cell transcriptome profiling reveals a temporal hierarchy, whereby cell-cycle arrest and appearance of a stumpy-like transcriptome precedes irreversible commitment and morphological change. Unexpectedly, we show that proliferating parasites are exceptionally scarce in the blood after infections are established. This challenges the ability of bloodstream trypanosomes to sustain infection by proliferation or antigenic variation, these parasites instead being overwhelmingly adapted for transmission.

Purpose: Highly aggressive triple-negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate receptor alpha (FRα) is a central mediator of cell growth regulation that could serve as an important target for cancer therapy.Experimental Design: We evaluated FRα expression in breast cancers by genomic (n = 3,414) and IHC (n = 323) analyses and its association with clinical parameters and outcomes. We measured the functional contributions of FRα in TNBC biology by RNA interference and the antitumor functions of an antibody recognizing FRα (MOv18-IgG1), in vitro, and in human TNBC xenograft models.Results: FRα is overexpressed in significant proportions of aggressive basal like/TNBC tumors, and in postneoadjuvant chemotherapy–residual disease associated with a high risk of relapse. Expression is associated with worse overall survival. TNBCs show dysregulated expression of thymidylate synthase, folate hydrolase 1, and methylenetetrahydrofolate reductase, involved in folate metabolism. RNA interference to deplete FRα decreased Src and ERK signaling and resulted in reduction of cell growth. An anti-FRα antibody (MOv18-IgG1) conjugated with a Src inhibitor significantly restricted TNBC xenograft growth. Moreover, MOv18-IgG1 triggered immune-dependent cancer cell death in vitro by human volunteer and breast cancer patient immune cells, and significantly restricted orthotopic and patient-derived xenograft growth.Conclusions: FRα is overexpressed in high-grade TNBC and postchemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as ADCs, or passive immunotherapy priming Fc-mediated antitumor immune cell responses. Clin Cancer Res; 24(20); 5098–111. ©2018 AACR.

Supplementary Figure Legends, Materials and Methods

Supplementary figures

Funder: Gates Cambridge Trust; Id: http://dx.doi.org/10.13039/501100005370, Funder: Linnean Society of London; Id: http://dx.doi.org/10.13039/501100001264, Funder: Marsden Fund; Id: http://dx.doi.org/10.13039/501100009193, Funder: Newnham College, University of Cambridge; Id: http://dx.doi.org/10.13039/501100000663, Funder: Society of Systematic Biologists; Id: http://dx.doi.org/10.13039/100006069, Funder: Swedish Research Council; Id: http://dx.doi.org/10.13039/501100004359, Aim: How mountains accumulate species diversity remains poorly understood, particularly the relative role of in situ cladogenesis compared with colonization from lower elevations. Here, we estimated the contributions of in situ cladogenesis and colonization in generating biodiversity of a large mountain plant radiation and determined the importance of niche adaptation and divergence in these processes. We expected cladogenesis would accompany novel habitats formed by mountain uplift, but colonization would become more important with time as dispersal opportunities accrue. Location: New Zealand, Southern Alps. Taxon: Veronica sect. Hebe (Plantaginaceae). Methods: We estimated the most complete time‐calibrated phylogeny to date for Veronica sect. Hebe to quantify rates of in situ cladogenesis and colonization of mountain habitat based on historical biogeographical models. We used environmental niche modelling to quantify species' climate niches and estimate niche disparity and divergence over time. Results: In situ cladogenesis generated more species in the mountains than colonization from lowlands. Whereas cladogenesis slowed over time, colonization increased, especially in the alpine zone. Both adaptive ecological speciation along climate niche axes and non‐adaptive, vicariant speciation contributed to cladogenesis. However, climate niche disparity through time became saturated, suggesting competition for niche space was important. Colonization brought more divergent species into mountain niches. Main Conclusions: We suggest mountain diversity accumulates through three main stages: high cladogenesis after initial colonization, decreasing cladogenesis with increasing competition and increasing colonization after niches saturate, likely promoted by niche divergence. Combining lineage and mountain uplift trajectories, these stages provide a conceptual model to understand how diversity accumulates elsewhere. Assuming these deep‐time findings apply to anthropogenic conditions, alpine specialists could struggle to outcompete colonizers facilitated by climate change, especially from generalist clades. Considering novel competitive interactions alongside niche traits and biogeographical processes will be crucial for predicting the fate of alpine biodiversity in a changing world.

Biodiesel, which can be made from a variety of natural oils, is currently promoted as a sustainable, healthier replacement for commercial mineral diesel despite little experimental data supporting this. The aim of our research was to investigate the health impacts of exposure to exhaust generated by the combustion of diesel and two different biodiesels. Male BALB/c mice (n = 24 per group) were exposed for 2 h/day for 8 days to diluted exhaust from a diesel engine running on ultra-low sulfur diesel (ULSD) or Tallow or Canola biodiesel, with room air exposures used as control. A variety of respiratory-related end-point measurements were assessed, including lung function, responsiveness to methacholine, airway inflammation and cytokine response, and airway morphometry. Exposure to Tallow biodiesel exhaust resulted in the most significant health impacts compared to Air controls, including increased airway hyperresponsiveness and airway inflammation. In contrast, exposure to Canola biodiesel exhaust resulted in fewer negative health effects. Exposure to ULSD resulted in health impacts between those of the two biodiesels. The health effects of biodiesel exhaust exposure vary depending on the feedstock used to make the fuel.