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Take me to your weeder
\"Jack doesn't want the responsibility of watching the class pet over the weekend so he leaves the hamster with Spork, the new alien at school\"-- Provided by publisher.
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Physical activity, sedentary behaviour and colorectal cancer risk in the UK Biobank
This corrects the article DOI: 10.1038/bjc.2017.85
Journal Article
Pathogens that infect mammalian cells via sulfonated glycosaminoglycans
Sulfonated glycosaminoglycans, such as heparan sulfate and dermatan sulfate, form major components of the cell surface and extracellular matrix, and display vital roles in mammalian physiology, including growth and development. The identification of specific binding to different glycosaminoglycans by a variety of pathogens has led to increased interest in this mechanism for understanding infection. Over the past four decades there have been more than 300 studies on various pathogens that utilize glycosaminoglycans in their infection process. Currently, no articles have collated all known pathogens that use this process. So it is timely that this article provides an overview of all known pathogens that use glycosaminoglycans to enhance their binding and/or infection in human cells. This was done by using the search terms “sulfate/sulphate” “pathogen”, “virus”, “bacteria”, “parasite”, “infection” and “glycosaminoglycans” to curate peer-reviewed and relevant original research articles from PubMed. This search found that glycosaminoglycans are used in the infection process for 59 viruses, 28 bacteria, and 8 other pathogens (i.e. parasitic protozoa, prions). These findings highlight the conserved and widespread use of glycosaminoglycans for enhancing pathogen infection. In addition, the curated list of pathogens in this study provides a resource for future studies to consider potential therapeutic approaches for targeted disruption of the interaction between pathogens and glycosaminoglycans.
Journal Article
Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b
Contact of Mycobacterium tuberculosis (M.tb) with the immune system requires interactions between microbial surface molecules and host pattern recognition receptors. Major M.tb-exposed cell envelope molecules, such as lipomannan (LM), contain subtle structural variations that affect the nature of the immune response. Here we show that LM from virulent M.tb (TB-LM), but not from avirulent Myocobacterium smegmatis (SmegLM), is a potent inhibitor of TNF biosynthesis in human macrophages. This difference in response is not because of variation in Toll-like receptor 2-dependent activation of the signaling kinase MAPK p38. Rather, TB-LM stimulation leads to destabilization of TNF mRNA transcripts and subsequent failure to produce TNF protein. In contrast, SmegLM enhances MAPKactivated protein kinase 2 phosphorylation, which is critical for maintaining TNF mRNA stability in part by contributing microRNAs (miRNAs). In this context, human miRNA miR-125b binds to the 3 UTR region of TNF mRNA and destabilizes the transcript whereas miR-155 enhances TNF production by increasing TNF mRNA half-life and limiting expression of SHIP1, a negative regulator of the PI3K/Akt pathway. We show that macrophages incubated with TB-LM and live M. tb induce high miR-125b expression and low miR-155 expression with correspondingly low TNF production. In contrast, SmegLM and live M. smegmatis induce high miR-155 expression and low miR-125b expression with high TNF production. Thus, we identify a unique cellular mechanism underlying the ability of a major M. tb cell wall component, TB-LM, to block TNF biosynthesis in human macrophages, thereby allowing M. tb to subvert host immunity and potentially increase its virulence.
Journal Article
CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression
Chimeric antigen receptor (CAR) T-cells targeting CD19 demonstrate remarkable efficacy in treating B-lineage acute lymphoblastic leukemia (BL-ALL), yet up to 39% of treated patients relapse with CD19(−) disease. We report that CD19(−) escape is associated with downregulation, but preservation, of targetable expression of CD20 and CD22. Accordingly, we reasoned that broadening the spectrum of CD19CAR T-cells to include both CD20 and CD22 would enable them to target CD19(−) escape BL-ALL while preserving their upfront efficacy. We created a CD19/20/22-targeting CAR T-cell by coexpressing individual CAR molecules on a single T-cell using one tricistronic transgene. CD19/20/22CAR T-cells killed CD19(−) blasts from patients who relapsed after CD19CAR T-cell therapy and CRISPR/Cas9 CD19 knockout primary BL-ALL both in vitro and in an animal model, while CD19CAR T-cells were ineffective. At the subcellular level, CD19/20/22CAR T-cells formed dense immune synapses with target cells that mediated effective cytolytic complex formation, were efficient serial killers in single-cell tracking studies, and were as efficacious as CD19CAR T-cells against primary CD19(+) disease. In conclusion, independent of CD19 expression, CD19/20/22CAR T-cells could be used as salvage or front-line CAR therapy for patients with recalcitrant disease.
Journal Article
Measuring Physical Health in Patients on Antipsychotic Medications
AimsMental illness is associated with poorer physical health and reduced life expectancy in comparison to the general population. This is influenced by many factors, one of which is medication related. Antipsychotics can have multi system effects on the body such as increasing the risk of metabolic syndrome and cardiovascular disease. Our objective was to understand current challenges when monitoring patients' physical health and thereby improve overall health outcomes.MethodsUtilising a clinical audit template, the study group was 9 inpatients during cycle 1 and 10 inpatients during cycle 2, who were prescribed antipsychotics on an Old Age Psychiatry ward. Northumberland, Tyne and Wear (NTW) antipsychotic monitoring guidelines were used as criteria which stipulate that blood tests, ECGs, BMI, waist circumference, side effects and lifestyle effects should be recorded at defined intervals. A proforma highlighting these guidelines was created following audit cycle 1 and utilised by the MDT on the ward, the purpose of cycle 2 was to compare findings following the implementation of the proforma. The standard to meet was that 100% of patients should fulfil the guidelines. Data was collected by retrospectively reviewing paper and electronic notes.ResultsAudit cycle 1 revealed 0 of the patients met the physical health criteria. 0 had the full set of required bloods in the correct timeframe, 0 had waist circumference checked and 2 and 1 patients had side effect and lifestyle effects documented respectively. By comparison, ECGs and BMIs were recorded well. Audit cycle 2 demonstrated significant improvement in all areas. 9 patients had bloods accurately measured. 3 and 6 had side effect and lifestyle reviews respectively. ECGs and BMIs continued to be monitored well. However, waist circumference remained poor with 1 patient recorded. Qualitative feedback when presenting these findings to the MDT highlighted an interest debate into the cost/benefit of measuring waist circumference with the main point being not wishing to cause undue anxiety to the patient.ConclusionThe use of an accessible proforma clearly outlining the criteria to meet for each patient proved valuable in improving the monitoring of physical health parameters. This study highlighted a need for increased awareness of metabolic syndrome and the importance of empowering patients with knowledge regarding their healthcare to help tailor a patient-centred approach to physical health monitoring. Our presentation aims to encourage discussion among attendees around measuring waist circumference and raise awareness of metabolic syndrome.
Journal Article
A Prospective Investigation of Body Size, Body Fat Composition and Colorectal Cancer Risk in the UK Biobank
Obesity has been consistently associated with a greater colorectal cancer risk, but this relationship is weaker among women. In the UK Biobank, we investigated the associations between body size (body mass index [BMI], height, waist circumference, and waist-to-hip ratio) and body fat composition (total body fat percentage and trunk fat percentage) measurements with colorectal cancer risk among 472,526 men and women followed for 5.6 years on average. Multivariable hazard ratios (HRs) and 95% confidence intervals (95%CI) for developing colorectal cancer (2,636 incident cases) were estimated using Cox proportional hazards models. Among men, when the highest and lowest fifths were compared, BMI (HR = 1.35, 95%CI: 1.13–1.61; P
trend
< 0.0001), waist circumference (HR = 1.66, 95%CI: 1.39–1.99; P
trend
< 0.0001), waist-to-hip ratio (HR = 1.58, 95%CI: 1.31–1.91; P
trend
< 0.0001), total body fat percentage (HR = 1.27, 95%CI: 1.06–1.53; P
trend
= 0.002), and trunk fat percentage (HR = 1.31, 95%CI: 1.09–1.58; P
trend
= 0.002) were associated with greater colorectal cancer risk. For women, only waist-to-hip ratio (HR for highest versus lowest fifth = 1.33, 95%CI: 1.08–1.65; P
trend
= 0.005) was positively associated with colorectal cancer risk. Greater body size (overall and abdominal adiposity) was positively associated with colorectal cancer development in men. For women, abdominal adiposity, rather than overall body size, was associated with a greater colorectal cancer risk.
Journal Article
Improvements in the South African HIV care cascade: findings on 90‐90‐90 targets from successive population‐representative surveys in North West Province
Introduction To achieve epidemic control of HIV by 2030, countries aim to meet 90‐90‐90 targets to increase knowledge of HIV‐positive status, initiation of antiretroviral therapy (ART) and viral suppression by 2020. We assessed the progress towards these targets from 2014 to 2016 in South Africa as expanded treatment policies were introduced using population‐representative surveys. Methods Data were collected in January to March 2014 and August to November 2016 in Dr. Ruth Segomotsi Mompati District, North West Province. Each multi‐stage cluster sample included 46 enumeration areas (EA), a target of 36 dwelling units (DU) per EA, and a single resident aged 18 to 49 per DU. Data collection included behavioural surveys, rapid HIV antibody testing and dried blood spot collection. We used weighted general linear regression to evaluate differences in the HIV care continuum over time. Results Overall, 1044 and 971 participants enrolled in 2014 and 2016 respectively with approximately 77% undergoing HIV testing. Despite increases in reported testing, known status among people living with HIV (PLHIV) remained similar at 68.7% (95% Confidence Interval (CI) = 60.9–75.6) in 2014 and 72.8% (95% CI = 63.6–80.4) in 2016. Men were consistently less likely than women to know their status. Among those with known status, PLHIV on ART increased significantly from 80.9% (95% CI = 71.9–87.4) to 91.5% (95% CI = 84.4–95.5). Viral suppression (<5000 copies/mL using DBS) among those on ART increased significantly from 55.0% (95% CI = 39.6–70.4) in 2014 to 81.4% (95% CI = 72.0–90.8) in 2016. Among all PLHIV an estimated 72.0% (95% CI = 63.8–80.1) of women and 45.8% (95% CI = 27.0–64.7) of men achieved viral suppression by 2016. Conclusions Over a period during which fixed‐dose combination was introduced, ART eligibility expanded, and efforts to streamline treatment were implemented, major improvements in the second and third 90‐90‐90 targets were achieved. Achieving the first 90 target will require targeted and improved testing models for men.
Journal Article
Health-Related Quality of Life Among Pregnant Women With and Without Depression in Hubei, China
The role of prenatal depression on physical and mental health among women in mainland China has not been previously investigated. The aim of this research was to (a) calculate the prevalence of depression during pregnancy, (b) explore the relationship between depression sample characteristics and quality of life and (c) identify predictors of physical and mental health among pregnant women. This study was designed as a cross-sectional and exploratory survey. A total of 454 pregnant women participated in the study between December 2009 and June 2010 in central China. The data was collected using the Medical Outcomes Study short form 36 v2 and the Edinburgh Postnatal Depression Scale. Participants were recruited at outpatient departments of obstetrics and gynecology. Findings show that almost 40% of pregnant women experience prenatal depression. Depression was significantly associated with physical and mental health-related quality of life (HRQoL). Depression, increased age, higher gestational age, being employed and married were significant predictors of lower physical HRQoL. Depression, lower BMI and having an unintended pregnancy were significant predictors of lower mental HRQoL. Prenatal depression is very common in women from mainland China. Depressed women suffer from impaired physical and mental health; prenatal depression has a negative impact on women’s HRQoL. We recommend that antenatal services integrate screening for depression into routine antenatal care.
Journal Article