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1.
Zhangjie Su Federico Roncaroli Rainer Hinz Konstantina Karabatsou David Coope Federico Turkheimer Michael Jenkinson Alan Jackson Karl Herholz Alexander Gerhard 《Lancet》2017
Background
Translocator protein (TSPO) is overexpressed mainly in activated microglia under disease conditions. [11C]-(R)PK11195 is a radioligand for TSPO widely applied in PET studies. Previously we have found upregulated TSPO in neoplastic cells and its correlation with malignant transformation in human gliomas using [11C]-(R)PK11195 PET and neuropathological assessment. We aimed to investigate TSPO expression and microglial activation in normal-appearing brain regions of patients with glioma.Methods
14 patients with low-grade glioma (before tumour biopsy or debulking) and ten healthy controls underwent MRI and PET scans. Epilepsy history was reviewed. Binding potential (BPND) of [11C]-(R)PK11195 was calculated by the simplified reference tissue model. BPND of normal-appearing brain regions was compared with that in controls. Post-mortem brains with treatment-naive low-grade glioma were assessed for TSPO and microglia by immunohistochemistry.Findings
BPND of [11C]-(R)PK11195 in low-grade gliomas was lower than in normal-appearing cerebral regions in the contralateral hemisphere (mean ?0·108 [SD 0·148] vs 0·047 [0·101], p=0·0006). Compared with controls, BPND in patients' normal-appearing brain regions was increased (0·065 [0·062] vs 0·002 [0·024], p=0·001), being more prominent in the tumour-bearing hemisphere than in the tumour-free hemisphere (0·081 [0·064] vs 0·057 [0·063], p=0·002). The extratumoral BPND correlated with the length of epilepsy history (Spearman rank correlation coefficient r=0·5, p=0·016). An ipsilateral pattern of increased extratumoral BPND was seen in patients with partial seizures, whereas a bilateral pattern of increase was seen in those with generalised seizures. Post-mortem brain tissue showed a 10-fold increase in microglia and elevation in TSPO-expressing microglia in the gyri adjacent to the tumour and in the contralateral tissue compared with normal brains.Interpretation
[11C](R)PK11195 PET and neuropathological assessment revealed widespread microglial activation in normal-appearing brain regions of patients with glioma. That the magnitude of activation was associated with length of epilepsy history and seizure type suggests that modulation of microglial activation could be a novel target for seizure control in these patients. TSPO PET provides an in-vivo demonstration of this inflammatory response, which is undetectable by structural MRI.Funding
European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement INMiND (HEALTH-F2-2011-278850), Engineering and Physical Science Research Council grant MIMIT (EP/G041733/1), Astro Brain Tumour Fund (1133561). 相似文献2.
Meghan Perry Bram van Bunnik Luke McNally Bryan Wee Patrick Munk Amanda Warr Barbara Moore Pota Kalima Carol Philip Ana Maria de Roda Husman Frank Aarestrup Mark Woolhouse 《Lancet》2019
BackgroundAntimicrobial resistance (AMR) is a global health crisis. It is well established that hospital wastewater can contain organisms that are on the WHO priority list of antibiotic-resistant organisms. We aimed to use metagenomics to study whether the abundances of resistance genes in hospital wastewater reflects clinical activity within the hospital.MethodsHospital wastewater was collected over a 24-h period in June, 2017 from multiple collection points representing different specialties within a tertiary hospital site in Scotland, UK and simultaneously from community sewage works. High throughput shotgun sequencing was done using Illumina HiSeq4000. Sequence reads were assigned taxonomically and to the AMR genes in the ResFinder database. The measured AMR gene abundances were correlated to hospital antimicrobial usage in defined daily doses per 100 occupied bed-days, mean patient length of stay in hospital, mean patient age per hospital collection point, and resistance levels in clinical isolates.Findings1047 bacterial genera and 174 different AMR genes were detected across all samples. Microbiota composition and AMR gene abundance and diversity varied between each collection point and AMR gene abundance was higher in hospital wastewater than in community influent. The composition of AMR genes correlated with microbiota composition (Procrustes analysis, p=0·002). Increased antimicrobial consumption at a class level was associated with higher AMR gene abundance within that class in hospital wastewater (incidence rate ratio 2·80, 95% CI 1·2–6·5, p=0·016). Prolonged mean patient length of stay was associated with higher total AMR gene abundance in hospital wastewater (2·05, 1·39–3·01, p=0·0003). No overall association was found between resistance in clinical isolates at an antimicrobial class level and AMR gene abundance in hospital wastewater.InterpretationAntimicrobial usage is a major driver of AMR gene outflow from hospitals into the sewage environment. The positive relationship between length of stay and AMR gene abundance is consistent with prolonged admission being a risk factor for carriage and infection with resistant microorganisms. Our findings show that hospital wastewater does reflect inpatient activity. With further evaluation this method might represent a useful surveillance tool to monitor hospital AMR gene outflow and guide environmental policy on AMR.FundingAcademy of Medical Sciences. 相似文献
3.
Kenneth Mangion David Carrick Jaclyn Carberry Ahmed Mahrous Christie McComb Hao Gao Xiayou Luo Keith Oldroyd Hany Eteiba Margaret McEntegart Mitchell Lindsay Mark Petrie Xiaodong Zhong Caroline Haig Colin Berry 《Lancet》2017
Background
Infarct size assessed early after acute ST-segment elevation myocardial infarction (STEMI) can overestimate the true extent of infarction, limiting its usefulness as a prognostic biomarker. Myocardial strain derived from displacement encoding with stimulated echoes (DENSE) cardiovascular magnetic resonance (CMR) provides information on myocardial contractility with high precision and accuracy. We hypothesised that the prognostic value of peak circumferential strain is higher than infarct size.Methods
In a prospective, single centre study, participants underwent 1·5T CMR 2 days and 6 months after myocardial infarction. The 5-SD technique was used to quantify late gadolinium enhancement (LGE) as proportion of left ventricular mass. Mid-left ventricular DENSE acquisitions were analysed using postprocessing software. During longer-term follow-up, major adverse cardiac events (MACE) were independently assessed by masked cardiologists. Participants provided written informed consent and ethics approval was given (reference 10/S0703/28). This study is registered with ClinicalTrials.gov, number NCT02072850.Findings
300 patients underwent CMR (mean age 58·6 years [SD 13·2], 237 men [79%], 118 anterior myocardial infarction [39%], 30 with diabetes [10%], 284 with normal flow [Thrombolysis in Myocardial Infarction grade 3] after percutaneous coronary intervention [95%]). 259 of these patients had DENSE acquired, of whom 21 (8%) experienced a MACE at 3 years' follow-up. DENSE and baseline LGE had reasonable power for prediction of adverse events (area under the curve [AUC] DENSE 0·712, p=0·001; AUC LGE 0·644, p=0·028). For MACE (receiver operating characteristic analysis), optimal cut-offs for peak circumferential strain using DENSE was ?10·51%, and LGE 24·05 g. Cox-regression analysis showed that DENSE (hazard ratio 1·175, 95% CI 0·036–1·334; p=0·012) offered an incremental prognostic benefit over LGE (1·040, 1·010–1·070; p=0·008) to predict MACE.Interpretation
DENSE-derived peak circumferential strain offers an incremental prognostic benefit over infarct size revealed by LGE to predict MACE; a cut-off of ?10·51% can identify STEMI patients at higher risk of events. This is the first time, to our knowledge, that CMR-derived strain has been shown to provide prognostic utility in patients with STEMI.Funding
This research was supported by project grants from the Chief Scientist Office (SC01), Medical Research Scotland (343 FRG), and the British Heart Foundation (BHF-PG/14/64/31043). 相似文献4.
5.
Background
Toxic liver injury from drugs including paracetamol is the main cause of acute liver failure in developed countries. The mechanisms that drive irreversible liver failure are poorly understood; platelets could have an important role in this process given their roles beyond haemostasis, including liver regeneration. Ligation of the platelet receptor CLEC-2 with its cognate ligand podoplanin (PDPN) powerfully activates platelets; we sought to investigate the role of CLEC-2 in the pathogenesis of acute liver failure.Methods
Paracetamol or carbon tetrachloride (CCl4) were used to induce acute liver damage in mice. The role of CLEC-2-mediated platelet activation was investigated in mice with conditional deletions for either the platelet CLEC-2 receptor (PF4creCLEC1bfl/fl) or PDPN (Vav1-iCre+PDPNfl/fl), or with specific function blocking antibodies. Liver necrosis, and the subsequent inflammatory response, was gauged by assessment of hepatic leucocyte infiltration and measurement of liver histological and serum markers.Findings
Initial liver injury after CCl4 and paracetamol administration was similar in both wild-type (WT) and CLEC-2-deficient mice. Abrogating CLEC-2-driven platelet activation accelerated liver healing from both toxic insults: mean serum alanine aminotransferase [ALT] after paracetamol administration was 1264 IU/L (SE 296·5) in WT mice versus 52·00 (5·00) in CLEC-2-deficient mice (n=5–8, p=0·0078); and after CCl4 4451 (886·3) versus 367 (99·35) (n=4–8, p=0·0015). Targeting this pathway therapeutically with a specific PDPN function blocking antibody in WT mice also enhanced liver healing: after CCl4 administration mean ALT in control antibody treated mice was 5482 (SE 785·4) versus 598·8 (102·4) in anti-PDPN antibody treated mice (n=6, p=0·0001), and after paracetamol 2850 (1128) versus 194·5 (61·26) (p=0·0176). In-vitro experiments showed that CLEC-2-deficient platelets interacted with Kupffer cells to enhance production of tumour necrosis factor α (TNFα) and increase accumulation of hepatic neutrophils. Healing was prevented by either blocking TNFα or depleting neutrophils in mice. Upregulation of PDPN on Kupffer cells in human acute liver failure suggests that this pathway is also activated in human beings.Interpretation
Platelets are involved in determining the outcome of the sterile inflammatory response to toxic liver injury. Platelet activation via CLEC-2 in the context of an acute liver injury inhibits TNFα-driven reparative inflammation mediated by neutrophils. The fact that blocking CLEC-2-mediated platelet activation enhances neutrophil-driven liver repair without causing bleeding, suggests that this could be a completely novel treatment for human acute liver failure.Funding
Wellcome Trust. 相似文献6.
Background
Diastolic Ca2+ waves in cardiac myocytes lead to arrhythmias by inducing delayed after-depolarisations. Waves occur when sarcoplasmic reticulum (SR) content reaches a threshold level. The phosphodiesterase-5 inhibitor, sildenafil, is antiarrhythmic in mammalian myocardial ischaemia models, and in rat myocytes it reduces Ca2+ transient amplitude and SR Ca2+ content. We sought to determine effects of sildenafil on propensity to Ca2+ waves in the large mammal.Methods
Sheep ventricular myocytes were voltage clamped and Ca2+ fluorescence measured using fura-2. Cells were paced at 0·5 Hz with depolarisations from ?40mV to +10mV. When at steady state, waves were induced with 7·5–15 mM Ca2+. Upon regular waving, sildenafil (1 μM) was applied. To determine threshold SR Ca2+ content, caffeine (10 mM) was added immediately after a wave, and both wave and caffeine-induced Na+/Ca2+ exchanger current (INCX)were integrated.Findings
Increasing external Ca2+ increased SR content and induced diastolic waves. Sildenafil abolished waves in seven of 11 cells. In cells where sildenafil terminated waves, SR content was reduced below threshold. In addition, sildenafil treatment was associated with reduced rate constant of SERCA (kSERCA ?68·4% of control, p<0·0001), initial (first 4 s) increase in sarcolemmal efflux via INCX tail current (+190%, p=0·022), and reduced sarcolemmal influx via L-type Ca2+ current (ICa-L) (?29·8%, p=0·0015). In cells continuing to wave in sildenafil, SR threshold for waves was unchanged (123·8 μmol/L sildenafil vs 150·7, p=0·57). In unstimulated cells spontaneously waving in 10–15 mM Ca2+, sildenafil reduced wave frequency (6·3 waves per 20 s vs 2·7, p=0·0034). The effect of sildenafil on both wave models was abolished when cells were preincubated with the protein kinase G inhibitor, KT5823.Interpretation
Sildenafil suppresses waves induced by elevated external Ca2+ via a protein kinase G-dependent mechanism. This suppression is mediated by reduced SR content, which itself is caused by reduced SERCA function and possible reduced ICa-L. These findings highlight novel antiarrhythmic properties of phosphodiesterase-5 inhibition.Funding
British Heart Foundation. 相似文献7.
Suzanne Spence John N S Matthews Lorraine McSweeney Maisie Rowland Phoebe Orango Ashley J Adamson 《Lancet》2019
BackgroundIn 2013, a government-commissioned review of school food recommended that all key stage 1 pupils in England should receive free school meals. In 2014, Universal Infant Free School Meals (UIFSM) were implemented, costing £450 million. There has been no evaluation of this policy change on pupil's diets. We assessed the effect of UIFSM on pupil's lunch and total daily intake.MethodsWe used cross-sectional surveys in 2008–09 (before) and 2017–18 (after UIFSM) in two primary schools in Newcastle (school A in most deprived ward; school B in least deprived ward) and a validated, prospective 4-day food diary. All pupils (4–7 years) were eligible to participate with written parental consent (2008–09: n=112; 2017–18 n=84). A linear regression model explored the effect of year, school, level of deprivation (pupil postcode), and the interactions between these factors on mean change in percent energy non-milk extrinsic sugars (%E NMES), calcium, yoghurt, and cake; analyses were adjusted for gender. Ethical approval for this study was granted by Newcastle University.FindingsAt lunchtime, we found evidence of a decrease in pupils mean ENMES before and after UIFSM (mean change –4·6% [95% CI –6·3 to –2·9]), which was reflected in total daily intake (–3·8% [–5·2 to –2·7]). We found a year and school interaction on mean calcium: pupils in School B had a similar mean intake before and after UIFSM; in school A, calcium intake had increased (difference between schools in calcium change –120 mg [95% CI –179 to –62]); no evidence was found of an effect in total daily intake. After UIFSM, mean portions of yoghurt decreased in school B and increased in school A (–0·25 portions [–0·46 to –0·04]); mean portions of cake increased in School B and remained similar in school A (0·23 [0·43–0·42]).InterpretationWithin the limitations of this study (repeat cross-sectional survey; only two schools) there is evidence that UIFSM contributed to a reduction in ENMES. Schools should consider implementation of healthier policies (eg, removing the daily cake choice).FundingDepartment of Health and Social Care's Policy Research Programme (Public Health Research Consortium), Newcastle University. 相似文献
8.
Background
About 2·1 million Palestinians live in Jordan, and 370?000 Palestinians live in Jordanian refugee camps. Conflict in their country of origin, poverty, unemployment, and squalid camp conditions are some of the environmental factors that render Palestine refugees susceptible to mental health problems. The aim of this study was to identify the barriers that contribute to the treatment gap in mental health-care services for Palestinian refugees in the Baqa'a refugee camp north of Amman, Jordan.Methods
In this cross-sectional study, qualitative, semi-structured interviews of health-care professionals working at health centres for Palestine refugees in Jordan were done by a British researcher in the English language in the presence of an interpreter. All interviews were recorded, transcribed, and thematically analysed. Ethical approval was granted by the United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) and the University of Leeds. Written consent was obtained from all participants.Findings
16 health-care professionals were interviewed during a 3 week period in May, 2015. 14 participants were based in health-care centres at the Baqa'a refugee camp, and two participants were based at the Field Office of the UNRWA in Amman, Jordan. All (100%) participants reported that underfunding was the most common barrier to accessing treatment. Other major barriers were sex (reported by 15 [94%] participants), stigma and religion (12 [75%]), and culture (ten [63%]).Interpretation
We suggest the following policy recommendations to overcome the barriers to accessing and using mental health-care services in Palestinian refugee camps in Jordan: (1) allocation of more resources for the provision of mental health-care services; (2) establishing a health and social care model that adopts a holistic approach to treating mental health problems in Palestinian refugees, incorporating a framework that facilitates enhanced communication and cooperation between faith leaders and health-care providers; and (3) launching anti-stigma campaigns that are culturally and religiously sensitive and specific.Funding
None. 相似文献9.
BackgroundA primary school musical—“The Mould that Changed the World”—was developed as a unique public engagement strategy to combat antimicrobial resistance (AMR) by engaging children in the story of the discovery of antibiotics, the risks of drug-resistant infections, and the importance of prudent antibiotic use.MethodsThe musical intervention was implemented in two UK primary schools. Parental consent was obtained for all participating children. All 182 participating children, aged 9–11 years, were given an online questionnaire in the classroom before rehearsals began and at 2 weeks after performance with a 6-month evaluation in one school. The effect of the musical was analysed using generalised linear models to control for confounding factors. For the qualitative evaluation, 15 participating children were selected randomly from each school to take part in semi-structured focus groups (n=5 per group) before rehearsals began and 2 weeks after performance. This study was approved by the University of Edinburgh research governance office as an evaluation of an intervention.FindingsConsistent with other intervention studies, knowledge gain was shown with children being more likely to answer questions on key messages of the musical correctly 2 weeks after performance (n=161) compared with the pre-rehearsal questionnaire (n=180; odds ratio 4·63 [95% CI 2·46–9·31], p<0·0001 for knowledge that bacteria can become resistant to antibiotics; 3·26 [1·75–6·32], p=0·00014 for knowledge that antibiotic resistant infections can be life threatening; 2·16 [1·39–3·38], p=0·00059 for knowledge that prudent use of antibiotics will halt rise of antibiotic resistant infections). Long-term knowledge gain was shown by a consistent level of correct answers on key messages between 2 weeks (response rate 95%, n=89) and 6 months after the musical (response rate 71%, n=67). Following the musical children participating in the focus groups (n=30) articulated a greater understanding of AMR and the risks of antibiotic overuse. They discussed intention to minimise personal antibiotic use and influence attitudes to antibiotics in their family and friends.InterpretationAlthough only evaluated in two schools, this study shows that initiatives such as musical theatre can improve both short-term and long-term knowledge in children. It shows a hitherto infrequently reported change in attitude and intention to behaviour change in children at an influential age for health beliefs. This unique public health tool has the potential for national roll-out in primary schools across the UK.FundingBritish Society of Antimicrobial Chemotherapy. 相似文献
10.
11.
Background
Social isolation is recognised for its substantial impact on mortality, ranking above many established public health threats. The end of life can compound this problem; with escalating acute care costs due to poor social support and rising numbers of deaths, new solutions are needed. Examples of peers providing social support exist within end-of-life care but have not been well characterised. We aimed to understand the impacts and facilitative processes of a home visiting intervention.Methods
A qualitative study with mixed methods of data collection (in-depth interviews, participant observation, documentary analysis) was done. Volunteers and beneficiaries matched for more than three home visits, staff members leading the project, and family carers were included. Data were analysed according to modified grounded theory. Participants were recruited by theoretical sampling, and recruitment was concluded when theoretical saturation was reached. Ethics approval was obtained.Findings
Data included 21 in-depth interviews, 19 episodes of participant observation, and 19 documents. Three central impacts emerged from the data. Participants stated that peer-support filled a gap in social support that neither professionals nor family could meet. Participants described becoming socially connected and linked this connection to increased wellbeing. Volunteers viewed themselves and those they visited as peers, despite differences in age or diagnosis. This view explained how compassion could be expressed, instead of a more detached form of empathy. A key facilitative process was the development of a relationship based on mutuality rather than passivity and dependence. On this basis, the relationship could be reconstructed outside the professional domain and could develop a depth and sustainability beyond the formal intervention.Interpretation
This study highlights the role of social networks in promoting wellbeing at the end of life. For sustainable changes to occur, relationships must be reciprocal rather than passive. These findings have important implications for how social care interventions are structured at the end of life. Peer support networks are a sustainable and appropriate care model, and this study provides evidence of their utility and sheds light on the fundamental components of compassionate care.Funding
None. 相似文献12.
Background
An estimated 15% of the UK population has gallstones. Gallstones in the biliary tree can result in complications such as cholangitis and pancreatitis, which have high morbidity and mortality rates. To prevent such complications, patients can undergo endoscopic sphincterotomy. In our centre, an initial study was undertaken in 2002 to examine outcomes of endoscopic sphincterotomy in patients under the age of 50 years. The aim of our current project was to examine the long-term outcomes until Nov 30, 2015.Methods
Data from the study in 2002 were used to identify patients who had undergone endoscopic sphincterotomy between 1984 and 1992. The case notes for these patients were examined to identify outpatient hepatobiliary appointments, serial liver function tests, further investigations or procedures, and development of upper gastrointestinal malignancy or death. Data available included letters and scan reports. In the case of patient death, patients' general practitoners and the coroner's office were contacted.Findings
42 patients (32 women [76%]) had undergone endoscopic sphincterotomy between 1984 and 1992. At data collection in November, 2015, mean age was 55 years (SD 6·49), and mean follow-up since endoscopic sphincterotomy was 25 years (SD 2·40). Eight patients (19%) had died, two during the 2002 study, and six between 2002 and 2016. Two deaths were due to pancreatic adenocarcinoma at 8 months and 19 years after endoscopic sphincterotomy. One patient died from hepatocellular carcinoma; no other deaths were due to hepatobiliary or pancreatic disease or malignancy. Ten patients had no follow-up scans, imaging, or outpatient appointments. Of the 32 patients who had follow-up or investigations, two required further endoscopic sphincterotomy for recurrent stone disease at 22 and 25 years after their initial endoscopic sphincterotomy. Three patients had abnormal liver function tests but had no further investigations; three patients underwent further imaging but had no further interventions.Interpretation
To our knowledge this is the first cohort study with such lengthy follow-up after endoscopic sphincterotomy. Our results suggest that endoscopic sphincterotomy is generally a safe and effective long-term treatment option that is not associated with major levels of recurrent disease or malignancy. This was a small single-centre cohort study and future population based studies should be conducted to better evaluate these findings in a larger cohort of patients.Funding
None. 相似文献13.
Background
Long-term sitting is associated with increased risks of chronic disease and premature mortality. Since workplaces contribute to a large proportion of daily sitting time, reducing sitting in the workplace is a relevant public health objective. To develop effective interventions, factors that can influence reduced sitting behaviour at work must be understood. This study aimed to explore these barriers and facilitators and determine how they might differ by organisation type.Methods
Four organisations based in Yorkshire, UK, which varied by size and sector, were opportunistically selected to participate; they included a local authority, corporation, charity, and small business. Convenience samples of office-based employees (n=40) were then recruited via email. Focus groups (n=10) took place in participants' workplaces and were audiorecorded and transcribed verbatim. Data were coded and thematically analysed. Further analysis explored differences in barriers and facilitators across the four organisations.Findings
Four main themes were identified—namely, factors at the individual, social, organisational, and environmental level. Many of the themes were consistent across the four organisations, but there were some key discrepancies. Organisational-level factors were less pronounced in the small business, where subthemes relating to presenteeism, the role of managers, or the ways of working were not raised, but were common among the other organisations. Social-level factors, such as “doing things as a group”, were key facilitators for sitting less in the small business compared with the other organisations.Interpretation
These finding demonstrate a variety of barriers and facilitators to sitting less at work, which can vary by organisation. Variations can be explained by organisation size, structure or culture. When developing sit less at work interventions, it is important to understand an organisation's barriers and facilitators to sitting less so that these can be addressed or harnessed by the intervention. The need to understand organisation-specific barriers and facilitators may also be relevant to other workplace health promotion initiatives.Funding
Supported by the National Institute for Health Research (NIHR) (doctoral research fellowship for KM DRF-2016-09-023). The funder was not involved in the design of the study, or the collection, analysis, and interpretation of data, or in writing the abstract. 相似文献14.
BackgroundStandardised packaging for factory made and roll your own tobacco was implemented in the UK in May, 2017, alongside a minimum excise tax for factory made products. As other jurisdictions attempt to implement standardised packaging, the tobacco industry continues to suggest that it would be counterproductive, in part by leading to falls in price due to commoditisation. Here, we assess the impact of the introduction of these policies on the UK tobacco market.MethodsWe did a prospective study of UK commercial electronic point-of-sale data from 11 constituent geographic areas. The main outcomes were changes in sales volumes, volume-weighted real prices, and tobacco industry revenue. These were assessed using trend estimation from generalised additive mixed models. Products distributed to less than 10% of stores were excluded for sample design reasons; nevertheless, the analysis included an estimated 91% of the UK tobacco market products. The study did not require ethical approval.Findings107 572 monthly observations of products from May, 2015, to April,2018were included in the analysis. Introduction of standardised packaging and a minimum excise tax was associated with a doubling of the rate of sales decline. The most marked change in sales volumes was among the cheapest factory-made brands, where substantial sales growth stopped and prices rose markedly (prices increased by 0·035 p for the cheapest factory-made brands compared with 0·016 p across all factory-made brands and a 0·004 p increase across all products from May, 2015, to April, 2018). There was no evidence of commoditisation as market segmentation (price differentiation and different price trajectories for premium and lower priced products) continued. Company monthly net revenues declined from GBP £231 million (95% CI £222 million to £240 million) in May, 2015, to £192 million (£182 million to £201 million) in April, 2018.InterpretationThe concurrently introduced policies of standardised packaging and minimum excise tax were associated with declining tobacco sales and tobacco industry revenue, which might underpin the tobacco industry's opposition to the policies. Prices at the end of the period were higher than the at the start, implying no long-term price falls. A minimum excise tax might limit the tobacco industry's ability to keep low-priced tobacco, which is popular with young and disadvantaged smokers, available. The complementary introduction of standardised packaging and the minimum excise tax meant effects could not be distinguished statistically.FundingCancer Research UK and British Heart Foundation (grant number C27260/A23168). 相似文献
15.
Background
Small for gestational age (SGA) babies have increased risk of later morbidity. Birth of the first child is a life-changing event that affects biology, behaviour, and social circumstances. We aimed to examine socioeconomic inequalities in SGA risk, and explore potential mediators and effect modification by parity.Methods
We used the first antenatal care record for each mother aged 18 years or older presenting before 24 weeks' gestation with a live singleton birth at University Hospital Southampton, UK (2004–16). Logistic regression models estimated SGA risk by maternal educational qualification, employment, partner's employment status, and lone motherhood, recorded at the first antenatal appointment, adjusting for maternal age, ethnicity, blood pressure, baby's sex, and mediators (maternal body-mass index and smoking status). Lone mothers were those who provided information on their employment status, but not on their partner's. We tested for effect modification by parity, and then stratified by it if there was evidence of interaction. We used 5% statistical significance level for the interaction analysis and 1% for all other analyses.Findings
There were 44?168 births (28?470 primiparous and 15?698 multiparous women). The association with SGA was modified by parity status for maternal education status and employment (interaction p values 0·03 and 0·02, respectively). In fully-adjusted stratified models, women with no university degree had higher SGA risk than did those with a degree, with the association being stronger in multiparous mothers (adjusted odds ratio primiparous 1·16, 99% CI 1·04–1·30; multiparous 1·35, 1·08–1·68). Women in unemployment had higher SGA risk than those in employment (primiparous 1·32, 1·17–1·50; multiparous 1·22, 1·03–1·43). Smoking mediated the association between lone motherhood and SGA (1·16, 1·00–1·34).Interpretation
Inequalities in SGA risk using all socioeconomic indicators were evident, with a stronger association with maternal educational attainment in multiparous women. Maternal smoking is a possible explanation for the association for lone motherhood. Socioeconomic variables were self-reported at one point during pregnancy, which is a limitation. Excluding teenage pregnancies and those booked after 24 weeks' gestation may have diluted the socioeconomic differences in SGA risk. SGA preventive interventions should target the socially disadvantaged including postpartum smoking cessation.Funding
Supported by an Academy of Medical Sciences and Wellcome Trust grant to NAA (grant no AMS_HOP001\1060) and the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre. The funders had no role in designing the research or writing the abstract. 相似文献16.
Background
Epigallocathechin-3-gallate (EGCG), the major bioactive polyphenol in green tea, has anticarcinogenic properties in vitro and in vivo. Several recent reports have shown that EGCG affects the expression of human papillomavirus (HPV)-encoded E6 and E7, two oncoproteins required for HPV-driven oncogenesis. Here, we aimed to explore the effects of EGCG on keratinocyte proliferation and differentiation, in addition to HPV18 replication, in a three-dimensional organotypic raft culture system.Methods
Organotypic raft cultures of HPV18-infected keratinocytes cultured at the air–liquid interface for 10 days were treated with EGCG for an additional 10 days before fixation and processing. Raft sections were stained with antibodies specific for various cell proliferation and keratinocyte differentiation markers in addition to tumour suppressor genes. Western blotting was performed on EGCG-treated cells to measure the level of HPV18 E6 and E7 protein expression.Findings
EGCG treatment blocked the ability of HPV18-positive keratinocytes to generate hyperplastic epithelium in raft culture. EGCG reduced cell proliferation as assessed by bromodeoxyuridine label incorporation and Ki67 staining; it upregulated expression of several tumour suppressor genes (p53 [TP53], p21, pRb), and impaired productive viral replication (as assessed by HPV18 E4 protein expression), but did not have an effect on keratinocyte differentiation. In culture, EGCG treatment promoted degradation of the E6 and E7 proteins and restored tumour suppressor gene expression.Interpretation
The results of our preclinical study suggest that EGCG inhibits the proliferation of HPV18-infected keratinocytes by enhancing the turnover and degradation of the E6 and E7 proteins, resulting in re-expression of several key tumour suppressor genes. These findings suggest that EGCG could potentially reverse the dysplastic changes induced by oncogenic HPV strains and could be used clinically to treat HPV-induced neoplasia.Funding
Cancer Research UK. 相似文献17.
Elaine Rutherford Elizabeth Bell Kenneth Mangion Rajan K Patel Christie McComb Patrick B Mark 《Lancet》2017
Background
Patients with end-stage renal disease undergoing haemodialysis are at high risk of sudden cardiac death. Advanced renal disease is associated with cardiac hypertrophy, which increases risk of life-threatening arrhythmias. Using a new MRI technique, T1 mapping, and the blood biomarker brain natriuretic peptide (BNP), we aimed to measure changes in function and structure of the heart muscle during the first year of haemodialysis treatment in the Cardiac Uraemic Fibrosis Detection in Dialysis Patients study.Methods
28 adults with kidney disease on haemodialysis within Glasgow, UK, participated in this single-centre observational study. To be eligible for the study patients had to have been on haemodialysis for less than 1 year. Patients with MRI contraindications or who were expected to be on dialysis for less than 6 months were excluded. Primary outcome was volume of myocardial fibrosis (septal T1 time) on MRI at baseline and at 6 months' follow-up. Secondary outcome was change in serum BNP. Patients gave written consent, and ethics approval was given (13/WS/0301). This study is registered with the ISCTRN registry, number ISCTRN99591655.Findings
22 patients completed both baseline and follow-up visits. There was no significant change in septal T1 time after 6 months of haemodialysis (septal T1 time baseline 1276·727 ms, follow-up 1271·837 ms). Left ventricular mass index (LVMI) was reduced at follow-up (baseline mean LVMI 78·3 g/m2 [SD 18·2], follow-up 67·9 [19·0]; p<0·0001). Differences in septal T1 times correlated with difference in LVMI (r=0·545, p=0·009). Median BNP did not significantly change between baseline and follow-up (2908 pg/mL [IQR 1639–5215] vs 2274·5 [1550–7055]). Change in LVMI was correlated with baseline BNP (r=0·492, p=0·02). Correlation between change in BNP and difference in septal T1 time was not significant.Interpretation
6 months of haemodialysis therapy was associated with significant improvement in left ventricular hypertrophy but no significant change in T1 mapping markers of cardiac fibrosis or BNP. This small study suggests that starting haemodialysis might be associated with changes in myocardial structure. These changes could potentially be linked to control of uraemia, blood pressure, or both, which commonly occur on starting renal replacement therapy.Funding
Kidney Research UK (Innovation Grant IN02/2013). 相似文献18.
Background
With mental ill-health on the rise globally, it is crucial to investigate whether the needs of individuals with mental ill-health are fully addressed. Attempts to measure negative consequences of unmet needs have been limited by the use of cross-sectional study designs or self-report measures. We aimed to investigate the interplay between perceived mental ill-health and unmet need in relation to mental health on a population level.Methods
A record linkage methodology was implemented drawing information from the 2011 Northern Ireland Census returns and a population-wide prescribing database (n=286?717). Chronic mental ill-health was assessed through the Census self-reported mental health question (presence of an emotional, psychological, or mental health condition that has lasted or is expected to last at least 12 months) and compared with regular psychotropic medication use (monthly dosage of antidepressant, anxiolytic, antipsychotic, or antimania medication) in the 6 and 12 months after the Census. Logistic regression models adjusted for demography (age, sex, ethnicity, marital status, educational attainment, occupational social class), household (tenure, car availability), and area variables (urbanicity, deprivation).Findings
Overall, 23?803 individuals (8%) aged 25–74 years reported a chronic mental health condition, with low rates among ethnic minorities (129 [3%] of 3897 non-White individuals in receipt of medication). Of the individuals with self-reported mental ill-health, 5246 (22%) did not use psychotropic medication over the following 6 months, and 4412 (19%) did not use them by 12 months. Lower uptake was noted among men (odds ratio 0·56, 95% CI 0·52–0·60), non-white ethnic minorities (0·38, 0·26–0·54), and individuals separated, divorced, or widowed (0·75, 0·68–0·82) or unemployed (0·65, 0·53–0·81).Interpretation
Discrepancies between population mental ill-health and uptake of pharmacological treatment were more evident among men, ethnic minorities, and the economically disadvantaged. This study indicates that administrative data linkages can provide a valuable resource to define population characteristics, and inform policy and practice. However, the findings might be limited by availability of data on psychosocial and non-pharmacological interventions, use of proxy measures of mental health treatment, and the self-reported nature of the Census. Further research should explore whether this variation is due to stigma or lack of understanding or knowledge of available health-care services.Funding
None. 相似文献19.
Shishir Shetty Daniel Patten Pia Rantakari Chris Weston Sirpa Jalkanen Marko Salmi David Adams 《Lancet》2017
Background
Organ fibrosis is a major cause of global mortality. Few medical therapies are available to treat this condition. We have previously demonstrated increased expression of stabilin-1 at sites of chronic liver disease. Using models of chronic liver injury, we aimed to elucidate the role of stabilin-1 during fibrosis and repair.Methods
We used full knockout and cell specific knockouts of stabilin-1 in murine models of chronic liver injury including carbon tetrachloride treatment and a methionine and choline deficient diet. A resolution phase after carbon tetrachloride treatment was used to study tissue repair. Tissue was analysed for fibrosis by confocal microscopy, collagen quantification, and immune cell infiltrate analysis. RNA sequencing and cell transfer experiments were done to elucidate underlying mechanisms. Human tissue was also analysed for stabilin-1 expression in chronic liver injury.Findings
We detected a subset of stabilin-1 macrophages that were induced at sites of cellular injury close to the hepatic scar in mouse models of liver fibrosis and in human liver disease. Stabilin-1 deficiency abrogated malondialdehyde-LDL uptake by hepatic macrophages and was associated with excess collagen III deposition. Mechanistically, the lack of stabilin-1 led to elevated intrahepatic levels of the profibrogenic chemokine CCL3 and an increase in GFAP+ fibrogenic cells. Stabilin-1 knockout macrophages demonstrated a proinflammatory phenotype during liver injury and this led to delayed wound healing.Interpretation
We have demonstrated a pathway in which the evolutionarily conserved receptor stabilin-1 on tissue-infiltrating macrophages promotes the uptake of products of lipid peroxidation and thus prevents excess scarring. We propose that macrophage stabilin-1 is a crucial defence against oxidative tissue damage and thereby maintains tissue homoeostasis.Funding
Wellcome Trust. 相似文献20.
Mapping alcohol and tobacco tax interventions for health in the UK: a qualitative framework analysis
BackgroundAlcohol and tobacco use undermine population health, generating substantial costs. Increasing price is an effective means to reduce consumption and tax is a key harm reduction tool. In the UK, alcohol and tobacco tax are managed within fiscal policy, which does not necessarily prioritise health promotion. We aimed to map the objectives and options for alcohol and tobacco tax change in the UK, including the potential for greater coordination to improve health.MethodsWe did five semi-structured interviews with ten participants selected for their expertise in alcohol or tobacco tax policy. Interviews occurred in pairs (ie, one alcohol and one tobacco expert in each interview) to elicit comparison between substances and were supported by a rapid literature review of tax options. Participants were from government, arms-length governmental organisations, and advocacy groups. Informed by a rapid literature review, comparative framework analysis of alcohol and tobacco tax policy objectives, options, and factors pertaining to coordination between tobacco and alcohol was done.FindingsParticipants raised common health objectives (reducing consumption, harm, inequalities) and fiscal objectives (raising revenue, mitigating societal costs). Drawing on options identified in the rapid review, participants discussed common tax options to achieve these objectives: tax rate increases (sudden rises, annual increases, minimum thresholds), changing tax structures (taxing products differently, tax proportional to harm), levies (taxing retailers and manufacturers), and revenue hypothecation (for prevention or treatment of addiction, local services). Participants were positive about policy exchange across alcohol and tobacco and modelling the combined effect of tax changes, but uncertain about formally linking tax policy across substances.InterpretationRaising tax is often considered to improve health by making products less affordable, but a tax regime that raises additional revenue can support prevention and treatment services and mitigate the social and economic costs of consumption. An unresolved issue for policy debate is who should pay this revenue and how revenue would be maintained if the health objective of falling consumption were met. Although more input from fiscal policymakers would deepen findings, our rapid review and interview approach facilitated discussion across alcohol and tobacco, and use of the framework approach ensured consistent analysis.FundingNational Institute of Health Research Public Health Research programme. 相似文献