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Abstract Our objective was to examine differences in cytokine/chemokine response in chronic hepatitis B(CHB) patients to understand the immune mechanism of HBsAg loss (functional cure) during antiviral therapy. We used an unbiased machine learning strategy to unravel the immune pathways in CHB nucleo(t)side analogue-treated patients who achieved HBsAg loss with peg-interferon-α(peg-IFN-α) add-on or switch treatment in a randomised clinical trial. Cytokines/chemokines from plasma were compared between those with/without HBsAg loss, at baseline, before and after HBsAg loss. Peg-IFN-α treatment resulted in higher levels of IL-27, IL-12p70, IL-18, IL-13, IL-4, IL-22 and GM-CSF prior to HBsAg loss. Probabilistic network analysis of cytokines, chemokines and soluble factors suggested a dynamic dendritic cell driven NK and T cell immune response associated with HBsAg loss. Bayesian network analysis showed a dominant myeloid-driven type 1 inflammatory response with a MIG and I-TAC central module contributing to HBsAg loss in the add-on arm. In the switch arm, HBsAg loss was associated with a T cell activation module exemplified by high levels of CD40L suggesting T cell activation. Our findings show that more than one immune pathway to HBsAg loss was found with peg-IFN-α therapy; by myeloid-driven Type 1 response in one instance, and T cell activation in the other.

Summary: Pharmacological studies established a role for AMPARs in the mammalian forebrain in spatial memory performance. Here we generated global GluA1/3 double knockout mice (Gria1/3−/−) and conditional knockouts lacking GluA1 and GluA3 AMPAR subunits specifically from principal cells across the forebrain (Gria1/3ΔFb). In both models, loss of GluA1 and GluA3 resulted in reduced hippocampal GluA2 and increased levels of the NMDAR subunit GluN2A. Electrically-evoked AMPAR-mediated EPSPs were greatly diminished, and there was an absence of tetanus-induced LTP. Gria1/3−/− mice showed premature mortality. Gria1/3ΔFb mice were viable, and their memory performance could be analyzed. In the Morris water maze (MWM), Gria1/3ΔFb mice showed profound long-term memory deficits, in marked contrast to the normal MWM learning previously seen in single Gria1−/− and Gria3−/− knockout mice. Our results suggest a redundancy of function within the pool of available ionotropic glutamate receptors for long-term spatial memory performance.

Abstract Background In 2020, the long‐lasting effects of the Covid‐19 virus were not included in public messages of risks to public health. Long Covid emerged as a novel and enigmatic illness with a serious and life‐changing impact. Long Covid is poorly explained by objective medical tests, leading to widespread disbelief and stigma associated with the condition. The aim of this organic research is to explore the physical and epistemic challenges of living with Long Covid. Methods Unlike any previous pandemic in history, online Covid communities and ‘citizen science’ have played a leading role in advancing our understanding of Long Covid. As patient‐led research of this grassroots Covid community, a team approach to thematic analysis was undertaken of 66 patient stories submitted online to covid19‐recovery.org at the beginning of the Covid‐19 pandemic between April and September 2020. Results The overriding theme of the analysis highlights the complexities and challenges of living with Long Covid. Our distinct themes were identified: the life‐changing impact of the condition, the importance of validation and how, for many, seeking alternatives was felt to be their only option. Conclusions Long Covid does not easily fit into the dominant evidence‐based practice and the biomedical model of health, which rely on objective indicators of the disease process. Patient testimonies are vital to understanding and treating Long Covid, yet patients are frequently disbelieved, and their testimonies are not taken seriously leading to stigma and epistemic injustice, which introduces a lack of trust into the therapeutic relationship. Patient Contribution The research was undertaken in partnership with our consumer representative(s) and all findings and subsequent recommendations have been coproduced.

Rates of food insecurity are high among adults with serious mental illness (SMI); this population also engages in less physical activity than the general population. However, the relationship between food insecurity and physical activity in this group has not been explored. We examined food insecurity prevalence and its association with physical activity in 314 adults with SMI living in supportive housing in New York City and Philadelphia and enrolled in an institutional review board-approved randomized controlled trial of a Peer Group Lifestyle Balance (PGLB) program. We analyzed 2014 baseline survey data, including demographic data and self-reported food security, and four self-reported physical activity outcomes: any physical activity per week (yes/no) and 2) total, 3) moderate, or 4) vigorous physical activity minutes per week. A logistic regression model examined food security as a predictor of any physical activity; zero-inflated negative binomial regression models were used for the other three physical activity outcomes; demographic and clinical predictors were assessed for inclusion in models. Over half of participants (51.7%) reported low or very low levels of food security. Relationships between food insecurity and three physical activity measures (any physical activity, total weekly minutes, and moderate weekly minutes) were non-significant; those with lower food security were more likely to engage in vigorous physical activity. The high food insecurity prevalence highlights the importance of measuring and addressing food security in populations experiencing SMI; measuring physical activity is also important for tailored lifestyle recommendations. Future studies should examine longitudinal changes in food security and physical activity.

Abstract Phenotype-based assortative mating is well established in humans, with the potential for further convergence through a shared environment. To assess the correlation within infertile couples of physical, social, and behavioural characteristics and 155 circulating metabolic measures. Cross sectional study at a tertiary medical center of 326 couples undertaking IVF. Serum lipids, lipoprotein subclasses, and low-molecular weight metabolites as quantified by NMR spectroscopy (155 metabolic measures). Multivariable and quantile regression correlations within couples of metabolite profiles. Couples exhibited statistical correlations of varying strength for most physical, social, and behavioural characteristics including age, height, alcohol consumption, education, smoking status, physical activity, family history and ethnicity, with correlation coefficients ranging from 0.22 to 0.73. There was no evidence of within couple associations for BMI and weight, where the correlation coefficients were − 0.03 (95% CI − 0.14, 0.08) and 0.01 (95% CI − 0.10, 0.12), respectively. Within spousal associations of the metabolite measurements were all positive but with weak to modest magnitudes, with the median correlation coefficient across all 155 measures being 0.12 (range 0.01–0.37 and interquartile range 0.10–0.18). With just four having associations stronger than 0.3: docosahexaenoic acid (0.37, 95% CI 0.22, 0.52), omega-3 fatty acids (0.32, 95% CI 0.20, 0.43) histidine (0.32, 95% CI 0.23, 0.41) and pyruvate (0.32, 95% CI 0.22, 0.43). Infertile couples exhibit spousal similarities for a range of demographic and serum metabolite measures, supporting initial assortative mating, with diet-derived metabolites suggesting possible subsequent convergence of their individual metabolic profile.

Introduction Surgery remains the mainstay for treatment of primary glioblastoma, followed by radiotherapy and chemotherapy. Current standard of care during surgery involves the intraoperative use of image-guidance and 5-aminolevulinic acid (5-ALA). There are multiple other surgical adjuncts available to the neuro-oncology surgeon. However, access to, and usage of these varies widely in UK practice, with limited evidence of their use. The aim of this trial is to investigate whether the addition of diffusion tensor imaging (DTI) and intraoperative ultrasound (iUS) to the standard of care surgery (intraoperative neuronavigation and 5-ALA) impacts on deterioration free survival (DFS).Methods and analysis This is a two-stage, randomised control trial (RCT) consisting of an initial non-randomised cohort study based on the principles of the IDEAL (Idea, Development, Exploration, Assessment and Long-term follow-up) stage-IIb format, followed by a statistically powered randomised trial comparing the addition of DTI and iUS to the standard of care surgery. A total of 357 patients will be recruited for the RCT. The primary outcome is DFS, defined as the time to either 10-point deterioration in health-related quality of life scores from baseline, without subsequent reversal, progressive disease or death.Ethics and dissemination The trial was registered in the Integrated Research Application System (Ref: 264482) and approved by a UK research and ethics committee (Ref: 20/LO/0840). Results will be published in a peer-reviewed journal. Further dissemination to participants, patient groups and the wider medical community will use a range of approaches to maximise impact.Trial registration number ISRCTN38834571.

OBJECTIVES:. The reported mortality rates of cancer patients admitted to ICUs vary widely. In addition, there are no studies that examined the outcomes of critically ill cancer patients based on the geographical regions. Therefore, we aimed to evaluate the mortality rates among critically ill cancer patients and provide a comparison based on geography. DATA SOURCES:. PubMed, EMBASE, and Web of Science. STUDY SELECTION:. We included observational studies evaluating adult patients with cancer treated in ICUs. We excluded non-English studies, those with greater than 30% hematopoietic stem cell transplant or postsurgical patients, and those that evaluated a specific type of critical illness, stage of malignancy, or age group. DATA EXTRACTION:. Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. Studies were classified based on the continent in which they were conducted. Primary outcomes were ICU and hospital mortality. We pooled effect sizes by geographical region. DATA SYNTHESIS:. Forty-six studies were included (n = 110,366). The overall quality of studies was moderate. Most of the published literature was from Europe (n = 22), followed by North America (n = 9), Asia (n = 8), South America (n = 5), and Oceania (n = 2). Pooled ICU mortality rate was 38% (95% CI, 33–43%); the lowest mortality rate was in Oceania (26%; 95% CI, 22–30%) and highest in Asia (51%; 95% CI, 44–57%). Pooled hospital mortality rate was 45% (95% CI, 41–49%), with the lowest in North America (37%; 95% CI, 31–43%) and highest in Asia (54%; 95% CI, 37–71%). CONCLUSIONS:. More than half of cancer patients admitted to ICUs survived hospitalization. However, there was wide variability in the mortality rates, as well as the number of available studies among geographical regions. This variability suggests an opportunity to improve outcomes worldwide, through optimizing practice and research.

There is growing interest around the world in more effectively linking public payments to the provision of public goods from agriculture. However, published evidence syntheses suggest mixed, weak or uncertain evidence for many agri-environment scheme options. To inform any future “public money for public goods” based policy, further synthesis work is needed to assess the evidence-base for the full range of interventions currently funded under agri-environment schemes. Further empirical research and trials should then focus on interventions for which there is mixed or limited evidence. Furthermore, to ensure the data collected is comparable and can be synthesised effectively, it is necessary to reach agreement on essential variables and methods that can be prioritised by those conducting research and monitoring. Future policy could then prioritise public money for the public goods that can most reliably be delivered, offering better value for taxpayers and improving the provision of ecosystem services from agricultural landscapes.

Abstract Background Women with diminished ovarian reserve are known to have increased cardiovascular risk, whether there is a continuous association between the ovarian reserve biomarkers; anti-Müllerian hormone (AMH), antral follicle count (AFC) and cardio-metabolic risk factors are unknown. Methods A cross-sectional study of 398 women intending to undergo IVF with pre-treatment early follicular AMH and AFC measurements. Serum lipids, lipoprotein subclasses and low-molecular-weight metabolites were quantified by NMR spectroscopy (155 metabolic measures). Associations were analysed using multivariable regression. Results Participants were mean 35.5 (SD 4.43) years old and had a median AMH of 16 pmol/l (IQR 8.8, 28.0 pmol/l) and a median AFC of 12 (IQR 7.16). AMH showed positive associations with HDL, omega-6 and polyunsaturated fatty acids and the amino acids isoleucine, leucine and tyrosine, with effects ranging from 0.11 (95%CI 0.004 to 0.21) for total lipids in small HDL to 0.16 (0.06 to 0.26) for isoleucine, for a mean difference of one SD of metabolite per one SD increment in AMH, and negatively with acetate: − 0.31(− 0.22, − 0.004) SD per 1 SD AMH. AFC was positively associated with alanine, glutamine and glycine. Results were consistent, though less precisely estimated, when restricted to those women who were preparing for treatment because of their partner’s infertility. Conclusions In women intending to have IVF, AMH and AFC were not associated with traditional lipid measured but were associated with a number of novel cardiovascular risk factors. Prospective studies will be required for replication, determination of causality and confirmation that ovarian reserve is impacting on metabolism rather than variation in metabolism is influencing ovarian reserve.

Encoded Library Technology (ELT) has streamlined the identification of chemical ligands for protein targets in drug discovery. Here, the authors optimize the ELT approach to screen multiple proteins in parallel and identify promising targets and antibacterial compounds forS. aureus, A. baumannii and M. tuberculosis.

Abstract Background Evidence from the US Truth campaign suggests that interventions focusing on tobacco industry tactics can be effective in preventing smoking uptake by children. Operation Smoke Storm is the first school-based intervention based on this premise and comprises three classroom sessions in which students act as secret agents uncovering tobacco industry tactics through videos, quizzes, discussions, and presentations. We report a qualitative evaluation of its acceptability. Methods We conducted eight focus groups with 79 students aged 11-12 who participated in Operation Smoke Storm at two UK schools in Autumn 2013, and 20 interviews with teachers who delivered the intervention. These were digitally audio-recorded, transcribed verbatim and analysed using the framework method. Results Students enjoyed the secret agent scenario and reported acquiring new knowledge about smoking and the tobacco industry, which seemed to strengthen their aversion to smoking. Teachers felt confident delivering the ‘off the shelf’ resource, although they would have welcomed more background information about the topic and guidance on steering discussions. Teachers highlighted a need for the resource to be flexible and not dependent on lesson length, teacher confidence, or expertise. Students and teachers endorsed the idea of developing a booster component for older students and supported the development of printed information complementing the resource to encourage parents to support their child not to smoke. Conclusions These findings demonstrate that Operation Smoke Storm can be delivered by teachers to raise awareness about smoking-related issues. The ideas and issues raised are now being used to improve and extend the resource for further evaluation.

Background: Smokers who start smoking at an early age are less likely to quit and more likely to die from their habit. Evidence from the US Truth® campaign suggests that interventions focusing on tobacco industry practices and ethics may be effective in preventing smoking uptake. Objectives: In an exploratory study, to develop, pilot and provide preliminary evidence of the acceptability and effectiveness of Operation Smoke Storm, a school-based intervention based on the premise of the Truth® campaign, to prevent smoking uptake. Design: Mixed-methods, non-randomised controlled study. Component 1 was delivered to Year 7 students, and student focus groups and teacher interviews were conducted to refine the lessons and to develop components 2 and 3. The revised Year 7 lessons and accompanying family booklet were delivered to new Year 7 students 1 year later in one school only; Year 8 students in both schools received the booster session. Setting and participants: Students in Years 7–8 (aged 11–13 years) in two UK schools. Intervention: A three-component intervention comprising (1) three 50-minute classroom-based sessions in Year 7 in which students acted as secret agents to uncover industry practices through videos, quizzes, discussions and presentations; (2) an accompanying family booklet containing activities designed to stimulate discussions about smoking between parents and students; and (3) a 1-hour interactive classroom-based booster session for Year 8 students, in which students learnt about tobacco marketing strategies from the perspectives of an industry executive, a marketing company and a health campaigner. Main outcome measures: Odds ratios to compare the self-reported prevalence of ever smoking and susceptibility to smoking in Year 8 students after the delivery of the booster session in study schools compared with students in local control schools. Qualitative data on acceptability of the intervention. Results: The combined prevalence of ever smoking and susceptibility increased from 18.2% in Year 7 to 33.8% in Year 8. After adjusting for confounders there was no significant difference in the odds of a Year 8 student in an intervention school being an ever smoker or susceptible never smoker compared with controls [adjusted odds ratio (aOR) 1.28, 95% confidence interval (CI) 0.83 to 1.97; p = 0.263] and no significant difference in the odds of ever smoking (aOR 0.82, 95% CI 0.42 to 1.58; p = 0.549). Students mostly enjoyed the intervention and acquired new knowledge that appeared to strengthen their aversion to smoking. Teachers liked the ‘off-the-shelf’ nature of the resource, although they highlighted differences by academic ability in the extent to which students understood the messages being presented. Use of the family component was low but it was received positively by those parents who did engage with it. Limitations: Logistical difficulties meant that students’ responses in Year 7 and Year 8 could not be linked; however, baseline smoking behaviours differed little between intervention and control schools, and analyses were adjusted for confounders measured at follow-up. Conclusions: Operation Smoke Storm is an acceptable resource for delivering smoking-prevention education but it does not appear to have reduced smoking and susceptibility. Future work: The lack of a strong signal for potential effectiveness, considered alongside logistical difficulties in recruiting and working with schools, suggests that a fully powered cluster randomised trial of the intervention is not warranted. Funding: The National Institute for Health Research (NIHR) Public Health Research programme.

Nature Communications 8: Article number: 16081 (2017); Published: 17 July 2017, Updated: 13 July 2018 The original version of this Article omitted the following from the Acknowledgements: ‘We thank Robert Kirkpatrick for implementing the high throughput protein design strategy that enabled screeningand triage of essential A.

The function of adult neurogenesis in the rodent brain remains unclear. Ablation of adult born neurons has yielded conflicting results about emotional and cognitive impairments. One hypothesis is that adult neurogenesis in the hippocampus enables spatial pattern separation, allowing animals to distinguish between similar stimuli. We investigated whether spatial pattern separation and other putative hippocampal functions of adult neurogenesis were altered in a novel genetic model of neurogenesis ablation in the rat. In rats engineered to express thymidine kinase (TK) from a promoter of the rat glial fibrillary acidic protein (GFAP), ganciclovir treatment reduced new neurons by 98%. GFAP-TK rats showed no significant difference from controls in spatial pattern separation on the radial maze, spatial learning in the water maze, contextual or cued fear conditioning. Meta-analysis of all published studies found no significant effects for ablation of adult neurogenesis on spatial memory, cue conditioning or ethological measures of anxiety. An effect on contextual freezing was significant at a threshold of 5% (P = 0.04), but not at a threshold corrected for multiple testing. The meta-analysis revealed remarkably high levels of heterogeneity among studies of hippocampal function. The source of this heterogeneity remains unclear and poses a challenge for studies of the function of adult neurogenesis.

Obesity is an established risk factor for type 2 diabetes (T2D) and they are metabolically related through the mechanism of insulin resistance. In order to explore how common genetic variants associated with T2D correlate with body mass index (BMI), we examined the influence of 25 T2D associated loci on obesity risk. We used 5056 individuals (2528 sib-pairs) recruited in Indian Migration Study and conducted within sib-pair analysis for six obesity phenotypes. We found associations of variants in CXCR4 (rs932206) and HHEX (rs5015480) with higher body mass index (BMI) (β=0.13, p=0.001) and (β=0.09, p=0.002), respectively and weight (β=0.13, p=0.001) and (β=0.09, p=0.001), respectively. CXCR4 variant was also strongly associated with body fat (β=0.10, p=0.0004). In addition, we demonstrated associations of CXCR4 and HHEX with overweight/obesity (OR=1.6, p=0.003) and (OR=1.4, p=0.002), respectively, in 1333 sib-pairs (2666 individuals). We observed marginal evidence of associations between variants at six loci (TCF7L2, NGN3, FOXA2, LOC646279, FLJ39370 and THADA) and waist hip ratio (WHR), BMI and/or overweight which needs to be validated in larger set of samples. All the above findings were independent of daily energy consumption and physical activity level. The risk score estimates based on eight significant loci (including nominal associations) showed associations with WHR and body fat which were independent of BMI. In summary, we establish the role of T2D associated loci in influencing the measures of obesity in Indian population, suggesting common underlying pathophysiology across populations.