The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction:absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADME studies

The conceptual technology of small molecule glycomimetics, exemplified by compounds C1–4, has shown promising protective effects against lipid-induced endothelial dysfunction, restorative effects on diabetic endothelial colony forming cells, and preventative effects on downstream vascular calcification amongst other important in vitro and ex vivo studies. We report the optimised synthesis of an array of 17 small molecule glycomimetics, including the regio-, enantio- and diastereo-meric sulfated scaffolds of a hit structure along with novel desulfated examples. For the first time, the absolute stereochemical configurations of C1–4 have been clarified based on an identified and consistent anomaly with the Sharpless asymmetric dihydroxylation reaction. We have investigated the role and importance of sulfation pattern, location, regioisomers, and spatial orientation of distal sulfate groups on the modulation of endothelial dysfunction through their interaction with hepatocyte growth factor (HGF). In silico studies demonstrated the key interactions the persulfated glycomimetics make with HGF and revealed the importance of both sulfate density and positioning (both point chirality and vector) to biological activity. In vitro biological data of the most efficient binding motifs, along with desulfated comparators, support the modulatory effects of sulfated small molecule glycomimetics in the downstream signaling cascade of endothelial dysfunction. In vitro absorption, distribution, metabolism, elimination and toxicity (ADMET) data demonstrate the glycomimetic approach to be a promising approach for hit-to-lead studies

The interaction of Escherichia coli O157 :H7 and Salmonella Typhimurium flagella with host cell membranes and cytoskeletal components

Bacterial flagella have many established roles beyond swimming motility. Despite clear evidence of flagella-dependent adherence, the specificity of the ligands and mechanisms of binding are still debated. In this study, the molecular basis of Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium flagella binding to epithelial cell cultures was investigated. Flagella interactions with host cell surfaces were intimate and crossed cellular boundaries as demarcated by actin and membrane labelling. Scanning electron microscopy revealed flagella disappearing into cellular surfaces and transmission electron microscopy of S. Typhiumurium indicated host membrane deformation and disruption in proximity to flagella. Motor mutants of E. coli O157:H7 and S. Typhimurium caused reduced haemolysis compared to wild-type, indicating that membrane disruption was in part due to flagella rotation. Flagella from E. coli O157 (H7), EPEC O127 (H6) and S. Typhimurium (P1 and P2 flagella) were shown to bind to purified intracellular components of the actin cytoskeleton and directly increase in vitro actin polymerization rates. We propose that flagella interactions with host cell membranes and cytoskeletal components may help prime intimate attachment and invasion for E. coli O157:H7 and S. Typhimurium, respectively

Incentives as connectors : insights into a breastfeeding incentive intervention in a disadvantaged area of North-West England

PMID: 22458841 [PubMed - indexed for MEDLINE] PMCID: PMC3414740 Free PMC ArticlePeer reviewedPublisher PD

Imparting carrier status results detected by universal newborn screening for sickle cell and cystic fibrosis in England: a qualitative study of current practice and policy challenges

<p>Abstract</p> <p>Background</p> <p>Universal newborn screening for early detection of children affected by sickle cell disorders and cystic fibrosis is currently being implemented across England. Parents of infants identified as carriers of these disorders must also be informed of their baby's result. However there is a lack of evidence for most effective practice internationally when doing so. This study describes current or proposed models for imparting this information in practice and explores associated challenges for policy.</p> <p>Methods</p> <p>Thematic analysis of semi-structured interviews with Child Health Coordinators from all English Health Regions.</p> <p>Results</p> <p>Diverse methods for imparting carrier results, both within and between regions, and within and between conditions, were being implemented or planned. Models ranged from result by letter to in-person communication during a home visit. Non-specialists were considered the best placed professionals to give results and a similar approach for both conditions was emphasised. While national guidance has influenced choice of models, other factors contributed such as existing service structures and lack of funding. Challenges included uncertainty about guidance specifying face to face notification; how best to balance allaying parental anxiety by using familiar non-specialist health professionals with concerns about practitioner competence; and extent of information parents should be given. Inadequate consideration of resource and service workload was seen as the main policy obstacle. Clarification of existing guidance; more specific protocols to ensure consistent countrywide practice; integration of the two programmes; and 'normalising' carrier status were suggested as improvements.</p> <p>Conclusion</p> <p>Differing models for communicating carrier results raise concerns about equity and clinical governance. However, this variation provides opportunity for evaluation. Timely and more detailed guidance on protocols with clarification of existing recommendations is needed.</p

All-cause hospitalisation among people living with HIV according to gender, mode of HIV acquisition, ethnicity, and geographical origin in Europe and North America: findings from the ART-CC cohort collaboration

BACKGROUND: Understanding demographic disparities in hospitalisation is crucial for the identification of vulnerable populations, interventions, and resource planning. METHODS: Data were from the Antiretroviral Therapy Cohort Collaboration (ART-CC) on people living with HIV in Europe and North America, followed up between January, 2007 and December, 2020. We investigated differences in all-cause hospitalisation according to gender and mode of HIV acquisition, ethnicity, and combined geographical origin and ethnicity, in people living with HIV on modern combination antiretroviral therapy (cART). Analyses were performed separately for European and North American cohorts. Hospitalisation rates were assessed using negative binomial multilevel regression, adjusted for age, time since cART intitiaion, and calendar year. FINDINGS: Among 23 594 people living with HIV in Europe and 9612 in North America, hospitalisation rates per 100 person-years were 16·2 (95% CI 16·0-16·4) and 13·1 (12·8-13·5). Compared with gay, bisexual, and other men who have sex with men, rates were higher for heterosexual men and women, and much higher for men and women who acquired HIV through injection drug use (adjusted incidence rate ratios ranged from 1·2 to 2·5 in Europe and from 1·2 to 3·3 in North America). In both regions, individuals with geographical origin other than the region of study generally had lower hospitalisation rates compared with those with geographical origin of the study country. In North America, Indigenous people and Black or African American individuals had higher rates than White individuals (adjusted incidence rate ratios 1·9 and 1·2), whereas Asian and Hispanic people living with HIV had somewhat lower rates. In Europe there was a lower rate in Asian individuals compared with White individuals. INTERPRETATION: Substantial disparities exist in all-cause hospitalisation between demographic groups of people living with HIV in the current cART era in high-income settings, highlighting the need for targeted support. FUNDING: Royal Free Charity and the National Institute on Alcohol Abuse and Alcoholism

Heterogeneity in outcomes of treated HIV-positive patients in Europe and North America: relation with patient and cohort characteristics

Background HIV cohort collaborations, which pool data from diverse patient cohorts, have provided key insights into outcomes of antiretroviral therapy (ART). However, the extent of, and reasons for, between-cohort heterogeneity in rates of AIDS and mortality are unclear. Methods We obtained data on adult HIV-positive patients who started ART from 1998 without a previous AIDS diagnosis from 17 cohorts in North America and Europe. Patients were followed up from 1 month to 2 years after starting ART. We examined between-cohort heterogeneity in crude and adjusted (age, sex, HIV transmission risk, year, CD4 count and HIV-1 RNA at start of ART) rates of AIDS and mortality using random-effects meta-analysis and meta-regression. Results During 61 520 person-years, 754/38 706 (1.9%) patients died and 1890 (4.9%) progressed to AIDS. Between-cohort variance in mortality rates was reduced from 0.84 to 0.24 (0.73 to 0.28 for AIDS rates) after adjustment for patient characteristics. Adjusted mortality rates were inversely associated with cohorts' estimated completeness of death ascertainment [excellent: 96-100%, good: 90-95%, average: 75-89%; mortality rate ratio 0.66 (95% confidence interval 0.46-0.94) per category]. Mortality rate ratios comparing Europe with North America were 0.42 (0.31-0.57) before and 0.47 (0.30-0.73) after adjusting for completeness of ascertainment. Conclusions Heterogeneity between settings in outcomes of HIV treatment has implications for collaborative analyses, policy and clinical care. Estimated mortality rates may require adjustment for completeness of ascertainment. Higher mortality rate in North American, compared with European, cohorts was not fully explained by completeness of ascertainment and may be because of the inclusion of more socially marginalized patients with higher mortality ris

Generation tourism: towards a common identity

The purpose of this article is to highlight the implications of the indiscipline of tourism academia for a new generation of tourism academics. Generation Tourism is characterised by scholars with a multi-disciplinary education associated with a broad field of study and commonly considered to lack the advantages of a discipline-focused education with its strong theoretical and methodological foundations. The problem this article addresses relates to how new generations of scholars and their views on knowledge creation achieve ascendancy in ways that move on from existing paradigms and earlier cohorts of scholars. Our main argument is that Generation Tourism scholars would benefit from a more clearly developed and common academic identity. To begin the critical conversation around the identity of Generation Tourism we outline five possible points of departure. These points are: (1) learning from historical developments in parent disciplines; (2) spearheading inter-disciplinary scholarship; (3) working towards theoretical developments; (4) embracing mediating methodologies and (5) forming tourism nodes and networks. Recognising these as starting points rather than final statements, we hope that the conversation about Generation Tourism identity will continue in other forums

Life expectancy after 2015 of adults with HIV on long-term antiretroviral therapy in Europe and North America: a collaborative analysis of cohort studies

BACKGROUND: The life expectancy of people with HIV taking antiretroviral therapy (ART) has increased substantially over the past 25 years. Most previous studies of life expectancy were based on data from the first few years after starting ART, when mortality is highest. However, many people with HIV have been successfully treated with ART for many years, and up-to-date prognosis data are needed. We aimed to estimate life expectancy in adults with HIV on ART for at least 1 year in Europe and North America from 2015 onwards. METHODS: We used data for people with HIV taking ART from the Antiretroviral Therapy Cohort Collaboration and the UK Collaborative HIV Cohort Study. Included participants started ART between 1996 and 2014 and had been on ART for at least 1 year by 2015, or started ART between 2015 and 2019 and survived for at least 1 year; all participants were aged at least 16 years at ART initiation. We used Poisson models to estimate the associations between mortality and demographic and clinical characteristics, including CD4 cell count at the start of follow-up. We also estimated the remaining years of life left for people with HIV aged 40 years who were taking ART, and stratified these estimates by variables associated with mortality. These estimates were compared with estimates for years of life remaining in a corresponding multi-country general population. FINDINGS: Among 206 891 people with HIV included, 5780 deaths were recorded since 2015. We estimated that women with HIV at age 40 years had 35·8 years (95% CI 35·2-36·4) of life left if they started ART before 2015, and 39·0 years (38·5-39·5) left if they started ART after 2015. For men with HIV, the corresponding estimates were 34·5 years (33·8-35·2) and 37·0 (36·5-37·6). Women with CD4 counts of fewer than 49 cells per μL at the start of follow-up had an estimated 19·4 years (18·2-20·5) of life left at age 40 years if they started ART before 2015 and 24·9 years (23·9-25·9) left if they started ART after 2015. The corresponding estimates for men were 18·2 years (17·1-19·4) and 23·7 years (22·7-24·8). Women with CD4 counts of at least 500 cells per μL at the start of follow-up had an estimated 40·2 years (39·7-40·6) of life left at age 40 years if they started ART before 2015 and 42·0 years (41·7-42·3) left if they started ART after 2015. The corresponding estimates for men were 38·0 years (37·5-38·5) and 39·2 years (38·7-39·7). INTERPRETATION: For people with HIV on ART and with high CD4 cell counts who survived to 2015 or started ART after 2015, life expectancy was only a few years lower than that in the general population, irrespective of when ART was started. However, for people with low CD4 counts at the start of follow-up, life-expectancy estimates were substantially lower, emphasising the continuing importance of early diagnosis and sustained treatment of HIV. FUNDING: US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council

Assets-based infant feeding help Before and After birth: a randomised controlled feasibility trial for improving breastfeeding initiation and continuation

Background The UK has low levels of breastfeeding initiation and continuation, with evident socioeconomic disparities. To be inclusive, peer support interventions should be woman-centred rather than breastfeeding-centred. Assets-based approaches to public health focus on positive capabilities of individuals and communities, rather than their deficits and problems. The Assets-based feeding help Before and After birth (ABA) intervention offers an assets-based approach based on behaviour change theory. Objective To investigate the feasibility of delivering the ABA infant feeding intervention within a randomised controlled trial. Design Individually randomised controlled feasibility trial; women randomised on a 1:1 ratio to either the intervention or the comparator (usual care). Setting Two separate English sites, selected for having an existing breastfeeding peer support service, relatively high levels of socioeconomic disadvantage, and low rates of breastfeeding. Participants Women aged 16 years or older, pregnant with their first child, irrespective of feeding intention (n=103), recruited by researchers in antenatal clinics. Intervention Proactive, woman-centred support, using an assets-based approach and including Behaviour Change Techniques, provided by an Infant Feeding Helper (a breastfeeding peer supporter trained in ABA intervention), delivered through face-to-face contact, telephone conversations and text messages. The intervention commenced at around 30 weeks gestation and could continue until 5 months postnatally. Main outcome measures Feasibility of intervention delivery with the requisite intensity and duration; acceptability to women, Infant Feeding Helpers and maternity services; feasibility of a future randomised controlled trial. Outcomes included recruitment rates and follow up rates at 3 days, 8 weeks and 6 months postnatal, with collection of outcomes for a future full trial via participant questionnaires. A mixed methods process evaluation included qualitative interviews with women, Infant Feeding Helpers and maternity services; Infant Feeding Helper logs; and audio recordings of antenatal contacts to check intervention fidelity. Results Of 135 eligible women approached, 103 (76.3%) agreed to participate. The study was successful in recruiting teenagers (8.7%) and women living in areas of socioeconomic disadvantage (37.3% resided in the most deprived 40% of small areas in England). Postnatal follow up rates were 68.0%, 85.4% and 80.6% at 3 days, 8 weeks and 6 months respectively. Feeding status at 8-weeks was obtained for 95.1% of participants. Recruitment took place February-August 2017. It was possible to recruit and train existing peer supporters to the Infant Feeding Helper role. The intervention was delivered with relatively high fidelity to most women. Of 50 women, 39 received antenatal visits and 40 postnatal support. Qualitative data showed the intervention to be acceptable. There was no evidence of intervention-related harms. Limitations Birth notification delays resulted in delays in collection of postnatal feeding status data, and the offer of postnatal support. In addition, the intervention needs to better consider all infant feeding types and did not adequately accommodate women who delivered prematurely. Conclusions It is feasible to deliver the intervention and trial. Future work The intervention should be tested in a fully powered randomised controlled trial. Study registration ISRCTN1476097