Snus: a compelling harm reduction alternative to cigarettes

Snus is an oral smokeless tobacco product which is usually placed behind the upper lip, either in a loose form or in portioned sachets, and is primarily used in Sweden and Norway. The purpose of this review is to examine the reported effects of snus use in relation to specified health effects, namely lung cancer, cardiovascular disease, pancreatic cancer, diabetes, oral cancer and non-neoplastic oral disease. The review also examines the harm reduction potential of snus as an alternative to cigarettes by comparing the prevalence of snus use and cigarette smoking, and the reported incidence of tobacco-related diseases across European Union countries. The scientific literature generally indicates that the use of snus is not a significant risk factor for developing lung cancer, cardiovascular disease, pancreatic cancer or oral cancer. Studies investigating snus use and diabetes have reported that high consumption of snus (estimated as being four or more cans per week) may be associated with a higher risk of developing diabetes or components of metabolic syndrome; however, overall results are not conclusive. Snus use is associated with the presence of non-neoplastic oral mucosal lesions which are reported to heal rapidly once use has stopped. The most recent Eurobarometer data from 2017 reported that Sweden had the lowest prevalence of daily cigarette use in the European Union at 5% whilst daily “oral tobacco” use was reported to be 20%. European data published by the World Health Organisation in 2018 indicated that Sweden had the lowest rate of tobacco-related mortality and the lowest incidence of male lung cancer. Overall, prevalence statistics and epidemiological data indicate that the use of snus confers a significant harm reduction benefit which is reflected in the comparatively low levels of tobacco-related disease in Sweden when compared with the rest of Europe. The available scientific data, including long-term population studies conducted by independent bodies, demonstrates that the health risks associated with snus are considerably lower than those associated with cigarette smoking

Development of a stabilized trimer pre-fusion RSV F recombinant viral glycoprotein vaccine

It has been known that the RSV fusion protein F is a target vaccine protein to produce a protective immune response. The VRC has shown (Ngwuta, et.al.) through binding competition assays that the amount of pre-fusion site Ø–specific antibodies correlates with neutralizing (NT) activity, whereas the pre/post-fusion site II mAbs does not correlate with neutralization. Our results indicate that RSV NT activity in human sera is primarily derived from pre-F–specific antibodies, and therefore, inducing or boosting NT activity by vaccination will be facilitated by using pre-F antigens that preserve site Ø. Therefore, the instability of the RSV pre-fusion conformation has limited the potential of this as a vaccine antigen. Therefore, the VRC has designed a structurally stabilized glycoprotein pre-fusion RSV F trimer vaccine antigen and has shown it to be highly immunogenic in preclinical studies. A description of challenges in the development of a high productivity CHO cell line, production process and product quality and antigenic characterization assays for Phase I clinical material will be presented along with comparison of pre-clinical results of research to development material. Please click Additional Files below to see the full abstract

Reciprocal Interactions of Pit1 and GATA2 Mediate Signaling Gradient–Induced Determination of Pituitary Cell Types

AbstractThe mechanisms by which transient gradients of signaling molecules lead to emergence of specific cell types remain a central question in mammalian organogenesis. Here, we demonstrate that the appearance of four ventral pituitary cell types is mediated via the reciprocal interactions of two transcription factors, Pit1 and GATA2, which are epistatic to the remainder of the cell type–specific transcription programs and serve as the molecular memory of the transient signaling events. Unexpectedly, this program includes a DNA binding–independent function of Pit1, suppressing the ventral GATA2-dependent gonadotrope program by inhibiting GATA2 binding to gonadotrope- but not thyrotrope-specific genes, indicating that both DNA binding–dependent and –independent actions of abundant determining factors contribute to generate distinct cell phenotypes

Ancylostoma ceylanicum Hookworm in Myanmar Refugees, Thailand, 2012–2015

During 2012–2015, US-bound refugees living in Myanmar– Thailand border camps (n = 1,839) were surveyed for hookworm infection and treatment response by using quantitative PCR. Samples were collected at 3 time points: after each of 2 treatments with albendazole and after resettlement in the United States. Baseline prevalence of Necator americanus hookworm was 25.4%, Ancylostoma duodenale 0%, and Ancylostoma ceylanicum (a zoonosis) 5.4%. Compared with N. americanus prevalence, A. ceylanicum hookworm prevalence peaked in younger age groups, and blood eosinophil concentrations during A. ceylanicum infection were higher than those for N. americanus infection. Female sex was associated with a lower risk for either hookworm infection. Cure rates after 1 dose of albendazole were greater for A. ceylanicum (93.3%) than N. americanus (65.9%) hookworm (p\u3c0.001). Lower N. americanus hookworm cure rates were unrelated to β-tubulin single-nucleotide polymorphisms at codons 200 or 167. A. ceylanicum hookworm infection might be more common in humans than previously recognized

What happened to anti-malarial markets after the Affordable Medicines Facility-malaria pilot? Trends in ACT availability, price and market share from five African countries under continuation of the private sector co-payment mechanism

BACKGROUND: The private sector supplies anti-malarial treatment for large proportions of patients in sub-Saharan Africa. Following the large-scale piloting of the Affordable Medicines Facility-malaria (AMFm) from 2010 to 2011, a private sector co-payment mechanism (CPM) provided continuation of private sector subsidies for quality-assured artemisinin combination therapies (QAACT). This article analyses for the first time the extent to which improvements in private sector QAACT supply and distribution observed during the AMFm were maintained or intensified during continuation of the CPM through 2015 in Kenya, Madagascar, Nigeria, Tanzania and Uganda using repeat cross-sectional outlet survey data. RESULTS: QAACT market share in all five countries increased during the AMFm period (p < 0.001). According to the data from the last ACTwatch survey round, in all study countries except Madagascar, AMFm levels of private sector QAACT availability were maintained or improved. In 2014/15, private sector QAACT availability was greater than 70% in Nigeria (84.3%), Kenya (70.5%), Tanzania (83.0%) and Uganda (77.1%), but only 11.2% in Madagascar. QAACT market share was maintained or improved post-AMFm in Nigeria, Tanzania and Uganda, but statistically significant declines were observed in Kenya and Madagascar. In 2014/5, QAACT market share was highest in Kenya and Uganda (48.2 and 47.5%, respectively) followed by Tanzania (39.2%), Nigeria (35.0%), and Madagascar (7.0%). Four of the five countries experienced significant decreases in median QAACT price during the AMFm period. Private sector QAACT prices were maintained or further reduced in Tanzania, Nigeria and Uganda, but prices increased significantly in Kenya and Madagascar. SP prices were consistently lower than those of QAACT in the AMFm period, with the exception of Kenya and Tanzania in 2011, where they were equal. In 2014/5 QAACT remained two to three times more expensive than the most popular non-artemisinin therapy in all countries except Tanzania. CONCLUSIONS: Results suggest that a private sector co-payment mechanism for QAACT implemented at national scale for 5 years was associated with positive and sustained improvements in QAACT availability, price and market share in Nigeria, Tanzania and Uganda, with more mixed results in Kenya, and few improvements in Madagascar. The subsidy mechanism as implemented over time across countries was not sufficient on its own to achieve optimal QAACT uptake. Supporting interventions to address continued availability and distribution of non-artemisinin therapies, and to create demand for QAACT among providers and consumers need to be effectively implemented to realize the full potential of this subsidy mechanism. Furthermore, there is need for comprehensive market assessments to identify contemporary market barriers to high coverage with both confirmatory testing and appropriate treatment

1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model

Uveal melanoma (UM) is an intraocular cancer with propensity for liver metastases. The median overall survival (OS) for metastatic UM (MUM) is 1.07 years, with a reported range of 0.84-1.34. In primary UM, high cysteinyl leukotriene receptor 1 (CysLT(1)) expression associates with poor outcomes. CysLT(1) antagonists, quininib and 1,4-dihydroxy quininib, alter cancer hallmarks of primary and metastatic UM cell lines in vitro. Here, the clinical relevance of CysLT receptors and therapeutic potential of quininib analogs is elaborated in UM using preclinical in vivo orthotopic xenograft models and ex vivo patient samples. Immunohistochemical staining of an independent cohort (n = 64) of primary UM patients confirmed high CysLT(1) expression significantly associates with death from metastatic disease (p = 0.02; HR 2.28; 95% CI 1.08-4.78), solidifying the disease relevance of CysLT(1) in UM. In primary UM samples (n = 11) cultured as ex vivo explants, 1,4-dihydroxy quininib significantly alters the secretion of IL-13, IL-2, and TNF-alpha. In an orthotopic, cell line-derived xenograft model of MUM, 1,4-dihydroxy quininib administered intraperitoneally at 25 mg/kg significantly decreases ATP5B expression (p = 0.03), a marker of oxidative phosphorylation. In UM, high ATP5F1B is a poor prognostic indicator, whereas low ATP5F1B, in combination with disomy 3, correlates with an absence of metastatic disease in the TCGA-UM dataset. These preclinical data highlight the diagnostic potential of CysLT(1) and ATP5F1B in UM, and the therapeutic potential of 1,4-dihydroxy quininib with ATP5F1B as a companion diagnostic to treat MUM

Identification of a new p53/MDM2 inhibitor motif inspired by studies of chlorofusin

Previous studies on the natural product chlorofusin have shown that the full peptide and azaphilone structure are required for inhibition of the interaction between MDM2 and p53. In the current work, we utilized the cyclic peptide as a template and introduced an azidonorvaline amino acid in place of the ornithine/azaphilone of the natural product and carried out click chemistry with the resulting peptide. From this small library the first ever non-azaphilone containing chlorofusin analogue with MDM2/p53 activity was identified. Further studies then suggested that the simple structure of the Fmoc-norvaline amino acid that had undergone a click reaction was also able to inhibit MDM2/p53 interaction. This is an example where studies of a natural product have led to the serendipitous identification of a new small molecule inhibitor of a protein-protein interaction

It’s a girl thing: menstruation, school attendance, spatial mobility and wider gender inequalities in Kenya

Recent attention has been drawn to possible linkages between poor sanitation in sub-Saharan African schools and low attendance rates amongst post-pubescent girls. In particular, questions have been raised about the influence of menstruation and access to sanitary products on schoolgirl absenteeism but research on this topic is scarce. Moreover, the few detailed empirical studies that have been conducted in sub-Saharan Africa on this topic have produced contradictory results. These uncertainties coupled with theories of how concepts of pollution and taboo are used to construct or police spatial boundaries (and maintain power relations within society) provide an interesting context for examining everyday geographies of menstruation. Kisumu, Kenya provides the context for the study which utilises a feminist political ecology framework to investigate cultural and spatial limitations associated with menstruation and puberty. Drawing on schoolgirls’ lived experiences, we illustrate how emotional geographies of puberty and menstruation are productive of and help to reproduce gender inequalities in mobility and access to social capital resources (especially education). At the same time we show how poverty coupled with low levels of sexual and reproductive health and rights education can exacerbate gendered bodily inequalities as girls face an increased risk of sexual exploitation when they reach puberty

What is the economic cost of providing an all Wales postpartum haemorrhage quality improvement initiative (OBS Cymru)? A cost-consequences comparison with standard care

Background and Objective: A postpartum haemorrhage quality improvement initiative (the Obstetric Bleeding Strategy for Wales [OBS Cymru]), including about 60,000 maternities, was adopted across Wales (2017–2018). We performed a cost-consequences analysis to inform ongoing provision and wider uptake. Methods: Analysis was based on primary data from the All Wales postpartum haemorrhage database, with a UK National Health Services perspective, a time horizon from delivery until hospital discharge and no discounting. Costs were based on UK published sources with viscoelastic haemostatic assay costs provided by the OBS Cymru national team. Mean costs per eligible patient (postpartum haemorrhage > 1000 mL) were calculated for OBS Cymru, using the early implementation period as a comparator. Modelling allowed comparisons of three scenarios (two predefined and one post hoc) and implementation in different sizes of maternity unit. Results: All analyses demonstrated consistent savings in blood products, critical care and haematology time, and also a reduced occurrence of massive postpartum haemorrhage (> 2500 mL). Incremental postnatal length of stay varied between scenarios, substantially impacting on total costs. Mean incremental cost of OBS Cymru, compared with standard care, across Wales was £18.41 per patient (postpartum haemorrhage > 1000 mL) or − £10.66 if the length of stay was excluded. Modelling a maternity unit of 5000 births per annum, OBS Cymru incurred an incremental cost of £9.53 per patient with postpartum haemorrhage > 1000 mL. Conclusions: OBS Cymru reduces the occurrence of massive postpartum haemorrhage, need for transfusions, quantity of blood products and intensive care. In medium-to-large maternity units (>3000 maternities per annum), the OBS Cymru intervention approaches cost neutrality compared to standard care

Capturing the whole-school food environment in primary schools

Abstract Objective: The school food environment is an ideal setting for encouraging healthy dietary behaviour. We aimed to develop an instrument to assess whole-school food environments; test the instrument in the school setting; and demonstrate its use to make food environment recommendations. Design: School food environment literature and UK school food guidance was searched to inform instrument items. The instrument consisted of (i) an observation proforma capturing canteen areas systems, food presentation and monitoring of food intake, and (ii) a questionnaire assessing food policies, provision and activities. The instrument was tested in schools and used to develop school food environment recommendations. Descriptive analyses enabled narrative discussion. Setting: Primary schools. Participants: An observation was undertaken at schools in urban and rural geographical regions of Northern Ireland of varying socio-economic status (n=18). School senior management completed the questionnaire with input from school caterers (n=16). Results: The instrument captured desired detail and potential instrument modifications were identified. School food environments varied. Differences existed between food policies and how policies were implemented and monitored. At many schools there was scope to enhance physical eating environments (n=12, 67%) and food presentation (n=15, 83%); emphasise healthy eating through food activities (n=7, 78%); and increase parental engagement in school food (n=9, 56%). Conclusions: The developed instrument can measure whole-school food environments in primary schools and also enabled identification of recommendations to enhance school food environments. Further assessment and adaptation of the instrument is required to enable future use as a research tool or for self-assessment use by schools