Inducing remission of Type 2 diabetes in the Caribbean: findings from a mixed methods feasibility study of a low-calorie liquid diet-based intervention in Barbados.

AIM: In a high proportion of people with recently diagnosed Type 2 diabetes, a short (2-3-month) low-calorie diet is able to restore normal glucose and insulin metabolism. The aim of this study was to determine the feasibility of this approach in Barbados. METHODS: Twenty-five individuals with Type 2 diabetes diagnosed within past 6 years, not on insulin, BMI ≥ 27 kg/m2 were recruited. Hypoglycaemic medication was stopped on commencement of the 8-week liquid (760 calorie) diet. Insulin response was assessed in meal tests at baseline, 8 weeks and 8 months. Semi-structured interviews, analysed thematically, explored participants' experiences. 'Responders' were those with fasting plasma glucose (FPG) < 7 mmol/l at 8 weeks. RESULTS: Ten men and 15 women (mean age 48, range 26-68 years) participated. Mean (sd) BMI was 34.2 kg/m2 (6.0); FPG 9.2 mmol/l (2.2). Mean weight loss at 8 weeks and 8 months was 10.1 kg [95% confidence interval (CI) 8.1, 12.0] and 8.2 kg (95% CI 5.8, 10.6); FPG was lower by 2.2 mmol/l (95% CI 1.2, 3.2) and 1.7 mmol/l (95% CI 0.8, 2.7) respectively. Nine of 11 (82%) of those who lost ≥ 10 kg were 'responders' compared with 6 of 14 (43%) who lost < 10 kg (P = 0.048). The 30-min insulin increment was higher in responders at baseline and follow-up (P ≤ 0.01). A food culture based on starchy foods and pressures to eat large amounts at social events were among the challenges identified by participants. CONCLUSIONS: The feasibility of this approach to weight loss and diabetes remission in a predominantly black population in Barbados was demonstrated

Evolution of viral variants in remdesivir-treated and untreated SARS-CoV-2-infected pediatrics patients

Detailed information on intrahost viral evolution in SARS-CoV-2 with and without treatment is limited. Sequential viral loads and deep sequencing of SARS-CoV-2 from the upper respiratory tract of nine hospitalized children, three of whom were treated with remdesivir, revealed that remdesivir treatment suppressed viral load in one patient but not in a second infected with an identical strain without any evidence of drug resistance found. Reduced levels of subgenomic RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication. Haplotype reconstruction uncovered persistent SARS-CoV-2 variant genotypes in four patients. These likely arose from within-host evolution, although superinfection cannot be excluded in one case. Although our dataset is small, observed sample-to-sample heterogeneity in variant frequencies across four of nine patients suggests the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalization could compromise the penetration of remdesivir into the lung, limiting the drugs in vivo efficacy, as has been observed in other lung infections

Identification of CD4+ T Cell Epitopes in C. burnetii Antigens Targeted by Antibody Responses

Coxiella burnetii is an obligate intracellular Gram-negative bacterium that causes acute Q fever and chronic infections in humans. A killed, whole cell vaccine is efficacious, but vaccination can result in severe local or systemic adverse reactions. Although T cell responses are considered pivotal for vaccine derived protective immunity, the epitope targets of CD4+ T cell responses in C. burnetii vaccination have not been elucidated. Since mapping CD4+ epitopes in a genome with over 2,000 ORFs is resource intensive, we focused on 7 antigens that were known to be targeted by antibody responses. 117 candidate peptides were selected from these antigens based on bioinformatics predictions of binding to the murine MHC class II molecule H-2 IAb. We screened these peptides for recognition by IFN-γ producing CD4+ T cell in phase I C. burnetii whole cell vaccine (PI-WCV) vaccinated C57BL/6 mice and identified 8 distinct epitopes from four different proteins. The identified epitope targets account for 8% of the total vaccination induced IFN-γ producing CD4+ T cells. Given that less than 0.4% of the antigens contained in C. burnetii were screened, this suggests that prioritizing antigens targeted by antibody responses is an efficient strategy to identify at least a subset of CD4+ targets in large pathogens. Finally, we examined the nature of linkage between CD4+ T cell and antibody responses in PI-WCV vaccinated mice. We found a surprisingly non-uniform pattern in the help provided by epitope specific CD4+ T cells for antibody production, which can be specific for the epitope source antigen as well as non-specific. This suggests that a complete map of CD4+ response targets in PI-WCV vaccinated mice will likely include antigens against which no antibody responses are made

The PI3K p110δ regulates expression of CD38 on regulatory T cells.

The PI3K pathway has emerged as a key regulator of regulatory T cell (Treg) development and homeostasis and is required for full Treg-mediated suppression. To identify new genes involved in PI3K-dependent suppression, we compared the transcriptome of WT and p110δ(D910A) Tregs. Among the genes that were differentially expressed was the gene for the transmembrane cyclic ADP ribose hydrolase CD38. Here we show that CD38 is expressed mainly by a subset of Foxp3(+)CD25(+)CD4(+) T cells originating in the thymus and on Tregs in the spleen. CD38(high) WT Tregs showed superior suppressive activity to CD38(low) Tregs, which failed to upregulate CD73, a surface protein which is important for suppression. However, Tregs from heterozygous CD38(+/-) mice were unimpaired despite lower levels of CD38 expression. Therefore, CD38 can be used as a marker for Tregs with high suppressive activity and the impaired Treg function in p110δ(D910A) mice can in part be explained by the failure of CD38(high) cells to develop

Mid-late quaternary fluvial archives near the margin of the MIS 12 glaciation in Southern East Anglia, UK: amalgamation of multi-disciplinary and citizen-science data sources

This paper presents an updated geological reconstruction of the Quaternary evolution of the River Thames at its downstream extremities, close to the North Sea coast, based on new data from multi-disciplinary and citizen-science sources. In this area, the interaction of the Thames with the MIS 12 (Anglian) glaciation is an important part of the Quaternary archive. The Anglian ice sheet, which reached parts of north and east London, was responsible for diverting the Thames southwards into its present course, although the footprint of the maximum ice sheet(s) does not reach the North Sea coast south of Hollesley, Suffolk. Further south, the coastal zone hosts pre-Anglian and early Anglian river-terrace deposits of the pre-diversion Thames system, superimposed upon which are products of later post-Anglian rivers, of both Middle and Late Pleistocene age. On the peninsula between the Stour and Blackwater–Colne estuaries, the lowest and most recent terrace of the pre-diversion Thames includes evidence directly pertaining to the glacial disruption event, for which geochronological data are reported here for the first time. The first post-diversion terrace of the Thames also reaches this peninsula, the river having essentially re-joined its original valley before crossing the alignment of the modern coastline. This terrace passes beneath Clacton-on-Sea, where it includes the type locality of the Clactonian Palaeolithic Industry. The area of interest to this paper, in NE Essex and southern Suffolk, includes a number of interglacial and Palaeolithic sites, the data from which assist in constraining the chronostratigraphy of the sequence. In some cases, there has been uncertainty as to whether these sites represent pre-Anglian environments and hominin occupations, part of the palaeo-Thames sequence, or whether they are the product of later post-Anglian streams, formed after the Thames had migrated southwards. This paper compiles evidence from a wide range of recent sources, including developer-funded archaeological appraisal and citizen-science activities, to explore and update the evidence from sites at Ipswich, Upper Dovercourt and Thorpe-le-Soken, as well as a number of localities associated with the Clacton Channel Deposits (host to the type-Clactonian), amongst others. The resulting new data are placed within the wider context of the Quaternary fluvial archives in southern Britain, with a discussion of how disparate sources of information, including the work of citizen scientists, have contributed

Ireland: Submerged Prehistoric Sites and Landscapes

Evidence of Ireland's drowned landscapes and settlements presently comprises 50 sites spread across the entire island. These comprise mainly intertidal find spots or small collections of flint artefacts. A handful of fully subtidal sites are known, generally from nearshore regions and consisting, with one exception, of isolated single finds. Evidence of organic remains is also sparse, with the exception of Mesolithic and Neolithic wooden fish traps buried in estuarine sediments under Dublin. The relatively small number of sites is probably due to lack of research as much as taphonomic issues, and thus the current evidence hints at the potential archaeological record which may be found underwater. Such evidence could contribute to knowledge of the coastal adaptations and seafaring abilities of Ireland's earliest inhabitants. Nonetheless, taphonomic considerations, specifically relating to Ireland's history of glaciation, sea-level change and also modern oceanographic conditions likely limit the preservation of submerged landscapes and their associated archaeology. Realistically, the Irish shelf is likely characterised by pockets of preservation, which makes detection and study of submerged landscapes difficult but not impossible. A range of potential routes of investigation are identifiable, including site-scale archaeological survey, landscape-scale seabed mapping, archival research and community engagement

Infection Prevention and Control Guideline for Cystic Fibrosis: 2013 Update

The 2013 Infection Prevention and Control (IP&amp;C) Guideline for Cystic Fibrosis (CF) was commissioned by the CF Foundation as an update of the 2003 Infection Control Guideline for CF. During the past decade, new knowledge and new challenges provided the following rationale to develop updated IP&amp;C strategies for this unique population: 1. The need to integrate relevant recommendations from evidence-based guidelines published since 2003 into IP&amp;C practices for CF . These included guidelines from the Centers for Disease Control and Prevention (CDC)/Healthcare Infection Control Practices Advisory Committee (HICPAC), the World Health Organization (WHO), and key professional societies, including the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA). During the past decade, new evidence has led to a renewed emphasis on source containment of potential pathogens and the role played by the contaminated healthcare environment in the transmission of infectious agents. Furthermore, an increased understanding of the importance of the application of implementation science, monitoring adherence, and feedback principles has been shown to increase the effectiveness of IP&amp;C guideline recommendations. 2. Experience with emerging pathogens in the non-CF population has expanded our understanding of droplet transmission of respiratory pathogens and can inform IP&amp;C strategies for CF . These pathogens include severe acute respiratory syndrome coronavirus and the 2009 influenza A H1N1. Lessons learned about preventing transmission of methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant gram-negative pathogens in non-CF patient populations also can inform IP&amp;C strategies for CF

Resolution of inflammation: a new therapeutic frontier

Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes — a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field