An app-, web- and social support-based weight loss intervention for adults with obesity: the HelpMeDoIt! feasibility RCT

Background: Finding solutions to rising levels of obesity continues to be a major public health focus. Social support has an important role in successful weight loss, and digital interventions can reach a large proportion of the population at low cost. Objective: To develop and assess the feasibility and acceptability of an application (app), web- and social support-based intervention in supporting adults with obesity to achieve weight loss goals. Design: Stage 1 – intervention development phase involved three focus groups (n = 10) with users, and think-aloud interviews and field testing with another group (n = 28). Stage 2 – the intervention and evaluation methods were explored in a feasibility randomised controlled trial with economic and process evaluation. Setting: Greater Glasgow and Clyde, UK. Participants: Adults with a body mass index of ≥ 30kg/m2 who owned a smartphone and were interested in losing weight were randomised 2 : 1 (intervention : control) and followed up at 12 months. Recruitment took place in April–October 2016. Interventions: The intervention group had access to HelpMeDoIt! for 12 months. This encouraged them to (1) set goals, (2) monitor progress and (3) harness social support by inviting ‘helpers’ from their existing social network. The control group received a healthy lifestyle leaflet. Main outcome measures: Data from stage 1 informed the intervention design. Key measures in stage 2 assessed the feasibility and acceptability of the intervention and trial methods against prespecified progression criteria. Three primary outcomes were explored: body mass index, diet and physical activity. Secondary outcomes included weight, waist and hip circumference, social support, self-efficacy, motivation, mental health, health-related quality of life, NHS resource use, participant-borne costs and intervention costs. Qualitative interviews with participants (n = 26) and helpers (n = 9) explored the feasibility and acceptability of the trial methods and intervention. Results: Stage 1 produced (1) a website that provided evidence-based information for lifestyle change and harnessing social support, and (2) an app that facilitated goal-setting, self-monitoring and supportive interaction between participants and their helper(s). Progression criteria were met, demonstrating that the intervention and trial methods were feasible and acceptable. A total of 109 participants (intervention, n = 73; control, n = 36) were recruited, with 84 participants (77%: intervention, 71%; control, 89%) followed up at 12 months. Data were successfully collected for most outcome measures (≥ 82% completion). Participants and helpers were generally positive, although helper engagement with the app was low. Of the 54 (74%) participants who downloaded the app, 48 (89%) used it twice or more, 28 helpers enrolled via the app, and 19 (36%) participants interacted with their helper(s) via the app. Interview data indicated that HelpMeDoIt! prompted support from helpers that often occurred without the helpers using the app. Limitations: Early technical problems meant that some participants and helpers had difficulty accessing the app. Ethical constraints meant that we were unable to contact helpers directly for interview. Conclusions: The HelpMeDoIt! study demonstrated that a weight loss intervention delivered via an app and a website is feasible and acceptable. Progression criteria were met, supporting further evaluation of the intervention. Future work: To further explore (1) the motivation and engagement of helpers, (2) the programme theory and (3) the effectiveness and cost-effectiveness of the intervention. Trial registration: Current Controlled Trials ISRCTN85615983. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 8, No. 3. See the NIHR Journals Library website for further project information

Genome-wide signatures of complex introgression and adaptive evolution in the big cats.

The great cats of the genus Panthera comprise a recent radiation whose evolutionary history is poorly understood. Their rapid diversification poses challenges to resolving their phylogeny while offering opportunities to investigate the historical dynamics of adaptive divergence. We report the sequence, de novo assembly, and annotation of the jaguar (Panthera onca) genome, a novel genome sequence for the leopard (Panthera pardus), and comparative analyses encompassing all living Panthera species. Demographic reconstructions indicated that all of these species have experienced variable episodes of population decline during the Pleistocene, ultimately leading to small effective sizes in present-day genomes. We observed pervasive genealogical discordance across Panthera genomes, caused by both incomplete lineage sorting and complex patterns of historical interspecific hybridization. We identified multiple signatures of species-specific positive selection, affecting genes involved in craniofacial and limb development, protein metabolism, hypoxia, reproduction, pigmentation, and sensory perception. There was remarkable concordance in pathways enriched in genomic segments implicated in interspecies introgression and in positive selection, suggesting that these processes were connected. We tested this hypothesis by developing exome capture probes targeting ~19,000 Panthera genes and applying them to 30 wild-caught jaguars. We found at least two genes (DOCK3 and COL4A5, both related to optic nerve development) bearing significant signatures of interspecies introgression and within-species positive selection. These findings indicate that post-speciation admixture has contributed genetic material that facilitated the adaptive evolution of big cat lineages

Cytotoxicity effect of alkaloidal extract from Prosopis juliflora Sw. D.C. (Algaroba) pods on glial cells

A Prosopis juliflora é amplamente utilizada na alimentação humana e de várias espécies animais, especialmente bovinos. Quadros de intoxicação por esta planta, nesta espécie, têm sido relatados, principalmente quando a mesma é oferecida como única fonte alimentar, desencadeando uma doença de sintomatologia nervosa. Neste estudo, objetivou-se avaliar os efeitos in vitro da fração de alcalóides totais (FA) extraída das vagens da Prosopis juliflora utilizando cultura primária de astrócitos obtidos do córtex cerebral de ratos como modelo de estudo. A avaliação da atividade mitocondrial pelo teste do MTT demonstrou a citotoxicidade em 30 µg/ml da FA após 24 h. As concentrações de 0,3 e 3 µg/ml da FA induziram um aumento da atividade mitocondrial, indicando reatividade celular. Testes imunocitoquímicos para a GFAP, principal proteína de citoesqueleto de astrócitos, revelaram alterações morfológicas nas células após tratamento com 0,3 e 3 µg/ml da FA por 72 h. Tais resultados são consoantes à análise desta proteína por westernblot, quando as culturas foram tratadas com 0,3 e 3 µg/ml da FA por 72 h, demonstrando interferências na regulação da expressão da GFAP. A expressão de vimentina não foi significativamente alterada em nenhuma das concentrações testadas. Estes resultados sugerem que os alcalóides da P. juliflora induzem a reatividade astrocitária, o que pode estar envolvido nos efeitos neurotóxicos providos pelo consumo desta planta.Prosopis juliflora is largely used for feeding cattle and humans. Neurological signals have been reported in cattle due to intoxication with this plant. In this study, an alkaloidal fraction (AF) obtained from P. juliflora pods was tested on astrocyte primary cultures. Astrocytes display physiological functions essential to development, homeostasis and detoxification in the central nervous system (CNS). These cells are known for their role on energetic support and immune response in the CNS. Concentrations between 0.03 to 30 µg/ml AF were assayed for 24 - 72 h. The mitochondrial activity, assayed by MTT test, showed cytotoxicity at 30 µg/ml AF after 24 h. At concentrations ranging between 0.3 - 3 µg/ml, the AF induced an increase on mitochondrial activity, indicating cell reactivity. Immunocytochemistry assay for GFAP cytoskeletal protein, revealed alterations on cell morphology after treatment with 0.3 - 3 µg/ml AF for 72 h. This result corroborates with western blot analysis when cells treated with 0.3 - 3 µg/ml AF for 72 h showed GFAP upregulation. The vimentin expression was not significantly altered in all tested concentrations. These results suggest that alkaloids induce astrocyte reactivity and might be involved in the neurotoxic effects induced by P. juliflora consumption

CLK1/CLK2 driven signalling at the Leishmania kinetochore is captured by spatially referenced proximity phosphoproteomics

Kinetochores in the parasite Leishmania and related kinetoplastids appear to be unique amongst eukaryotes and contain protein kinases as core components. Using the kinetochore kinases KKT2, KKT3 and CLK2 as baits, we developed a BirA* proximity biotinylation methodology optimised for sensitivity, XL-BioID, to investigate the composition and function of the Leishmania kinetochore. We could detect many of the predicted components and also discovered two novel kinetochore proteins, KKT24 and KKT26. Using KKT3 tagged with a fast-acting promiscuous biotin ligase variant, we took proximity biotinylation snapshots of the kinetochore in synchronised parasites. To quantify proximal phosphosites at the kinetochore as the parasite progressed through the cell cycle, we further developed a spatially referenced proximity phosphoproteomics approach. This revealed a group of phosphosites at the kinetochore that were highly dynamic during kinetochore assembly. We show that the kinase inhibitor AB1 targets CLK1/CLK2 (KKT10/KKT19) in Leishmania leading to defective cytokinesis. Using AB1 to uncover CLK1/CLK2 driven signalling pathways important for kinetochore function at G2/M, we found a set of 16 inhibitor responsive kinetochore-proximal phosphosites. Our results exploit new proximity labelling approaches to provide a direct analysis of the Leishmania kinetochore, which is emerging as a promising drug target

Accessing decavanadate chemistry with tris(hydroxymethyl)aminomethane, and evaluation of methylene blue bleaching

Two decavanadates (trisH)4[H2V10O28]·10H2O ( 1 ) and (trisH)6[V10O28] ( 2 ) have been synthesised from NaVO3 or V2O5 in an aqueous solution of tris(hydroxymethyl)aminomethane (tris). Bimetallic derivatives [Cu(OH2)5(trisH)]2[V10O28]·6H2O ( 3 ) and [Cu(OH2)3(2–amp)]2(trisH)2 [V10O28]·2H2O ( 4 ) were obtained by the addition of CuCl2 or CuCl2 / 2–amp (2–(aminomethyl)pyridine) to the route that gave 2 . The products were characterised by single-crystal X-ray diffractometry, thermogravimetric analysis, FTIR, Raman and EPR spectroscopies. Moreover, 4 was effective in bleaching a methylene blue (MB) solution under natural light in acidic media by either degradation of the dye or precipitation of a MB-decavanadate salt depending on the experimental conditions

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Plasma viral loads during early HIV-1 infection are similar in subtype C- and non-subtype C-infected African seroconverters.

Recent data suggest that infection with human immunodeficiency virus type 1 (HIV-1) subtype C results in prolonged high-level viremia (>5 log10 copies/mL) during early infection. We examined the relationship between HIV-1 subtype and plasma viremia among 153 African seroconverters. Mean setpoint viral loads were similar for C and non-C subtypes: 4.36 vs 4.42 log10 copies/mL (P = .61). The proportion of subtype C-infected participants with viral loads >5 log10 copies/mL was not greater than the proportion for those with non-C infection. Our data do not support the hypothesis that higher early viral load accounts for the rapid spread of HIV-1 subtype C in southern Africa

Genomewide Association Study for Determinants of HIV-1 Acquisition and Viral Set Point in HIV-1 Serodiscordant Couples with Quantified Virus Exposure

Host genetic factors may be important determinants of HIV-1 sexual acquisition. We performed a genome-wide association study (GWAS) for host genetic variants modifying HIV-1 acquisition and viral control in the context of a cohort of African HIV-1 serodiscordant heterosexual couples. To minimize misclassification of HIV-1 risk, we quantified HIV-1 exposure, using data including plasma HIV-1 concentrations, gender, and condom use.We matched couples without HIV-1 seroconversion to those with seroconversion by quantified HIV-1 exposure risk. Logistic regression of single nucleotide polymorphisms (SNPs) for 798 samples from 496 HIV-1 infected and 302 HIV-1 exposed, uninfected individuals was performed to identify factors associated with HIV-1 acquisition. In addition, a linear regression analysis was performed using SNP data from a subset (n = 403) of HIV-1 infected individuals to identify factors predicting plasma HIV-1 concentrations.After correcting for multiple comparisons, no SNPs were significantly associated with HIV-1 infection status or plasma HIV-1 concentrations.This GWAS controlling for HIV-1 exposure did not identify common host genotypes influencing HIV-1 acquisition. Alternative strategies, such as large-scale sequencing to identify low frequency variation, should be considered for identifying novel host genetic predictors of HIV-1 acquisition