Podoconiosis in East and West Gojam Zones, Northern Ethiopia

Background: Podoconiosis is a neglected tropical disease (NTD) that is prevalent in red clay soil-covered highlands of tropical Africa, Central and South America, and northern India. It is estimated that up to one million cases exist in Ethiopia. This study aimed to estimate the prevalence of podoconiosis in East and West Gojam Zones of Amhara Region in northern Ethiopia. Methodology/Principal Findings: A cross-sectional household survey was conducted in Debre Eliyas and Dembecha woredas (districts) in East and West Gojam Zones, respectively. The survey covered all 17,553 households in 20 kebeles (administrative subunits) randomly selected from the two woredas. A detailed structured interview was conducted on 1,704 cases of podoconiosis identified in the survey. Results: The prevalence of podoconiosis in the population aged 15 years and above was found to be 3.3% (95% CI, 3.2% to 3.6%). 87% of cases were in the economically active age group (15–64 years). On average, patients sought treatment five years after the start of the leg swelling. Most subjects had second (42.7%) or third (36.1%) clinical stage disease, 97.9% had mossy lesions, and 53% had open wounds. On average, patients had five episodes of acute adenolymphangitis (ALA) per year and spent a total of 90 days per year with ALA. The median age of first use of shoes and socks were 22 and 23 years, respectively. More men than women owned more than one pair of shoes (61.1% vs. 50.5%; x2 = 11.6 p = 0.001). At the time of interview, 23.6% of the respondents were barefoot, of whom about two-thirds were women. Conclusions: This study showed high prevalence of podoconiosis and associated morbidities such as ALA, mossy lesions and open wounds in northern Ethiopia. Predominance of cases at early clinical stage of podoconiosis indicates the potential for reversing the swelling and calls for disease prevention interventions

Development of practice principles for the management of ongoing suicidal ideation in young people diagnosed with major depressive disorder

Objectives: There is a lack of clear guidance regarding the management of ongoing suicidality in young people experiencing major depressive disorder. This study utilised an expert consensus approach in identifying practice principles to complement relevant clinical guidelines for the treatment of major depressive disorder in young people. The study also sought to outline a broad treatment framework for clinical intervention with young people experiencing ongoing suicidal ideation. Methods: In-depth focus groups were undertaken with a specialist multidisciplinary clinical team (the Youth Mood Clinic at Orygen Youth Health Clinical Program, Melbourne) working with young people aged 15–25 years experiencing ongoing suicidal ideation. Each focus group was audio recorded and transcribed verbatim using orthographic conventions. Principles of grounded theory and thematic analysis were used to analyse and code the resultant data. Results: The identified codes were subsequently synthesised into eight practice principles reflecting engagement and consistency of care, ongoing risk assessment and documentation, individualised crisis planning, engaging systems of support, engendering hopefulness, development of adaptive coping, management of acute risk, and consultation and supervision. Conclusions: The identified practice principles provide a broad management framework, and may assist to improve treatment consistency and clinical management of young people experiencing ongoing suicidal ideation. The practice principles may be of use to health professionals working within a team-based setting involved in the provision of care, even if peripherally, to young people with ongoing suicidal ideation. Findings address the lack of treatment consistency and shared terminology and may provide containment and guidance to multidisciplinary clinicians working with this at-risk group

Individual correlates of podoconiosis in areas of varying endemicity: a case-control study

BACKGROUND Podoconiosis is a non-filarial form of elephantiasis resulting in lymphedema of the lower legs. Previous studies have suggested that podoconiosis arises from the interplay of individual and environmental factors. Here, our aim was to understand the individual-level correlates of podoconiosis by comparing 460 podoconiosis-affected individuals and 707 unaffected controls. METHODS/PRINCIPAL FINDINGS This was a case-control study carried out in six kebeles (the lowest governmental administrative unit) in northern Ethiopia. Each kebele was classified into one of three endemicity levels: 'low' (prevalence 5%). A total of 142 (30.7%) households had two or more cases of podoconiosis. Compared to controls, the majority of the cases, especially women, were less educated (OR = 1.7, 95% CI = 1.3 to 2.2), were unmarried (OR = 3.4, 95% CI = 2.6-4.6) and had lower income (t = -4.4, p<0.0001). On average, cases started wearing shoes ten years later than controls. Among cases, age of first wearing shoes was positively correlated with age of onset of podoconiosis (r = 0.6, t = 12.5, p<0.0001). Among all study participants average duration of shoe wearing was less than 30 years. Between both cases and controls, people in 'high' and 'medium' endemicity kebeles were less likely than people in 'low' endemicity areas to 'ever' have owned shoes (OR = 0.5, 95% CI = 0.4-0.7). CONCLUSIONS Late use of shoes, usually after the onset of podoconiosis, and inequalities in education, income and marriage were found among cases, particularly among females. There were clustering of cases within households, thus interventions against podoconiosis will benefit from household-targeted case tracing. Most importantly, we identified a secular increase in shoe-wearing over recent years, which may give opportunities to promote shoe-wearing without increasing stigma among those at high risk of podoconiosis

Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells

Cisplatin produces good responses in solid tumours including small cell lung cancer (SCLC) but this is limited by the development of resistance. Oxaliplatin is reported to show activity against some cisplatin-resistant cancers but there is little known about oxaliplatin in SCLC and there are no reports of oxaliplatin resistant SCLC cell lines. Studies of drug resistance mainly focus on the cellular resistance mechanisms rather than how the cells develop resistance. This study examines the development of cisplatin and oxaliplatin resistance in H69 human SCLC cells in response to repeated treatment with clinically relevant doses of cisplatin or oxaliplatin for either 4 days or 2h. Treatments with 200ng/ml cisplatin or 400ng/ml oxaliplatin for 4 days produced sublines (H69CIS200 and H69OX400 respectively) that showed low level (approximately 2-fold) resistance after 8 treatments. Treatments with 1000ng/ml cisplatin or 2000ng/ml oxaliplatin for 2h also produced sublines, however these were not stably resistant suggesting shorter treatment pulses of drug may be more effective. Cells survived the first five treatments without any increase in resistance, by arresting their growth for a period and then regrowing. The period of growth arrest was reduced after the sixth treatment and the H69CIS200 and H69OX400 sublines showed a reduced growth arrest in response to cisplatin and oxaliplatin treatment suggesting that "regrowth resistance" initially protected against drug treatment and this was further upregulated and became part of the resistance phenotype of these sublines. Oxaliplatin dose escalation produced more surviving sublines than cisplatin dose escalation but neither set of sublines were associated with increased resistance as determined by 5-day cytotoxicity assays, also suggesting the involvement of regrowth resistance. The resistant sublines showed no change in platinum accumulation or glutathione levels even though the H69OX400 subline was more sensitive to buthionine sulfoximine treatment. The H69CIS200 cells were cross-resistant to oxaliplatin demonstrating that oxaliplatin does not have activity against low level cisplatin resistance. Relative to the H69 cells, the H69CIS200 and H69OX400 sublines were more sensitive to paclitaxel and taxotere suggests the taxanes may be useful in the treatment of platinum resistant SCLC. These novel cellular models of cisplatin and oxaliplatin resistant SCLC will be useful in developing strategies to treat platinum-resistant SCLC

Mapping and modelling the geographical distribution and environmental limits of podoconiosis in Ethiopia

BACKGROUND Ethiopia is assumed to have the highest burden of podoconiosis globally, but the geographical distribution and environmental limits and correlates are yet to be fully investigated. In this paper we use data from a nationwide survey to address these issues. METHODOLOGY Our analyses are based on data arising from the integrated mapping of podoconiosis and lymphatic filariasis (LF) conducted in 2013, supplemented by data from an earlier mapping of LF in western Ethiopia in 2008-2010. The integrated mapping used woreda (district) health offices' reports of podoconiosis and LF to guide selection of survey sites. A suite of environmental and climatic data and boosted regression tree (BRT) modelling was used to investigate environmental limits and predict the probability of podoconiosis occurrence. PRINCIPAL FINDINGS Data were available for 141,238 individuals from 1,442 communities in 775 districts from all nine regional states and two city administrations of Ethiopia. In 41.9% of surveyed districts no cases of podoconiosis were identified, with all districts in Affar, Dire Dawa, Somali and Gambella regional states lacking the disease. The disease was most common, with lymphoedema positivity rate exceeding 5%, in the central highlands of Ethiopia, in Amhara, Oromia and Southern Nations, Nationalities and Peoples regional states. BRT modelling indicated that the probability of podoconiosis occurrence increased with increasing altitude, precipitation and silt fraction of soil and decreased with population density and clay content. Based on the BRT model, we estimate that in 2010, 34.9 (95% confidence interval [CI]: 20.2-51.7) million people (i.e. 43.8%; 95% CI: 25.3-64.8% of Ethiopia's national population) lived in areas environmentally suitable for the occurrence of podoconiosis. CONCLUSIONS Podoconiosis is more widespread in Ethiopia than previously estimated, but occurs in distinct geographical regions that are tied to identifiable environmental factors. The resultant maps can be used to guide programme planning and implementation and estimate disease burden in Ethiopia. This work provides a framework with which the geographical limits of podoconiosis could be delineated at a continental scale

Disgust sensitivity is not associated with health in a rural Bangladeshi sample.

Disgust can be considered a psychological arm of the immune system that acts to prevent exposure to infectious agents. High disgust sensitivity is associated with greater behavioral avoidance of disease vectors and thus may reduce infection risk. A cross-sectional survey in rural Bangladesh provided no strong support for this hypothesis. In many species, the expression of pathogen- and predator-avoidance mechanisms is contingent on early life exposure to predators and pathogens. Using childhood health data collected in the 1990s, we examined if adults with more infectious diseases in childhood showed greater adult disgust sensitivity: no support for this association was found. Explanations for these null finding and possible directions for future research are discussed

Global epidemiology of podoconiosis: a systematic review

Background Podoconiosis is one of the few diseases that could potentially be eliminated within one generation. Nonetheless, the global distribution of the disease remains largely unknown. The global atlas of podoconiosis was conceived to define the epidemiology and distribution of podoconiosis through dedicated surveys and assembling the available epidemiological data. Methods We have synthesized the published literature on the epidemiology of podoconiosis. Through systematic searches in SCOPUS and MEDLINE from inception to February 14, 2018, we identified observational and population-based studies reporting podoconiosis. To establish existence of podoconiosis, we used case reports and presence data. For a study to be included in the prevalence synthesis, it needed to be a population-based survey that involved all residents within a specific area. Studies that did not report original data were excluded. We undertook descriptive analyses of the extracted data. This study is registered with PROSPERO, number CRD42018084959. Results We identified 3,260 records, of which 27 studies met the inclusion criteria. Podoconiosis was described to exist or be endemic in 32 countries, 18 from the African Region, 3 from Asia and 11 from Latin America. Overall, podoconiosis prevalence ranged from 0·10% to 8.08%, was highest in the African region, and was substantially higher in adults than in children and adolescents. The highest reported prevalence values were in Africa (8.08% in Cameroon, 7.45% in Ethiopia, 4.52% in Uganda, 3.87% in Kenya and 2.51% in Tanzania). In India, a single prevalence of 0.21% was recorded from Manipur, Mizoram and Rajasthan states. None of the Latin American countries reported prevalence data. Conclusion Our data suggest that podoconiosis is more widespread in the African Region than in the rest of the regions, although this could be related to the fact that most podoconiosis epidemiological research has been focused in the African continent. The assembled dataset confirms that comprehensive podoconiosis control strategies such as promotion of footwear and personal hygiene are urgently needed in endemic parts of Africa. Mapping, active surveillance and a systematic approach to the monitoring of disease burden must accompany the implementation of podoconiosis control activities

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Competitive and Cooperative Interactions Mediate RNA Transfer from Herpesvirus Saimiri ORF57 to the Mammalian Export Adaptor ALYREF

The essential herpesvirus adaptor protein HVS ORF57, which has homologs in all other herpesviruses, promotes viral mRNA export by utilizing the cellular mRNA export machinery. ORF57 protein specifically recognizes viral mRNA transcripts, and binds to proteins of the cellular transcription-export (TREX) complex, in particular ALYREF. This interaction introduces viral mRNA to the NXF1 pathway, subsequently directing it to the nuclear pore for export to the cytoplasm. Here we have used a range of techniques to reveal the sites for direct contact between RNA and ORF57 in the absence and presence of ALYREF. A binding site within ORF57 was characterized which recognizes specific viral mRNA motifs. When ALYREF is present, part of this ORF57 RNA binding site, composed of an a-helix, binds preferentially to ALYREF. This competitively displaces viral RNA from the a-helix, but contact with RNA is still maintained by a flanking region. At the same time, the flexible N-terminal domain of ALYREF comes into contact with the viral RNA, which becomes engaged in an extensive network of synergistic interactions with both ALYREF and ORF57. Transfer of RNA to ALYREF in the ternary complex, and involvement of individual ORF57 residues in RNA recognition, were confirmed by UV cross-linking and mutagenesis. The atomic-resolution structure of the ORF57-ALYREF interface was determined, which noticeably differed from the homologous ICP27-ALYREF structure. Together, the data provides the first site-specific description of how viral mRNA is locked by a herpes viral adaptor protein in complex with cellular ALYREF, giving herpesvirus access to the cellular mRNA export machinery. The NMR strategy used may be more generally applicable to the study of fuzzy protein-protein-RNA complexes which involve flexible polypeptide regions