Local Increase of Arginase Activity in Lesions of Patients with Cutaneous Leishmaniasis in Ethiopia

The leishmaniases are a complex of diseases caused by Leishmania parasites. Currently, the diseases affect an estimated 12 million people in 88 countries, and approximately 350 million more people are at risk. The leishmaniases belong to the most neglected tropical diseases, affecting the poorest populations, for whom access to diagnosis and effective treatment are often not available. Leishmania parasites infect cells of the immune system called macrophages, which have the capacity to eliminate the intracellular parasites when they receive the appropriate signals from other cells of the immune system. In nonhealing persistent leishmaniasis, lymphocytes are unable to transmit the signals to macrophages required to kill the intracellular parasites. The local upregulation of the enzyme arginase has been shown to impair lymphocyte effector functions at the site of pathology. In this study, we tested the activity of this enzyme in skin lesions of patients presenting with localized cutaneous leishmaniasis. Our results show that arginase is highly upregulated in these lesions. This increase in arginase activity coincides with lower expression of a signalling molecule in lymphocytes, which is essential for efficient activation of these cells. These results suggest that increased arginase expression in the localized cutaneous lesions might contribute to persistent disease in patients presenting with cutaneous leishmaniasis

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Borrelia recurrentis in head lice, Ethiopia

Since the 1800s, the only known vector of Borrelia recurrentis has been the body louse. In 2011, we found B. recurrentis DNA in 23% of head lice from patients with louse-borne relapsing fever in Ethiopia. Whether head lice can transmit these bacteria from one person to another remains to be determined

Poor WASH (Water, Sanitation, and Hygiene) Conditions Are Associated with Leprosy in North Gondar, Ethiopia

Access to safe water, sanitation, and hygiene (WASH) is critical for preventing the spread of neglected tropical diseases (NTDs) including leprosy. WASH-related transmission factors remain largely unexplored in the leprosy transmission cycle. The aim of this project is to better understand WASH exposures among leprosy cases through a case-control study in North Gondar, Ethiopia. We hypothesized that leprosy cases were more likely to have inadequate WASH access and were more likely to have concurrent schistosomiasis, as schistosomiasis immune consequences may facilitate leprosy infection. Forty leprosy cases (forty-one controls) were enrolled, tested for Schistosomamansoni, administered a demographic and WASH survey, and assigned a WASH index score. WASH factors significantly associated with leprosy on adjusted analyses included open defecation (aOR = 19.9, 95% CI 2.2, 176.3) and lack of access to soap (aOR = 7.3, 95% CI 1.1, 49.9). S. mansoni was detected in 26% of participants and in stratified analysis those with leprosy had a 3.6 (95% CI (0.8, 15.9)) greater odds of schistosomiasis in districts bordering the lake, compared to 0.33 lower odds of schistosomiasis in districts not bordering the lake (95% CI (0.09, 1.2)). Overall, results suggest that leprosy transmission may be related to WASH adequacy and access as well as to schistosomiasis co-infection

Second-generation sequencing of entire mitochondrial coding-regions (~15.4kb) holds promise for study of the phylogeny and taxonomy of human body lice and head lice

The Illumina Hiseq platform was used to sequence the entire mitochondrial coding-regions of 20 body lice, Pediculus humanus Linnaeus, and head lice, P. capitis De Geer (Phthiraptera: Pediculidae), from eight towns and cities in five countries: Ethiopia, France, China, Australia and the U.S.A. These data (∼310 kb) were used to see how much more informative entire mitochondrial coding-region sequences were than partial mitochondrial coding-region sequences, and thus to guide the design of future studies of the phylogeny, origin, evolution and taxonomy of body lice and head lice. Phylogenies were compared from entire coding-region sequences (∼15.4 kb), entire cox1 (∼1.5 kb), partial cox1 (∼700 bp) and partial cytb (∼600 bp) sequences. On the one hand, phylogenies from entire mitochondrial coding-region sequences (∼15.4 kb) were much more informative than phylogenies from entire cox1 sequences (∼1.5 kb) and partial gene sequences (∼600 to ∼700 bp). For example, 19 branches had > 95% bootstrap support in our maximum likelihood tree from the entire mitochondrial coding-regions (∼15.4 kb) whereas the tree from 700 bp cox1 had only two branches with bootstrap support > 95%. Yet, by contrast, partial cytb (∼600 bp) and partial cox1 (∼486 bp) sequences were sufficient to genotype lice to Clade A, B or C. The sequences of the mitochondrial genomes of the P. humanus, P. capitis and P. schaeffi Fahrenholz studied are in NCBI GenBank under the accession numbers KC660761-800, KC685631-6330, KC241882-97, EU219988-95, HM241895-8 and JX080388-407

SNPs in entire mitochondrial genome sequences (≈15.4 kb) and cox1 sequences (≈486 bp) resolve body and head lice from doubly infected people from Ethiopia, China, Nepal, and Iran but not France

Some people host lice on the clothing as well as the head. Whether body lice and head lice are distinct species or merely variants of the same species remains contentious. We sought to ascertain the extent to which lice from these different habitats might interbreed on doubly infected people by comparing their entire mitochondrial genome sequences. Toward this end, we analyzed two sets of published genetic data from double-infections of body lice and head lice: 1) entire mitochondrial coding regions (≈ 15.4 kb) from body lice and head lice from seven doubly infected people from Ethiopia, China, and France; and 2) part of the cox1 gene (≈486 bp) from body lice and head lice from a further nine doubly infected people from China, Nepal, and Iran. These mitochondrial data, from 65 lice, revealed extraordinary variation in the number of single nucleotide polymorphisms between the individual body lice and individual head lice of double-infections: from 1.096 kb of 15.4 kb (7.6%) to 2 bps of 15.4 kb (0.01%). We detected coinfections of lice of Clades A and C on the scalp hair of three of the eight people from Nepal: one person of the two people from Kathmandu and two of the six people from Pokhara. Lice of Clades A and B coinfected the scalp hair of one person from Atherton, Far North Queensland, Australia. These findings argue for additional large-scale studies of the body lice and head lice of double-infected people

Novel filaggrin mutation but no other loss-of-function variants found in Ethiopian patients with atopic dermatitis

Atopic dermatitis (AD) is a common, complex inflammatory skin disorder where a defect skin barrier is central in the pathogenesis. Mutations in the filaggrin gene cause ichthyosis vulgaris (IV). IV is one of several keratinization disorders named ichthyoses where mutations in skin barrier genes are a common underlying genetic factor. Furthermore, filaggrin mutations are a major risk factor for moderate to severe AD. The aim of the work reported in this thesis is to improve the understanding of the genetic mechanisms of skin barrier defects associated with AD, and to identify whether AD and other common disorders of keratinisation may share genetic susceptibility factors related to skin barrier dysfunction. Paper I presents data suggesting that filaggrin mutations may be rare in Ethiopian AD and IV patients, implying other mechanisms should be more important in the pathogenesis of IV and AD in this ethnic group. Paper II presents a novel mutation in the steroid sulfatase gene in a patient with clinical signs of common ichthyosis type. In paper III association between filaggrin mutations and childhood onset of psoriasis was tested. No association to any prevalent filaggrin mutations was found, and no novel mutations. This indicates that filaggrin loss-of- function variants do not have a strong effect on the onset of psoriasis in childhood. In paper IV it is demonstrated that functional parameters and gene expression in molecular pathways in vivo is altered in patients suffering from AD and IV and depend on filaggrin genotype. Patients with filaggrin mutations displayed a severe phenotype with impaired barrier function measured as increased trans-epidermal water loss, and significantly altered pH levels. Furthermore, the numbers of genes with altered expression were significantly higher in patients with low or absent filaggrin expression. These pathways include many genes involved in inflammation, epidermal differentiation, lipid metabolism, cell signalling and adhesion. Paper V represents a candidate gene study where expression analysis links the epidermal transglutaminases 1 and 3 to the manifestation of AD and genetic analysis suggests that genetic variation at the transglutaminase 1 locus could be involved in the development of the disease. The results of the work reported in this thesis provides additional descriptive information and further elucidates the pathogenesis underlying AD and other disorders of keratinization, in particular in relation to filaggrin deficiency. Better understanding of the genetic factors and molecular and functional consequences should hopefully enable future individually designed barrier restoring therapy