scholarly journals A population genomics approach to assessing the genetic basis of within-host microevolution underlying recurrent cryptococcal meningitis infection

2016 ◽  
Author(s):  
Johanna Rhodes ◽  
Mathew A. Beale ◽  
Mathieu Vanhove ◽  
Joseph N. Jarvis ◽  
Shichina Kannambath ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Cryptococcal Meningitis ◽  
Genetic Basis ◽  
Population Genomics ◽  
Antifungal Drugs ◽  
Sub Saharan Africa ◽  
Gene Encoding ◽  
Nonsense Mutations ◽  
Before And After ◽  
Sub Saharan

AbstractRecurrence of meningitis due toCryptococcus neoformansafter treatment causes substantial mortality in HIV/AIDS patients across sub-Saharan Africa. In order to determine whether recurrence occurred due to relapse of the original infecting isolate or reinfection with a different isolate weeks or months after initial treatment, we used whole-genome sequencing to assess the genetic basis of infection in 17 HIV-infected individuals with recurrent cryptococcal meningitis. Comparisons revealed a clonal relationship for 15 pairs of isolates recovered before and after recurrence showing relapse of the original infection. The two remaining pairs showed high levels of genetic heterogeneity; in one pair we found this to be a result of infection by mixed genotypes, whilst the second was a result of nonsense mutations in the gene encoding the DNA mismatch repair proteinsMSH2, MSH5andRAD5. These nonsense mutations led to a hypermutator state, leading to dramatically elevated rates of synonymous and non-synonymous substitutions. Hypermutator phenotypes owing to nonsense mutations in these genes have not previously been reported inCryptococcus neoformansand represent a novel pathway for rapid within-host adaptation and evolution of resistance to firstline antifungal drugs.

scholarly journals Physiological Differences in Cryptococcus neoformans Strains In Vitro versus In Vivo and Their Effects on Antifungal Susceptibility

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Nina T. Grossman ◽  
Arturo Casadevall
Keyword(s):  
Cryptococcus Neoformans ◽  
Cryptococcal Meningitis ◽  
Antifungal Susceptibility ◽  
Sub Saharan Africa ◽  
Content Type ◽  
Laboratory Conditions ◽  
Physiological Differences ◽  
Sub Saharan

ABSTRACT Cryptococcus neoformans is an environmentally ubiquitous fungal pathogen that primarily causes disease in people with compromised immune systems, particularly those with advanced AIDS. There are estimated to be almost 1 million cases per year of cryptococcal meningitis in patients infected with human immunodeficiency virus, leading to over 600,000 annual deaths, with a particular burden in sub-Saharan Africa. Amphotericin B (AMB) and fluconazole (FLC) are key components of cryptococcal meningitis treatment: AMB is used for induction, and FLC is for consolidation, maintenance and, for occasional individuals, prophylaxis. However, the results of standard antifungal susceptibility testing (AFST) for AMB and FLC do not correlate well with therapeutic outcomes and, consequently, no clinical breakpoints have been established. While a number of explanations for this absence of correlation have been proffered, one potential reason that has not been adequately explored is the possibility that the physiological differences between the in vivo infection environment and the in vitro AFST environment lead to disparate drug susceptibilities. These susceptibility-influencing factors include melanization, which does not occur during AFST, the size of the polysaccharide capsule, which is larger in infecting cells than in those grown under normal laboratory conditions, and the presence of large polyploid “titan cells,” which rarely occur under laboratory conditions. Understanding whether and how C. neoformans differentially expresses mechanisms of resistance to AMB and FLC in the AFST environment compared to the in vivo environment could enhance our ability to interpret AFST results and possibly lead to the development of more applicable testing methods.

scholarly journals Population genomics ofCryptococcus neoformansvar.grubiireveals new biogeographic relationships and finely maps hybridization

2017 ◽  
Author(s):  
Johanna Rhodes ◽  
Christopher A. Desjardins ◽  
Sean M. Sykes ◽  
Mathew A. Beale ◽  
Mathieu Vanhove ◽  
...  
Keyword(s):  
South America ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Population Genomics ◽  
Natural Populations ◽  
Sub Saharan Africa ◽  
Large Set ◽  
Serotype A ◽  
Sub Saharan ◽  
Genetic Substructure

AbstractCryptococcus neoformansvar.grubiiis the causative agent of cryptococcal meningitis, a significant source of mortality in immunocompromised individuals, typically HIV/AIDS patients from developing countries. Despite the worldwide emergence of this ubiquitous infection, little is known about the global molecular epidemiology of this fungal pathogen. Here we sequence the genomes of 188 diverse isolates and characterized the major subdivisions, their relative diversity and the level of genetic exchange between them. While most isolates ofC. neoformansvar.grubiibelong to one of three major lineages (VNI, VNII, and VNB), some haploid isolates show hybrid ancestry including some that appear to have recently interbred, based on the detection of large blocks of each ancestry across each chromosome. Many isolates display evidence of aneuploidy, which was detected for all chromosomes. In diploid isolates ofC. neoformansvar.grubii (serotype A/A) and of hybrids withC. neoformansvar.neoformans(serotype A/D) such aneuploidies have resulted in loss of heterozygosity, where a chromosomal region is represented by the genotype of only one parental isolate. Phylogenetic and population genomic analyses of isolates from Brazil revealed that the previously ‘African’ VNB lineage occurs naturally in the South American environment. This suggests migration of the VNB lineage between Africa and South America prior to its diversification, supported by finding ancestral recombination events between isolates from different lineages and regions. The results provide evidence of substantial population structure, with all lineages showing multi-continental distributions demonstrating the highly dispersive nature of this pathogen.Author SummaryCryptococcus neoformansvar.grubiiis a human fungal pathogen of immunocompromised individuals that has global clinical impact, causing half a million deaths per year. Substantial genetic substructure exists for this pathogen, with two lineages found globally (VNI, VNII) whereas a third has appeared confined to sub-Saharan Africa (VNB). Here, we utilized genome sequencing of a large set of global isolates to examine the genetic diversity, hybridization, and biogeography of these lineages. We found that while the three major lineages are well separated, recombination between the lineages has occurred, notably resulting in hybrid isolates with segmented ancestry across the genome. In addition, we showed that isolates from South America are placed within the VNB lineage, formerly thought to be confined to Africa, and that there is phylogenetic separation between these geographies that substantially expands the diversity of these lineages. Our findings provide a new framework for further studies of the dynamics of natural populations ofC. neoformansvar.grubii.

scholarly journals Kelch 13-propeller polymorphisms in Plasmodium falciparum from Jazan region, southwest Saudi Arabia

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Ommer Mohammed Dafalla ◽  
Mohammed Alzahrani ◽  
Ahmed Sahli ◽  
Mohammed Abdulla Al Helal ◽  
Mohammad Mohammad Alhazmi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Saudi Arabia ◽  
Parasite Clearance ◽  
Sub Saharan Africa ◽  
Local Alignment ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Synonymous Mutations ◽  
Search Tool ◽  
Sub Saharan

Abstract Background Artemisinin-based combination therapy (ACT) is recommended at the initial phase for treatment of Plasmodium falciparum, to reduce morbidity and mortality in all countries where malaria is endemic. Polymorphism in portions of P. falciparum gene encoding kelch (K13)-propeller domains is associated with delayed parasite clearance after ACT. Of about 124 different non-synonymous mutations, 46 have been identified in Southeast Asia (SEA), 62 in sub-Saharan Africa (SSA) and 16 in both the regions. This is the first study designed to analyse the prevalence of polymorphism in the P. falciparum k13-propeller domain in the Jazan region of southwest Saudi Arabia, where malaria is endemic. Methods One-hundred and forty P. falciparum samples were collected from Jazan region of southwest Saudi Arabia at three different times: 20 samples in 2011, 40 samples in 2016 and 80 samples in 2020 after the implementation of ACT. Plasmodium falciparum kelch13 (k13) gene DNA was extracted, amplified, sequenced, and analysed using a basic local alignment search tool (BLAST). Results This study obtained 51 non-synonymous (NS) mutations in three time groups, divided as follows: 6 single nucleotide polymorphisms (SNPs) ‘11.8%’ in samples collected in 2011 only, 3 (5.9%) in 2011and 2016, 5 (9.8%) in 2011 and 2020, 5 (9.8%) in 2016 only, 8 (15.7%) in 2016 and 2020, 14 (27.5%) in 2020 and 10 (19.6%) in all the groups. The BLAST revealed that the 2011 isolates were genetically closer to African isolates (53.3%) than Asian ones (46.7%). Interestingly, this proportion changed completely in 2020, to become closer to Asian isolates (81.6%) than to African ones (18.4%). Conclusions Despite the diversity of the identified mutations in the k13-propeller gene, these data did not report widespread artemisinin-resistant polymorphisms in the Jazan region where these samples were collected. Such a process would be expected to increase frequencies of mutations associated with the resistance of ACT.

Characteristics Associated With Migration Among Older Women and Men in Rural Malawi

2017 ◽  
Vol 25 (4) ◽  
pp. 283-308 ◽  
Author(s):  
Jacob Kendall ◽  
Philip Anglewicz
Keyword(s):  
Physical Health ◽  
Older Women ◽  
Religious Affiliation ◽  
Older Men ◽  
Household Size ◽  
Sub Saharan Africa ◽  
Older Individuals ◽  
Before And After ◽  
Sub Saharan ◽  
And Migration

The older population in sub-Saharan Africa is growing rapidly, but little is known about the migration patterns of older individuals in this setting. In this article, we identify the determinants of migration for older individuals in a rural African setting. To do so, we use rare longitudinal data with information for older individuals both before and after migration. We first identify premigration factors associated with moving in the future and then identify differences in characteristics between migrants and nonmigrants after migration. In addition to basic sociodemographic information, we examine differences between migrants and nonmigrants in land ownership, number of lifetime marriages, number of living offspring, previous migration experience, household size, social and religious participation, and religious affiliation. Results show that (a) migration in older age is related to marriage, health and HIV status, household size, and religion; (b) older women who are HIV-positive are more likely to move, and older men with better physical health are more likely to move; (c) older female migrants have worse postmigration physical health; and (d) the relationship between health and migration for older men disappears after migration.

A comparison of global suicide terrorism by region before and after 9/11 terrorist attacks

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Ahmet Guler ◽  
Mustafa Demir
Keyword(s):  
Time Series ◽  
Interrupted Time Series ◽  
Sub Saharan Africa ◽  
Terrorist Attacks ◽  
Suicide Terrorism ◽  
Content Type ◽  
The World ◽  
Before And After ◽  
Sub Saharan ◽  
Global Terrorism Database

Purpose This study aims to examine the effect of the 9/11 terrorist attacks on suicide terrorism in different regions of the world and changes in the trends in suicide terrorism according to regions before and after 9/11. Design/methodology/approach Using the data obtained from the Global Terrorism Database from 1981 to 2019, the descriptive statistics were computed first and then, independent samples t-tests were run to compare the monthly mean percentage of suicide-terrorism incidents that occurred in each region between the pre-9/11 and the post-9/11 periods. Finally, to statistically assess the effect of the 9/11 attacks and changes in the trends for the dependent variables over time, monthly interrupted time-series analyzes were conducted. Findings The results of monthly interrupted time series analyzes showed that after the 9/11 attacks, the trends for suicide-terrorism rates decreased significantly in three regions including South Asia, the Middle East and North Africa and Europe, while the trend for suicide-terrorism rates increased significantly in Sub-Saharan Africa. However, no statistically significant changes in the trends in suicide-terrorism rates occurred in three regions including North America, East Asia and Central Asia and Southeast Asia before 9/11, during November 2001 or after 9/11. Originality/value This study indicates the critical importance of the 9/11 terrorist attacks in suicide terrorism and its impact on these events in different regions of the world. The research also provides some recommendations concerning the effectiveness of defensive and offensive counterterrorism policies against suicide terrorism.

scholarly journals Towards Pragmatic Economic Policies: Economic Transformation and Industrialization for Revival of Zimbabwe in the New Dispensation Era

2020 ◽  
Vol 10 (5) ◽  
pp. 75-81
Author(s):  
Charles Mazhazhate ◽  
Tapiwa C Mujakachi ◽  
Shakerod Munuhwa
Keyword(s):  
Economic History ◽  
Land Reform ◽  
Economic Transformation ◽  
Sub Saharan Africa ◽  
Economic Policies ◽  
Consumer Prices ◽  
Before And After ◽  
Sub Saharan ◽  
The Government ◽  
Economic Institute

Whilst literature has many monetary and economic policies that were enacted before and after the dawn of the New Dispensation in Zimbabwe the country still faces a downward trend in terms of economic recovery. This study reviews the various policies put in place by the government and their impact on socio-economic development of Zimbabwe. A review of Zimbabwe’s economic history shows that the country dropped from being one of the best economies in Sub-Saharan Africa and now ailing and characterised by hyperinflation, agricultural challenges, corruption, very high tax regime, huge domestic and foreign debts, increase in consumer prices and being a chief net importer of most goods or services. The study was underpinned by a case study survey from Singapore’s revival with both qualitative and quantitative instruments used. The study found out that even though the land reform had an impact on economic performance, corruption, party-power politics and absence of an economic institute eroded any necessary contribution to economic transformation and industrialization in Zimbabwe. The study also revealed that the bilateral and multi-lateral agreements that were enacted in the dawn of the new dispensation have not yielded the desired economic revival transformations. The study recommended establishment of an economic institute to direct policy as well as removal of unethical practices in both public and private sectors so as to ensure financial and economic discipline.

scholarly journals Study of the genetic heterogeneity of SAT-2 foot-and-mouth disease virus in sub-Saharan Africa with specific focus on East Africa

2007 ◽  
Vol 74 (4) ◽  
Author(s):  
M. Sahle ◽  
R.M. Dwarka ◽  
E.H. Venter ◽  
W. Vosloo
Keyword(s):  
East Africa ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Sub Saharan Africa ◽  
Gene Encoding ◽  
Western Africa ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Sub Saharan ◽  
Unrelated Strain

The epidemiology of serotype SAT-2 foot-and-mouth disease was investigated in sub-Saharan Africa by phylogenetic analysis using the 1D gene encoding the major antigenic determinant. Fourteen genotypes were identified of which three are novel and belong to East Africa, bringing the total number of genotypes for that region to eight. The genotypes clustered into three lineages that demonstrated surprising links between East, southern and south-western Africa. One lineage was unique to West Africa. These results established numerous incursions across country borders in East Africa and long term conservation of sequences for periods up to 41 years. Ethiopia, Kenya and Uganda have all experienced outbreaks from more than one unrelated strain, demonstrating the potential for new introductions. The amount of variation observed within this serotype nearly equalled that which was found between serotypes; this has severe implications for disease control using vaccination.

scholarly journals Rapid tranquillisation: practice in Zambia, before and after training

2013 ◽  
Vol 10 (4) ◽  
pp. 95-97
Author(s):  
Mahesh Jayaram ◽  
Ranga Rattehalli ◽  
Lindsay Moran ◽  
John Mwanza ◽  
Paul Banda ◽  
...  
Keyword(s):  
Evidence Base ◽  
Sub Saharan Africa ◽  
Collaborative Partnerships ◽  
Inappropriate Use ◽  
Short Time Span ◽  
Safety Awareness ◽  
Before And After ◽  
Sub Saharan ◽  
Therapeutic Doses ◽  
Short Time

The evidence base for rapid tranquillisation is small in higher-income countries but is even smaller in sub-Saharan Africa. We initiated the first ever survey on the use of rapid tranquillisation in Zambia in 2009; a further survey was then done in 2010, after a programme of teaching and training. It demonstrated an overall improvement in clinical practice, safety, awareness and use of medications within therapeutic doses. It also led to a reduction in inappropriate use of medications. These improvements in practice occurred within a short time span and with minimal effort. Further international collaborative partnerships are required to build stronger mental health infrastructure in Zambia.

scholarly journals Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

2019 ◽  
Vol 116 (21) ◽  
pp. 10430-10434 ◽  
Author(s):  
Gaspard Kerner ◽  
Noe Ramirez-Alejo ◽  
Yoann Seeleuthner ◽  
Rui Yang ◽  
Masato Ogishi ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Genetic Basis ◽  
Sub Saharan Africa ◽  
European Ancestry ◽  
Uk Biobank ◽  
The United Kingdom ◽  
The Common ◽  
Sub Saharan ◽  
The Uk ◽  
High Level

The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96–10.31, P = 2 × 10−3]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for ∼1% of TB cases in Europeans.

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