Whole genome sequencing reveals large deletions and other loss of function mutations in Mycobacterium tuberculosis drug resistance genes.

Drug resistance in Mycobacterium tuberculosis, the causative agent of tuberculosis disease, arises from genetic mutations in genes coding for drug-targets or drug-converting enzymes. SNPs linked to drug resistance have been extensively studied and form the basis of molecular diagnostics and sequencing-based resistance profiling. However, alternative forms of functional variation such as large deletions and other loss of function (LOF) mutations have received much less attention, but if incorporated into diagnostics they are likely to improve their predictive performance. Our work aimed to characterize the contribution of LOF mutations found in 42 established drug resistance genes linked to 19 anti-tuberculous drugs across 32689 sequenced clinical isolates. The analysed LOF mutations included large deletions (n=586), frameshifts (n=4764) and premature stop codons (n=826). We found LOF mutations in genes strongly linked to pyrazinamide (pncA), isoniazid (katG), capreomycin (tlyA), streptomycin (e.g. gid) and ethionamide (ethA, mshA) (P<10-5), but also in some loci linked to drugs where relatively less phenotypic data is available [e.g. cycloserine, delaminid, bedaquiline, para-aminosalicylic acid (PAS), and clofazimine]. This study reports that large deletions (median size 1115 bp) account for a significant portion of resistance variants found for PAS (+7.1% of phenotypic resistance percentage explained), pyrazinamide (+3.5%) and streptomycin (+2.6%) drugs, and can be used to improve the prediction of cryptic resistance. Overall, our work highlights the importance of including LOF mutations (e.g. large deletions) in predicting genotypic drug resistance, thereby informing tuberculosis infection control and clinical decision-making

A molecular barcode to inform the geographical origin and transmission dynamics of Plasmodium vivax malaria.

Although Plasmodium vivax parasites are the predominant cause of malaria outside of sub-Saharan Africa, they not always prioritised by elimination programmes. P. vivax is resilient and poses challenges through its ability to re-emerge from dormancy in the human liver. With observed growing drug-resistance and the increasing reports of life-threatening infections, new tools to inform elimination efforts are needed. In order to halt transmission, we need to better understand the dynamics of transmission, the movement of parasites, and the reservoirs of infection in order to design targeted interventions. The use of molecular genetics and epidemiology for tracking and studying malaria parasite populations has been applied successfully in P. falciparum species and here we sought to develop a molecular genetic tool for P. vivax. By assembling the largest set of P. vivax whole genome sequences (n = 433) spanning 17 countries, and applying a machine learning approach, we created a 71 SNP barcode with high predictive ability to identify geographic origin (91.4%). Further, due to the inclusion of markers for within population variability, the barcode may also distinguish local transmission networks. By using P. vivax data from a low-transmission setting in Malaysia, we demonstrate the potential ability to infer outbreak events. By characterising the barcoding SNP genotypes in P. vivax DNA sourced from UK travellers (n = 132) to ten malaria endemic countries predominantly not used in the barcode construction, we correctly predicted the geographic region of infection origin. Overall, the 71 SNP barcode outperforms previously published genotyping methods and when rolled-out within new portable platforms, is likely to be an invaluable tool for informing targeted interventions towards elimination of this resilient human malaria

Perceived neighborhood safety and incident mobility disability among elders: the hazards of poverty

<p>Abstract</p> <p>Background</p> <p>We investigated whether lack of perceived neighborhood safety due to crime, or living in high crime neighborhoods was associated with incident mobility disability in elderly populations. We hypothesized that low-income elders and elders at retirement age (65 – 74) would be at greatest risk of mobility disability onset in the face of perceived or measured crime-related safety hazards.</p> <p>Methods</p> <p>We conducted the study in the New Haven Established Populations for Epidemiologic Studies of the Elderly (EPESE), a longitudinal cohort study of community-dwelling elders aged 65 and older who were residents of New Haven, Connecticut in 1982. Elders were interviewed beginning in 1982 to assess mobility (ability to climb stairs and walk a half mile), perceptions of their neighborhood safety due to crime, annual household income, lifestyle characteristics (smoking, alcohol use, physical activity), and the presence of chronic co-morbid conditions. Additionally, we collected baseline data on neighborhood crime events from the New Haven Register newspaper in 1982 to measure local area crime rates at the census tract level.</p> <p>Results</p> <p>At baseline in 1982, 1,884 elders were without mobility disability. After 8 years of follow-up, perceiving safety hazards was associated with increased risk of mobility disability among elders at retirement age whose incomes were below the federal poverty line (HR 1.56, 95% CI 1.02 – 2.37). No effect of perceived safety hazards was found among elders at retirement age whose incomes were above the poverty line. No effect of living in neighborhoods with high crime rates (measured by newspaper reports) was found in any sub-group.</p> <p>Conclusion</p> <p>Perceiving a safety hazard due to neighborhood crime was associated with increased risk of incident mobility disability among impoverished elders near retirement age. Consistent with prior literature, retirement age appears to be a vulnerable period with respect to the effect of neighborhood conditions on elder health. Community violence prevention activities should address perceived safety among vulnerable populations, such as low-income elders at retirement age, to reduce future risks of mobility disability.</p

Distinctive genetic structure and selection patterns in Plasmodium vivax from South Asia and East Africa.

Despite the high burden of Plasmodium vivax malaria in South Asian countries, the genetic diversity of circulating parasite populations is not well described. Determinants of antimalarial drug susceptibility for P. vivax in the region have not been characterised. Our genomic analysis of global P. vivax (n = 558) establishes South Asian isolates (n = 92) as a distinct subpopulation, which shares ancestry with some East African and South East Asian parasites. Signals of positive selection are linked to drug resistance-associated loci including pvkelch10, pvmrp1, pvdhfr and pvdhps, and two loci linked to P. vivax invasion of reticulocytes, pvrbp1a and pvrbp1b. Significant identity-by-descent was found in extended chromosome regions common to P. vivax from India and Ethiopia, including the pvdbp gene associated with Duffy blood group binding. Our investigation provides new understanding of global P. vivax population structure and genomic diversity, and genetic evidence of recent directional selection in this important human pathogen

Early childhood feeding practices and dental caries in preschool children: a multi-centre birth cohort study

Extent: 7p.Background Dental caries (decay) is an international public health challenge, especially amongst young children. Early Childhood Caries is a rapidly progressing disease leading to severe pain, anxiety, sepsis and sleep loss, and is a major health problem particularly for disadvantaged populations. There is currently a lack of research exploring the interactions between risk and protective factors in the development of early childhood caries, in particular the effects of infant feeding practises. Methods/Design This is an observational cohort study and involves the recruitment of a birth cohort from disadvantaged communities in South Western Sydney. Mothers will be invited to join the study soon after the birth of their child at the time of the first home visit by Child and Family Health Nurses. Data on feeding practices and dental health behaviours will be gathered utilizing a telephone interview at 4, 8 and 12 months, and thereafter at 6 monthly intervals until the child is aged 5 years. Information collected will include a) initiation and duration of breastfeeding, b) introduction of solid food, c) intake of cariogenic and non-cariogenic foods, d) fluoride exposure, and e) oral hygiene practices. Children will have a dental and anthropometric examination at 2 and 5 years of age and the main outcome measures will be oral health quality of life, caries prevalence and caries incidence. Discussion This study will provide evidence of the association of early childhood feeding practices and the oral health of preschool children. In addition, information will be collected on breastfeeding practices and the oral health concerns of mothers living in disadvantaged areas in South Western Sydney.Amit Arora, Jane A Scott, Sameer Bhole, Loc Do, Eli Schwarz and Anthony S Blinkhor

Are Differences in Disability-Free Life Expectancy by Gender, Race, and Education Widening at Older Ages?

To examine change from 1991 to 2001 in disability-free life expectancy in the age range 60-90 by gender, race, and education in the United States. Mortality is estimated over two 10-year follow-up periods for persons in the National Health Interview Surveys of 1986/1987 and 1996/1997. Vital status is ascertained through the National Death Index. Disability prevalence is estimated from the National Health and Nutrition Examination Surveys of 1988-1994 and 1999-2002. Disability is defined as ability to perform four activities of daily living without difficulty. Disability-free life expectancy increased only among white men. Disabled life expectancy increased for all groups-black and white men and women. Racial differences in disability-free life expectancy widened among men; gender differences were reduced among whites. Expansion of socioeconomic differentials in disability-free life at older ages occurred among white men and women and black women. The 1990s was a period where the increased years of life between ages 60 and 90 were concentrated in disabled years for most population groups