A personalised medicine approach for ponatinib-resistant chronic myeloid leukaemia.

BACKGROUND: Chronic myeloid leukaemia (CML) is characterised by the presence of a fusion driver oncogene, BCR-ABL1, which is a constitutive tyrosine kinase. Tyrosine kinase inhibitors (TKIs) are the central treatment strategy for CML patients and have significantly improved survival rates, but the T315I mutation in the kinase domain of BCR-ABL1 confers resistance to all clinically approved TKIs, except ponatinib. However, compound mutations can mediate resistance even to ponatinib and remain a clinical challenge in CML therapy. Here, we investigated a ponatinib-resistant CML patient through whole-genome sequencing (WGS) to identify the cause of resistance and to find alternative therapeutic targets. PATIENTS AND METHODS: We carried out WGS on a ponatinib-resistant CML patient and demonstrated an effective combination therapy against the primary CML cells derived from this patient in vitro. RESULTS: Our findings demonstrate the emergence of compound mutations in the BCR-ABL1 kinase domain following ponatinib treatment, and chromosomal structural variation data predicted amplification of BCL2. The primary CD34(+) CML cells from this patient showed increased sensitivity to the combination of ponatinib and ABT-263, a BCL2 inhibitor with a negligible effect against the normal CD34(+) cells. CONCLUSION: Our results show the potential of personalised medicine approaches in TKI-resistant CML patients and provide a strategy that could improve clinical outcomes for these patients

Barriers to utilisation of physiotherapy services among the elderly in the Livingstone district, Zambia

AIM: The purpose of this study was to identify the barriers to utilisation of physiotherapy services among elderly people in Zambia. METHODS: By means of a convenience sampling technique, 200 elderly people, both males and females aged 60 years and above, were recruited from the Livingstone District in Zambia. A structured questionnaire, developed from literature, was used for collecting data. The Excel software programme and Statistical Package for Social Science (SPSS) were used for the capturing and analyses of the data, using descriptive and inferential statistical analyses. RESULTS: The factors that influenced the utilization of physiotherapy services by the participants were: non-referral to the service, long distances, transport, unavailability of the service in the communities and lack of awareness of physiotherapy. Income was significantly associated (p<0.05) with their inability to go for physiotherapy services. DISCUSSION: The results of this study show that physiotherapy services are not meeting the needs of the elderly in the Livingstone District in Zambia there is a need for the physiotherapy profession to raise awareness of their role in the elderly and become promoters of healthy and active aging by providing services at primary health care level through outreach programmes. CONCLUSION: Well-coordinated health services that integrate social, economical and physical services for the elderly in the district are recommended in order to achieve active and healthy ageing

Common physical problems among the elderly in the Livingstone district in Zambia: opportunities for physiotherapists

INTRODUCTION: The study identified prevalent physical problems with regard to physiotherapy needs in elderly people in the Livingstone District in Zambia. OBJECTIVES: To identify the physiotherapy needs of common physical problems in the elderly. METHODS: A cross-sectional study design, utilising a quantitative research method and a convenience sampling technique. Participants: A total of 200 elderly people from the age of 60 years SETTING: Livingstone District in Zambia INTERVENTION: A structured self-administered questionnaire was used to collect data. RESULTS: The most common self-reported physical problems identified were musculoskeletal problems, physical inactivity, decreased ability to walk and the need for walking aids. Hypertension was a common cardiovascular disorder. CONCLUSION: Physiotherapists are ideally suited to alleviate the discomfort, activity limitation and participation restriction associated with ageing

The diagnosis and medical management of tuberculous meningitis in adults

Tuberculous meningitis (TBM) is a medical emergency for which tuberculosis (TB) treatment should be initiated as soon as possible after diagnosis. Owing to the low diagnostic yields of confirmatory tests, TBM is often diagnosed based on suggestive clinical and cerebrospinal fluid findings, evidence for TB outside the central nervous system (CNS), typical brain imaging features and exclusion of other causes of meningitis. TB drug regimens used in TBM may be suboptimal as they are informed by studies of TB outside the CNS, rather than being based on randomised controlled trials in TBM. TBM has a high mortality and the management of HIV-co-infected patients is further complicated by neurological TB-immune reconstitution inflammatory syndrome (IRIS), which frequently occurs after starting antiretroviral therapy (ART) during TBM treatment and contributes to the poor outcome in HIV-associated TBM. HIV-infected TBM patients due to start ART should be counselled about the risk of developing neurological TB-IRIS, typical symptoms that could be expected and need to return to hospital should any of these develop. Currently, the only evidence-based treatment for TB-IRIS is with corticosteroids, which should be considered in all cases of neurological TB-IRIS

Air Pollution and Climate Forcing of the Charcoal Industry in Africa

The demand for charcoal in Africa is growing rapidly, driven by urbanization and lack of access to electricity. Charcoal production and use, including plastic burning to initiate combustion, release large quantities of trace gases and particles that impact air quality and climate. Here, we develop an inventory of current (2014) and future (2030) emissions from the charcoal supply chain in Africa that we implement in the GEOS-Chem model to quantify the contribution of charcoal to surface concentrations of PM2.5 and ozone and direct radiative forcing due to aerosols and ozone. We estimate that the charcoal industry in 2014 required 140–460 Tg of biomass and 260 tonnes of plastic and that industry emissions could double by 2030, so that methane emissions from the charcoal industry could outcompete those from open fires by 2025. In 2014, the largest enhancements in PM2.5 (0.5–1.4 μg m–3) and ozone (0.4–0.7 ppbv) occur around the densely populated cities in East and West Africa. Cooling due to aerosols (−100 to −300 mW m–2) is concentrated over dense cities, whereas warming due to ozone is widespread, peaking at 4.2 mW m–2 over the Atlantic Ocean. These effects will worsen with ongoing dependence on this energy source, spurred by rapid urbanization and absence of viable cleaner alternatives

Short communications: The first documented record of Western Reef Heron Egretta (gularis) schistacea for Tanzania

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Natural variation in abiotic stress responsive gene expression and local adaptation to climate in Arabidopsis thaliana.

Gene expression varies widely in natural populations, yet the proximate and ultimate causes of this variation are poorly known. Understanding how variation in gene expression affects abiotic stress tolerance, fitness, and adaptation is central to the field of evolutionary genetics. We tested the hypothesis that genes with natural genetic variation in their expression responses to abiotic stress are likely to be involved in local adaptation to climate in Arabidopsis thaliana. Specifically, we compared genes with consistent expression responses to environmental stress (expression stress responsive, "eSR") to genes with genetically variable responses to abiotic stress (expression genotype-by-environment interaction, "eGEI"). We found that on average genes that exhibited eGEI in response to drought or cold had greater polymorphism in promoter regions and stronger associations with climate than those of eSR genes or genomic controls. We also found that transcription factor binding sites known to respond to environmental stressors, especially abscisic acid responsive elements, showed significantly higher polymorphism in drought eGEI genes in comparison to eSR genes. By contrast, eSR genes tended to exhibit relatively greater pairwise haplotype sharing, lower promoter diversity, and fewer nonsynonymous polymorphisms, suggesting purifying selection or selective sweeps. Our results indicate that cis-regulatory evolution and genetic variation in stress responsive gene expression may be important mechanisms of local adaptation to climatic selective gradients

Critical Values for Yen’s Q3: Identification of Local Dependence in the Rasch model using Residual Correlations

The assumption of local independence is central to all IRT models. Violations can lead to inflated estimates of reliability and problems with construct validity. For the most widely used fit statistic Q3 there are currently no well-documented suggestions of the critical values which should be used to indicate local dependence, and for this reason a variety of arbitrary rules of thumb are used. In this study, we used an empirical data example and Monte Carlo simulation to investigate the different factors that can influence the null distribution of residual correlations, with the objective of proposing guidelines that researchers and practitioners can follow when making decisions about local dependence during scale development and validation. We propose that a parametric bootstrapping procedure should be implemented in each separate situation in order to obtain the critical value of local dependence applicable to the data set, and provide example critical values for a number of data structure situations. The results show that for the Q3 fit statistic no single critical value is appropriate for all situations, as the percentiles in the empirical null distribution are influenced by the number of items, the sample size, and the number of response categories. Furthermore, our results show that local dependence should be considered relative to the average observed residual correlation, rather than to a uniform value, as this results in more stable percentiles for the null distribution of an adjusted fit statistic

Spectral and stratigraphic mapping of hydrated sulfate and phyllosilicate-bearing deposits in northern Sinus Meridiani, Mars

We present detailed stratigraphic and spectral analyses that focus on a region in northern Sinus Meridiani located between 1°N to 5°N latitude and 3°W to 1°E longitude. Several stratigraphically distinct units are defined and mapped using morphologic expression, spectral properties, and superposition relationships. Previously unreported exposures of hydrated sulfates and Fe/Mg smectites are identified using MRO CRISM and MEX OMEGA near‐infrared (1.0 to 2.5 µm) spectral reflectance observations. Layered deposits with monohydrated and polyhydrated sulfate spectral signatures that occur in association with a northeast‐southwest trending valley are reexamined using highresolution CRISM, HiRISE, and CTX images. Layers that are spectrally dominated by monohydrated and polyhydrated sulfates are intercalated. The observed compositional layering implies that multiple wetting events, brine recharge, or fluctuations in evaporation rate occurred. We infer that these hydrated sulfate‐bearing layers were unconformably deposited following the extensive erosion of preexisting layered sedimentary rocks and may postdate the formation of the sulfate‐ and hematite‐bearing unit analyzed by the MER Opportunity rover. Therefore, at least two episodes of deposition separated by an unconformity occurred. Fe/Mg phyllosilicates are detected in units that predate the sulfateand hematite‐bearing unit. The presence of Fe/Mg smectite in older units indicates that the relatively low pH formation conditions inferred for the younger sulfate‐ and hematitebearing unit are not representative of the aqueous geochemical environment that prevailed during the formation and alteration of earlier materials. Sedimentary deposits indicative of a complex aqueous history that evolved over time are preserved in Sinus Meridiani, Mars