Publications by authors named "Thomas Williams"

527 Publications

CARMN Loss Regulates Smooth Muscle Cells and Accelerates Atherosclerosis in Mice.

Circ Res 2021 Feb 24. Epub 2021 Feb 24.

Centre for Cardiovascular Science, University of Edinburgh, UNITED KINGDOM.

In the microenvironment of atherosclerotic lesions, vascular smooth muscle cells (vSMCs) switch to a dedifferentiated state but the underlying molecular mechanisms driving this switch are not fully understood. Long noncoding RNAs (lncRNAs) are dysregulated during vascular pathology, but relatively little is known about their involvement in controlling vSMCs function. CARMN is a lncRNA located immediately upstream of the microRNAs (miRNAs) miR-143 and miR-145, both involved in vSMCs function. We investigated the role of the lncRNA CARMN, independent from miR-143 and miR-145, as potential a regulator of vSMC phenotypes in vitro and the consequences of its loss during the development of atherosclerosis in vivo. We hypothesized that loss of CARMN is a primary event controlling the functional switch towards pro-atherogenic vSMC phenotype and accelerates the development of the plaques in vivo. Expression of CARMN lncRNA was silenced using GapmeRs in human coronary arterial smooth muscle cells (hCASMCs), revealing that GapmeR-mediated loss of CARMN negatively affects miR-143 and miR-145 miRNA expression. RNA sequencing of CARMN-depleted hCASMCs revealed large transcriptomic changes, associated with vSMC proliferation, migration, inflammation, lipid metabolism and dedifferentiation. The use of miR-143 and miR-145 mimics revealed that CARMN regulates hCASMC proliferation in a miRNA-independent manner. In human and mouse, CARMN and associated miRNAs were downregulated in advanced versus early atherosclerotic lesions. Using a CRISPR-Cas9 knock-out approach, we explored the implications of CARMN depletion during atherosclerosis in vivo. Consistent with in vitro results, the knock-out of CARMN impaired the expression of miR-143 and miR-145 under homeostatic conditions. Importantly, when atherosclerosis was induced in these mice, CARMN knock-out increased the volume, size, pro-inflammatory LGALS3-expressing cells content and altered plaque composition, yielding an advanced phenotype. We identified the early loss of CARMN lncRNA as critical event which primes vSMCs towards a pro-atherogenic phenotype in vitro and accelerates the development of atherosclerosis in vivo.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318688DOI Listing
February 2021

Malaria is a cause of iron deficiency in African children.

Nat Med 2021 Feb 22. Epub 2021 Feb 22.

Kenya Medical Research Institute (KEMRI), Centre for Geographic Medicine Research, Coast, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.
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http://dx.doi.org/10.1038/s41591-021-01238-4DOI Listing
February 2021

A review of alterations to the brain during spaceflight and the potential relevance to crew in long-duration space exploration.

NPJ Microgravity 2021 Feb 16;7(1). Epub 2021 Feb 16.

National Aeronautics and Space Administration, Johnson Space Center, Houston, TX, USA.

During spaceflight, the central nervous system (CNS) is exposed to a complex array of environmental stressors. However, the effects of long-duration spaceflight on the CNS and the resulting impact to crew health and operational performance remain largely unknown. In this review, we summarize the current knowledge regarding spaceflight-associated changes to the brain as measured by magnetic resonance imaging, particularly as they relate to mission duration. Numerous studies have reported macrostructural changes to the brain after spaceflight, including alterations in brain position, tissue volumes and cerebrospinal fluid distribution and dynamics. Changes in brain tissue microstructure and connectivity were also described, involving regions related to vestibular, cerebellar, visual, motor, somatosensory and cognitive function. Several alterations were also associated with exposure to analogs of spaceflight, providing evidence that brain changes likely result from cumulative exposure to multiple independent environmental stressors. Whereas several studies noted that changes to the brain become more pronounced with increasing mission duration, it remains unclear if these changes represent compensatory phenomena or maladaptive dysregulations. Future work is needed to understand how spaceflight-associated changes to the brain affect crew health and performance, with the goal of developing comprehensive monitoring and countermeasure strategies for future long-duration space exploration.
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http://dx.doi.org/10.1038/s41526-021-00133-zDOI Listing
February 2021

SARS-CoV-2 evolution and vaccines: cause for concern?

Lancet Respir Med 2021 Jan 29. Epub 2021 Jan 29.

Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.

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http://dx.doi.org/10.1016/S2213-2600(21)00075-8DOI Listing
January 2021

Sensing the future of bio-informational engineering.

Nat Commun 2021 01 15;12(1):388. Epub 2021 Jan 15.

Chancellery, Macquarie University, Sydney, NSW, 2109, Australia.

The practices of synthetic biology are being integrated into 'multiscale' designs enabling two-way communication across organic and inorganic information substrates in biological, digital and cyber-physical system integrations. Novel applications of 'bio-informational' engineering will arise in environmental monitoring, precision agriculture, precision medicine and next-generation biomanufacturing. Potential developments include sentinel plants for environmental monitoring and autonomous bioreactors that respond to biosensor signaling. As bio-informational understanding progresses, both natural and engineered biological systems will need to be reimagined as cyber-physical architectures. We propose that a multiple length scale taxonomy will assist in rationalizing and enabling this transformative development in engineering biology.
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http://dx.doi.org/10.1038/s41467-020-20764-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810845PMC
January 2021

Indirect effects of the COVID-19 pandemic on paediatric healthcare use and severe disease: a retrospective national cohort study.

Arch Dis Child 2021 Jan 15. Epub 2021 Jan 15.

Department of Paediatric Respiratory and Sleep Medicine, Royal Hospital for Children, Glasgow, UK

Objectives: To determine the indirect consequences of the COVID-19 pandemic on paediatric healthcare utilisation and severe disease at a national level following lockdown on 23 March 2020.

Design: National retrospective cohort study.

Setting: Emergency childhood primary and secondary care providers across Scotland; two national paediatric intensive care units (PICUs); statutory death records.

Participants: 273 455 unscheduled primary care attendances; 462 437 emergency department attendances; 54 076 emergency hospital admissions; 413 PICU unplanned emergency admissions requiring invasive mechanical ventilation; and 415 deaths during the lockdown study period and equivalent dates in previous years.

Main Outcome Measures: Rates of emergency care consultations, attendances and admissions; clinical severity scores on presentation to PICU; rates and causes of childhood death. For all data sets, rates during the lockdown period were compared with mean or aggregated rates for the equivalent dates in 2016-2019.

Results: The rates of emergency presentations to primary and secondary care fell during lockdown in comparison to previous years. Emergency PICU admissions for children requiring invasive mechanical ventilation also fell as a proportion of cases for the entire population, with an OR of 0.52 for likelihood of admission during lockdown (95% CI 0.37 to 0.73), compared with the equivalent period in previous years. Clinical severity scores did not suggest children were presenting with more advanced disease. The greatest reduction in PICU admissions was for diseases of the respiratory system; those for injury, poisoning or other external causes were equivalent to previous years. Mortality during lockdown did not change significantly compared with 2016-2019.

Conclusions: National lockdown led to a reduction in paediatric emergency care utilisation, without associated evidence of severe harm.
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http://dx.doi.org/10.1136/archdischild-2020-321008DOI Listing
January 2021

Undernutrition: a major but potentially preventable cause of poor outcomes in children living with sickle cell disease in Africa.

BMC Med 2021 Jan 15;19(1):17. Epub 2021 Jan 15.

Department of Epidemiology and Demography, KEMRI-Wellcome Trust Research Programme, PO Box 230, Kilifi, 80108, Kenya.

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http://dx.doi.org/10.1186/s12916-020-01892-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809728PMC
January 2021

Genomic epidemiology reveals multiple introductions of SARS-CoV-2 from mainland Europe into Scotland.

Nat Microbiol 2021 01 21;6(1):112-122. Epub 2020 Dec 21.

MRC-University of Glasgow Centre for Virus Research (CVR), Glasgow, UK.

Coronavirus disease 2019 (COVID-19) was first diagnosed in Scotland on 1 March 2020. During the first month of the outbreak, 2,641 cases of COVID-19 led to 1,832 hospital admissions, 207 intensive care admissions and 126 deaths. We aimed to identify the source and number of introductions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into Scotland using a combined phylogenetic and epidemiological approach. Sequencing of 1,314 SARS-CoV-2 viral genomes from available patient samples enabled us to estimate that SARS-CoV-2 was introduced to Scotland on at least 283 occasions during February and March 2020. Epidemiological analysis confirmed that early introductions of SARS-CoV-2 originated from mainland Europe (the majority from Italy and Spain). We identified subsequent early outbreaks in the community, within healthcare facilities and at an international conference. Community transmission occurred after 2 March, 3 weeks before control measures were introduced. Earlier travel restrictions or quarantine measures, both locally and internationally, would have reduced the number of COVID-19 cases in Scotland. The risk of multiple reintroduction events in future waves of infection remains high in the absence of population immunity.
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http://dx.doi.org/10.1038/s41564-020-00838-zDOI Listing
January 2021

Transferability of N-terminal mutations of pyrrolysyl-tRNA synthetase in one species to that in another species on unnatural amino acid incorporation efficiency.

Amino Acids 2021 Jan 17;53(1):89-96. Epub 2020 Dec 17.

School of Chemistry, Cardiff University, Cardiff, CF10 3AT, UK.

Genetic code expansion is a powerful technique for site-specific incorporation of an unnatural amino acid into a protein of interest. This technique relies on an orthogonal aminoacyl-tRNA synthetase/tRNA pair and has enabled incorporation of over 100 different unnatural amino acids into ribosomally synthesized proteins in cells. Pyrrolysyl-tRNA synthetase (PylRS) and its cognate tRNA from Methanosarcina species are arguably the most widely used orthogonal pair. Here, we investigated whether beneficial effect in unnatural amino acid incorporation caused by N-terminal mutations in PylRS of one species is transferable to PylRS of another species. It was shown that conserved mutations on the N-terminal domain of MmPylRS improved the unnatural amino acid incorporation efficiency up to five folds. As MbPylRS shares high sequence identity to MmPylRS, and the two homologs are often used interchangeably, we examined incorporation of five unnatural amino acids by four MbPylRS variants at two temperatures. Our results indicate that the beneficial N-terminal mutations in MmPylRS did not improve unnatural amino acid incorporation efficiency by MbPylRS. Knowledge from this work contributes to our understanding of PylRS homologs which are needed to improve the technique of genetic code expansion in the future.
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http://dx.doi.org/10.1007/s00726-020-02927-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822784PMC
January 2021

Commentary: Descent from the aerial palace.

Int J Epidemiol 2021 Jan;49(6):1870-1873

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, UK.

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http://dx.doi.org/10.1093/ije/dyaa206DOI Listing
January 2021

Glucose-6-phosphate dehydrogenase deficiency and susceptibility to childhood diseases in Kilifi, Kenya.

Blood Adv 2020 Dec;4(23):5942-5950

Department of Epidemiology and Demography, Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme, Kilifi, Kenya.

Few previous studies have reported the effects of glucose-6-phosphate dehydrogenase (G6PD)-deficiency on child health in Africa. We conducted a case-control study in which cases (n = 6829) were children admitted, for any reason, to Kilifi County Hospital, Kenya, while controls (n = 10 179) were recruited from the surrounding community. Cases were subclassified based on their clinical and laboratory findings at admission. We calculated the prevalence of specific diseases by G6PD c.202 genotype, the only significant cause of G6PD-deficiency in this area, then estimated the association between genotype and admission with specific conditions using logistic regression.  Among neonates, the prevalence of jaundice was higher in both G6PD c.202T heterozygotes (40/88; 45.5%; P = .004) and homo/hemizygotes (81/134; 60.5%; P < .0001) than in wild-type homozygotes (157/526; 29.9%). Median bilirubin levels also increased across the groups, being highest (239 mmol/L; interquartile range 96-390 mmol/L) in G6PD c.202T homo/hemizygotes. No differences were seen in admission hemoglobin concentrations or the prevalence of anemia or severe anemia by G6PD c.202 genotype. On case control analysis, G6PD heterozygosity was negatively associated with all-cause hospital admission (odds ratio 0.81; 95% confidence interval 0.73-0.90; P < .0001) and, specifically, admission with either pneumonia or Plasmodium falciparum parasitemia; while, conversely, it was positively associated with Gram-positive bacteremia. G6PD c.202T homo/heterozygosity was positively associated with neonatal jaundice, severe pneumonia, the receipt of a transfusion, and in-patient death. Our study supports the conclusion that G6PD c.202T is a balanced polymorphism in which a selective advantage afforded to heterozygous females against malaria is counterbalanced by increased risks of neonatal jaundice, invasive bacterial infections, and anemia.
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http://dx.doi.org/10.1182/bloodadvances.2020003015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724908PMC
December 2020

Enabling protein-hosted organocatalytic transformations.

RSC Adv 2020 Apr 23;10(27):16147-16161. Epub 2020 Apr 23.

School of Chemistry, Cardiff University, Main Building, Cardiff, CF10 3AT, UK. Email:

In this review, the development of organocatalytic artificial enzymes will be discussed. This area of protein engineering research has underlying importance, as it enhances the biocompatibility of organocatalysis for applications in chemical and synthetic biology research whilst expanding the catalytic repertoire of enzymes. The approaches towards the preparation of organocatalytic artificial enzymes, techniques used to improve their performance (selectivity and reactivity) as well as examples of their applications are presented. Challenges and opportunities are also discussed.
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http://dx.doi.org/10.1039/d0ra01526aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654312PMC
April 2020

Clustering of health risk behaviors among adolescents in Kilifi, Kenya, a rural Sub-Saharan African setting.

PLoS One 2020 12;15(11):e0242186. Epub 2020 Nov 12.

Centre for Geographic Medicine Research Coast, Kenya Medical Research Institute (KEMRI), Kilifi, Kenya.

Background: Adolescents tend to experience heightened vulnerability to risky and reckless behavior. Adolescents living in rural settings may often experience poverty and a host of risk factors which can increase their vulnerability to various forms of health risk behavior (HRB). Understanding HRB clustering and its underlying factors among adolescents is important for intervention planning and health promotion. This study examines the co-occurrence of injury and violence, substance use, hygiene, physical activity, and diet-related risk behaviors among adolescents in a rural setting on the Kenyan coast. Specifically, the study objectives were to identify clusters of HRB; based on five categories of health risk behavior, and to identify the factors associated with HRB clustering.

Methods: A cross-sectional survey was conducted of a random sample of 1060 adolescents aged 13-19 years living within the area covered by the Kilifi Health and Demographic Surveillance System. Participants completed a questionnaire on health behaviors which was administered via an Audio Computer-Assisted Self-Interview. Latent class analysis on 13 behavioral factors (injury and violence, hygiene, alcohol tobacco and drug use, physical activity, and dietary related behavior) was used to identify clustering and stepwise ordinal logistic regression with nonparametric bootstrapping identified the factors associated with clustering. The variables of age, sex, education level, school attendance, mental health, form of residence and level of parental monitoring were included in the initial stepwise regression model.

Results: We identified 3 behavioral clusters (Cluster 1: Low-risk takers (22.9%); Cluster 2: Moderate risk-takers (67.8%); Cluster 3: High risk-takers (9.3%)). Relative to the cluster 1, membership of higher risk clusters (i.e. moderate or high risk-takers) was strongly associated with older age (p<0.001), being male (p<0.001), depressive symptoms (p = 0.005), school non-attendance (p = 0.001) and a low level of parental monitoring (p<0.001).

Conclusion: There is clustering of health risk behaviors that underlies communicable and non-communicable diseases among adolescents in rural coastal Kenya. This suggests the urgent need for targeted multi-component health behavior interventions that simultaneously address all aspects of adolescent health and well-being, including the mental health needs of adolescents.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242186PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660520PMC
January 2021

Adaptive laboratory evolution of native methanol assimilation in Saccharomyces cerevisiae.

Nat Commun 2020 11 4;11(1):5564. Epub 2020 Nov 4.

Department of Molecular Sciences, ARC Centre of Excellence in Synthetic Biology, Macquarie University, 2109, North Ryde, NSW, Australia.

Utilising one-carbon substrates such as carbon dioxide, methane, and methanol is vital to address the current climate crisis. Methylotrophic metabolism enables growth and energy generation from methanol, providing an alternative to sugar fermentation. Saccharomyces cerevisiae is an important industrial microorganism for which growth on one-carbon substrates would be relevant. However, its ability to metabolize methanol has been poorly characterised. Here, using adaptive laboratory evolution and C-tracer analysis, we discover that S. cerevisiae has a native capacity for methylotrophy. A systems biology approach reveals that global rearrangements in central carbon metabolism fluxes, gene expression changes, and a truncation of the uncharacterized transcriptional regulator Ygr067cp supports improved methylotrophy in laboratory evolved S. cerevisiae. This research paves the way for further biotechnological development and fundamental understanding of methylotrophy in the preeminent eukaryotic model organism and industrial workhorse, S. cerevisiae.
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http://dx.doi.org/10.1038/s41467-020-19390-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643182PMC
November 2020

Immunotherapeutic approaches for fungal infections.

Curr Opin Microbiol 2020 12 2;58:130-137. Epub 2020 Nov 2.

MRC Centre for Molecular Bacteriology and Infection, Imperial College London, 14 Armstrong Rd, South Kensington, London SW7 2DD, United Kingdom. Electronic address:

Despite the availability of antifungal treatments, fungal infections are still causing morbidity all around the globe with unacceptably high mortality rates. A major driver for the rising incidence of serious fungal infections is due to a substantial increase in immunocompromised individuals with autoimmune diseases, cancers and transplants. Because of growing resistance in fungus to frontline triazole antifungals and the association of fungal disease with the immunocompromised host, adjunctive host-directed therapy is seen as a promising choice to improve patient outcomes. Immunotherapeutic treatments being explored as adjunct therapies to existing antifungal treatments include cytokine therapy, monoclonal antibodies and cellular immunotherapy. In this review, we give a brief overview of potential immunotherapies and recent developments in the field, which are needed to tackle the growing problem of fungal diseases.
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http://dx.doi.org/10.1016/j.mib.2020.09.007DOI Listing
December 2020

Microdroplet enabled cultivation of single yeast cells correlates with bulk growth and reveals subpopulation phenomena.

Biotechnol Bioeng 2021 Feb 21;118(2):647-658. Epub 2020 Oct 21.

School of Engineering, Macquarie University, Sydney, NSW, Australia.

Yeast has been engineered for cost-effective organic acid production through metabolic engineering and synthetic biology techniques. However, cell growth assays in these processes were performed in bulk at the population level, thus obscuring the dynamics of rare single cells exhibiting beneficial traits. Here, we introduce the use of monodisperse picolitre droplets as bioreactors to cultivate yeast at the single-cell level. We investigated the effect of acid stress on growth and the effect of potassium ions on propionic acid tolerance for single yeast cells of different species, genotypes, and phenotypes. The results showed that the average growth of single yeast cells in microdroplets experiences the same trend to those of yeast populations grown in bulk, and microdroplet compartments do not significantly affect cell viability. This approach offers the prospect of detecting cell-to-cell variations in growth and physiology and is expected to be applied for the engineering of yeast to produce value-added bioproducts.
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http://dx.doi.org/10.1002/bit.27591DOI Listing
February 2021

How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children.

Int J Mol Sci 2020 Sep 22;21(18). Epub 2020 Sep 22.

Kenya Medical Research Institute (KEMRI) Center for Geographical Medicine Research-Coast, KEMRI-Wellcome Trust Research Programme, Kilifi P.O. Box 230-80108, Kenya.

Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. Severe anaemia is characterized by increased haemolysis, erythropoietic drive, gut permeability, and disruption of immune regulatory systems. These pathways are associated with dysregulation of iron homeostasis, including the downregulation of the hepatic hormone hepcidin. Increased haemolysis and low hepcidin levels potentially increase plasma, tissue and intracellular iron levels. Pathogenic bacteria require iron and/or haem to proliferate and have evolved numerous strategies to acquire labile and protein-bound iron/haem. In this review, we discuss how severe anaemia may mediate the risk of invasive bacterial infections through dysregulation of hepcidin and/or iron homeostasis, and potential studies that could be conducted to test this hypothesis.
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http://dx.doi.org/10.3390/ijms21186976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555399PMC
September 2020

Risk factors for anaemia among Ghanaian women and children vary by population group and climate zone.

Matern Child Nutr 2020 Sep 18:e13076. Epub 2020 Sep 18.

GroundWork, Fläsch, Switzerland.

Anaemia has serious effects on human health and has multifactorial aetiologies. This study aimed to determine putative risk factors for anaemia in children 6-59 months and 15- to 49-year-old non-pregnant women living in Ghana. Data from a nationally representative cross-sectional survey were analysed for associations between anaemia and various anaemia risk factors. National and stratum-specific multivariable regressions were constructed separately for children and women to calculate the adjusted prevalence ratio (aPR) for anaemia of variables found to be statistically significantly associated with anaemia in bivariate analysis. Nationally, the aPR for anaemia was greater in children with iron deficiency (ID; aPR 2.20; 95% confidence interval [CI]: 1.88, 2.59), malaria parasitaemia (aPR 1.96; 95% CI: 1.65, 2.32), inflammation (aPR 1.26; 95% CI: 1.08, 1.46), vitamin A deficiency (VAD; aPR 1.38; 95% CI: 1.19, 1.60) and stunting (aPR 1.26; 95% CI: 1.09, 1.46). In women, ID (aPR 4.33; 95% CI: 3.42, 5.49), VAD (aPR 1.61; 95% CI: 1.24, 2.09) and inflammation (aPR 1.59; 95% CI: 1.20, 2.11) were associated with anaemia, whereas overweight and obese women had lower prevalence of anaemia (aPR 0.74; 95% CI: 0.56, 0.97). ID was associated with child anaemia in the Northern and Middle belts, but not in the Southern Belt; conversely, inflammation was associated with anaemia in both children and women in the Southern and Middle belts, but not in the Northern Belt. Anaemia control programmes should be region specific and aim at the prevention of ID, malaria and other drivers of inflammation as they are the main predictors of anaemia in Ghanaian children and women.
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http://dx.doi.org/10.1111/mcn.13076DOI Listing
September 2020

Characterization of raffinose metabolism genes uncovers a wild Arachis galactinol synthase conferring tolerance to abiotic stresses.

Sci Rep 2020 09 17;10(1):15258. Epub 2020 Sep 17.

EMBRAPA Recursos Genéticos e Biotecnologia. Parque Estação Biológica, Final W5 Norte, Brasília, DF, CP 02372, Brazil.

Raffinose family oligosaccharides (RFOs) are implicated in plant regulatory mechanisms of abiotic stresses tolerance and, despite their antinutritional proprieties in grain legumes, little information is available about the enzymes involved in RFO metabolism in Fabaceae species. In the present study, the systematic survey of legume proteins belonging to five key enzymes involved in the metabolism of RFOs (galactinol synthase, raffinose synthase, stachyose synthase, alpha-galactosidase, and beta-fructofuranosidase) identified 28 coding-genes in Arachis duranensis and 31 in A. ipaënsis. Their phylogenetic relationships, gene structures, protein domains, and chromosome distribution patterns were also determined. Based on the expression profiling of these genes under water deficit treatments, a galactinol synthase candidate gene (AdGolS3) was identified in A. duranensis. Transgenic Arabidopsis plants overexpressing AdGolS3 exhibited increased levels of raffinose and reduced stress symptoms under drought, osmotic, and salt stresses. Metabolite and expression profiling suggested that AdGolS3 overexpression was associated with fewer metabolic perturbations under drought stress, together with better protection against oxidative damage. Overall, this study enabled the identification of a promising GolS candidate gene for metabolic engineering of sugars to improve abiotic stress tolerance in crops, whilst also contributing to the understanding of RFO metabolism in legume species.
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http://dx.doi.org/10.1038/s41598-020-72191-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498584PMC
September 2020

Correction for Theofel et al., "Microorganisms Move a Short Distance into an Almond Orchard from an Adjacent Upwind Poultry Operation".

Appl Environ Microbiol 2020 09 17;86(19). Epub 2020 Sep 17.

Department of Food Science and Technology, University of California, Davis, Davis, California, USA

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http://dx.doi.org/10.1128/AEM.01905-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499045PMC
September 2020

Red blood cell tension protects against severe malaria in the Dantu blood group.

Nature 2020 09 16;585(7826):579-583. Epub 2020 Sep 16.

Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.

Malaria has had a major effect on the human genome, with many protective polymorphisms-such as the sickle-cell trait-having been selected to high frequencies in malaria-endemic regions. The blood group variant Dantu provides 74% protection against all forms of severe malaria in homozygous individuals, a similar degree of protection to that afforded by the sickle-cell trait and considerably greater than that offered by the best malaria vaccine. Until now, however, the protective mechanism has been unknown. Here we demonstrate the effect of Dantu on the ability of the merozoite form of the malaria parasite Plasmodium falciparum to invade red blood cells (RBCs). We find that Dantu is associated with extensive changes to the repertoire of proteins found on the RBC surface, but, unexpectedly, inhibition of invasion does not correlate with specific RBC-parasite receptor-ligand interactions. By following invasion using video microscopy, we find a strong link between RBC tension and merozoite invasion, and identify a tension threshold above which invasion rarely occurs, even in non-Dantu RBCs. Dantu RBCs have higher average tension than non-Dantu RBCs, meaning that a greater proportion resist invasion. These findings provide both an explanation for the protective effect of Dantu, and fresh insight into why the efficiency of P. falciparum invasion might vary across the heterogenous populations of RBCs found both within and between individuals.
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http://dx.doi.org/10.1038/s41586-020-2726-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116803PMC
September 2020

The clinical spectrum of severe childhood malaria in Eastern Uganda.

Malar J 2020 Sep 3;19(1):322. Epub 2020 Sep 3.

KEMRI-Wellcome Trust Research Programme, Centre for Geographic Medicine Research-Coast, Kilifi, Kenya.

Background: Few recent descriptions of severe childhood malaria have been published from high-transmission regions. In the current study, the clinical epidemiology of severe malaria in Mbale, Eastern Uganda, is described, where the entomological inoculation rate exceeds 100 infective bites per year.

Methods: A prospective descriptive study was conducted to determine the prevalence, clinical spectrum and outcome of severe Plasmodium falciparum malaria at Mbale Regional Referral Hospital in Eastern Uganda. All children aged 2 months-12 years who presented on Mondays to Fridays between 8.00 am and 5.00 pm from 5th May 2011 until 30th April 2012 were screened for parasitaemia. Clinical and laboratory data were then collected from all P. falciparum positive children with features of WHO-defined severe malaria by use of a standardized proforma.

Results: A total of 10 208 children were screened of which 6582 (64%) had a positive blood film. Of these children, 662 (10%) had clinical features of severe malaria and were consented for the current study. Respiratory distress was the most common severity feature (554; 83.7%), while 365/585 (62.4%) had hyperparasitaemia, 177/662 (26.7%) had clinical jaundice, 169 (25.5%) had severe anaemia, 134/660 (20.2%) had hyperlactataemia (lactate ≥ 5 mmol/L), 93 (14.0%) had passed dark red or black urine, 52 (7.9%) had impaired consciousness and 49/662 (7.4%) had hypoxaemia (oxygen saturations < 90%). In-hospital mortality was 63/662 (9.5%) overall but was higher in children with either cerebral malaria (33.3%) or severe anaemia (19.5%). Factors that were independently associated with mortality on multivariate analysis included severe anaemia [odds ratio (OR) 5.36; 2.16-1.32; P = 0.0002], hyperlactataemia (OR 3.66; 1.72-7.80; P = 0.001), hypoxaemia (OR) 3.64 (95% CI 1.39-9.52; P = 0.008), and hepatomegaly (OR 2.29; 1.29-4.06; P = 0.004). No independent association was found between mortality and either coma or hyperparasitaemia.

Conclusions: Severe childhood malaria remains common in Eastern Uganda where it continues to be associated with high mortality. An unusually high proportion of children with severe malaria had jaundice or gave a history of having recently passed dark red or black urine, an issue worthy of further investigation.
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http://dx.doi.org/10.1186/s12936-020-03390-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470679PMC
September 2020

Characterising demographics, knowledge, practices and clinical care among patients attending sickle cell disease clinics in Eastern Uganda.

Wellcome Open Res 2020 7;5:87. Epub 2020 Jul 7.

Mbale Clinical Research Institute, Mbale, Uganda.

: In Uganda to date, there are neither established registries nor descriptions of facility-based sickle cell disease (SCD) patient characteristics beyond the central region. Here, we summarize data on the baseline clinical characteristics and routine care available to patients at four clinics in Eastern Uganda as a prelude to a clinical trial. : Between February and August 2018, we conducted a cross-sectional survey of patients attending four SCD clinics in Mbale, Soroti, Atutur and Ngora, all in Eastern Uganda, the planned sites for an upcoming clinical trial (H-PRIME:  ISRCTN15724013). Data on socio-demographic characteristics, diagnostic methods, clinic schedules, the use of prophylactic and therapeutic drugs, clinical complications and patient understanding of SCD were collected using a structured questionnaire. : Data were collected on 1829 patients. Their ages ranged from 0 to 64 years with a median (IQR) of 6 (3-11) years. 49.1% of participants were male. The majority (1151; 62.9%) reported a positive family history for SCD. Approximately half knew that SCD is inherited from both parents but a substantial proportion did not know how SCD is transmitted and small numbers believed that it is acquired by either transfusion or from other people. Only 118/1819 (6.5%) participants had heard about or were using hydroxyurea while 356/1794 (19.8%) reported stigmatization. Participants reported a median of three (IQR 1-4) hospital admissions during the preceding 12 months; 80.8% had been admitted at least once, while 14.2% had been admitted more than five times. Pain was the most common symptom, while 83.9% of those admitted had received at least one blood transfusion.  The majority of patients attending SCD clinics in Eastern Uganda are children and few are currently being treated with hydroxyurea. The data collected through this facility-based survey will provide background data that will be useful in planning for the H-PRIME trial.
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http://dx.doi.org/10.12688/wellcomeopenres.15847.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406951PMC
July 2020

The continued urbanization of American surgery: A threat to rural hospitals.

Surgery 2021 Mar 6;169(3):543-549. Epub 2020 Aug 6.

Department of Surgery, The Ohio State University College of Medicine, Columbus, OH.

Background: In 2011, we predicted that surgeon shortages for rural hospitals would contribute to closures of rural hospitals. Here, we update population trends, the distribution of rural and urban hospitals, and surgeon supply to estimate surgeon demand for rural and urban hospital settings by 2040.

Methods: Surgeon supply was based on new certifications for general surgery, orthopedic surgery, and obstetrics and gynecology adjusted for retirement. Surgeon demand from 2020 to 2040 was projected based on the US Census and published practice ratios: general surgery 10.7/100,000, orthopedic surgery 7.9/100,000, and obstetrics and gynecology 13.0/100,000.

Results: The US population grew from 309 million in 2011 to 327 million in 2017 with rural populations unchanged at 56 million. By 2040, the US population will be 374 million (urban 85% and rural 15%) creating shortages of general surgery (-31.5%), orthopedic surgery (-34.3%), and obstetrics and gynecology (-25.3). Future hiring needs for urban hospitals will be 5 times greater than rural hospitals. Urban hospitals will likely recruit most newly certified surgeons.

Conclusion: Increases in surgery trainees will not meet the demand. The continued urbanization of American surgery may push rural hospitals into a vicious financial cycle leading to additional closures of rural hospitals and worsening issues of access. An alternative training paradigm for the rural surgeon is recommended to meet the unique demands of rural hospitals.
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http://dx.doi.org/10.1016/j.surg.2020.06.027DOI Listing
March 2021

Plasma Plasmodium falciparum Histidine-Rich Protein-2 concentrations in children with malaria infections of differing severity in Kilifi, Kenya.

Clin Infect Dis 2020 Aug 9. Epub 2020 Aug 9.

KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.

Background: Most previous studies support a direct link between total parasite load and the clinical severity of Plasmodium falciparum malaria infections.

Methods: We estimated P. falciparum parasite loads in three groups of children with malaria infections of differing severity: (1) children with WHO-defined severe malaria (n=1,544); (2) children admitted with malaria but without features of severity (n=200) and; (3) children in the community with asymptomatic parasitemia (n=33).

Results: Peripheral parasitemias were highest in those with uncomplicated malaria (geometric mean 111,064; 95%CI 86,798-141,819 parasites/μl), being almost three times higher than those with severe malaria (39,588; 34,990-44,791 parasites/μl) and >100 times higher than in those with asymptomatic malaria (1,092; 523-2,280 parasites/μl). However, geometric mean PfHRP2 values (95% CI) increased with severity, being 7 (4-12) ng/ml in asymptomatic malaria, 843 (655-1,084) ng/ml in uncomplicated malaria and 1,369 (1,244-1,506) ng/ml in severe malaria. PfHRP2 concentrations were markedly lower in the sub-group of severe malaria patients with concomitant invasive bacterial infections (IBIs) of blood or CSF (GM 312 ng/ml; 95%CI 175-557; p<0.0001) than in those without IBIs (GM 1,439 ng/ml; 1,307-1,584; P<0.001).

Conclusions: The clinical severity of malaria infections related strongly to the total burden of P. falciparum parasites. A quantitative test for plasma concentrations of PfHRP2 could be useful in identifying children at the greatest clinical risk and to identify critically ill children in whom malaria is not the primary cause.
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http://dx.doi.org/10.1093/cid/ciaa1141DOI Listing
August 2020

A network physiology approach to oxygen saturation variability during normobaric hypoxia.

Exp Physiol 2021 Jan 20;106(1):151-159. Epub 2020 Jul 20.

Network Physiology Laboratory, UCL Division of Medicine, University College London, London, UK.

New Findings: What is the central question of this study? What is the physiological interpretation of fluctuations observed during normobaric hypoxia in healthy individuals? What is the main finding and its importance? There is a significant flow of information between and other cardio-respiratory time series during graded hypoxia. Analysis of the pattern of variations has potential for non-invasive assessment of the engagement of respiratory control system in health and disease.

Abstract: Peripheral capillary oxygen saturation ( ) exhibits a complex pattern of fluctuations during hypoxia. The physiological interpretation of variability is not well understood. In this study, we tested the hypothesis that fluctuation carries information about integrated cardio-respiratory control in healthy individuals using a network physiology approach. We explored the use of transfer entropy in order to compute the flow of information between cardio-respiratory signals during hypoxia. Twelve healthy males (mean (SD) age 22 (4) years) were exposed to four simulated environments (fraction of inspired oxygen ( ): 0.12, 0.145, 0.17, and 0.2093) for 45 min, in a single blind randomized controlled design. The flow of information between different physiological parameters ( , respiratory frequency, tidal volume, minute ventilation, heart rate, end-tidal pressure of O and CO ) were analysed using transfer entropy. Normobaric hypoxia was associated with a significant increase in entropy of the time series. The transfer entropy analysis showed that, particularly at 0.145 and 0.12, the flow of information between and other physiological variables exhibits a bidirectional relationship. While reciprocal interactions were observed between different cardio-respiratory parameters during hypoxia, remained the main hub of this network. fluctuations during graded hypoxia exposure carry information about cardio-respiratory control. Therefore, entropy analysis has the potential for non-invasive assessment of the functional connectivity of respiratory control system in various healthcare settings.
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http://dx.doi.org/10.1113/EP088755DOI Listing
January 2021

Creating the Successful Global Maxillofacial Surgeon: A 35-Year Perspective.

Oral Maxillofac Surg Clin North Am 2020 Aug;32(3):489-493

1870 Links Glen, Dubuque, IA 52003, USA. Electronic address:

The success of global outreach surgical programs depends on many factors including the preparation of the surgeons involved in the program. Surgeons in preparing for global outreach programs often focus on surgical procedures or techniques as the most important aspect of the preparation for the program. Just as important to success of the outreach program is the surgeon's familiarity with the language, cultural, and social norms of the host country or region. This article provides valuable information on these issues from three oral and maxillofacial surgeons who have been engaged in global oral and maxillofacial surgery outreach programs for decades.
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http://dx.doi.org/10.1016/j.coms.2020.04.011DOI Listing
August 2020