Factors Associated with the Performance of a Blood-Based Interferon-γ Release Assay in Diagnosing Tuberculosis

Background: Indeterminate results are a recognised limitation of interferon-γ release assays (IGRA) in the diagnosis of latent tuberculosis (TB) infection (LTBI) and TB disease, especially in children. We investigated whether age and common co-morbidities were associated with IGRA performance in an unselected cohort of resettled refugees. Methods: A retrospective cross-sectional study of refugees presenting for their post-resettlement health assessment during 2006 and 2007. Refugees were investigated for prevalent infectious diseases, including TB, and for common nutritional deficiencies and haematological abnormalities as part of standard clinical screening protocols. Tuberculosis screening was performed by IGRA; QuantiFERON-TB Gold in 2006 and QuantiFERON-TBGold In-Tube in 2007. Results: Complete data were available on 1130 refugees, of whom 573 (51%) were children less than 17 years and 1041 (92%) were from sub-Saharan Africa. All individuals were HIV negative. A definitive IGRA result was obtained in 1004 (89%) refugees, 264 (26%) of which were positive; 256 (97%) had LTBI and 8 (3%) had TB disease. An indeterminate IGRA result was obtained in 126 (11%) refugees (all failed positive mitogen control). In multivariate analysis, younger age (linear OR = 0.93 [95% CI 0.91-0.95],

Community outreach midwifery-led model improves antenatal access in a disadvantaged population

Objective: This study aimed to assess the impact of a new model of antenatal care for women living in a very remote area. Design: This is a retrospective 2-year evaluation of antenatal care. Setting and participants: Two hundred thirteen pregnant women in Aboriginal communities in the Fitzroy Valley of Western Australia participated in this study. Intervention: The implementation of a midwifery-led interdisciplinary model of antenatal outreach care. Main outcome measures: The indicators measured were numbers of antenatal visits, their location and quality care indicators (presentation in first trimester, alcohol and smoking, ultrasound and blood-borne virus screening) and outcome indicators (birth weight, prematurity, in utero deaths and mode of delivery). Results: There was an increase in access to antenatal care and improvements in quality-of-care indicators. The proportion of visits provided in local Aboriginal communities increased from 10% to 24%. There were statistically significant increases in women presenting in the first trimester (40-58%), screening for alcohol and smoking (48-93%) and having an ultrasound in pregnancy (59-94%). There were no significant improvements in neonatal outcome indicators. Conclusion: There is a large disparity in maternal and child health outcomes between Aboriginal and Torres Strait Islander (Indigenous) and non-Indigenous Australians thought to be due to decreased access to antenatal care, poorer socioeconomic status and the associated risk factors. The change in model of care resulted in earlier presentation for antenatal care, increased numbers of antenatal visits and increased screening for risk factors. Regular auditing of services enables the identification of opportunity for improvement with the goal of improving health outcomes

An internal thioester in a pathogen surface protein mediates covalent host binding

This work was supported by the MRC, UK grant MR/K001485 for MW, JME, MR, MJB, USL; the BBSRC, UK grant BB/J00453 and the John Innes Foundation for MJB; the Wellcome Trust Institutional Strategic Support Fund 097831/Z/11/B for AMD; Wellcome Trust/JIF award 063597 and Wellcome Trust grants WT079272AIA and 094476/Z/10/Z to CHB for the BSRC Mass Spectrometry and Proteomics Facility; University of St Andrews and School of Biology for SYK; The Carnegie Trust for OKM.To cause disease and persist in a host, pathogenic and commensal microbes must adhere to tissues. Colonization and infection depend on specific molecular interactions at the host-microbe interface that involve microbial surface proteins, or adhesins. To date, adhesins are only known to bind to host receptors non-covalently. Here we show that the streptococcal surface protein SfbI mediates covalent interaction with the host protein fibrinogen using an unusual internal thioester bond as a ‘chemical harpoon’. This cross-linking reaction allows bacterial attachment to fibrin and SfbI binding to human cells in a model of inflammation. Thioester-containing domains are unexpectedly prevalent in Gram-positive bacteria, including many clinically relevant pathogens. Our findings support bacterial-encoded covalent binding as a new molecular principle in host-microbe interactions. This represents an as yet unexploited target to treat bacterial infection and may also offer novel opportunities for engineering beneficial interactions.Publisher PDFPeer reviewe

The probability of an indeterminate IGRA based on age.

<p>This figure shows the estimated proportion of indeterminate IGRA results depending on the age at the MHU visit. <i>Not adjusted for other covariates in the multivariate model.</i></p

Clinical characteristics of study population (n = 1130).

*<p>Estimate values represent mean ± standard deviation or median (interquartile range) or frequency (percent) of study population.</p>**<p>Screening through only the QuantiFERON®-TB Gold or QuantiFERON®-TB Gold In-tube assays.</p>+<p>Defined as a positive serology to either <i>Schistosoma</i> or <i>S. stercoralis</i>, or an eosinophil count >0.7×10⁹/L.</p>++<p>Defined as deficient (<27.5 nmol/L), insufficient (27.5–78 nmol/L) and sufficient (>78 nmol/L).</p

Characteristics associated with an indeterminate IGRA result (n = 1130).

*<p>CI = confidence interval.</p>+<p>Multivariate odds ratio and p value reported if significant (<i>P</i><0.05).</p>++<p>Age- and gender-adjusted variable.</p

The probability of a positive IGRA based on age.

<p>This figure shows the estimated proportion of positive IGRA results, compared to negative IGRA results, depending on the age at assessment. <i>Not adjusted for other covariates in the multivariate model.</i></p

Demographic characteristics of study population (n = 1130).

*<p>Estimate values represent mean ± standard deviation or median (interquartile range) or frequency (percent) of study population.</p>**<p>Other represents 17 countries of birth in Africa with <4% of study population.</p>+<p>Other represents 2 countries of birth in Asia with <4% of study population.</p>++<p>Other represents 1 country of birth outside of Asia or Africa with <4% of study population.</p

Allelic compatibility in plant immune receptors facilitates engineering of new effector recognition specificities

Engineering the plant immune system offers genetic solutions to mitigate crop diseases caused by diverse agriculturally significant pathogens and pests. Modification of intracellular plant immune receptors of the nucleotide-binding leucine-rich repeat (NLR) receptor superfamily for expanded recognition of pathogen virulence proteins (effectors) is a promising approach for engineering disease resistance. However, engineering can cause NLR autoactivation, resulting in constitutive defense responses that are deleterious to the plant. This may be due to plant NLRs associating in highly complex signaling networks that coevolve together, and changes through breeding or genetic modification can generate incompatible combinations, resulting in autoimmune phenotypes. The sensor and helper NLRs of the rice (Oryza sativa) NLR pair Pik have coevolved, and mismatching between noncoevolved alleles triggers constitutive activation and cell death. This limits the extent to which protein modifications can be used to engineer pathogen recognition and enhance disease resistance mediated by these NLRs. Here, we dissected incompatibility determinants in the Pik pair in Nicotiana benthamiana and found that heavy metal-associated (HMA) domains integrated in Pik-1 not only evolved to bind pathogen effectors but also likely coevolved with other NLR domains to maintain immune homeostasis. This explains why changes in integrated domains can lead to autoactivation. We then used this knowledge to facilitate engineering of new effector recognition specificities, overcoming initial autoimmune penalties. We show that by mismatching alleles of the rice sensor and helper NLRs Pik-1 and Pik-2, we can enable the integration of synthetic domains with novel and enhanced recognition specificities. Taken together, our results reveal a strategy for engineering NLRs, which has the potential to allow an expanded set of integrations and therefore new disease resistance specificities in plants