Development of fibrosis and subsequent stricture formation in Crohn's disease (CD) increases morbidity and rates of surgery and reduces patients' quality of life. There are currently no biomarkers of ...intestinal fibrosis that might allow earlier identification and better management of patients at increased risk of stricture formation.
MicroRNA profiling of serum from CD patients was used to identify microRNAs associated with stricture formation. Differential expression of miR-19a-3p and miR-19b-3p was validated by quantitative PCR in independent CD cohort of stricturing and nonstricturing patients (n = 46 and n = 62, respectively). Levels of miR-19a-3p and miR-19b-3p were also quantified in baseline serum samples, and expression compared between CD patients who subsequently developed stricture and those who did not (n = 11 and n = 44, respectively).
Serum levels of miR-19a-3p and miR-19b-3p in the array were lower in CD patients with a stricturing phenotype than in control CD patients (P = 0.007 and 0.008, respectively). The reduction in miR-19a-3p and 19b-3p was verified in a second cohort (P = 0.002). The association of miR-19-3p with stricturing CD was independent of potential confounding clinical variables, including disease duration, disease activity, site, gender, and age. Serum analyses in patients with 4 years of follow-up support the hypothesis that reduced miR-19a-3p and miR-19b-3p predate stricture development with a trend toward significance (P = 0.077 and P = 0.060, respectively).
These data identify miR-19-3p as a potential circulating marker of stricturing CD. Our data show that microRNAs have utility as noninvasive biomarkers of stricturing CD. Further longitudinal studies are required to determine the prognostic value of miR-19-3p at diagnosis.
Nickel catalysts have shown unique ligand control of stereoselectivity in the Suzuki-Miyaura cross-coupling of boronates with benzylic pivalates and derivatives involving C(sp
)-O cleavage. The SIMes ...ligand (1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) produces the stereochemically inverted C-C coupling product, while the tricyclohexylphosphine (PCy
) ligand delivers the retained stereochemistry. We have explored the mechanism and origins of the ligand-controlled stereoselectivity with density functional theory (DFT) calculations. The oxidative addition determines the stereoselectivity with two competing transition states, an S
2 back-side attack type transition state that inverts the benzylic stereogenic center and a concerted oxidative addition through a cyclic transition state, which provides stereoretention. The key difference between the two transition states is the substrate-nickel-ligand angle distortion; the ligand controls the selectivity by differentiating the ease of this angle distortion. For the PCy
ligand, the nickel-ligand interaction involves mainly σ-donation, which does not require a significant energy penalty for the angle distortion. The facile angle distortion with PCy
ligand allows the favorable cyclic oxidative addition transition state, leading to the stereoretention. For the SIMes ligand, the extra d-p back-donation from nickel to the coordinating carbene increases the rigidity of the nickel-ligand bond, and the corresponding angle distortion is more difficult. This makes the concerted cyclic oxidative addition unfavorable with SIMes ligand, and the back-side S
2-type oxidative addition delivers the stereoinversion.
The ART program in low- and middle-income countries (LMIC) like India, follows a public health approach with a standardized regimen for all people living with HIV (PLHIV). Based on the evidence from ...high-income countries (HIC), the risk of an enhanced, and accentuated onset of premature-aging or age-related diseases has been observed in PLHIV. However, very limited data is available on residual inflammation and immune activation in the populations who are on first-generation anti-HIV drugs like zidovudine and lamivudine that have more toxic side effects. Therefore, the aim of the present study was to evaluate the levels of systemic inflammation and understand the risk of age-associated diseases in PLHIV on long-term suppressive ART using a large number of biomarkers of inflammation and immune activation. Blood samples were obtained from therapy naïve PLHIV (Pre-ART,
= 43), PLHIV on ART for >5 years (ART,
= 53), and HIV-negative healthy controls (HIVNC,
= 41). Samples were analyzed for 92 markers of inflammation, sCD14, sCD163, and telomere length. Several statistical tests were performed to compare the groups under study. Multivariate linear regression was used to investigate the associations. Despite a median duration of 8 years of successful ART, sCD14 (
< 0.001) and sCD163 (
= 0.04) levels continued to be significantly elevated in ART group as compared to HIVNC. Eleven inflammatory markers, including 4E-BP1, ADA, CCL23, CD5, CD8A, CST5, MMP1, NT3, SLAMF1, TRAIL, and TRANCE, were found to be significantly different (
< 0.05) between the groups. Many of these markers are associated with age-related co-morbidities including cardiovascular disease, neurocognitive decline and some of these markers are being reported for the first time in the context of HIV-induced inflammation. Linear regression analysis showed a significant negative association between HIV-1-positivity and telomere length (
< 0.0001). In ART-group CXCL1 (
= 0.048) and TGF-α (
= 0.026) showed a significant association with the increased telomere length and IL-10RA was significantly associated with decreased telomere length (
= 0.042). This observation warrants further mechanistic studies to generate evidence to highlight the need for enhanced treatment monitoring and special interventions in HIV-infected individuals.
The World Health Organization (WHO) recently changed its guidance for tuberculosis (TB) preventive treatment (TPT) recommending TPT for all pulmonary TB (PTB) exposed household contacts (HHC) to ...prevent incident TB disease (iTBD), regardless of TB infection (TBI) status. However, this recommendation was conditional as the strength of evidence was not strong. We assessed risk factors for iTBD in recently-exposed adult and pediatric Indian HHC, to determine which HHC subgroups might benefit most from TPT. We prospectively enrolled consenting HHC of adult PTB patients in Pune and Chennai, India. They underwent clinical, microbiologic and radiologic screening for TB disease (TBD) and TBI, at enrollment, 4-6, 12 and 24 months. TBI testing was performed by tuberculin skin test (TST) and Quantiferon®- Gold-in-Tube (QGIT) assay. HHC without baseline TBD were followed for development of iTBI and iTBD. Using mixed-effect Poisson regression, we assessed baseline characteristics including TBI status, and incident TBI (iTBI) using several TST and/or QGIT cut-offs, as potential risk factors for iTBD. Of 1051 HHC enrolled, 42 (4%) with baseline TBD and 12 (1%) with no baseline TBI test available, were excluded. Of the remaining 997 HHC, 707 (71%) had baseline TBI (TST #x2265; 5 mm or QGIT #x2265; 0.35 IU/ml). Overall, 20 HHC (2%) developed iTBD (12 cases/1000 person-years, 95%CI: 8-19). HIV infection (aIRR = 29.08, 95% CI: 2.38-355.77, p = 0.01) and undernutrition (aIRR = 6.16, 95% CI: 1.89-20.03, p = 0.003) were independently associated with iTBD. iTBD was not associated with age, diabetes mellitus, smoking, alcohol, and baseline TBI, or iTBI, regardless of TST (#x2265; 5 mm, #x2265; 10 mm, #x2265; 6 mm increase) or QGIT (#x2265; 0.35 IU/ml, #x2265; 0.7 IU/ml) cut-offs. Given the high overall risk of iTBD among recently exposed HHCs, and the lack of association between TBI status and iTBD, our findings support the new WHO recommendation to offer TPT to all HHC of PTB patients residing in a high TB burden country such as India, and do not suggest any benefit of TBI testing at baseline or during follow-up to risk stratify recently-exposed HHC for TPT.
Biomarkers of unfavourable tuberculosis (TB) treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavourable TB treatment ...outcomes is unclear.
We identified and internally validated the association between 20
selected plasma inflammatory markers and unfavourable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary TB in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV co-infected TB patients in India and South Africa, respectively.
Pre-treatment interferon-γ, interleukin (IL)-13 and IL-6 were associated with treatment failure in the discovery analysis. Internal validation confirmed higher pre-treatment IL-6 concentrations among failure cases compared with controls. External validation among predominantly diabetic TB patients found an association between pre-treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV co-infected TB patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 TB cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted OR (aOR) 2.16, 95% CI 1.08-4.33; p=0.02), recurrence (aOR 5.36, 95% CI 2.48-11.57; p<0.001) and death (aOR 4.62, 95% CI 1.95-10.95; p<0.001). Adding baseline IL-6 to a risk prediction model comprised of low body mass index, high smear grade and cavitation improved model performance by 15% (C-statistic 0.66
0.76; p=0.02).
Pre-treatment IL-6 is a biomarker for unfavourable TB treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction.
Studies relating to long-term virological outcomes among children on first-line antiretroviral therapy (ART) from low and middle-income countries are limited.
Perinatally HIV infected, ART-naive ...children, between 2 and 12 years of age, initiating NNRTI-based ART during 2010-2015, with at least 12 months of follow-up, were included in the analysis. CD4 cell counts and plasma HIV-1 RNA were measured every 24 weeks post-ART initiation. Immunologic failure was defined as a decrease in the CD4 count to pre-therapy levels or below and virologic failure as HIV-RNA of > 1000 copies/ml at 48 weeks after ART initiation. Genotypic resistance testing was performed for children with virologic failure. Logistic regression analysis was done to identify predictors of virologic failure.
Three hundred and ninety-three ART-naïve children living with HIV mean (SD) age: 7.6 (3) years; mean (SD) CD4%: 16% (8); median (IQR) HIV-RNA: 5.1 (3.5-5.7) log
copies/ml were enrolled into the study. At 48 weeks, significant improvement occurred in weight-for-age and height-for-age z-scores from baseline (all p < 0.001). The immunologic response was good; almost 90% of children showing an increase in their absolute CD4
T cell count to more than 350 cells/mm
. Immunological failure was noted among 11% (28/261) and virologic failure in 29% (94/328) of children. Of the 94 children with virologic failure at 12 months, 36 children showed immunologic failure while the rest had good immunologic improvement. There was no demonstrable correlation between virologic and immunologic failure. 62% had reported > 90% adherence to ART. At the time of virologic failure, multiple NNRTI-associated mutations were observed: 80%-K103N and Y181C being the major NNRTI mutations-observed. Sensitivity (95% CI) of immunologic failure to detect virologic failure was 7% (2-12), specificity 97% (92.4-98.9), PPV 44% (13.7-78.8) and NPV was 72% (65-77.9). There were no statistically significant predictors to detect children who will develop virologic failure on treatment.
Considerable immunological improvement is seen in children with ART initiation, but may not be an effective tool to monitor treatment response in the long-term. There is a lack of correlation between immunologic and virologic response while on ART, which may lead to a delay in identifying treatment failures. Periodic viral load monitoring is, therefore, a priority.
Forests are being converted to agriculture throughout the Afrotropics, driving declines in sensitive rainforest taxa such as understorey birds. The ongoing expansion of cocoa agriculture, a common ...small‐scale farming commodity, has contributed to the loss of 80% rainforest cover in some African countries. African cocoa farms may provide habitat for biodiversity, yet little is known about their suitability for vertebrate fauna, or the effect of farm management on animal communities.
Here, we report the first in‐depth investigation into avian diversity and community composition in African cocoa, by assembling a dataset of 9,566 individual birds caught across 83 sites over 30 years in Southern Cameroon. We compared bird diversity in mature forest and cocoa using measures of alpha, beta and gamma diversity, and we investigated the effect of cocoa farm shade and forest cover on bird communities.
Gamma diversity was higher in cocoa than forest, though alpha diversity was similar, indicating a higher dissimilarity (beta diversity) between cocoa farms. Cocoa farms differed from forest in community composition, with a distinctive decrease in relative abundance of insectivores, forest specialists and ant‐followers and an increase in frugivores.
Within cocoa farms, we found that farms with high shade cover in forested landscapes resulted in higher relative abundance and richness of sensitive forest species; shady farms contained up to five times the proportion of forest specialists than sunny farms.
Synthesis and applications. Sunny African cocoa farms were less able to support sensitive bird guilds compared with shaded farms in forested landscapes. Our findings support the notion that certain ecological and dietary guilds, such as ant‐followers and forest specialists are disproportionately affected by land‐use change. In light of the current push to increase cocoa production in sub‐Saharan Africa, our results provide policymakers opportunities for more wildlife‐friendly cocoa schemes that maximize avian diversity.
Sunny African cocoa farms were less able to support sensitive bird guilds compared with shaded farms in forested landscapes. Our findings support the notion that certain ecological and dietary guilds, such as ant‐followers and forest specialists are disproportionately affected by land‐use change. In light of the current push to increase cocoa production in sub‐Saharan Africa, our results provide policymakers opportunities for more wildlife‐friendly cocoa schemes that maximize avian diversity.
The Simons Foundation Autism Research Initiative (SFARI) has launched SPARKForAutism.org, a dynamic platform that is engaging thousands of individuals with autism spectrum disorder (ASD) and ...connecting them to researchers. By making all data accessible, SPARK seeks to increase our understanding of ASD and accelerate new supports and treatments for ASD.
The Simons Foundation Autism Research Initiative (SFARI) has launched SPARKForAutism.org, a dynamic platform that is engaging thousands of individuals with autism spectrum disorder (ASD) and connecting them to researchers. By making all data accessible, SPARK seeks to increase our understanding of ASD and accelerate new supports and treatments for ASD.
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