Chemodivergence in Fluorine Source-Controlled Cascade Reaction of Aryne Precursors to Synthesize Pyrrolo[3,4-b]indoles and 3-Arylated Maleimides.

Reactions allowing chemodivergence prove to be attractive strategies in synthetic organic chemistry. We herein described a highly practical, transition-metal-free, highly regioselective and chemodivergent cascade reaction controlled by fluorine sources, which involved a [3 + 2] cycloaddition or C-arylation process between aryne precursors and 3-aminomaleimides. These two pathways led to a wide scope of structurally diverse pyrrolo[3,4-b]indoles (19 examples) and 3-arylated maleimides (25 examples) in good-to-excellent yields. Furthermore, the reaction could be scaled up, and several synthetic transformations were accomplished for the preparation of functionalized molecules and might provide new opportunities for the discovery of N-heterocyclic drugs.

NBS-Promoted Synthesis of Thiocyanated Aminomaleimides and Site-Selective Intramolecular Cyclization Access to 1,4-Benzothiazepines via S-CN Bond Cleavage.

A transition metal-free concise and efficient protocol for the synthesis of thiocyanated aminomaleimides and benzo[e][1,4]thiazepine derivatives has been developed. The method involves an initial α-C-H thiocyanation of aminomaleimides with KSCN and TEMPO-mediated tandem S-CN bond cleavage/intramolecular cyclization substitution processes, which enables the formation of seven-membered S/N-heterocycles. This synthetic strategy provides a reliable method for the synthesis of biologically interesting benzo[e][1,4]thiazepine derivatives by using KSCN as sulfur sources as well as expands the application of enaminones thiocyanation reactions in heterocycles synthesis.

Exploring the underlying mechanisms of enteritis impact on golden pompano (Trachinotus ovatus) through multi-omics analysis.

Enteritis posed a significant health challenge to golden pompano (Trachinotus ovatus) populations. In this research, a comprehensive multi-omics strategy was implemented to elucidate the pathogenesis of enteritis by comparing both healthy and affected golden pompano. Histologically, enteritis was characterized by villi adhesion and increased clustering after inflammation. Analysis of the intestinal microbiota revealed a significant increase (P < 0.05) in the abundance of specific bacterial strains, including Photobacterium and Salinivibrio, in diseased fish compared to the healthy group. Metabolomic analysis identified 5479 altered metabolites, with significant impacts on terpenoid and polyketide metabolism, as well as lipid metabolism (P < 0.05). Additionally, the concentrations of several compounds such as calcitetrol, vitamin D2, arachidonic acid, and linoleic acid were significantly reduced in the intestines of diseased fish post-enteritis (P < 0.05), with the detection of harmful substances such as Efonidipine. In transcriptomic profiling, enteritis induced 68 upregulated and 73 downregulated genes, predominantly affecting steroid hormone receptor activity (P < 0.05). KEGG pathway enrichment analysis highlighted upregulation of SQLE and CYP51 in steroidogenesis, while the HSV-1 associated MHC1 gene exhibited significant downregulation. Integration of multi-omics results suggested a potential pathogenic mechanism: enteritis may have resulted from concurrent infection of harmful bacteria, specifically Photobacterium and Salinivibrio, along with HSV-1. Efonidipine production within the intestinal tract may have blocked certain calcium ion channels, leading to downregulation of MHC1 gene expression and reduced extracellular immune recognition. Upregulation of SQLE and CYP51 genes stimulated steroid hormone synthesis within cells, which, upon binding to G protein-coupled receptors, influenced calcium ion transport, inhibited immune activation reactions, and further reduced intracellular synthesis of anti-inflammatory substances like arachidonic acid. Ultimately, this cascade led to inflammation progression, weakened intestinal peristalsis, and villi adhesion. This study utilized multi-level omics detection to investigate the pathological symptoms of enteritis and proposed a plausible pathogenic mechanism, providing innovative insights into enteritis verification and treatment in offshore cage culture of golden pompano.

Cu(II)-Catalyzed Cascade of N-Phenyl-o-phenylenediamine with Benzaldehyde: One-Step Direct Construction of 2-(1-Phenyl-1H-benzo[d]imidazol-2-yl)phenols.

A practical protocol for the construction of hydroxylated 2-(1-phenyl-1H-benzo[d]imidazol-2-yl)phenols (PBIs) from N-phenyl-o-phenylenediamine with benzaldehydes was developed. The cascade reaction was enabled by heating a mixture of the two substrates in the presence of air as an oxidant and anhydrous Cu(OAc)2 as a catalyst in dimethyl sulfoxide, and a diverse series of PBIs were synthesized in moderate to good yields (69-81%). Furthermore, the synthesis of the PBIs was enabled via a one-pot cascade reaction that proceeded through subsequent dehydration condensation, intramolecular cyclization, and aromatic C-H hydroxylation. This protocol can be used for the synthesis of hydroxylated PBI via a one-pot annulation C-H hydroxylation reaction rather than through a series of multistep reactions, which provides the possibility of further modification.

Microwave-assisted DABCO-promoted regioselective [3 + 3] tandem cyclization: synthesis of pyrrolo[3,4-b]pyridine-4-ones from trifluoromethyl-alkynyl esters and α-aminomaleimide.

A microwave-assisted DABCO-promoted strategy for the regioselective synthesis of pyrrolo[3,4-b]pyridine-4-one derivatives has been developed from the [3 + 3] annulation of α-aminomaleimide with substituted ethyl 2-butynoate. The characteristic features of this methodology include operational simplicity, high regioselectivity, metal-free reaction conditions, and short reaction times. The potential utility of these methods in biological chemistry and medicinal science applications is highlighted.

Predictors of discordant latent tuberculosis infection test results amongst South African health care workers.

BACKGROUND: The tuberculin skin test (TST) and interferon-gamma-release-assays (IGRAs) are utilized in screening programmes for presumed latent tuberculosis infection (LTBI) in health care workers (HCWs). However, inter-test comparison yields high rates of discordance, which is poorly understood. The aim of the study was therefore to identify factors associated with discordance amongst HCWs in a TB and HIV endemic setting. METHODS: 505 HCWs were screened for LTBI in South Africa using the TST and two IGRA assays (QuantiFERON-TB-Gold-In-Tube (QFT-GIT) and TSPOT.TB). Factors associated with discordance were analyzed using a multinomial logistic regression model. RESULTS: TST-IGRA discordance was negatively associated with longer duration of employment for both TSPOT.TB (OR = 0.92; 95% confidence interval (CI) 0.85-0.99) and QFT-GIT (OR = 0.90; 95% CI 0.84-0.96). Marked test discordance occurred in HIV-infected individuals who were more likely to have TSPOT.TB + ve / TST-ve discordance (OR 4.44; 95% CI 1.14-17.27) or TSPOT.TB + ve / QFT-GIT-ve test discordance (OR 5.72; 95% CI 1.95-16.78). Those engaged in home care were less likely to have QFT-GIT + ve/TSPOT.TB -ve / discordance (OR 0.32; 95% CI 0.10-0.95). CONCLUSION: The marked TST-IGRA and IGRA-IGRA discordance in HIV-infected individuals suggest greater sensitivity of TSPOT.TB in immunocompromised persons or potential greater reactivity of TSPOT.TB in this population.

Understanding the effects of conditional dependence in research studies involving imperfect diagnostic tests.

When two imperfect diagnostic tests are carried out on the same subject, their results may be correlated even after conditioning on the true disease status. While past work has focused on the consequences of ignoring conditional dependence, the degree to which conditional dependence can be induced has not been systematically studied. We examine this issue in detail by introducing a hypothetical missing covariate that affects the sensitivities of two imperfect dichotomous tests. We consider four forms for this covariate, normal, uniform, dichotomous and trichotomous. In the case of a dichotomous covariate, we derive an expression showing that the conditional covariance is a function of the product of the changes in test sensitivities (or specificities) between the subgroups defined by the covariate. The maximum possible covariance is induced by a dichotomous covariate with a very strong effect on both tests. Through simulations, we evaluate the extent to which fitting a latent class model ignoring each type of covariate but including a general covariance term can adjust for the correlation induced by the covariate. We compare the results to when the conditional dependence is ignored. We find that the bias because of ignoring conditional dependence is generally small even for moderate covariate effects, and when bias is present, a model including a covariance term works well. We illustrate our methods by analyzing data from a childhood tuberculosis study. Copyright © 2016 John Wiley & Sons, Ltd.

Modeling conditional dependence among multiple diagnostic tests.

When multiple imperfect dichotomous diagnostic tests are applied to an individual, it is possible that some or all of their results remain dependent even after conditioning on the true disease status. The estimates could be biased if this conditional dependence is ignored when using the test results to infer about the prevalence of a disease or the accuracies of the diagnostic tests. However, statistical methods correcting for this bias by modelling higher-order conditional dependence terms between multiple diagnostic tests are not well addressed in the literature. This paper extends a Bayesian fixed effects model for 2 diagnostic tests with pairwise correlation to cases with 3 or more diagnostic tests with higher order correlations. Simulation results show that the proposed fixed effects model works well both in the case when the tests are highly correlated and in the case when the tests are truly conditionally independent, provided adequate external information is available in the form of fixed constraints or prior distributions. A data set on the diagnosis of childhood pulmonary tuberculosis is used to illustrate the proposed model.

Citrullus colocynthis NAC transcription factors CcNAC1 and CcNAC2 are involved in light and auxin signaling.

KEY MESSAGE: Two novel NAC transcription factors from C itrullus colocynthis implicated in light and auxin signaling pathway. NAC transcription factors (NAM, ATAF1, 2, CUC2) have multiple functions in plant growth and development. Two NACs, CcNAC1 and CcNAC2, were recently identified in the highly drought-tolerant cucurbit species, Citrullus colocynthis. This study examines the functional role of these genes under different qualities of light based on the in silico analysis of the CcNAC1 and CcNAC2 promoters that revealed the presence of several light-associated motifs. The impact of both light and auxin on CcNAC1 and CcNAC2 expression was examined in C. colocynthis leaves, and using reporter (pCcNAC1, 2::GUS) lines in Arabidopsis. Furthermore, the effects of constitutive overexpression (OE-CcNAC1, 2) in Arabidopsis were also examined under a range of conditions to confirm reporter line linkages. White, blue, red, and far-red light treatments resulted in similar patterns of quantitative changes in CcNAC1and CcNAC2 expression in both species, with the highest transcript increases following red light. Photomorphogenic changes in Arabidopsis hypocotyls were correlated with gene transcript levels. In the absence of light, hypocotyls of OE-CcNAC1/CcNAC2 lines were significantly longer as compared to WT. The addition of exogenous auxin (+IAA) to growth medium also resulted in changes to the hypocotyl lengths of overexpression lines and spatiotemporal reporter line changes in seedlings. Our data suggest that CcNAC1, 2 might be functionally important in the light signaling pathway, and appear connected to the hormone auxin. This is the first study to indicate that NAC genes might play a role in both light and auxin signaling pathways.

Chitosan modified graphene oxide with MnO2 deposition for high energy density flexible supercapacitors.

To obtain a flexible composite electrode material with excellent electrochemical performance, chitosan (CS)/graphene oxide (GO) composite pretreated from microwave hydrothermal is adopted as the carbon substrate, and MnO2 active material is uniformly deposited on their surface through anodic electrodeposition. In this composite system, CS penetrates into graphene sheets as small molecule units, forming NH-C=O groups with GO via dehydration condensation, which effectively inhibits the stacking of GO and improves the specific surface area, conductivity, as well as the wettability of the carbon support. MnO2 bonding with heteroatom N from CS enables high active material loadings and forms stable three-dimensional network structure, facilitating the enhanced electrochemical performance. Results indicate that increasing depositing MnO2 amount leads to more defective structures of the composite, which promotes their electrochemical performance when used as electrode material. The area specific capacitance of the optimal composite reaches 3553.74 mF/cm2 at 5 mA/cm2 in 1 M Na2SO4 electrolyte. Kinetic analysis shows the energy storage process is capacitance-dominated, with the redox reactions of MnO2 being the main contributor. The prepared asymmetric solid supercapacitor delivers an energy density high up to 0.585 mWh/cm2 at power density of 3000 mW/cm2, and their excellent flexibility makes them promising candidates as flexible sensor.

Tongqiao Huoxue Decoction inhibits ferroptosis by facilitating ACSL4 ubiquitination degradation for neuroprotection against cerebral ischemia-reperfusion injury.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) refers to brain tissue injury caused by the temporary interruption of cerebral blood flow ischemia followed by the restoration of reperfusion, which is the main cause of post-stroke brain injury. A traditional Chinese herbal preparation called Tongqiao Huoxue Decoction (TQHX) has shown promise in reducing CIRI in rats. However, the mechanism of this herbal preparation for CIRI remains unclear. PURPOSE: This study aimed to evaluate the therapeutic effect of TQHX extract on rats with CIRI and to further explore the underlying mechanisms. METHODS: The active ingredients of TQHX extract were quantified by the high-performance liquid chromatography (HPLC) condition. We conducted thorough investigations to assess the effects of TQHX on CIRI and ferroptosis using oxygen-glucose deprivation/reperfusion (OGD/R)-treated PC12 cells as an in vitro model and transient middle cerebral artery occlusion (tMCAO) animals as an in vivo model. The neurological score assessment was performed to evaluate the neuroprotective effects of TQHX extract on tMCAO rats. Using histologic methods to study the extent of cerebral infarction, blood-brain barrier, and rat brain tissue. We examined the impact of TQHX on ferroptosis-related markers of Fe2+, superoxide dismutase (SOD), reactive oxygen species (ROS), and malondialdehyde (MDA) in the brain tissue. In addition, the expression of key proteins and markers of ferroptosis, as well as key factors associated with Acyl-CoA synthetase long-chain family member 4 (ACSL4) were detected by Western blot and quantitative real-time PCR (RT-qPCR). RESULTS: TQHX extract could decrease the Longa score and extent of cerebral infarction of tMCAO rats, which exerted the function of neuroprotection. Additionally, TQHX treatment efficiently decreased levels of MDA and ROS while increasing the expression of SOD and ferroptosis-related proteins including ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) at the transcription and translation level. Meanwhile, TQHX provided strong protection against oxidative stress and ferritin accumulation by increasing the ubiquitination and degradation of ACSL4. The injection of OE-ACSL4 reversed the effects of TQHX on neuroprotection and ferroptosis inhibition in PC12 cells. The injection of shACSL4 reversely validate the crucial role of ACSL4 in CIRI rat treatment. CONCLUSION: This work shows that TQHX promotes the ubiquitination-mediated degradation of ACSL4, which improves oxidative stress and inhibits the beginning of ferroptosis in cells. TQHX provides a possible path for additional research in CIRI therapies, advancing translational investigations.

Base-Promoted [5 + 1 + 3] Cascade Cyclization of o-Nitrochalcones, Elemental Sulfur, and Guanidine to Benzo[4,5]thieno[3,2-d]pyrimidine Frameworks.

An unexpected [5 + 1 + 3] cascade cyclization to the preparation of benzo[4,5]thieno[3,2-d]pyrimidine derivatives has been disclosed. In the new protocol, o-nitrochalcones reacted with elemental sulfur and guanidine promoted by NaOH, which reacted in EtOH for 20 min, providing structurally diverse benzo[4,5]thieno[3,2-d]pyrimidines with good yields (77-89%) and wide substrate compatibility (33 examples).

Effect of infection with Aeromonas hydrophila on antioxidant capacity, inflammation response, and apoptosis proteins in Chinese mitten crab (Eriocheir sinensis).

Aeromonas hydrophila (A. hydrophila) as a serious bacterial disease endangering aquaculture and the Chinese mitten crabs (Eriocheir sinensis) industry. The present study was conducted to investigate the effects of A. hydrophila on the antioxidant, inflammation, immunity and apoptosis of the E. sinensis. The E. sinensis (female: 150 crabs and male: 150 crabs; 67.11 ± 0.76 g) were randomly divided into the control group (Foot injection with 200 µl PBS) and infection group (Foot injection with 200 µl A. hydrophila of 106 cfu/mL). The hepatopancreas and serum was collected to detect the related indicators after injection 24 h. The results showed that A. hydrophila significantly reduced the malondialdehyde (MDA) level and gamma-glutamyl-cysteine synthetase (γ-GCS) activity in the hepatopancreas of male and female crabs (P < 0.05). A.hydrophila also significantly decreased the total-superoxide dismutase (T-SOD) activity while the levels of total antioxidant capacity (T-AOC) and total glutathione (T-GSH) were significantly increased in the hepatopancreas and serum of male crabs (P < 0.05). At the transcriptional level, the expression of catalase (CAT) and glutathione peroxidases (GPx), Glutathione S-transferase (GST) in the hepatopancreas of male and female crabs was significantly reduced compared to the control group (P < 0.05). However, A. hydrophila could not significantly change the Kelch-like ECH-associated protein 1 (Keap1) gene expression level in both of male and female carbs. A. hydrophila injection for 24 h, the lysozyme (LZM) and phenoloxidase (PO) activity was significantly increased in the hepatopancreas and serum of the male and female crabs (P < 0.05). Simultaneous increase of immune-related enzyme activity (acid phosphatase and alkaline phosphatase) was found in the serum of male and female crabs (P < 0.05). However, the acid phosphatase (ACP) and alkaline phosphatase (ALP) activity was significantly decreased in the hepatopancreas of male and female crabs (P < 0.05). Meanwhile, the LZM mRNA level was significantly decreased in the hepatopancreas of E. sinensis (P < 0.05). Furthermore, A. hydrophila significantly inhibited the mRNA expression of immune regulated factors (Interleukin enhancer binding factor 2: ILF2, interleukin-16: IL-16, Toll-like receptor: TLR) in the male and female crabs. The levels of inflammatory cytokines (interleukin-1ß: IL-1ß, interleukin-6: IL-6, interleukin-8: IL-8, interleukin-10: IL-10) were significantly increased in the hepatopancreas of male and female crabs. Moreover, A.hydrophila increased the mRNA expression of apoptosis - related genes in male crabs (p38 mitogen-activated protein kinase: p38, adamalysin 17: ADAM17, Cysteine-aspartic acid protease 3: Caspase 3, and Bcl-2-associated X: BAX), but reduced the expression of p38, ADAM17, Caspase 3 and BAX genes in female crabs. In conclusion, A. hydrophila could induce oxidative stress and the response of inflammation and immunity, and also trigger the mRNA expression changes of apoptosis related-genes in E. sinensis. This study provides a theoretical basis for the study of E. sinensis diseases.

Emodin resists to Cyprinid herpesvirus 3 replication via the pathways of Nrf2/Keap1-ARE and NF-κB in the ornamental koi carp (Cyprinus carpio haematopterus).

Cyprinid herpesvirus 3 (CyHV-3) causes high mortality in carp. Emodin has been shown of the effects of antioxidant, anti-inflammatory and antiviral. In present study, we investigated the preventive effects and mechanism of emodin on CyHV-3 infection. The ornamental koi carp (Cyprinus carpio haematopterus) were intraperitoneally injected with emodin (10 mg/kg, 20 mg/kg, or 40 mg/kg). 72 h later, an intraperitoneal injection of CyHV-3 was administered, and collected the samples one week later to detect the antioxidant parameters, antioxidant genes, inflammatory genes and to perform histopathology assays. The results showed that emodin significantly suppressed CyHV-3 replication (P < 0.05), improved the koi survival rate and slowed the damage caused by CyHV-3. Emodin treatment increased the antioxidant activity and decreased the lipid peroxidation level of the koi. Compared to the CyHV-3 group, emodin treatment resulted in the same antioxidant parameters after CyHV-3 infection. Emodin treatment activated the Nuclear factorery throid 2-related factor 2/Kelch-like ECH-associated protein 1-antioxidatant response element (Nrf2/Keap1-ARE) pathway and upregulated the expression of heme oxygenase 1 (HO-1), superoxide dismutase (SOD), and catalase (CAT) in the hepatopancreas after CyHV-3 infection. Emodin activated the nuclear factor kappa-B (NF-κB) pathway and decreased the expression of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumour necrosis factor-α (TNF-α) in the koi induced by CyHV-3. In conclusion, emodin treatment can suppress CyHV-3 replication and reduce the mortality of koi caused by CyHV-3. Emodin improves antioxidant function, relieves oxidative stress and inflammation cytokines via Nrf2/Keap1-ARE and NF-κB pathways, and protects against the adverse effects induced by CyHV-3.

Evaluation of Neutrophil Gelatinase-Associated Lipocalin and Cystatin C in Early Diagnosis of Chronic Kidney Disease in the Absence of the Gold Standard.

BACKGROUND: Glomerular filtration rate (GFR) is considered as a gold standard of kidney function. However, using GFR as the gold standard is not common in clinical practice, because its direct measurement is usually expensive, cumbersome, and invasive. In the present study, we assessed the predictive power of two other biomarkers, Cystatin-C (Cys-C) and Neutrophil Gelatinase-Associated Lipocalin (NGAL) for early detection of chronic kidney diseases (CKD) in the absence of a gold standard. MATERIALS AND METHODS: In this study, 72 patients who referred to the Shohadaye Tajrish Hospital of Tehran, Iran, for measuring their kidney function were studied. The ELISA method was utilized for measuring plasma NGAL (PNGAL) and serum Cys-C (SCys-C). The Bayesian latent class modeling approach was applied to asses the predictive power of these biomarkers. RESULTS: While both the biomarkers had rather high sensitivities (PNGAL=91%, SCys-C= 89%), the specificity of SCys-C biomarker was very lower than the one of PNGAL (SCys-C=56%, PNGAL=94%). The estimated area under the receiver operating characteristic (ROC) curve for SCys-C as the single biomarker for the diagnosis of CKD was about 0.76, while a similar estimate for PNGAL was 0.93. The added value of PNGAL to SCys-C for the diagnosis of CKD in terms of the ROC curve was about 0.19, while the added value of SCys-C to PNGAL was less than 0.02. CONCLUSION: In general, our findings suggest that PNGAL can be utilized as a single reliable biomarker for early detection of CKD. In addition, results showed that when a perfect gold standard is not available, Bayesian approaches to latent class models could lead to more precise sensitivity and specificity estimates of imperfect tests.

Comparison of the expected rewards between probabilistic and deterministic analyses in a Markov model.

Objectives: In Markov models that evaluate the cost-effectiveness of health-care technologies, it is generally recommended to use probabilistic analysis instead of deterministic analysis. We sought to compare the performance of probabilistic and deterministic analysis in estimating the expected rewards in a Markov model.Methods: We applied Jensen's inequality to compare the expected Markov rewards between probabilistic and deterministic analysis and conducted a simulation study to compare the bias and accuracy between the two approaches.Results: We provided mathematical justification why probabilistic analysis is associated with greater Markov rewards (life-years and quality-adjusted life-years) compared with deterministic analysis. In our simulations, probabilistic analyses tended to generate greater life-years, bias, and mean square error for the estimated rewards compared with deterministic analyses. When the expected values of transition probabilities were the same, weaker evidence derived from smaller sample sizes resulted in larger Markov rewards compared with stronger evidence derived from larger sample sizes. When longer time horizons were applied in cases of weak evidence, there was a substantial increase in bias where the rewards in both probabilistic and deterministic analysis were overestimated.Conclusion: Authors should be aware that probabilistic analysis may lead to increased bias when the evidence is weak.

Development and internal validation of a multimorbidity index that predicts healthcare utilisation using the Canadian Longitudinal Study on Aging.

OBJECTIVES: We aimed to develop and internally validate a measure of multimorbidity burden using data from the Canadian Longitudinal Study on Aging (CLSA). DESIGN: Data from 40 264 CLSA participants (52% men) aged 45-85 years (a mean of 63 years) were analysed. We used logistic regression models to predict overnight hospitalisation in the last 12 months in the development dataset (random two-thirds of the total) and used these to construct 10 multimorbidity indices (5 models, each treated with and without an age interaction term). Thirty-five chronic conditions were considered for inclusion in these models, in addition to age and sex. We assessed predictive and convergent validity for these 10 different multimorbidity indices in the validation dataset (remaining one-third of the total). RESULTS: The absolute count of chronic conditions plus an interaction with age, displayed strong calibration properties, outperforming other candidate indices. Discrimination was modest for all of the indices that we internally validated, with C-statistics ranging from 0.66 to 0.68. The indices showed weak correlations (ie, convergent validity) with satisfaction with life, functional disability and mental health (absolute Pearson's correlation coefficients ranging from 0.11 to 0.30) but generally moderate correlations with self-rated general health (0.32-0.45). CONCLUSIONS: We investigated alternative methods to measure the multimorbidity burden of individuals, tailored to the CLSA. Our findings show that an absolute count of conditions, along with an age interaction term, has the strongest calibration for overnight hospitalisation in the last 12 months. The utility of an age interaction term in measuring multimorbidity burden may be applicable to the study of chronic disease in cohorts other than the CLSA.

Evaluating Latent Tuberculosis Infection Test Performance Using Latent Class Analysis in a TB and HIV Endemic Setting.

BACKGROUND: Given the lack of a gold standard for latent tuberculosis infection (LTBI) and paucity of performance data from endemic settings, we compared test performance of the tuberculin skin test (TST) and two interferon-gamma-release assays (IGRAs) among health-care workers (HCWs) using latent class analysis. The study was conducted in Cape Town, South Africa, a tuberculosis and human immunodeficiency virus (HIV) endemic setting Methods: 505 HCWs were screened for LTBI using TST, QuantiFERON-gold-in-tube (QFT-GIT) and T-SPOT.TB. A latent class model utilizing prior information on test characteristics was used to estimate test performance. RESULTS: LTBI prevalence (95% credible interval) was 81% (71-88%). TST (10 mm cut-point) had highest sensitivity (93% (90-96%)) but lowest specificity (57%, (43-71%)). QFT-GIT sensitivity was 80% (74-91%) and specificity 96% (94-98%), and for TSPOT.TB, 74% (67-84%) and 96% (89-99%) respectively. Positive predictive values were high for IGRAs (90%) and TST (99%). All tests displayed low negative predictive values (range 47-66%). A composite rule using both TST and QFT-GIT greatly improved negative predictive value to 90% (range 80-97%). CONCLUSION: In an endemic setting a positive TST or IGRA was highly predictive of LTBI, while a combination of TST and IGRA had high rule-out value. These data inform the utility of LTBI-related immunodiagnostic tests in TB and HIV endemic settings.

AtHKT1 gene regulating K+ state in whole plant improves salt tolerance in transgenic tobacco plants.

The status of K+ is important for plant health. However, little is known about if high-affinity potassium transporter HKTs may help K+ retention under salt stress. Here, we determined the effect of Arabidopsis thaliana transporter gene (AtHKT1) on the K+ status, Na+-induced toxicity, and salt tolerance in tobacco (Nicotiana tabacum L.). Six AtHKT1 transformed tobacco lines (T1, T2, … T6) were contrasted with a non-transgenic plantlet at the whole-plant and molecule levels. AtHKT1 gene was expressed in the xylems of stem, root and leaf vein in the transgenic tobacco, with the line T3 having highest expression. At Day 15, in the 200 mmol L-1 NaCl stress treatment, the transgenic plants remained a healthy K+ status, while the control plants decreased K+ content by 70% and Na+ contents in leaves and stems were 1.7 times that in the transgenic line. The AtHKT1 expression enhanced the activities of SOD, CAT and POD, raised chlorophyll and soluble sugar contents and root activity, and decreased MDA and proline contents and electrolyte leakage destruction. The constitutive over-expression of AtHKT1 that helps maintain a healthy K+ status while reducing Na+ toxicity may serve as a possible mechanism in maximizing productivity of tobacco under salt stress.

Investigating rectal toxicity associated dosimetric features with deformable accumulated rectal surface dose maps for cervical cancer radiotherapy.

BACKGROUND: Better knowledge of the dose-toxicity relationship is essential for safe dose escalation to improve local control in cervical cancer radiotherapy. The conventional dose-toxicity model is based on the dose volume histogram, which is the parameter lacking spatial dose information. To overcome this limit, we explore a comprehensive rectal dose-toxicity model based on both dose volume histogram and dose map features for accurate radiation toxicity prediction. METHODS: Forty-two cervical cancer patients treated with combined external beam radiotherapy (EBRT) and brachytherapy (BT) were retrospectively studied, including 12 with Grade ≥ 2 rectum toxicity and 30 patients with Grade 0-1 toxicity (non-toxicity patients). The cumulative equivalent 2-Gy rectal surface dose was deformably summed using the deformation vector fields obtained through a recent developed local topology preserved non-rigid point matching algorithm. The cumulative three-dimensional (3D) dose was flattened and mapped to a two-dimensional (2D) plane to obtain the rectum surface dose map (RSDM). The dose volume parameters (DVPs) were calculated from the 3D rectum surface, while the texture features and the dose geometric parameters (DGPs) were extracted from the 2D RSDM. Representative features further computed from DVPs, textures and DGPs by principle component analysis (PCA) and statistical analysis were respectively fed into a support vector machine equipped with a sequential feature selection procedure. The predictive powers of the representative features were compared with the GEC-ESTRO dosimetric parameters D0.1/1/2cm3. RESULTS: Satisfactory predictive accuracy of sensitivity 74.75 and 84.75%, specificity 72.67 and 79.87%, and area under the receiver operating characteristic curve (AUC) 0.82 and 0.91 were respectively achieved by the PCA features and statistical significant features, which were superior to the D0.1/1/2cm3 (AUC 0.71). The relative area in dose levels of 64Gy, 67Gy, 68Gy, 87Gy, 88Gy and 89Gy, perimeters in dose levels of 89Gy, as well as two texture features were ranked as the important factors that were closely correlated with rectal toxicity. CONCLUSIONS: Our extensive experimental results have demonstrated the feasibility of the proposed scheme. A future large patient cohort study is still needed for model validation.