Drug exposure and treatment outcomes in patients with multidrug resistant tuberculosis and diabetes mellitus: A multicenter prospective cohort study from China.

BACKGROUND: The management of multidrug-resistant tuberculosis (MDR-TB) remains challenging. Treatment outcome is influenced by multiple factors, the specific roles of diabetes and glycemic control remain uncertain. This study aims to assess the impact of glycemic control on drug exposure, to investigate the association between drug exposure and treatment outcomes, and to identify clinically-significant thresholds predictive of treatment outcome, among patients with diabetes. METHODS: This multicenter prospective cohort study involved patients with confirmed MDR-TB and diabetes. Drug exposure level was estimated by noncompartmental analysis. The minimum inhibitory concentrations were determined for the individual Mycobacterium tuberculosis isolates. The influence of poor glycemic control (hemoglobin A1c ≥ 7%) on drug exposure and the associations between drug exposure and treatment outcome were evaluated by univariate and multivariate analysis. Classification and regression tree analysis was used to identify the drug exposure/susceptibility thresholds. RESULTS: Among the 131 diabetic participants, 43 (32.8%) exhibited poor glycemic control. Poor glycemic control was independently associated with decreased exposure to moxifloxacin, linezolid, bedaquiline, and cycloserine, but not clofazimine. Additionally, a higher ratio of drug exposure to susceptibility was found to be associated with a favorable MDR-TB treatment outcome. Thresholds predictive of 6-month culture conversion and favorable outcome were bedaquiline AUC/MIC ≥ 245 and moxifloxacin AUC/MIC ≥ 67, demonstrating predictive accuracy in patients, regardless of their glycemic control status. CONCLUSIONS: Glycemic control and optimal TB drug exposure are associated with improved treatment outcomes. This dual management strategy should be further validated in randomized controlled trials of patients with MDR-TB and diabetes.

Dentate gyrus granule cells are a locus of pathology in Scn8a developmental encephalopathy.

Gain-of-function mutations in SCN8A cause developmental and epileptic encephalopathy (DEE), a disorder characterized by early-onset refractory seizures, deficits in motor and intellectual functions, and increased risk of sudden unexpected death in epilepsy. Altered activity of neurons in the corticohippocampal circuit has been reported in mouse models of DEE. We examined the effect of chronic seizures on gene expression in the hippocampus by single-nucleus RNA sequencing in mice expressing the patient mutation SCN8A-p.Asn1768Asp (N1768D). One hundred and eighty four differentially expressed genes were identified in dentate gyrus granule cells, many more than in other cell types. Electrophysiological recording from dentate gyrus granule cells demonstrated an elevated firing rate. Targeted reduction of Scn8a expression in the dentate gyrus by viral delivery of an shRNA resulted in doubling of median survival time from 4 months to 8 months, whereas delivery of shRNA to the CA1 and CA3 regions did not result in lengthened survival. These data indicate that granule cells of the dentate gyrus are a specific locus of pathology in SCN8A-DEE.

Natural allelic variation in a modulator of auxin homeostasis improves grain yield and nitrogen use efficiency in rice.

The external application of nitrogen (N) fertilizers is an important practice for increasing crop production. However, the excessive use of fertilizers significantly increases production costs and causes environmental problems, making the improvement of crop N-use efficiency (NUE) crucial for sustainable agriculture in the future. Here we show that the rice (Oryza sativa) NUE quantitative trait locus DULL NITROGEN RESPONSE1 (qDNR1), which is involved in auxin homeostasis, reflects the differences in nitrate (NO3-) uptake, N assimilation, and yield enhancement between indica and japonica rice varieties. Rice plants carrying the DNR1indica allele exhibit reduced N-responsive transcription and protein abundance of DNR1. This, in turn, promotes auxin biosynthesis, thereby inducing AUXIN RESPONSE FACTOR-mediated activation of NO3- transporter and N-metabolism genes, resulting in improved NUE and grain yield. We also show that a loss-of-function mutation at the DNR1 locus is associated with increased N uptake and assimilation, resulting in improved rice yield under moderate levels of N fertilizer input. Therefore, modulating the DNR1-mediated auxin response represents a promising strategy for achieving environmentally sustainable improvements in rice yield.

Spatial-temporal distribution characteristics of pulmonary tuberculosis in eastern China from 2011 to 2021.

China is still among the 30 high-burden tuberculosis (TB) countries in the world. Few studies have described the spatial epidemiological characteristics of pulmonary TB (PTB) in Jiangsu Province. The registered incidence data of PTB patients in 95 counties of Jiangsu Province from 2011 to 2021 were collected from the Tuberculosis Management Information System. Three-dimensional spatial trends, spatial autocorrelation, and spatial-temporal scan analysis were conducted to explore the spatial clustering pattern of PTB. From 2011 to 2021, a total of 347,495 newly diagnosed PTB cases were registered. The registered incidence rate of PTB decreased from 49.78/100,000 in 2011 to 26.49/100,000 in 2021, exhibiting a steady downward trend (χ2 = 414.22, P < 0.001). The average annual registered incidence rate of PTB was higher in the central and northern regions. Moran's I indices of the registered incidence of PTB were all >0 (P< 0.05) except in 2016, indicating a positive spatial correlation overall. Local autocorrelation analysis showed that 'high-high' clusters were mainly distributed in northern Jiangsu, and 'low-low' clusters were mainly concentrated in southern Jiangsu. The results of this study assist in identifying settings and locations of high TB risk and inform policy-making for PTB control and prevention.

Latent tuberculosis infection and infection-associated risk factors for miner workers with silicosis in eastern China.

OBJECTIVES: Silicosis people are at high risk of developing pulmonary tuberculosis. Whether silica exposure increases the likelihood of latent tuberculosis infection (LTBI) was not well understood, and potential factors involved in LTBI risk among silicosis people were not evaluated before. Thus, LTBI among silicosis people and potential risk factors for LTBI among silicosis people were evaluated in this study. METHODS: A cross-sectional study was undertaken for 130 miner workers with silicosis. The QFT-GIT was performed for LTBI detection. RESULTS: The LTBI was high to 31.6% (36/114) for silicosis participants, and 13.1% (13/99) had a history of tuberculosis. Drinking was associated with LTBI risk (OR = 6.92, 95%CI, 1.47-32.66, P = 0.015). Meanwhile, tunneling work was associated with an increased risk of LTBI compared with other mining occupations (OR = 3.91,95%CI,1.20-12.70, P = 0.024). CONCLUSIONS: The LTBI rate of silicosis participants was high and more than 10% had a history of tuberculosis. Drinking alcohol and tunneling were independent risk factors for LTBI in silicosis participants.

Migrating pyramidal neurons require DSCAM to bypass the border of the developing cortical plate.

During mammalian neocortex development, nascent pyramidal neurons migrate along radial glial cells and overtake earlier-born neurons to terminate at the front of the developing cortical plate (CP), leading to the outward expansion of the CP border. While much has been learned about the cellular and molecular mechanisms that underlie the migration of pyramidal neurons, how migrating neurons bypass the preceding neurons at the end of migration to reach their final positions remains poorly understood. Here, we report that Down syndrome cell adhesion molecule (DSCAM) is required for migrating neurons to bypass their post-migratory predecessors during the expansion of the upper cortical layers. DSCAM is a type I transmembrane cell adhesion molecule. It has been linked to Down syndrome through its location in the Down syndrome critical region of Chromosome 21 trisomy and to autism spectrum disorders through loss-of-function mutations. Ex vivo time-lapse imaging demonstrates that DSCAM is required for migrating neurons to bypass their post-migratory predecessors, crossing the CP border to expand the upper cortical layers. In DSCAM-deficient cortices, migrating neurons stop prematurely under the CP border, leading to thinner and denser upper cortical layers. We further show that DSCAM weakens cell adhesion mediated by N-cadherin in the upper cortical plate, allowing migrating neurons to traverse the CP border and expand the CP. These findings suggest that DSCAM is required for proper migratory termination and final positioning of nascent pyramidal neurons, which may provide insight into brain disorders that exhibit thinner upper layers of the cerebral cortex without neuronal loss.SIGNIFICANCE STATEMENTNewly born neurons in the developing mammalian neocortex migrate outward towards the cortical surface, bypassing earlier born neurons to expand the developing cortex. How migrating neurons bypass the preceding neurons and terminate at the front of the expanding cortex remains poorly understood. We demonstrate that Down syndrome cell adhesion molecule (DSCAM), linked to Down syndrome and autism spectrum disorder, is required by migrating neurons to bypass their post-migratory predecessors and terminate migration in the outwardly expanding cortical layer. Migrating neurons deficient in DSCAM stop prematurely, failing to expand the cortex. We further show that DSCAM likely mediates migratory termination by weakening cell-adhesion mediated by N-cadherin.

Yield and Efficiency of a Population-Based Mass Tuberculosis Screening Intervention Among Persons With Diabetes in Jiangsu Province, China.

BACKGROUND: The evidence-base for mass tuberculosis screening among persons with diabetes (PWD) is poor. We evaluated the yield and costs of mass screening among PWD in eastern China. METHODS: We included individuals with type 2 diabetes from 38 townships in Jiangsu Province. Screening comprised of physical examinations, symptom screening, and chest X-rays; smear and culture testing were performed through clinical triage. We assessed the yield and number needed to screen (NNS) to detect 1 tuberculosis case among all PWD, those with symptoms, and with suggestive chest X-rays. Unit costing was collected to estimate screening costs and to calculate cost per case detected. We performed a systematic review of other mass tuberculosis screening programs concentrated on PWD. RESULTS: Of 89 549 screened PWD, 160 were diagnosed with tuberculosis (179 cases per 100 000 persons; 95% confidence interval [CI]: 153-205). The NNS was 560 (95% CI: 513-606), 248 (95% CI: 217-279), and 36 (95% CI: 24-48) among all participants, with abnormal chest X-rays, and symptoms. The cost per case was high overall (US$13 930) but lower with symptoms (US$1037) and high fasting blood glucose levels (US$6807). From systematic review, the pooled NNS to detect one case among all PWD (regardless of symptoms or chest X-ray results) in high- versus low-burden settings was 93 (95% CI: 70-141) versus 395 (95% CI: 283-649). CONCLUSIONS: A mass tuberculosis screening program focused on PWD was feasible however, the overall yield was low and not cost-efficient. Risk-stratified approaches may be practical among PWD in low- and medium tuberculosis burden settings.

Population Pharmacokinetics and Dose Evaluation of Cycloserine among Patients with Multidrug-Resistant Tuberculosis under Standardized Treatment Regimens.

Although cycloserine is a recommended drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) according to World Health Organization (WHO), few studies have reported on pharmacokinetics (PK) and/or pharmacodynamics (PD) data of cycloserine in patients with standardized MDR-TB treatment. This study aimed to estimate the population PK parameters for cycloserine and to identify clinically relevant PK/PD thresholds, as well as to evaluate the current recommended dosage. Data from a large cohort with full PK curves was used to develop a population PK model. This model was used to estimate drug exposure in patients with MDR-TB from a multicentre prospective study in China. The classification and regression tree was used to identify the clinically relevant PK/PD thresholds. Probability of target attainment was analyzed to evaluate the currently recommended dosing strategy. Cycloserine was best described by a two-compartment disposition model. A percentage of time concentration above MICs (T>MIC) of 30% and a ratio of area under drug concentration-time curve (AUC0-24h) over MIC of 36 were the valid predictors for 6-month sputum culture conversion and final treatment outcome. Simulations showed that with WHO-recommended doses (500 mg and 750 mg for patients weighing <45 kg and ≥45 kg), the probability of target attainment exceeded 90% at MIC ≤16 mg/L in MGIT for both T>MIC of 30% and AUC0-24h/MIC of 36. New clinically relevant PK/PD thresholds for cycloserine were identified in patients with standardized MDR-TB treatment. WHO-recommended doses were considered adequate for the MGIT MIC distribution in our cohort of Chinese patients with MDR-TB.

Evaluation of ESAT6-CFP10 Skin Test for Mycobacterium tuberculosis Infection among Persons Living with HIV in China.

Recent global guidelines recommend Mycobacterium tuberculosis antigen-based skin tests, such as the ESAT6-CFP10 (EC) skin test, as acceptable alternatives to the tuberculin skin test (TST) and the QuantiFERON-TB Gold In-Tube test (QFT). However, the diagnostic value of these tests among persons living with HIV (PLHIV) is unknown. We aimed to assess the diagnostic accuracy of the EC among a cohort of PLHIV in China. We recruited PLHIV in Jiangsu Province, China, to assess sensitivity and specificity of the EC test. Participants were tested with the QFT, TST, and EC skin test. Results were stratified by age, M. tuberculosis BCG vaccination, and CD4 count. The sensitivity and specificity of the EC skin test was assessed using distinct cutoffs of the QFT and TST. Of 350 PLHIV enrolled in the study, 58 (16.6%), 89 (25.4%), and 59 (16.9%) tested positive with the EC test, the QFT, and the TST, respectively. Positivity increased with CD4 count; however, these trends were similar across tests. At a 5-mm cutoff, EC skin test specificity was high (99.6%, 95% confidence interval [CI] 95% CI = 97.7 to 100.0); however, sensitivity was moderate (81.4%; 95% CI = 66.6 to 91.6). After stratifying by BCG, the sensitivity and specificity were 86.4% (95% CI = 65.1 to 97.1) and 99.1% (95% CI = 95.0 to 100.0) among vaccinated PLHIV and 76.2% (95% CI = 52.8 to 91.8) and 100.0% (95% CI = 97.2 to 100.0) among unvaccinated PLHIV, respectively. Among PLHIV, the diagnostic value of the EC skin test remained high, regardless of BCG vaccination or CD4 count. The EC skin test performed comparably to TST and may be a valid alternative diagnostic test to use in settings or populations with high HIV prevalence and BCG vaccination. To our knowledge, this is the first study to evaluate the novel ESAT6-CFP10 skin test among PLHIV. Among 350 PLHIV, the test displayed high specificity and sensitivity, a finding which did not markedly differ based on BCG vaccination and CD4 count.

Glycemic Trajectories and Treatment Outcomes of Patients with Newly Diagnosed Tuberculosis: A Prospective Study in Eastern China.

Rationale: Patients with newly diagnosed tuberculosis often have inconsistent glycemic measurements during and after treatment. Distinct glycemic trajectories after the diagnosis of tuberculosis are not well characterized, and whether patients with stress hyperglycemia have poor treatment outcomes is not known.Objectives: To identify distinct glycemic trajectories from the point of tuberculosis diagnosis to the posttreatment period and to assess the relationship between glycemic trajectories and tuberculosis treatment outcomes.Methods: Patients with newly diagnosed, drug-susceptible tuberculosis and with at least three fasting plasma glucose tests at tuberculosis diagnosis and during the third and sixth month of treatment were identified and included from Jiangsu Province, China. Patients were also given an additional fasting plasma glucose test at 2 and 4 months after treatment.Measurements and Main Results: Several distinct glycemic trajectories from the point of tuberculosis diagnosis to the posttreatment period were found, including consistently normal glycemic testing results (43%), transient hyperglycemia (24%), erratic glycemic instability (12%), diabetes (16%), and consistent hyperglycemia without diabetes (6%). Compared with participants with a consistently normal glycemic trajectory, patients with transient hyperglycemia were more likely to experience treatment failure (adjusted odds ratio [AOR], 4.20; 95% confidence interval [CI], 1.57-11.25; P = 0.004) or erratic glycemic instability (AOR, 5.98; 95% CI, 2.00-17.87; P = 0.001). Patients living with diabetes also had a higher risk of experiencing treatment failure (AOR, 6.56; 95% CI, 2.22-19.35; P = 0.001), and this was modified by glycemic control and metformin use.Conclusions: Among patients with tuberculosis without diabetes, glycemic changes were common and may represent an important marker for patient response to tuberculosis treatment.

Collateral Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on Tuberculosis Control in Jiangsu Province, China.

The coronavirus disease 2019 (COVID-19) pandemic may impede global tuberculosis elimination goals. In Jiangsu Province, China, tuberculosis notifications dropped 52% in 2020 compared to 2015-2019. Treatment completion and screening for drug resistance decreased continuously in 2020. Urgent attention must be paid to tuberculosis control efforts during and after the COVID-19 pandemic.

Transmission Dynamics in Tuberculosis Patients With Human Immunodeficiency Virus: A Systematic Review and Meta-analysis of 32 Observational Studies.

BACKGROUND: There are large knowledge gaps on the transmission dynamics of Mycobacterium tuberculosis in settings where both tuberculosis and human immunodeficiency virus (HIV) are endemic. We aimed to assess the infectiousness of tuberculosis patients coinfected with HIV. METHODS: We systematically searched for studies of contacts of both HIV-positive and HIV-negative tuberculosis index cases. Our primary outcome was Mycobacterium tuberculosis infection in contacts. Data on sputum smear and lung cavitation status of index cases were extracted from each study to assess effect modification. Secondary outcomes included prevalent tuberculosis and HIV in contacts of HIV-positive and HIV-negative index cases. RESULTS: Of 5255 original citations identified, 32 studies met inclusion criteria, including 25 studies investigating M. tuberculosis infection (Nparticipants = 36 893), 13 on tuberculosis (Nparticipants = 18 853), and 12 on HIV positivity (Nparticipants = 18 424). Risk of M. tuberculosis infection was lower in contacts of HIV-positive index cases (odds ratio [OR], 0.67, 95% confidence interval [CI], .58-.77) but was heterogeneous (I2 = 75.1%). Two factors modified this relationship: the lung cavitary status of the index case and immunosuppression (measured through CD4 counts or HIV or acquired immunodeficiency syndrome diagnoses) among index people living with HIV. Rates of HIV were consistently higher in contacts of coinfected index cases (OR, 4.9; 95% CI, 3.0-8.0). This was modified by whether the study was in sub-Saharan Africa (OR, 2.8; 95% CI, 1.6-4.9) or in another global region (OR, 9.8; 95% CI, 5.9-16.3). CONCLUSIONS: Tuberculosis patients coinfected with HIV are less infectious than HIV-uninfected cases when they have severe immunosuppression or paucibacillary disease. Contacts of coinfected index cases are almost 5 times more likely to also have HIV.

Predictors of Discordant Tuberculin Skin Test and QuantiFERON-TB Gold In-tube Results in Eastern China: A Population-based, Cohort Study.

BACKGROUND: Discordance between the QuantiFERON-TB Gold In-tube (QFT) and tuberculin skin test (TST) is not well understood. We aimed to identify the factors that determine discordance between the TST and QFT when compared to either TST+QFT+ or TST-QFT- results in a medium tuberculosis (TB) burden setting. METHODS: We conducted a population-based study in Eastern China and administered TSTs and QFTs to participants. We calculated kappa values while constructing multivariable logistic regression models to evaluate predictors of test discordance. We analyzed the predictive value of discordant and concordant test results for progression to TB over 6 years of follow-up. RESULTS: Overall, 5405 participants were enrolled; 2043 (37.8%) and 1104 (20.4%) were TST and QFT positive, respectively. There was fair agreement between the TST and the QFT (kappa values between 0.30-0.39 at different TST cutoffs). Agreement was lower among participants vaccinated with Bacillus Calmette-Guerin (BCG; κ, 0.17 versus 0.47 in nonvaccinated participants). TST+QFT- results were associated with decreasing age, smoking, undiagnosed diabetes, and BCG vaccination (adjusted odds ratio, 1.45; 95% confidence interval [CI], 1.11-1.90). TST-QFT+ results were associated with increasing age, male sex, smoking, and diagnosed diabetes. Compared to participants with TST-QFT- results, QFT+ and TST+QFT+ participants were 6.3 (95% CI, 1.9-20.4) and 7.5 (95%CI, 2.3-25.1) times more likely to progress to TB, respectively. CONCLUSIONS: In this population-based study of over 5000 participants from a medium TB burden region, the test agreement between QFT and TST was fair overall and we found multiple novel predictors of discordant QFT/TST results. QFT provides a substantial improvement to the TST among these populations and was multi-fold better at predicting progression to TB.

Scorpion Toxins: Positive Selection at a Distal Site Modulates Functional Evolution at a Bioactive Site.

The bioactive sites of proteins are those that directly interact with their targets. In many immunity- and predation-related proteins, they frequently experience positive selection for dealing with the changes of their targets from competitors. However, some sites that are far away from the interface between proteins and their targets are also identified to evolve under positive selection. Here, we explore the evolutionary implication of such a site in scorpion α-type toxins affecting sodium (Na+) channels (abbreviated as α-ScNaTxs) using a combination of experimental and computational approaches. We found that despite no direct involvement in interaction with Na+ channels, mutations at this site by different types of amino acids led to toxicity change on both rats and insects in three α-ScNaTxs, accompanying differential effects on their structures. Molecular dynamics simulations indicated that the mutations changed the conformational dynamics of the positively selected bioactive site-containing functional regions by allosteric communication, suggesting a potential evolutionary correlation between these bioactive sites and the distant nonbioactive site. Our results reveal for the first time the cause of fast evolution at nonbioactive sites of scorpion neurotoxins, which is presumably to adapt to the change of their bioactive sites through coevolution to maintain an active conformation for channel binding. This might aid rational design of scorpion Na+ channel toxins with improved phyletic selectivity via modification of a distant nonbioactive site.

Zinc oxide nanoparticles from Corydalis yanhusuo attenuated the mycoplasmal pneumonia in mice through inhibiting the MAPKs signaling pathway.

BACKGROUND: The Mycoplasma pneumoniae (M.pneumoniae) was accounted to 3-10% of total pneumonia incidences. In recent decades, metallic nanoparticles were extensively examined as nano-antibiotics. OBJECTIVE: In this investigation, we intended to inspect the therapeutic potential of Zinc oxide nanoparticles (ZnONPs) from (Corydalis yanhusuo) C. yanhusuo against the mycoplasma infected pneumonia in mice. METHODOLOGY: The ZnONPs were formulated via green route technique and characterized by UV-vis spectroscopy, transmission electron microscopy, Fourier transform infrared technique, and atomic force microscopy. The antimicrobial activity of formulated ZnONPs was tested by well diffusion method. The total protein, interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α) and transforming growth factor (TGF) status in the BALF of M. pneumonia infected animals were investigated via kit method. The expressions of ERK1/2, JNK1/2, and NF-κB were examined through the Western blotting. The Histopathological analysis of lung tissues of experimental animals was done. RESULTS: The UV-vis spectroscopy and TEM examinations were proved the existence of CY-ZnONPs. The formulated CY-ZnONPs were displayed the potential antimicrobial activity. The supplementation of CY-ZnONPs were noticeably diminished the total protein and IL-6, IL-8, and TNF-α levels in the BALF of pneumonia mice. The ERK1/2, JNK1/2, and NF-κB expressions were appreciably diminished in the CY-ZnONPs supplemented mice. It also reduced the inflammatory cells penetration, and exhibited normal tissue arrangements in the lung tissues of pneumonia mice. CONCLUSION: The findings of this investigation were proved that the synthesized CY-ZnONPs has the potential to ameliorate the M. pneumoniae infected pneumonia in investigational mice.

Undiagnosed diabetes mellitus and tuberculosis infection: A population-based, observational study from eastern China.

BACKGROUND: China has the largest dual diabetes and tuberculosis epidemic globally. No studies from mainland China have assessed the relationship between tuberculosis infection and diabetes. We conducted a population-based, observational study in eastern China to further explore this relationship. METHODS: A blood glucose, Quantiferon, and tuberculin skin test were administered at baseline. We compared tuberculosis infection in nondiabetics and diabetics. The cohort was additionally screened for tuberculosis progression over 5 years. RESULTS: Among 5405 participants, diabetics had elevated levels of Quantiferon and tuberculin positivity, largely driven by undiagnosed diabetics (compared with nondiabetics, adjusted odds ratios of 1.53; 95% confidence interval [CI], 1.05-2.23 and 1.58; 95% CI, 1.07-2.35 for tuberculin and Quantiferon positivity). During follow-up, the annual tuberculosis incidence was three times higher for diabetics compared with the entire cohort. CONCLUSIONS: These results suggest improving diabetic control through rapidly identifying undiagnosed diabetes may have indirect benefits to tuberculosis control. Targeting of preventive therapy to newly diagnosed diabetics at high-risk for progressive tuberculosis in China should be considered.

A Risk Classification Model to Predict Mortality Among Laboratory-Confirmed Avian Influenza A H7N9 Patients: A Population-Based Observational Cohort Study.

BACKGROUND: Avian influenza A H7N9 (A/H7N9) is characterized by rapid progressive pneumonia and respiratory failure. Mortality among laboratory-confirmed cases is above 30%; however, the clinical course of disease is variable and patients at high risk for death are not well characterized. METHODS: We obtained demographic, clinical, and laboratory information on all A/H7N9 patients in Zhejiang province from China Centers for Disease Control and Prevention electronic databases. Risk factors for death were identified using logistic regression and a risk score was created using regression coefficients from multivariable models. We externally validated this score in an independent cohort from Jiangsu province. RESULTS: Among 305 A/H7N9 patients, 115 (37.7%) died. Four independent predictors of death were identified: older age, diabetes, bilateral lung infection, and neutrophil percentage. We constructed a score with 0-13 points. Mortality rates in low- (0-3), medium- (4-6), and high-risk (7-13) groups were 4.6%, 32.1%, and 62.7% (Ptrend < .0001). In a validation cohort of 111 A/H7N9 patients, 61 (55%) died. Mortality rates in low-, medium-, and high-risk groups were 35.5%, 55.8, and 67.4% (Ptrend = .0063). CONCLUSIONS: We developed and validated a simple-to-use, predictive risk score for clinical use, identifying patients at high mortality risk.

High admission rates and heavy inpatient service costs of urban tuberculosis patients in eastern China.

BACKGROUND: Tuberculosis patients often experience hospitalization. Inpatient services may result in high medical expenditures. It is important to explore the hospitalization rates of tuberculosis patients and the potential factors that are associated with admission rates and inpatient service expenditures. METHODS: Data from patients diagnosed and treated at the No.3 hospital of Zhenjiang City from Apr. 2014 to Mar. 2015 were obtained. Univariate and multivariate statistical analyses were applied for the analysis of potential factors associated with admission rates, average length of stay and cost. RESULTS: A total of 356 tuberculosis patients were treated at the No.3 hospital of Zhenjiang City. A total of 221 of the 356 patients were hospitalized. Sputum smear test results and type of health insurance were the potential factors associated with hospitalization rates. The average admission was (1.26 ± 0.64) per patient. The average length of stay of inpatients was 29.99 ± 25.83 days. Age, occupation, and sputum smear test were related to the average length of stay. The average total cost to inpatients was 13007.91 ± 5205.58 CNY. The sputum smear test results, type of health insurance, occupation and age were the main potential factors associated with TB inpatient expenditures. CONCLUSIONS: The admission rate of tuberculosis patients was high. Despite advances in TB insurance policies, there were substantial costs associated with TB diagnosis and treatment. TB patients still face a heavy financial burden. Health care providers should revise the service package and reform the health insurance regulations to ensure that TB patients receive appropriate care.

Factors affecting time to sputum culture conversion and treatment outcome of patients with multidrug-resistant tuberculosis in China.

BACKGROUND: Few prospective cohort studies, none in China, have investigated the relationship between treatment outcomes of multidrug-resistant tuberculosis (MDR-TB) patients and sputum culture conversion. Factors affecting the time of the culture conversion throughout the whole course of the treatment have rarely been investigated. METHODS: This study was performed in four cities in Jiangsu province, China. MDR-TB patients were consecutively enrolled between December 2011 and March 2014. Rates of sputum culture conversion were calculated and Cox proportional-hazards model was performed. Factors contributing to sputum culture conversion were investigated. RESULTS: In all, 139 MDR-TB patients with treatment outcomes were enrolled. Median time to culture conversion among those who converted was 91.5 days (interquartile range, 34.0-110.8 days). After multivariable analysis, smoking (HR = 0.44; 95% CI: 0.23-0.83), drinking (HR = 0.41; 95% CI: 0.21-0.81), ofloxacin resistance (HR = 0.43; 95% CI: 0.24-0.76) and sputum smear grade > 1 (HR = 0.51; 95% CI: 0.31-0.83) were less likely to have culture conversion. CONCLUSIONS: MDR-TB patients who smoke, drink, have ofloxacin resistance, or a high smear grade are less likely to respond to treatment and should be meticulously followed up.

Proteomic and metabolomic analysis of marine medaka (Oryzias melastigma) after acute ammonia exposure.

Ammonia is both a highly toxic environmental pollutant and the major nitrogenous waste produced by ammoniotelic teleosts. Although the acute toxic effects of ammonia have been widely studied in fish, the biochemical mechanisms of its toxicity have not been understood comprehensively. In this study, we performed comparative proteomic and metabolomic analysis between ammonia-challenged (1.2 and 2.6 mmol L-1 NH4Cl for 96 h) and control groups of marine medaka (Oryzias melastigma) to identify changes of the metabolite and protein profiles in response to ammonia stress. The metabolic responses included changes of multiple amino acids, carbohydrates (glucose and glycogen), energy metabolism products (ATP and creatinine), and other metabolites (choline and phosphocholine) after ammonia exposure, indicating that ammonia mainly caused disturbance in energy metabolism and amino acids metabolism. The two-dimensional electrophoresis-based proteomic study identified 23 altered proteins, which were involved in nervous system, locomotor system, cytoskeleton assembly, immune stress, oxidative stress, and signal transduction of apoptosis. These results suggested that ammonia not only induced oxidative stress, immune stress, cell injury and apoptosis but also affected the motor ability and central nervous system in marine medaka. It is the first time that metabolomic and proteomic approaches were integrated to elucidate ammonia toxicity in marine fishes. This study is of great value in better understanding the mechanisms of ammonia toxicity in marine fishes and in practical aspects of aquaculture.