The diagnostic performance of GeneXpert MTB/RIF in tuberculosis meningitis: A multicentre accuracy study.

OBJECTIVES: To evaluate the performance of GeneXpert MTB/RIF (Xpert) for tuberculous meningitis (TBM) and to identify additional indicators to improve diagnostic accuracy. METHODS: An accuracy study was conducted. During 2011-2019, 243 TBM with 140 non-TBM in three TB-designated facilities in China were enrolled. Microbiological evidence of M tuberculosis (Mtb) in CSF was used as the reference. Additional indicators were identified by Boosted-Classification and Regression Tree (CART), the improvement of diagnostic performance was evaluated by ROC. RESULTS: The diagnostic sensitivity of Xpert was 71.1 % for definite TBM, and 5.5 % for probable/possible TBM. The positive rate of Xpert was improved with cerebrospinal fluid (CSF) increasing volume and was associated with CSF color (yellow). The additional indicators obtained by CART were CSF lactate and glucose and increased the sensitivity to 96.1 % (definite TBM) and 84.6 % (probable/possible TBM). CONCLUSIONS: The diagnostic performance of Xpert was satisfactory in definite TBM and would significantly be improved by the additional use of CSF lactate and glucose.

Second-line antituberculosis drug exposure thresholds predictive of adverse events in multidrug-resistant tuberculosis treatment.

OBJECTIVES: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. METHODS: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. RESULTS: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). CONCLUSIONS: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.

Drug Exposure and Susceptibility of Pyrazinamide Correlate with Treatment Response in Pyrazinamide-Susceptible Patients with Multidrug-Resistant Tuberculosis.

Exploring the influence of pyrazinamide exposure and susceptibility on treatment response is crucial for optimizing the management of multidrug-resistant tuberculosis (MDR-TB). This study aimed to investigate the association between pyrazinamide exposure, susceptibility, and response to MDR-TB treatment, as well as find clinical thresholds for pyrazinamide. A prospective multi-center cohort study of participants with MDR-TB using pyrazinamide was conducted in three TB-designated hospitals in China. Univariate and multivariate analyses were applied to investigate the associations. Classification and Regression Tree (CART) analysis was used to identify clinical thresholds, which were further evaluated by multivariate analysis and receiver operating characteristic (ROC) curves. The study included 143 patients with MDR-TB. The exposure/susceptibility ratio of pyrazinamide was associated with two-month culture conversion (adjusted risk ratio (aRR), 1.1; 95% confidence interval (CI), 1.07-1.20), six-month culture conversion (aRR, 1.1; 95% CI, 1.06-1.16), treatment success (aRR, 1.07; 95% CI, 1.03-1.10), as well as culture conversion time (adjusted hazard ratio (aHR) 1.18; 95% CI,1.14-1.23). The threshold for optimal improvement in sputum culture results at the sixth month of treatment was determined to be a pyrazinamide AUC0-24h/MIC ratio of 7.8. In conclusion, the exposure/susceptibility ratio of pyrazinamide is associated with the treatment response of MDR-TB, which may change in different Group A drug-based regimens.

Population pharmacokinetics and model-based dosing evaluation of bedaquiline in multidrug-resistant tuberculosis patients.

Aims: Bedaquiline is now recommended to all patients in the treatment of multidrug-resistant tuberculosis (MDR-TB) using standard dosing regimens. As the ability to measure blood drug concentrations is very limited, little is known about drug exposure and treatment outcome. Thus, this study aimed to model the population pharmacokinetics as well as to evaluate the currently recommended dosage. Methodology: A bedaquiline population pharmacokinetic (PK) model was developed based on samples collected from the development cohort before and 1, 2, 3, 4, 5, 6, 8, 12, 18, and 24 h after drug intake on week 2 and week 4 of treatment. In a prospective validation cohort of patients with MDR-TB, treated with bedaquiline-containing standardized regimen, drug exposure was assessed using the developed population PK model and thresholds were identified by relating to 2-month and 6-month sputum culture conversion and final treatment outcome using classification and regression tree analysis. In an exploratory analysis by the probability of target attainment (PTA) analysis, we evaluated the recommended dosage at different MIC levels by Middlebrook 7H11 agar dilution (7H11). Results: Bedaquiline pharmacokinetic data from 55 patients with MDR-TB were best described by a three-compartment model with dual zero-order input. Body weight was a covariate of the clearance and the central volume of distribution, albumin was a covariate of the clearance. In the validation cohort, we enrolled 159 patients with MDR-TB. The 7H11 MIC mode (range) of bedaquiline was 0.06 mg (0.008-0.25 mg/L). The study participants with AUC0-24h/MIC above 175.5 had a higher probability of culture conversion after 2-month treatment (adjusted relative risk, aRR:16.4; 95%CI: 5.3-50.4). Similarly, those with AUC0-24h/MIC above 118.2 had a higher probability of culture conversion after 6-month treatment (aRR:20.1; 95%CI: 2.9-139.4), and those with AUC0-24h/MIC above 74.6 had a higher probability of successful treatment outcome (aRR:9.7; 95%CI: 1.5-64.8). Based on the identified thresholds, simulations showed that the WHO recommended dosage (400 mg once daily for 14 days followed by 200 mg thrice weekly) resulted in PTA >90% for the majority of isolates (94%; MICs ≤0.125 mg/L). Conclusion: We established a population PK model for bedaquiline in patients with MDR-TB in China. Based on the thresholds and MIC distribution derived in a clinical study, the recommended dosage of bedaquiline is sufficient for the treatment of MDR-TB.

Analysis of a Sabin-Strain Inactivated Poliovirus Vaccine Response to a Circulating Type 2 Vaccine-Derived Poliovirus Event in Sichuan Province, China 2019-2021.

Importance: The Sabin-strain inactivated poliovirus vaccine (IPV) may be a tool for polio outbreak response in certain situations. Objective: To investigate the response to a type 2 vaccine-derived poliovirus (VDPV2) outbreak. Design, Setting, and Participants: This case series was conducted in China after a VDPV2 was detected in stool specimens from a child with acute flaccid paralysis (AFP) in Sichuan Province in 2019, 3 years after the global withdrawal of live, attenuated type 2 oral poliovirus vaccine (OPV). Investigation followed National Health Commission and World Health Organization guidance and included searching hospitals for unreported AFP cases; testing stool specimens from the child, his contacts, and local children; enhanced environmental surveillance for VDPV2s in wastewater; and measuring vaccination coverage. Sabin-strain IPV campaigns were conducted in a wide geographic area. Main Outcomes and Measures: Any VDPV2 detection after completion of the supplementary immunization activities. Results: A 28-nucleotide-change VDPV2 was isolated from a young boy. Three VDPV2s were detected in healthy children; 2 were contacts of the original child, and none had paralysis. A search of 31 million hospital records found 10 unreported AFP cases; none were polio. No type 2 polioviruses were found in wastewater. Prior to the event, polio vaccine coverage was 65% among children younger than 5 years. Sabin-strain IPV campaigns reached more than 97% of targeted children, administering 1.4 million doses. No transmission source was identified. More than 1 year of enhanced poliovirus environmental and AFP surveillance detected no additional VDPVs. Conclusions and Relevance: These findings suggest that the circulating VPDV2 outbreak in 2019 was associated with low vaccine coverage. An investigation discovered 3 infected but otherwise healthy children and no evidence of the virus in wastewater. Following Sabin-strain IPV-only campaigns expanding from county to prefecture, the poliovirus was not detected, and the outbreak response was considered by an expert panel and the World Health Organization to have been successful. This success suggests that the Sabin-strain IPV may be a useful tool for responding to circulating VDPV2 outbreaks when high-quality supplementary immunization activities can be conducted and carefully monitored in settings with good sanitation.

Epigallocatechin gallate improves meiosis maturation against Diazinon exposure in porcine oocytes.

Diazinon (DZN) is a refractory organophosphorus pesticide (OP) in the surrounding environment due to its overuse in agriculture. The antioxidant activity of Epigallocatechin gallate (EGCG) from green tea is at least 100 times greater than that of vitamin C. This study aimed to study the effects of DZN on the meiotic maturation of porcine oocytes, as well as the protective roles of EGCG. Firstly, the effects of DZN and EGCG on meiotic nuclear maturation of porcine oocytes were detected, and then embryonic development was investigated by chemical parthenogenetic activation. Next, the spindle assembly, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), DNA damage, and finally the early apoptosis of oocytes were examined by immunofluorescence staining. The results revealed that DZN exposure significantly reduced the quality of porcine oocytes, such as failure of nuclear and cytoplasmic maturation, evidenced by abnormal spindle assembly, disordered chromosome alignment, low MMP, observably increased ROS, severe DNA damage, and early apoptosis. Appropriate EGCG could significantly reduce all these defects caused by DZN. In conclusion, EGCG can help prevent the harm that DZN exposure can do. These findings offer convincing support for enhancing the oocyte quality from EGCG through daily ordinary beverages.

The efficacy of nutritional supplements for the adjunctive treatment of schizophrenia in adults: A systematic review and network meta-analysis.

Nutritional supplementations have been widely used as adjunctive treatments for schizophrenia. However, among these supplementations, of which the most beneficial is currently unknown. This study aimed to compare and rank the effectiveness of nutritional supplementations in the adjunctive treatments of schizophrenia. The four nutritional supplementations evaluated were: 1) folate acid or vitamin B12; 2) vitamin D; 3) N-acetyl cysteine (NAC); 4) Omega-3 polyunsaturated fatty acid, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). 17 eligible RCTs with 1165 participants were included in this network meta-analysis based on study criteria. NAC supplementation was significantly more efficacious than folic acid or vitamin B12 [MD (95% CI): -6.6 (-10.8, -2.4)] and omega-3 polyunsaturated fatty acid [MD (95% CI): -5.1(-9.9, -0.8)] supplementation in the term of PANSS score changes. There were no significant differences in the PANSS score changes between NAC and vitamin D [MD (95% CI): -5.2 (-10.9, 0.5)] supplementations. The estimated ranking probabilities of treatments showed that NAC might be the most effective adjunctive intervention over all nutritional supplementations. These results indicate that NAC could improve PANSS score and it may be among the most effective nutritional supplementations in schizophrenia patients.

Olfactory Sensitivity Is Related to Erectile Function in Adult Males.

BACKGROUND: The olfactory system influences human social behavior, in particular the selection of a spouse. However, there is currently a lack of clinical research on the relationship between the olfactory system and erectile dysfunction (ED) in adult males. AIM: We explored the association between olfactory sensitivity and erectile function and its possible mechanisms. RESULTS: A total of 574 patients, adult males aged between 19 and 42 years, diagnosed with ED in the Department of Infertility and Sexual Medicine of the Third Affiliated Hospital of Sun Yat-sen University from 2015 to 2018 were analyzed retrospectively. Among them, 115 patients (20.03%) had rhinologic diseases (RDs). In addition, in 201 adult male patients who underwent nasal surgery in the ENT department from 2012 to 2016, including 29 (14.43%) with ED, nasal congestion, nasal discharge, and hyposmia were the most common complaints based on the numerical rating scale (NRS). Furthermore, a prospective study was performed in a total of 102 sequential outpatients (male adults) with RD only (n = 46), ED only (n = 42) and both RD and ED (n = 14) in 2019, together with 40 healthy (male adults) volunteers as controls. The results showed that ED patients with RD had severe nasal discomfort and decreased erectile function (P < 0.0001). The olfactory sensitivity of patients with ED was lower than that of the controls, and patients with both ED and RD had the worst olfactory sensitivity (P < 0.0001). Spearman correlation analyses showed that sense of smell was positively correlated with the International Index of Erectile Function-5 score (R = 0.507, P ≤ 0.0001) and the Erection Hardness Scale score (R = 0.341, P < 0.0001). Logistic regression analyses showed that having an olfactory disorder (OD), RD, age, and visual analog scale (VAS, over 5) score were risk factors for ED outcome, indicating that OD patients had a 16.479-fold increased risk for an ED outcome (P < 0.05). CONCLUSION: A significant correlation was detected between olfactory sensitivity and erectile function in adult males. In particularly, impairment of olfactory sensitivity is more common in patients with both ED and RD than in patients suffering from a single disease.

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia.

BACKGROUND: The initial cases of novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemiologic characteristics of NCIP. METHODS: We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020. We described characteristics of the cases and estimated the key epidemiologic time-delay distributions. In the early period of exponential growth, we estimated the epidemic doubling time and the basic reproductive number. RESULTS: Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9). CONCLUSIONS: On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.).

Detection and Initial Response to a Type 2 Vaccine-Derived Poliovirus - Sichuan Province, China, 2019.

WHAT IS ALREADY KNOWN ABOUT THIS TOPIC?: After the type 2 strain of the live, attenuated poliovirus vaccine was withdrawn globally in 2016, any identification of a type 2 poliovirus is a Public Health Emergency of International Concern. A vaccine-derived type 2 poliovirus (VDPV2) was identified in Sichuan, prompting an urgent, comprehensive investigation and response. WHAT IS ADDED BY THIS REPORT?: Type 2 monovalent, live, attenuated oral poliovirus vaccine (mOPV2) is being used to respond to the numerous VDPV2 outbreaks seen around the world. In contrast, the response in Sichuan used Sabin strain inactivated poliovirus (sIPV) to stop circulation of the VDPV2. In the 6 months following the vaccination response, there have been no VDPV2s detected in Sichuan, despite extensive search. WHAT ARE THE IMPLICATIONS FOR PUBLIC HEALTH PRACTICES?: Further search for the VDPV2 must continue in order to determine whether transmission has been stopped. The ongoing investigation and response to the Sichuan VDPV2 is providing evidence to the Global Polio Eradication Initiative on managing VDPV2 outbreaks.