Docosahexaenoic Acid Supplementation for Neonatal Hyperbilirubinemia: A Double-Blind, Randomized Clinical Trial.

Docosahexaenoic acid (DHA) is an essential component for brain development during fetal and early postnatal life. Hyperbilirubinemia is characterized by abnormally high levels of bilirubin in the bloodstream, frequently leading to jaundice in newborns. In severe instances, this condition can progress to neurological damage or kernicterus, a form of brain damage. Initial cell-based experiments conducted by our research team revealed that DHA significantly enhances the survival rate of nerve cells treated with bilirubin and diminishes the oxidative stress indicated by reduced peroxide activity caused by unconjugated bilirubin (UCB). Further investigations through animal studies demonstrated that DHA effectively mitigates bilirubin-induced brain injury in neonatal rats. However, the potential of DHA to decrease the incidence of bilirubin-induced brain damage in clinical settings has not been previously explored or reported. Infants with neonatal hyperbilirubinemia (n = 30 per group) participated in a double-blind, randomized, placebo-controlled parallel study. They received either 100 mg/d DHA or placebo syrup immediately when they were diagnosed. The study found that the bilirubin level at 48 hours of treatment, serum neuron-specific enolase (NSE) levels, mean phototherapy duration, and abnormal rate of cranial magnetic resonance imaging (MRI) were lower in the DHA group than those in the control group (P < .05). These results suggested that DHA is effective as an adjuvant treatment for hyperbilirubinemia in children. It can reduce the incidence of neonatal hyperbilirubinemia brain injury and plays a certain protective role. Clinical study on protective effect of DHA on neonatal bilirubin injury is registered at Chinese Clinical Trial Registry as ChiCTR2300070250.

Anti-GM-CSF autoantibodies predict outcome of cryptococcal meningitis in patients not infected with HIV: A cohort study.

OBJECTIVES: To explore the seroprevalence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies in non-HIV cryptococcal meningitis (CM) and assess its predictive value for survival. METHODS: This is a retrospective study of 12 years of non-HIV CM. We detected serum anti-GM-CSF autoantibodies, and evaluated the clinical features and outcomes, together with the exploration of prognostic factors for 2-week and 1-year survival. RESULTS: A total of 584 non-HIV CM cases were included. 301 of 584 patients (51.5%) were phenotypically healthy. 264 Cryptococcus isolates were obtained from cerebrospinal fluid (CSF) culture, of which 251 were identified as C. neoformans species complex and 13 as C. gattii species complex. Thirty-seven of 455 patients (8.1%) tested positive for serum anti-GM-CSF autoantibodies. Patients with anti-GM-CSF autoantibodies were more susceptible to C. gattii species complex infection (66.7% vs. 6.3%; p < 0.001) and more likely to develop pulmonary mass lesions with a diameter >3 centimetres (42.9% vs. 6.5%; p 0.001). Of 584 patients 16 (2.7%) died within 2 weeks, 77 of 563 patients (13.7%) died at 1 year, and 93 of 486 patients (19.1%) lived with disabilities at 1 year. Univariant Cox regression analysis found that anti-GM-CSF autoantibodies were associated with lower 1-year survival (HR, 2.66; 95% CI, 1.34-5.27; p 0.005). Multivariable Cox proportional hazards modelling revealed that CSF cryptococcal antigen titres ≥1:1280 were associated with both, reduced 2-week and 1-year survival rates (HR, 5.44; 95% CI, 1.23-24.10; p 0.026 and HR, 5.09; 95% CI, 1.95-13.26; p 0.001). DISCUSSION: Presence of serum anti-GM-CSF autoantibodies is predictive of poor outcomes, regardless of host immune status and the causative Cryptococcus species complex.

A single center retrospective study: Comparison between centrifugal separation plasma exchange with ACD-A and membrane separation plasma exchange with heparin on acute liver failure and acute on chronic liver failure.

The purpose of this retrospective study is to compare the efficacy and safety of the centrifugal separation therapeutic plasma exchange (TPE) using citrate anticoagulant (cTPEc) with membrane separation TPE using heparin anticoagulant (mTPEh) in liver failure patients. The patients treated by cTPEc were defined as cTPEc group and those treated by mTPEh were defined as mTPEh group, respectively. Clinical characteristics were compared between the two groups. Survival analyses of two groups and subgroups classified by the model for end-stage liver disease (MELD) score were performed by Kaplan-Meier method and were compared by the log-rank test. In this study, there were 51 patients in cTPEc group and 18 patients in mTPEh group, respectively. The overall 28-day survival rate was 76% (39/51) in cTPEc group and 61% (11/18) in mTPEh group (P > .05). The 90-day survival rate was 69% (35/51) in cTPEc group and 50% (9/18) in mTPEh group (P > .05). MELD score = 30 was the best cut-off value to predict the prognosis of patients with liver failure treated with TPE, in mTPEh group as well as cTPEc group. The median of total calcium/ionized calcium ratio (2.84, range from 2.20 to 3.71) after cTPEc was significantly higher than the ratio (1.97, range from 1.73 to 3.19) before cTPEc (P < .001). However, there was no significant difference between the mean concentrations of total calcium before cTPEc and at 48 h after cTPEc. Our study concludes that there was no statistically significant difference in survival rate and complications between cTPEc and mTPEh groups. The liver failure patients tolerated cTPEc treatment via peripheral vascular access with the prognosis similar to mTPEh. The prognosis in patients with MELD score < 30 was better than in patients with MELD score ≥ 30 in both groups. In this study, the patients with acute liver failure (ALF) and acute on chronic liver failure (ACLF) treated with cTPEc tolerated the TPE frequency of every other day without significant clinical adverse event of hypocalcemia with similar outcomes to the mTPEh treatment. For liver failure patients treated with cTPEc, close clinical observation and monitoring ionized calcium are necessary to ensure the patients' safety.

[The trend of changes in spine-pelvic sagittal parameters before and after surgery in patients with double-segment lumbar spondylolisthesis and their evaluating for surgery efficacy].

OBJECTIVE: To explore the trend of changes in the parameters of the spine-pelvic sagittal plane before and after surgery in patients with double-segment lumbar spondylolisthesis (LSL) and to evaluate the value of the surgical effect. METHODS: A retrospective analysis of 95 double-segment lumbar spondylolisthesis patients treated with posterior lumbar interbody fusion from October 2019 to October 2020 were analyzed, including 31 males and 64 females;age ranging from 41 to 63 years old, with an average of (52.10±4.35) years old;degree of lesion, 47 patients with gradeⅠand 48 patients with gradeⅡ. The surgical efficacy was evaluated according to the Oswestry dysfunction index(ODI) improvement rate at 3 months after operation. ODI improvement rate ≥50% was considered good, and <50% was considered bad. Ninety-five patients were divided into good curative effect group (74 cases) and poor curative effect group (21 cases) according to surgical curative effect. The clinical data, such as gender, age, body mass index, course of disease, degree of disease, operation time, intraoperative blood loss, and comorbidities were compared between two groups were compared. The parameters of spine pelvis sagittal plane were observed before and 3 months after operation, including spine sacral angle (SSA), T1 pelvic angle (TPA), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS). Clinical symptoms were evaluated using visual analogue scale (VAS) and ODI. The correlation between the changes of spine pelvis sagittal plane parameters and the changes of VAS and ODI before and after surgery were analyzed, and the value of spine pelvis sagittal plane parameters in evaluating the surgical efficacy of patients with double level lumbar spondylolisthesis at 3 months after surgery was evaluated. RESULTS: The courses of disease and surgical time in the group with poor efficacy were longer than those in the group with good efficacy, and the degree of lesion was higher in the group with poor efficacy (P<0.05). The SSA, TPA, LL, and SS of the group with good efficacy were higher than those of the group with poor efficacy before and 3 months after surgery, while the PT was lower than that of the group with poor efficacy (P<0.05). The changes in SSA, TPA, LL, PT, and SS before and after surgery in the group with good efficacy were greater than those in the group with poor efficacy (P<0.05). The VAS and ODI of both groups were lower at 3 months after surgery than before, and the group with good efficacy was lower(P<0.05). The changes in VAS and ODI before and after surgery in the group with good efficacy were greater than those in the group with poor efficacy (P<0.05). The changes in SSA, TPA, LL, PT, SS before and after surgery were positively correlated with the changes in VAS and ODI (P<0.05). Three months after surgery, SSA, TPA, LL, PT, and SS were used to evaluate the surgical efficacy of patients with dual level lumbar spondylolisthesis. The area under the curve (AUC) was 0.868, 0.797, 0.875, 0.822, and 0.853, respectively. The combined evaluation of all indicators resulted in the highest AUC, 0.927, and the best sensitivity and specificity were 90.50% and 91.89%, respectively. CONCLUSION: The spine pelvis sagittal plane parameters SSA, TPA, LL, and SS of patients with double level lumbar spondylolisthesis before and after surgery show an upward trend;PT shows a downward trend;PI do not change significantly. And the changes of SSA, TPA, LL, SS, and PT are closely related to the patient's pain level and the improvement of lumbar function, which can be used as parameters to evaluate the surgical efficacy.

Global histone H2B degradation regulates insulin/IGF signaling-mediated nutrient stress.

Eukaryotic organisms adapt to environmental fluctuations by altering their epigenomic landscapes and transcriptional programs. Nucleosomal histones carry vital epigenetic information and regulate gene expression, yet the mechanisms underlying chromatin-bound histone exchange remain elusive. Here, we found that histone H2Bs are globally degraded in Caenorhabditis elegans during starvation. Our genetic screens identified mutations in ubiquitin and ubiquitin-related enzymes that block H2B degradation in starved animals, identifying lysine 31 as the crucial residue for chromatin-bound H2B ubiquitination and elimination. Retention of aberrant nucleosomal H2B increased the association of the FOXO transcription factor DAF-16 with chromatin, generating an ectopic gene expression profile detrimental to animal viability when insulin/IGF signaling was reduced in well-fed animals. Furthermore, we show that the ubiquitin-proteasome system regulates chromosomal histone turnover in human cells. During larval development, C. elegans epidermal cells undergo H2B turnover after fusing with the epithelial syncytium. Thus, histone degradation may be a widespread mechanism governing dynamic changes of the epigenome.

Clinical application and drug-use-guidance value of metagenomic next-generation sequencing in central nervous system infection.

OBJECTIVE: Timely and precise etiology diagnosis is crucial for optimized medication regimens and better prognosis in central nervous system infections (CNS infections). We aimed to analyze the impact of mNGS tests on the management of patients with CNS infections. METHODS: We conducted a single-center retrospective cohort study to analyze the value of mNGS in clinical applications. Three hundred sixty-nine patients with a CNS infection diagnosis were enrolled, and their clinical data were collected. CDI and DDI were defined in our study to describe the intensity of drug use in different groups. We used LOH and mRS to evaluate if the application of mNGS can benefit CNS infected patients. RESULTS: mNGS reported a 91.67% sensitivity in culture-positive patients and an 88.24% specificity compared with the final diagnoses. Patients who participated with the mNGS test had less drug use, both total (58.77 vs. 81.18) and daily (22.6 vs. 28.12, P < 0.1, McNemar) intensity of drug use, and length of hospitalization (23.14 vs. 24.29). Patients with a consciousness grading 1 and 3 had a decrease in CDI (Grade 1, 86.49 vs. 173.37; Grade 3, 48.18 vs. 68.21), DDI (Grade 1, 1.52 vs. 2.72; Grade 3, 2.3 vs. 2.45), and LOH (Grade 1, 32 vs. 40; Grade 3, 21 vs. 23) with the application of mNGS. Patients infected with bacteria in the CNS had a reduced CDI, DDI, and LOH in the mNGS group. This was compared with the TraE group that had 49% of patients altered medication plans, and 24.7% of patients reduced drug intensity four days after mNGS reports. This was because of the reduction of drug types. CONCLUSION: mNGS showed its high sensitivity and specificity characteristics. mNGS may assist clinicians with more rational medication regimens and reduce the drug intensity for patients. The primary way of achieving this is to reduce the variety of drugs, especially for severe patients and bacterial infections. mNGS has the ability of improving the prognosis of CNS infected patients.

Intestine-specific removal of DAF-2 nearly doubles lifespan in Caenorhabditis elegans with little fitness cost.

Twenty-nine years following the breakthrough discovery that a single-gene mutation of daf-2 doubles Caenorhabditis elegans lifespan, it remains unclear where this insulin/IGF-1 receptor gene is expressed and where it acts to regulate ageing. Using knock-in fluorescent reporters, we determined that daf-2 and its downstream transcription factor daf-16 are expressed ubiquitously. Using tissue-specific targeted protein degradation, we determined that intracellular DAF-2-to-DAF-16 signaling in the intestine plays a major role in lifespan regulation, while that in the hypodermis, neurons, and germline plays a minor role. Notably, intestine-specific loss of DAF-2 activates DAF-16 in and outside the intestine, causes almost no adverse effects on development and reproduction, and extends lifespan by 94% in a way that partly requires non-intestinal DAF-16. Consistent with intestine supplying nutrients to the entire body, evidence from this and other studies suggests that altered metabolism, particularly down-regulation of protein and RNA synthesis, mediates longevity by reduction of insulin/IGF-1 signaling.

Corrigendum to: Do Stay at Home Orders and Cloth Face Coverings Control COVID-19 in New York City? Results From a SIER Model Based on Real-world Data.

[This corrects the article DOI: 10.1093/ofid/ofaa442.].

The direct application of plasma droplet digital PCR in the ultra-early pathogen detection and warning during sepsis: Case reports.

BACKGROUND: Sepsis is a severe and acute disease associated with high mortality, for those who survive, long-term morbidity. In-time detection of pathogen for proper and optimized treatment in the early stage of sepsis is crucial. METHODS: We performed droplet digital PCR (ddPCR) on two cases of sepsis. The clinical information, laboratory test results, and the therapeutic regimen was detailed recorded. RESULTS: ddPCR showed its clinical value of sepsis ultra-early diagnosis and the guidance of medication in both cases we provided. CONCLUSIONS: ddPCR has potential for rapid and precise diagnose in ultra-early stage of sepsis for its high sensitivity and short turn-around-time, thus benefiting in optimal and timely treatment of sepsis.

Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects.

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25-800 mg. T1/2 was within 4.80-6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

Recurrent pulmonary tuberculosis after treatment success: a population-based retrospective study in China.

OBJECTIVES: Post-treatment recurrence remains a challenge for the global control of tuberculosis (TB). This study investigated longitudinal data on pulmonary TB recurrence rates and risk factors for recurrence among successfully treated smear-positive tuberculosis cases in China. METHODS: Between 1st January 2009 and 31st December 2016 we evaluated 33 441 treatment-naïve patients diagnosed with sputum-smear-positive, non-multidrug-resistant TB in Hangzhou, China. We included the data of 9828 patients with TB who were treated successfully. RESULTS: A total of 4.9% of the cases were recurrent (479/9828), identified within a median observation period lasting 1565 days. Altogether, 51.1% (245/479) of the recurrences occurred within 1 year. The cumulative 2- and 5-year recurrence rates were 3.90% (95% confidence interval (CI) 3.3-4.5%) and 5.4% (95%CI 4.8-6.0%), respectively. Prolonged treatment (over 7 months) occurred in 64.7% (6363/9828), with a median treatment duration of 242 days (interquartile range 195-348 days). Male sex (adjusted hazard ratio (aHR) (95%CI) 1.61 (1.30-2.00), p < 0.001), age 60 years old or older (aHR (95%CI) 2.03 (1.70-2.44), p < 0.001), pulmonary cavity (aHR (95%CI) 1.51 (1.25-1.82), p < 0.001) and sputum positivity at 2 months (aHR (95%CI) 1.39 (1.05-1.81), p 0.02) all increased the risk of TB recurrence. Prolonged treatment was associated with reduced TB recurrence (aHR (95%CI) 0.73 (0.61-0.88), p 0.001). CONCLUSIONS: Recurrence remains a problem for successfully treated patients with sputum-smear-positive pulmonary TB, especially those with independent risk factors. Further analysis of prolonged treatment is required.

Tenofovir disoproxil fumarate in Chinese chronic hepatitis B patients: Results of a multicenter, double-blind, double-dummy, clinical trial at 96 weeks.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is a prodrug of a nucleotide analogue. As an antiviral drug, TDF has been proposed in the first-line treatment of chronic hepatitis B (CHB). Qingzhong, a brand name of TDF, commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd., and Viread, another brand name of TDF, commercialized by GlaxoSmithKline, have both been approved by the State Food and Drug Administration, China. AIM: To investigate the efficacy and safety of the two TDF agents in the treatment of Chinese CHB patients. METHODS: This trial was registered at ClinicalTrials.gov with the identifier number of NCT02287857. A total of 330 Chinese CHB patients, among which 232 were hepatitis B e antigen (HBeAg)-positive, were included in this 5-year-long, multicenter, double-blinded, double-dummy, randomized-controlled, non-inferiority phase III trial. The participants were initially randomized into two groups: Group A (n = 161), in which the participants received 300 mg Qingzhong once a day for 48 wk; and Group B, in which the participants received 300 mg Viread once a day for 48 wk. Starting from week 49, all the participants in Groups A and B received 300 mg Qingzhong once a day until the 96th week. In this study, the primary endpoint was the decrease in plasma level of hepatitis B virus (HBV) DNA at the 96th week, while the secondary endpoints were suppression of HBV replication, alanine aminotransferase (ALT) normalization, HBeAg loss, and HBeAg seroconversion rates. RESULTS: For the participants with HBeAg-positive CHB, the decrease in mean HBV DNA level relative to the baseline value was comparable between Groups A and B (5.77 vs 5.73 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-positive participants in the two groups exhibited undetectable levels of HBV DNA, HBeAg loss, and HBeAg seroconversion (71.05% vs 77.97%, 31.00% vs 27.27%, and 20.22% vs 15.79%, respectively, in Group A vs Group B; P > 0.05). For the participants with HBeAg-negative CHB, the decrease in mean HBV DNA level relative to the baseline value was also comparable between Groups A and B (4.46 vs 4.70 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-negative participants in the two groups exhibited undetectable levels of HBV DNA (87.23% vs 94.12% in Group A vs Group B, respectively; P > 0.05). Finally, similar percentages of CHB patients (HBeAg-positive or HBeAg-negative) in the two groups exhibited normalization of ALT (80.14% vs 84.57% in Group A vs Group B, respectively; P > 0.05), and similar incidences of adverse events were observed (106 vs 104 in Group A vs Group B, respectively; P > 0.05). CONCLUSION: Both Qingzhong and Viread are effective and safe in the treatment of Chinese CHB patients according to the results of our clinical trial.

Transcriptional signatures of human peripheral blood mononuclear cells can identify the risk of tuberculosis progression from latent infection among individuals with silicosis.

CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02430259).

The role of prophylactic antibiotics in hepatitis B virus-related acute-on-chronic liver failure patients at risk of bacterial infection: a retrospective study.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is characterized by an excessive systemic inflammatory response and organ failure and has high mortality. Bacterial infections (BIs) worsen the clinical course of ACLF and carry a poor prognosis in ACLF patients. The efficacy of third-generation cephalosporins has been challenged in recent years. The aim of this study was to characterize the difference between ACLF patients with and without BIs and to provide a reference for medical intervention. METHODS: A total of 140 patients with hepatitis B virus-related ACLF (HBV-ACLF) hospitalized at the Department of Infectious Diseases, Huashan Hospital, Fudan University (Shanghai, China) between May 2013 and January 2020 were enrolled. Mann-Whitney U test was used to compare the baseline characteristics of HBV-ACLF patients with and without BIs. Univariate and multivariate analyses were performed to find predictors of BIs. The characteristics of BIs and the role of prophylactic antibiotics were profiled. RESULTS: A total of 97 episodes of BIs occurred in patients during the course of HBV-ACLF. Patients with and without BIs differed in clinical characteristics. The incidence of BIs showed a positive correlation with the ACLF grade (P = 0.003) and the clinical course (P = 0.003). The 90-day transplant-free survival of patients with BIs was lower than those without BIs (P < 0.0001). Patients administered prophylactic antibiotics showed a lower incidence of BIs and had a higher transplant-free survival probability than those who did not (P = 0.046). No statistical differences in antibiotic efficacy between third-generation and other antibiotics were observed (P = 0.108). CONCLUSIONS: BIs affected the clinical course and prognosis of patients with HBV-ACLF. Prophylactic antibiotics were of potential clinical importance in the prevention of BIs and improving the clinical course and prognosis in HBV-ACLF patients. Third-generation cephalosporins were qualified for use in antibiotic prophylaxis.

Do Stay at Home Orders and Cloth Face Coverings Control COVID-19 in New York City? Results From a SIER Model Based on Real-world Data.

BACKGROUND: Public health interventions have been implemented to contain the outbreak of coronavirus disease 2019 (COVID-19) in New York City. However, the assessment of those interventions-for example, social distancing and cloth face coverings-based on real-world data from published studies is lacking. METHODS: The Susceptible-Exposed-Infectious-Removed (SEIR) compartmental model was used to evaluate the effect of social distancing and cloth face coverings on the daily culminative laboratory confirmed cases in New York City (NYC) and COVID-19 transmissibility. The latter was measured by Rt reproduction numbers in 3 phases that were based on 2 interventions implemented during this timeline. RESULTS: Transmissibility decreased from phase 1 to phase 3. The initial R0 was 4.60 in phase 1 without any intervention. After social distancing, the Rt value was reduced by 68%, while after the mask recommendation, it was further reduced by ~60%. CONCLUSIONS: Interventions resulted in significant reduction of confirmed case numbers relative to predicted values based on the SEIR model without intervention. Our findings highlight the effectiveness of social distancing and cloth face coverings in slowing down the spread of severe acute respiratory syndrome coronavirus 2 in NYC.

Patient pathway analysis of tuberculosis diagnostic delay: a multicentre retrospective cohort study in China.

OBJECTIVES: Delay in diagnosis of tuberculosis (TB) is an important but under-appreciated problem. Our study aimed to analyse the patient pathway and possible risk factors of long diagnostic delay (LDD). METHODS: We enrolled 400 new bacteriologically diagnosed patients with pulmonary TB from 20 hospitals across China. LDD was defined as an interval between the initial care visit and the confirmation of diagnosis exceeding 14 days. Its potential risk factors were investigated by multivariate logistic regression and multilevel logistic regression. Hospitals in China were classified by increasing size, from level 0 to level 3. TB laboratory equipment in hospitals was also evaluated. RESULTS: The median diagnostic delay was 20 days (IQR: 7-72 days), and 229 of 400 patients (57.3%, 95%CI 52.4-62.1) had LDD; 15% of participants were diagnosed at the initial care visit. Compared to level 0 facilities, choosing level 2 (OR 0.27, 95%CI 0.12-0.62, p 0.002) and level 3 facilities (OR 0.34, 95%CI 0.14-0.84, p 0.019) for the initial care visit was independently associated with shorter LDD. Equipping with smear, culture, and Xpert at initial care visit simultaneously also helped to avoid LDD (OR 0.28, 95%CI 0.09-0.82, p 0.020). The multilevel logistic regression yielded similar results. Availability of smear, culture, and Xpert was lower in level 0-1 facilities than in level 2-3 facilities (p < 0.001, respectively). CONCLUSIONS: Most patients failed to be diagnosed at the initial care visit. Patients who went to low-level facilities initially had a higher risk of LDD. Improvement of TB laboratory equipment, especially at low-level facilities, is urgently needed.

Evaluations of Clinical Utilization of Metagenomic Next-Generation Sequencing in Adults With Fever of Unknown Origin.

INTRODUCTION: The diagnosis of infection-caused fever of unknown origin (FUO) is still challenging, making it difficult for physicians to provide an early effective therapy. Therefore, a novel pathogen detection platform is needed. Metagenomic next-generation sequencing (mNGS) provides an unbiased, comprehensive technique for the sequence-based identification of pathogenic microbes, but the study of the diagnostic values of mNGS in FUO is still limited. METHODS: In a single-center retrospective cohort study, 175 FUO patients were enrolled, and clinical data were recorded and analyzed to compare mNGS with culture or traditional methods including as smears, serological tests, and nucleic acid amplification testing (NAAT) (traditional PCR, Xpert MTB/RIF, and Xpert MTB/RIF Ultra). RESULTS: The blood mNGS could increase the overall rate of new organisms detected in infection-caused FUO by roughly 22.9% and 19.79% in comparison to culture (22/96 vs. 0/96; OR, ∞; p = 0.000) and conventional methods (19/96 vs. 3/96; OR, 6.333; p = 0.001), respectively. Bloodstream infection was among the largest group of those identified, and the blood mNGS could have a 38% improvement in the diagnosis rate compared to culture (19/50 vs. 0/50; OR, ∞; p = 0.000) and 32.0% compared to conventional methods (16/50 vs. 3/50; OR, 5.333; p = 0.004). Among the non-blood samples in infection-caused FUO, we observed that the overall diagnostic performance of mNGS in infectious disease was better than that of conventional methods by 20% (9/45 vs. 2/45; OR, 4.5; p = 0.065), and expectedly, the use of non-blood mNGS in non-bloodstream infection increased the diagnostic rate by 26.2% (8/32 vs. 0/32; OR, ∞; p = 0.008). According to 175 patients' clinical decision-making, we found that the use of blood mNGS as the first-line investigation could effectively increase 10.9% of diagnosis rate of FUO compared to culture, and the strategy that the mNGS of suspected parts as the second-line test could further benefit infectious patients, improving the diagnosis rate of concurrent infection by 66.7% and 12.5% in non-bloodstream infection, respectively. CONCLUSION: The application of mNGS in the FUO had significantly higher diagnostic efficacy than culture or other conventional methods. In infection-caused FUO patients, application of blood mNGS as the first-line investigation and identification of samples from suspected infection sites as the second-line test could enhance the overall FUO diagnosis rate and serve as a promising optimized diagnostic protocol in the future.

Efficacy and safety of weekly rifapentine and isoniazid for tuberculosis prevention in Chinese silicosis patients: a randomized controlled trial.

OBJECTIVE: The aim was to evaluate the efficacy, safety and completion rate of 3-month, once-weekly rifapentine and isoniazid for tuberculosis (TB) prevention among Chinese silicosis patients. METHODS: Male silicosis patients without human immunodeficiency virus infection, aged 18 years to 65 years, with or without latent TB infection, were randomized 1:1 to receive rifapentine/isoniazid under direct observation (3RPT/INH group) or were untreated (observation group). Active TB incidence was compared between the two groups with 37 months of follow-up. Safety profile and complete rates were evaluated. RESULTS: A total of 1227 adults with silicosis were screened; 513 eligible participants were enrolled and assigned to 3RPT/INH (n = 254) vs. observation (n = 259). Twenty-eight participants were diagnosed with active TB, and 9 and 19 in the 3RPT/INH group and observation groups, respectively. In the intention-to-treat analysis, the cumulative active TB rate was 3.5% (9/254) in the 3RPT/INH group and 7.3% (19/259) in the observation group (log rank p 0.055). On per protocol analysis, the cumulative active TB rates were 0.7% (1/139) and 7.3% (19/259), respectively (log rank p 0.01). Owing to an unexpected high frequency of adverse events (70.4%) and Grade 3 or 4 AEs (7.9%), the completion rate of the 3RPT/INH regimen was 54.7% (139/254). Twenty-six (10.8%) participants had flu-like systemic drug reactions; five (2.1%) experienced hepatotoxicity. DISCUSSION: Weekly rifapentine/isoniazid prophylaxis prevented active TB among Chinese people with silicosis when taken, irrespective of LTBI screening; efficacy was reduced by lack of compliance. The regimen must be used with caution because of the high rates of adverse effects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02430259.