Experiences of patients living with venous leg ulcers: A qualitative meta-synthesis.

BACKGROUND: Venous Leg Ulcer is characterized by a prolonged course, delayed healing and high recurrence rate. Bringing challenges to patient treatment and care.Patients need to control the negative behavioral factors that affect wound healing and recurrence, which seriously affect their quality of life. OBJECTIVE: To integrate qualitative research related to the disease experience and feelings of patients with Venous Leg Ulcer and provide references for optimizing patient intervention measures. METHODS: We searched databases including Pubmed, CINAHL, EMBASE, Web of Science, PsycINFO, The Cochrane library, ProQuest, CNKI and Wan Fang Data from 2000 to February 2023 to collect qualitative studies on the experiences of patients living with venous leg ulcers. We used the Australian JBI evidence-based healthcare center qualitative research quality evaluation standard to evaluate the quality of literature. After quality assessment, meta-synthesis was used to summarize and explain the results. RESULTS: Sixteen studies were eligible for inclusion, and the total number of included individuals was 146. The perceptions of individuals with Venous Leg Ulcer synthesized three overarching themes and their subthemes: disease cognition (Understanding the cause of VLU,Understanding of VLU treatment, Recognition of VLU recurrence); physical experience (Pain symptoms, Other symptoms); and psychological and social experience (psychological impact, health education, economic burden, social relations, response strategies, doctor-patient/nurse-patient relationship). CONCLUSION: The lives of patients with venous leg ulcers are influenced by various complex and diverse factors. Healthcare professionals must recognize the patient's emotional needs, establish a multidimensional support system, and promote wound healing through patient self-adjustment.

Establishment of a mathematical prediction model for voriconazole stable maintenance dose: a prospective study.

Background: In patients with invasive fungal infection (IFI), the steady-state serum trough concentration (C min) of voriconazole (VCZ) is highly variable and can lead to treatment failure (C min < 0.5 mg/L) and toxicity (C min ≥ 5.0 mg/L). However, It remains challenging to determine the ideal maintenance dose to achieve the desired C min level quickly. Aims: This randomized, prospective observational single-center study aimed to identify factors affecting VCZ-C min and maintenance dose and create an algorithmic model to predict the necessary maintenance dose. MeThe study enrolled 306 adult IFI patients, split into two groups: non-gene-directed (A) (where CYP2C19 phenotype is not involved in determining VCZ dose) and gene-directed (B) (where CYP2C19 phenotype is involved in determining VCZ dose). Results: Results indicated that CYP2C19 genetic polymorphisms might significantly impact VCZ loading and maintenance dose selection. CYP2C19 phenotype, C-reaction protein (CRP), and average daily dose/body weight were significant influencers on VCZ-C min, while CYP2C19 phenotype, CRP, and body weight significantly impacted VCZ maintenance dose. A feasible predictive formula for VCZ stable maintenance dose was derived from the regression equation as a maintenance dose (mg) =282.774-0.735×age (year)+2.946×body weight(Kg)-19.402×CYP2C19 phenotype (UM/RM/NM:0, IM:1, PM:2)-0.316×CRP (mg/L) (p < 0.001). Discussion: DiThis formula may serve as a valuable supplement to the Clinical Pharmacogenetics Implementation Consortium (CPIC®) guideline for CYP2C19 and VCZ therapy, especially for IFI patients with highly variable inflammatory cytokines during VCZ therapy.

Psittacosis caused severe community-acquired pneumonia accompanied by acute hypoxic respiratory failure: a multicenter retrospective cohort study from China.

INTRODUCTION: Psittacosis can cause severe community-acquired pneumonia (CAP). The clinical manifestations of psittacosis range from subclinical to fulminant psittacosis with multi-organ failure. It is essential to summarize the clinical characteristic of patients with severe psittacosis accompanied by acute hypoxic respiratory failure (AHRF). METHODS: This retrospective study included patients with severe psittacosis caused CAP accompanied by AHRF from 19 tertiary hospitals of China. We recorded the clinical data, antimicrobial therapy, respiratory support, complications, and outcomes. Chlamydia psittaci was detected on the basis of metagenomic next-generation sequencing performed on bronchoalveolar lavage fluid samples. Patient outcomes were compared between the treatment methods. RESULTS: This study included 45 patients with severe CAP and AHRF caused by psittacosis from April 2018 to May 2021. The highest incidence of these infections was between September and April. There was a history of poultry contact in 64.4% of the patients. The median PaO2/FiO2 of the patients was 119.8 (interquartile range, 73.2 to 183.6) mmHg. Four of 45 patients (8.9%) died in the ICU, and the median ICU duration was 12 days (interquartile range, 8 to 21) days. There were no significant differences between patients treated with fluoroquinolone initially and continued after the diagnosis, fluoroquinolone initially followed by tetracycline, and fluoroquinolone combined with tetracycline. CONCLUSION: Psittacosis caused severe CAP seems not rare, especially in the patients with the history of exposure to poultry or birds. Empirical treatment that covers atypical pathogens may benefit such patients, which fluoroquinolones might be considered as an alternative.

Polymyxin B therapy based on therapeutic drug monitoring in carbapenem-resistant organisms sepsis: the PMB-CROS randomized clinical trial.

BACKGROUND: The appropriate administration regimen of polymyxin B is yet controversial. The present study aimed to explore the optimal dose of polymyxin B under therapeutic drug monitoring (TDM) guidance. METHODS: In China's Henan province, 26 hospitals participated in a randomized controlled trial. We included patients with sepsis caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) susceptible to polymyxin B. The patients were randomly divided into a high-dose (HD) group or a low-dose (LD) group and received 150 mg loading dose, 75 mg every 12 h and 100 mg loading dose, 50 mg every 12 h, respectively. TDM was employed to determine if the dose of polymyxin B needs adjustment based on the area under the concentration-time curve across 24 h at a steady state (ssAUC0-24) of 50-100 mg h/L. The primary outcome was the 14-day clinical response, and the secondary outcomes included 28- and 14-day mortality. RESULTS: This trial included 311 patients, with 152 assigned to the HD group and 159 assigned to the LD group. Intention-to-treat analysis showed that the 14-day clinical response was non-significant (p = 0.527): 95/152 (62.5%) in the HD group and 95/159 (59.7%) in the LD group. Kaplan-Meier's 180-day survival curve showed survival advantage in the HD group than in the LD group (p = 0.037). More patients achieved the target ssAUC0-24 in the HD than in the LD group (63.8% vs. 38.9%; p = 0.005) and in the septic shock subgroup compared to all subjects (HD group: 71.4% vs. 63.8%, p = 0.037; LD group: 58.3% vs. 38.9%, p = 0.0005). Also, the target AUC compliance was not correlated with clinical outcomes but with acute kidney injury (AKI) (p = 0.019). Adverse events did not differ between the HD and LD groups. CONCLUSION: A fixed polymyxin B loading dose of 150 mg and a maintenance dose of 75 mg every 12 h was safe for patients with sepsis caused by CR-GNB and improves long-term survival. The increased AUC was associated with increased incidence of AKI, and TDM results were valued to prevent AKI. Trial registration Trial registration ClinicalTrials.gov: ChiCTR2100043208, Registration date: January 26, 2021.

Incidence, clinical characteristics, risk factors and outcomes of patients with mixed Candida/bacterial bloodstream infections: a retrospective study.

PURPOSE: The mixed Candida/bacterial bloodstream infections (mixed C/B-BSIs) is worthy of particular attention recently, and we analyzed the incidence, co-pathogens, clinical characteristics, risk factors, and outcomes of mixed C/B-BSIs compared with monomicrobial candidemia (mono-candidemia) in adult patients in China. METHODS: All hospitalized adults with candidemia were recruited for this retrospective observational study from January 1, 2013, to December 31, 2019. RESULTS: Of the 296 patients with candidemia, 78 cases (26.3%) were mixed C/B-BSIs. Candida albicans (C. albicans) was the most common Candida species among all candidemia, and Klebsiella pneumoniae (K. pneumoniae) was the most concomitant bacteria (30.6%), followed by Acinetobacter baumannii (A. baumannii) (12.9%) and Enterococcus faecium (E. faecium) (11.8%) in mixed C/B-BSIs. In the multivariable analysis, prior ß-lactams exposure [adjusted odds ratio (aOR), 1.97; 95% confidence interval (CI), 1.01-3.87], burn injury (aOR, 6.35; 95% CI 1.82-22.21) and continuous renal replacement therapy (CRRT) (aOR, 3.00; 95% CI 1.46-6.17) were independent risk factors for mixed C/B-BSIs. Compared with mono-candidemia, patients with mixed C/B-BSIs developed with more proportion of septic shock (55.1% vs. 39.9%, P < 0.05), prolonged stay in ICU [22.0(12.0-57.0) vs. 9.5(0.0-37.0) days, P < 0.001] and longer mechanical ventilation time [19.0(4.5-40.8) vs. 6.0(0.0-24.8) days, P < 0.001]. The in-hospital mortality in patients with mixed C/B-BSIs was higher than those with mono-candidemia (59.0% vs. 34.9%, P < 0.001). Survival analysis revealed that 28-day and 60-day mortality were significantly higher in patients with mixed C/B-BSI than in those with mono-candidemia (57.7% vs. 31.7%, P < 0.001; 59.0% vs. 34.9%, P < 0.001; respectively). CONCLUSIONS: There is a high rate of mixed C/B-BSIs cases among candidemia, and K. pneumoniae is the predominant coexisting species. Prior ß-lactams exposure, burn injury, and CRRT are independent risk factors for mixed C/B-BSIs. The mortality of patients with mixed C/B-BSIs is significantly higher than those with mono-candidemia, this deserves further attention for clinicians.

Development and validation of a risk prediction score for the severity of acute hypertriglyceridemic pancreatitis in Chinese patients.

BACKGROUND: The frequency of acute hypertriglyceridemic pancreatitis (AHTGP) is increasing worldwide. AHTGP may be associated with a more severe clinical course and greater mortality than pancreatitis caused by other causes. Early identification of patients with severe inclination is essential for clinical decision-making and improving prognosis. Therefore, we first developed and validated a risk prediction score for the severity of AHTGP in Chinese patients. AIM: To develop and validate a risk prediction score for the severity of AHTGP in Chinese patients. METHODS: We performed a retrospective study including 243 patients with AHTGP. Patients were randomly divided into a development cohort (n = 170) and a validation cohort (n = 73). Least absolute shrinkage and selection operator and logistic regression were used to screen 42 potential predictive variables to construct a risk score for the severity of AHTGP. We evaluated the performance of the nomogram and compared it with existing scoring systems. Last, we used the best cutoff value (88.16) for severe acute pancreatitis (SAP) to determine the risk stratification classification. RESULTS: Age, the reduction in apolipoprotein A1 and the presence of pleural effusion were independent risk factors for SAP and were used to construct the nomogram (risk prediction score referred to as AAP). The concordance index of the nomogram in the development and validation groups was 0.930 and 0.928, respectively. Calibration plots demonstrate excellent agreement between the predicted and actual probabilities in SAP patients. The area under the curve of the nomogram (0.929) was better than those of the Bedside Index of Severity in AP (BISAP), Ranson, Acute Physiology and Chronic Health Evaluation (APACHE II), modified computed tomography severity index (MCTSI), and early achievable severity index scores (0.852, 0.825, 0.807, 0.831 and 0.807, respectively). In comparison with these scores, the integrated discrimination improvement and decision curve analysis showed improved accuracy in predicting SAP and better net benefits for clinical decisions. Receiver operating characteristic curve analysis was used to determine risk stratification classification for AHTGP by dividing patients into high-risk and low-risk groups according to the best cutoff value (88.16). The high-risk group (> 88.16) was closely related to the appearance of local and systemic complications, Ranson score ≥ 3, BISAP score ≥ 3, MCTSI score ≥ 4, APACHE II score ≥ 8, C-reactive protein level ≥ 190, and length of hospital stay. CONCLUSION: The nomogram could help identify AHTGP patients who are likely to develop SAP at an early stage, which is of great value in guiding clinical decisions.

The Application Value of Metagenomic and Whole-Genome Capture Next-Generation Sequencing in the Diagnosis and Epidemiological Analysis of Psittacosis.

Background: To evaluate the value of metagenomic next-generation sequencing (mNGS) for the early diagnosis of psittacosis, and to investigate its epidemiology by whole-genome capture. Methods: Twenty-one bronchoalveolar lavage fluid (BALF) and blood samples of 16 psittacosis patients from multiple centers during August 2019 to September 2021 were analyzed retrospectively. mNGS with normal datasets (10 M 75-bp single-end reads after sequencing) and larger datasets (30 M 150-bp paired-end reads after sequencing) as well as quantitative real-time polymerase chain reaction (qPCR) were used to detect the pathogen. Also, whole-genome capture of Chlamydophila psittaci was applied to draw the phylogenetic tree. Results: mNGS successfully detected the pathogen in all 16 cases (100%), while qPCR was positive only in 5 out of 10 cases (50%), indicating a significantly higher sensitivity of mNGS than qPCR (p < 0.01). BALF-mNGS performed better than blood-mNGS (16/16 versus 3/5, p < 0.05). In addition, larger datasets (the read counts have tripled, and the base number was 12-fold larger compared to clinical mNGS with a normal dataset) of mNGS showed significantly increased contents of human DNA (p < 0.05) and decreased reads per million of the pathogen, suggesting no improvement. Whole-genome capture results of five samples (>60% coverage and >1 depth) were used to construct the phylogenetic tree. Conclusion: Significant advantages of mNGS with normal datasets were demonstrated in early diagnosing psittacosis. It is the first study to use whole-genome capture to analyze C. psittaci epidemiological information.

Long noncoding RNA MIR3142HG accelerates lipopolysaccharide-induced acute lung injury via miR-95-5p/JAK2 axis.

The study aims to clarify the expression pattern of MIR3142HG in acute lung injury (ALI) and investigate the potential mechanisms for the regulatory role of MIR3142HG in JAK/STAT in ALI. Notably, the ALI patients presented the overexpression of MIR3142HG and JAK2 in their serum samples. Knockdown of MIR3142HG facilitated cell viability but impaired cell apoptosis and inflammatory response via targeting miR-95-5p in lipopolysaccharide (LPS)-treated ALI cells. Overexpression of miR-95-5p promoted cell viability but suppressed apoptosis and inflammatory response via targeting JAK2 in LPS-induced ALI cells. The rescue experiments indicated that inhibition of miR-95-5p could reverse the increased cell viability and promote the inhibited apoptosis and inflammatory response induced by MIR3142HG knockdown in LPS-induced ALI. In conclusion, MIR3142HG is increased in sepsis-induced ALI, and MIR3142HG could accelerate the progression of sepsis-induced ALI through miR-95-5p/JAK2 axis, providing theoretical evidence for MIR3142HG to be a promising target for the therapeutics of ALI.

Age-specific effectiveness of primary human papillomavirus screening versus cytology in a cervical cancer screening program: a nationwide cross-sectional study.

BACKGROUND: Primary human papillomavirus (HPV) screening is recommended for the detection of cervical intraepithelial neoplasia (CIN) in the general population; however, the triage for HPV-positive women remains a challenge. This study aimed to evaluate the age-specific effectiveness of primary HPV screening versus primary cytology screening for identifying optimal strategies for women of different ages. METHODS: The dataset of the prevalence round screening was derived from the National Cervical Cancer Screening Program in China. Primary cervical screening protocols included cytology only, HPV testing with cytology triage, and HPV testing with HPV-16/18 genotyping plus cytology triage. The primary outcomes were age-specific detection rate, colposcopy referral rate and positive predictive value (PPV) for CIN2+. Multivariate Poisson regression was used to evaluate the relative effectiveness of HPV testing and cytology according to age groups. The I2 statistic with a random-effect model was used to test the heterogeneity in relative effectiveness of HPV testing versus cytology between age groups. RESULTS: This study included 1,160,981 women. HPV testing with HPV-16/18 genotyping plus cytology triage significantly increased the CIN2+ detection by 36% (rate ratio [RR]: 1.36, 95% confidential interval [CI] 1.21-1.54) for women aged 35-44 years and by 34% (RR: 1.34, 95% CI 1.20-1.51) for women aged 45-54 years compared with cytology only. HPV testing with cytology triage had similar CIN2+ detection rate compared with cytology only. The PPVs were substantially increased for both HPV testing groups. Among women aged 55-64 years old, HPV testing with HPV-16/18 genotyping plus cytology triage increased the colposcopy referral rate by 19% (RR 1.19, 95% CI 1.10-1.29) compared with cytology only, but did not increase the CIN2+ detection (1.09, 0.91-1.30). The effectiveness of HPV testing with cytology triage did not change in older women. The between-age-group heterogeneity in the effectiveness was statistically significant for HPV testing with HPV-16/18 genotyping plus cytology triage versus cytology only. CONCLUSIONS: Our results suggested that the effectiveness of primary HPV screening with different triage strategies differed among age groups. HPV testing with HPV-16/18 genotyping plus cytology triage could be used for women aged 35-54 years to detect more lesions, and HPV testing with cytology triage could balance the CIN2+ detection and the number of colposcopies for women aged 55-64 years. Longitudinal data including both prevalence and incidence screening rounds are warranted to assess age-specific triage strategies.

Deep RNA Sequencing Revealed Fusion Junctional Heterogeneity May Predict Crizotinib Treatment Efficacy in ALK-Rearranged NSCLC.

INTRODUCTION: Gene fusion variants in ALK-rearranged NSCLC may predict patient outcomes, but previous results have been inconclusive. Fusion isoforms coexisting in the same tumor may affect the efficacy of targeted therapy, but they have not been investigated. METHODS: Patients with ALK-rearranged NSCLC who received crizotinib treatments were recruited. Precrizotinib tumor tissues were analyzed by the anchored multiplex polymerase chain reaction for targeted RNA sequencing. Kaplan-Meier and Cox regression were used to compare overall and progression-free survivals. RESULTS: Of the 51 studied subjects, EML4-ALK variant types v1, v2, v3, and others were detected in 23 (45.1%), five (9.8%), 19 (37.3%), and four patients (7.8%), respectively. Multiple EML4-ALK RNA isoforms were detected in 24 tumors (47.1%), and single isoform in 27 (52.9%). Most of the v3 tumors (16 of 19) harbored both v3a and v3b RNA isoforms. Multiple isoforms were also detected in eight non-v3 tumors (33.3% of all 24 multiple isoforms; five v1, two v5', and one v2). Compared with patients with single isoform, those with multiple isoforms had worse progression-free (hazard ratio and 95% confidence interval: 2.45 [1.06-5.69]) and overall (hazard ratio [95% confidence interval]: 3.74 [1.26-11.13]) survivals after adjusting for potential confounders including variant type. Using the patient-derived H2228 cells known to express v3a and v3b, our single-cell polymerase chain reaction detected either v3a or v3b in most single cells. Treatment of H2228 cells by three ALK inhibitors revealed increased ratios of v3a-to-v3b expression over time. CONCLUSIONS: Intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted.

Real-world effectiveness of primary screening with high-risk human papillomavirus testing in the cervical cancer screening programme in China: a nationwide, population-based study.

BACKGROUND: Randomized controlled trials have shown a higher sensitivity and longer negative predictive value of high-risk human papillomavirus (HPV) testing than cytology for cervical cancer screening; however, little is known about the effectiveness of HPV testing in middle-income countries. Understanding the characteristics of HPV testing may increase the priority of HPV testing in health policies. The study aims to evaluate the effectiveness of HPV testing in the national cervical cancer screening programme in China. METHODS: We performed a nationwide, population-based study using individual data from the national cervical cancer screening programme in rural China between 2015 and 2017. The analyses included 1,160,981 women aged 35-64 years who underwent cytology alone or high-risk HPV testing with cytology or genotyping triage. The main outcome was cervical intraepithelial neoplasia 2 or worse (CIN2+). We used multivariate logistic regressions and performed sensitivity analyses with propensity score matching to compare the screening positive, colposcopy referral, detection rate, and positive predictive value (PPV). RESULTS: The screening positive rates for HPV testing and cytology were 10.1% and 4.0%, respectively. The per protocol colposcopy referral rate of HPV testing was significantly lower than that of cytology (3.5% vs 4.0%), and this difference was mostly due to the low referral threshold of cytology (≥ASC-US). Overall, HPV testing detected more CIN2+ (5.5 vs. 4.4 per 1000, adjusted odds ratio [aOR]=1.18, 95% confidence interval 1.11-1.25) and had a higher PPV (13.8% vs 10.9%, aOR 1.29, 95% CI 1.21-1.37) than cytology. The colposcopy referrals of HPV testing in comparison to cytology differed by income status; it significantly increased in lower-middle-income areas (3.7% vs 3.1%, aOR 1.21, 95% CI 1.17-1.25) and significantly decreased in upper-middle-income areas (3.4% vs 4.9%, aOR 0.69, 95% CI 0.67-0.71). Sensitivity analyses demonstrated the reliability and robustness of the results. CONCLUSIONS: The introduction of HPV testing could improve both the CIN2+ detection rate and efficiency of cervical cancer screening programme, supporting the introduction of primary screening with high-risk HPV testing in China. Further study is needed to investigate the long-term effect of this change.

Endothelin receptor antagonists for pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension is a devastating disease that leads to right heart failure and premature death. Endothelin receptor antagonists have shown efficacy in the treatment of pulmonary arterial hypertension. OBJECTIVES: To evaluate the efficacy of endothelin receptor antagonists (ERAs) in pulmonary arterial hypertension. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the reference sections of retrieved articles. The searches are current as of 4 November 2020. SELECTION CRITERIA: We included randomised trials and quasi-randomised trials involving participants with pulmonary arterial hypertension. DATA COLLECTION AND ANALYSIS: Two of five review authors selected studies, extracted data and assessed study quality according to established criteria. We used standard methods expected by Cochrane. The primary outcomes were exercise capacity (six-minute walk distance, 6MWD), World Health Organization (WHO) or New York Heart Association (NYHA) functional class, Borg dyspnoea scores and dyspnoea-fatigue ratings, and mortality. MAIN RESULTS: We included 17 randomised controlled trials involving a total of 3322 participants. Most trials were of relatively short duration (12 weeks to six months). Sixteen trials were placebo-controlled, and of these nine investigated a non-selective ERA and seven a selective ERA.   We evaluated two comparisons in the review: ERA versus placebo and ERA versus phosphodiesterase type 5 (PDE5) inhibitor. The abstract focuses on the placebo-controlled trials only and presents the pooled results of selective and non-selective ERAs. After treatment, participants receiving ERAs could probably walk on average 25.06 m (95% confidence interval (CI) 17.13 to 32.99 m; 2739 participants; 14 studies; I2 = 34%, moderate-certainty evidence) further than those receiving placebo in a 6MWD. Endothelin receptor antagonists probably improved more participants' WHO functional class (odds ratio (OR) 1.41, 95% CI 1.16 to 1.70; participants = 3060; studies = 15; I2 = 5%, moderate-certainty evidence) and probably lowered the odds of functional class deterioration (OR 0.43, 95% CI 0.26 to 0.72; participants = 2347; studies = 13; I2 = 40%, moderate-certainty evidence) compared with placebo. There may be a reduction in mortality with ERAs (OR 0.78, 95% CI 0.58, 1.07; 2889 participants; 12 studies; I2 = 0%, low-certainty evidence), and pooled data suggest that ERAs probably improve cardiopulmonary haemodynamics and may reduce Borg dyspnoea score in symptomatic patients. Hepatic toxicity was not common, but may be increased by ERA treatment from 37 to 67 (95% CI 34 to 130) per 1000 over 25 weeks of treatment (OR 1.88, 95% CI 0.91 to 3.90; moderate-certainty evidence). Although ERAs were well tolerated in this population, several cases of irreversible liver failure caused by sitaxsentan have been reported, which led the licence holder for sitaxsentan to withdraw the product from all markets worldwide.  As planned, we performed subgroup analyses comparing selective and non-selective ERAs, and with the exception of mean pulmonary artery pressure, did not detect any clear subgroup differences for any outcome. AUTHORS' CONCLUSIONS: For people with pulmonary arterial hypertension with WHO functional class II and III, endothelin receptor antagonists probably increase exercise capacity, improve WHO functional class, prevent WHO functional class deterioration, result in favourable changes in cardiopulmonary haemodynamic variables compared with placebo. However, they are less effective in reducing dyspnoea and mortality. The efficacy data were strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in people treated with ERAs. The question of the effects of ERAs on pulmonary arterial hypertension has now likely been answered.. The combined use of ERAs and phosphodiesterase inhibitors may provide more benefit in pulmonary arterial hypertension; however, this needs to be confirmed in future studies.

[The value of growth differentiation factor-15 and extravascular lung water index in severity grading of acute respiratory distress syndrome patients and their prognosis prediction].

OBJECTIVE: To investigate the value of growth differentiation factor-15 (GDF-15) and extravascular lung water index (EVLWI) in severity grading and prognosis prediction of patients with acute respiratory distress syndrome (ARDS). METHODS: Patients with ARDS aged 18-75 years admitted to the department of respiratory intensive care unit (RICU) of Zhengzhou Central Hospital Affiliated to Zhengzhou University from January 2019 to February 2020 were enrolled. All patients were treated with conventional therapies such as mechanical ventilation, anti-infection, stabilization of water, electrolytes and acid-base environment, blood purification and nutritional support according to their conditions. Besides, the pulse-indicated continuous cardiac output (PiCCO) was performed after admission to the department, and EVLWI before treatment and at 24, 48 and 72 hours of treatment were recorded. Serum GDF-15 level was measured by enzyme linked immunosorbent assay (ELISA) during the same period. Patients were classified as mild, moderate, and severe degree according to the 2012 Berlin Definition of ARDS, and EVLWI and GDF-15 levels in patients with different disease levels before and after treatment were compared. In addition, the length of intensive care unit (ICU) stay, ICU mortality, and 28-day mortality of patients with different GDF-15 or EVLWI levels were analyzed comparatively, with the GDF-15 3 458 ng/L and EVLWI 15 mL/kg as the cut point. RESULTS: A total of 82 patients with ARDS were enrolled, including 22 patients with mild ARDS, 28 patients with moderate ARDS, and 32 patients with severe ARDS. The GDF-15 and EVLWI levels in patients with moderate and severe ARDS at each time point before and after treatment were higher than those in patients with mild ARDS. Both GDF-15 and EVLWI levels in patients with severe ARDS were higher than those in the patients with moderate ARDS. The differences were statistically significant at all the time points except for the difference of GDF-15 levels at 24 hours after treatment (ng/L: 3 900.41±546.43 vs. 3 695.66±604.73, P > 0.05). [GDF-15 (ng/L): 3 786.11±441.45 vs. 3 106.83±605.09 before treatment, 3 895.48±558.96 vs. 3 333.29±559.66 at 48 hours, 3 397.33±539.56 vs. 3 047.53±499.57 at 72 hours; EVLWI (mL/kg): 19.06±1.91 vs. 14.31±1.50 before treatment, 18.56±2.23 vs. 13.26±1.69 at 24 hours, 17.23±1.76 vs. 12.45±1.36 at 48 hours, 15.47±1.81 vs. 11.13±2.19 at 72 hours, all P < 0.05]. According to the cut-off value, there were 23 patients with GDF-15 ≥ 3 458 ng/L and GDF-15 < 3 458 ng/L respectively and there were 23 patients with EVLWI ≥ 15 mL/kg and EVLWI < 15 mL/kg respectively. The length of ICU stay and 28-day mortality in patients with high GDF-15 were significantly higher than those in patients with low GDF-15 [length of ICU stay (days): 21.22±2.69 vs. 15.37±3.14, 28-day mortality: 56.5% vs. 21.7%, both P < 0.05]. The length of ICU stay and 28-day mortality in patients with high EVLWI were also significantly higher than those in patients with low EVLWI [length of ICU stay (days): 18.45±2.61 vs. 14.98±2.75, 28-day mortality: 47.8% vs. 17.4%, both P < 0.05]. CONCLUSIONS: To some extent, GDF-15 and EVLWI levels reflect the severity of patients with ARDS, and high GDF-15 and EVLWI levels are significantly associated with poor prognosis in patients with ARDS.

Simultaneous Detection of Gene Fusions and Base Mutations in Cancer Tissue Biopsies by Sequencing Dual Nucleic Acid Templates in Unified Reaction.

BACKGROUND: Targeted next-generation sequencing is a powerful method to comprehensively identify biomarkers for cancer. Starting material is currently either DNA or RNA for different variations, but splitting to 2 assays is burdensome and sometimes unpractical, causing delay or complete lack of detection of critical events, in particular, potent and targetable fusion events. An assay that analyzes both templates in a streamlined process is eagerly needed. METHODS: We developed a single-tube, dual-template assay and an integrated bioinformatics pipeline for relevant variant calling. RNA was used for fusion detection, whereas DNA was used for single-nucleotide variations (SNVs) and insertion and deletions (indels). The reaction chemistry featured barcoded adaptor ligation, multiplexed linear amplification, and multiplexed PCR for noise reduction and novel fusion detection. An auxiliary quality control assay was also developed. RESULTS: In a 1000-sample lung tumor cohort, we identified all major SNV/indel hotspots and fusions, as well as MET exon 14 skipping and several novel or rare fusions. The occurrence frequencies were in line with previous reports and were verified by Sanger sequencing. One noteworthy fusion event was HLA-DRB1-MET that constituted the second intergenic MET fusion ever detected in lung cancer. CONCLUSIONS: This method should benefit not only a majority of patients carrying core actionable targets but also those with rare variations. Future extension of this assay to RNA expression and DNA copy number profiling of target genes such as programmed death-ligand 1 may provide additional biomarkers for immune checkpoint therapies.

Association of China's universal two child policy with changes in births and birth related health factors: national, descriptive comparative study.

OBJECTIVE: To measure the association of China's universal two child policy, announced in October 2015, with changes in births and health related birth characteristics. DESIGN: National, descriptive before-and-after comparative study. SETTING: Every county in 28 of 31 provinces of mainland China. PARTICIPANTS: Births included in two national databases: 67 786 749 births from county level monthly aggregated data between January 2014 and December 2017; and 31 786 279 deliveries from individual level delivery information records between January 2015 and December 2017. MAIN OUTCOME MEASURES: Monthly mean number of births and mean proportion of multiparous mothers and mothers aged 35 and over, preterm deliveries, and caesarean deliveries. RESULTS: The study had two phases: the baseline period (up to and including June 2016, nine months after the policy announcement) and the effective period (from July 2016 to December 2017). The estimated number of additional births attributable to the new policy between July 2016 and December 2017 was 5.40 million (95% confidence interval 4.34 to 6.46). The monthly mean percentage of multiparous mothers and mothers aged 35 and over increased by 9.1 percentage points (95% confidence interval 6.4 to 11.7) and 5.8 percentage points (5.2 to 6.4), respectively. This increase in older mothers, however, was not associated with a concurrent increase in the overall rate of preterm birth. The monthly mean caesarean delivery rate among multiparous mothers increased by 1.2 percentage points (0.8 to 1.6) from 39.7% to 40.9%, and decreased by 3.0 percentage points (-3.5 to -2.5) among nulliparous mothers from 39.6% to 36.6%. CONCLUSIONS: Since its announcement in October 2015, the universal two child policy has been associated with a rise in births in China and with changes in health related birth characteristics: women giving birth have been more likely to be multiparous, and more likely to be aged 35 and over. No evidence of concurrent worsening outcomes (that is, premature births) was seen.

Retrospective analysis of relationships among the dose regimen, trough concentration, efficacy, and safety of teicoplanin in Chinese patients with moderate-severe Gram-positive infections.

OBJECTIVES: Teicoplanin, an antibiotic, has poor clinical efficacy when using the current drug label's recommended regimen, which is approved by the China Food and Drug Administration. This study explores the appropriate loading and maintenance doses of teicoplanin and evaluates the therapeutic target of teicoplanin trough concentration (minimum concentration [Cmin]). SUBJECTS AND METHODS: All patients treated with teicoplanin from February 2015 to August 2016 at Zhengzhou Central Hospital were screened for enrollment. A total of 113 subjects were included and then divided into four groups: A (received three to six doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 400 mg/day), B (received three doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 400 mg/day), C (received two doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 200 mg/day), and D (received one to three doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 200 mg/day). Cmin values of teicoplanin were detected with high-performance liquid chromatography on day 4, 30 minutes before maintenance-dose administration. Teicoplanin Cmin, efficacy, and safety were compared among the four groups. RESULTS: Mean Cmin differed significantly among the four groups (A, 18.11±6.37 mg/L; B, 15.91±4.94 mg/L; C, 17.06±5.66 mg/L; D, 11.97±3.76 mg/L) (P<0.001), with creatinine clearance of 89.62 (53.72-162.48), 49.66 (40.69-59.64), 27.17 (9.7-39.45), and 96.6 (17.63-394.73) mL/min, respectively. The ratio of loading dose for 3 days to creatinine clearance and serum Cmin were significantly correlated (R=0.59, P<0.001). The correlation between the estimated probability of success and teicoplanin Cmin was assessed using binary logistic regression (OR 2.049, P<0.001). Hepatotoxicity- and nephrotoxicity-incidence rates did not significantly differ among the four groups (P=0.859 and P=0.949, respectively). CONCLUSION: A loading dose of 400 mg at 12-hour intervals three to six times is needed to achieve the early target range (15-20 mg/L) and improve the clinical efficacy rate for normal-renal-function patients. It is urgently necessary to amend the drug label for the recommended regimen.

Progress and challenges in maternal health in western China: a Countdown to 2015 national case study.

BACKGROUND: China is one of the few Countdown countries to have achieved Millennium Development Goal 5 (75% reduction in maternal mortality ratio between 1990 and 2015). We aimed to examine the health systems and contextual factors that might have contributed to the substantial decline in maternal mortality between 1997 and 2014. We chose to focus on western China because poverty, ethnic diversity, and geographical access represent particular challenges to ensuring universal access to maternal care in the region. METHODS: In this systematic assessment, we used data from national census reports, National Statistical Yearbooks, the National Maternal and Child Health Routine Reporting System, the China National Health Accounts report, and National Health Statistical Yearbooks to describe changes in policies, health financing, health workforce, health infrastructure, coverage of maternal care, and maternal mortality by region between 1997 and 2014. We used a multivariate linear regression model to examine which contextual and health systems factors contributed to the regional variation in maternal mortality ratio in the same period. Using data from a cross-sectional survey in 2011, we also examined equity in access to maternity care in 42 poor counties in western China. FINDINGS: Maternal mortality declined by 8·9% per year between 1997 and 2014 (geometric mean ratio for each year 0·91, 95% CI 0·91-0·92). After adjusting for GDP per capita, length of highways, female illiteracy, the number of licensed doctors per 1000 population, and the proportion of ethnic minorities, the maternal mortality ratio was 118% higher in the western region (2·18, 1·44-3·28) and 41% higher in the central region (1·41, 0·99-2·01) than in the eastern region. In the rural western region, the proportion of births in health facilities rose from 41·9% in 1997 to 98·4% in 2014. Underpinning such progress was the Government's strong commitment to long-term strategies to ensure access to delivery care in health facilities-eg, professionalisation of maternity care in large hospitals, effective referral systems for women medically or socially at high risk, and financial subsidies for antenatal and delivery care. However, in the poor western counties, substantial disparity by education level of the mother existed in access to health facility births (44% of illiterate women vs 100% of those with college or higher education), antenatal care (17% vs 69%) had at least four visits), and caesarean section (8% vs 44%). INTERPRETATION: Despite remarkable progress in maternal survival in China, substantial disparities remain, especially for the poor, less educated, and ethnic minority groups in remote areas in western China. Whether China's highly medicalised model of maternity care will be an answer for these populations is uncertain. A strategy modelled after China's immunisation programme, whereby care is provided close to the women's homes, might need to be explored, with township hospitals taking a more prominent role. FUNDING: Government of Canada, UNICEF, and the Bill & Melinda Gates Foundation.