Prognostic evaluation of quick sequential organ failure assessment score in ICU patients with sepsis across different income settings.

BACKGROUND: There is conflicting evidence on association between quick sequential organ failure assessment (qSOFA) and sepsis mortality in ICU patients. The primary aim of this study was to determine the association between qSOFA and 28-day mortality in ICU patients admitted for sepsis. Association of qSOFA with early (3-day), medium (28-day), late (90-day) mortality was assessed in low and lower middle income (LLMIC), upper middle income (UMIC) and high income (HIC) countries/regions. METHODS: This was a secondary analysis of the MOSAICS II study, an international prospective observational study on sepsis epidemiology in Asian ICUs. Associations between qSOFA at ICU admission and mortality were separately assessed in LLMIC, UMIC and HIC countries/regions. Modified Poisson regression was used to determine the adjusted relative risk (RR) of qSOFA score on mortality at 28 days with adjustments for confounders identified in the MOSAICS II study. RESULTS: Among the MOSAICS II study cohort of 4980 patients, 4826 patients from 343 ICUs and 22 countries were included in this secondary analysis. Higher qSOFA was associated with increasing 28-day mortality, but this was only observed in LLMIC (p < 0.001) and UMIC (p < 0.001) and not HIC (p = 0.220) countries/regions. Similarly, higher 90-day mortality was associated with increased qSOFA in LLMIC (p < 0.001) and UMIC (p < 0.001) only. In contrast, higher 3-day mortality with increasing qSOFA score was observed across all income countries/regions (p < 0.001). Multivariate analysis showed that qSOFA remained associated with 28-day mortality (adjusted RR 1.09 (1.00-1.18), p = 0.038) even after adjustments for covariates including APACHE II, SOFA, income country/region and administration of antibiotics within 3 h. CONCLUSIONS: qSOFA was independently associated with 28-day mortality in ICU patients admitted for sepsis. In LLMIC and UMIC countries/regions, qSOFA was associated with early to late mortality but only early mortality in HIC countries/regions.

Biofilm-Forming Capacity and Drug Resistance of Different Gardnerella Subgroups Associated with Bacterial Vaginosis.

Bacterial vaginosis (BV) is the most common infection of the lower reproductive tract among women of reproductive age. Recurrent infections and antibiotic resistance associated with biofilms remain significant challenges for BV treatment. Gardnerella species are commonly found in women with and without BV, indicating that genetic differences among Gardnerella isolates may distinguish pathogenic from commensal subgroups. This study isolated 11 Gardnerella strains from vaginal samples obtained from women with BV before or after treatment. The biofilm formation ability of each strain was examined by crystal violet staining. Eight strains were selected using phylogenetic analysis of the cpn60 sequences and classified as subgroups A (6/8), B (1/8), and D (1/8). The biofilm formation ability and antibiotic resistance profile of these strains was compared among the subgroups. Subgroup D had the strongest biofilm formation ability. Six of the planktonic strains exhibited resistance to the first-line BV drug, metronidazole, and one to clindamycin. Moreover, biofilm formation in vitro increased strain resistance to clindamycin. Two strains with strong biofilm ability, S20 and S23, and two with weak biofilm ability, S24 and S25, were selected for comparative genomic analysis. S20 and S23 were found to contain four key genes associated with biofilm formation and more genes involved in carbohydrate synthesis and metabolism than S24 and S25. Identifying differences in the expression of virulence factors between Gardnerella subgroups could inform the development of novel treatments for BV.

Single-Molecule Approach to 16S rRNA for Vaginal Microbiome Signatures in Response to Metronidazole Treatment.

Bacterial vaginosis (BV) is the most common infection of the lower reproductive tract among women of reproductive age, characterized by a depletion of health-associated Lactobacillus and an overgrowth of anaerobes. Metronidazole has been recommended as a first-line therapy for treating BV for decades. Although most cases are cured by the treatment, recurrent infections of BV seriously affect women's reproductive health. Until now, limited information on the vaginal microbiota has been explored at the species level. Here, we adopted a single molecular sequencing approach for the 16S rRNA gene, named FLAST (full-length assembly sequencing technology), to analyze the human vaginal microbiota that improved species-level resolution for taxonomy and identified microbiota alterations in the vaginal tract in response to treatment with metronidazole. Appling high-throughput sequencing, we identified 96 and 189 novel full-length 16S rRNA gene sequences in Lactobacillus and Prevotella, respectively, which had not previously been reported in vaginal samples. Moreover, we found that Lactobacillus iners was significantly enriched in the cured group before metronidazole treatment, and that was maintained in a high frequency after the treatment, suggesting an important role for this species in response to metronidazole treatment. Our research also highlights the importance of the single-molecule paradigm for progressing the field of microbiology and applying these insights to better understand the dynamic microbiota during BV treatment. Subsequent novel treatment approaches should be proposed to improve BV treatment outcomes, optimize the vaginal microbiome, and reduce gynecological and obstetric sequelae. IMPORTANCE Bacterial vaginosis (BV) is a common infectious disease of the reproductive tract. Metronidazole treatment, as the first line of treatment, frequently fails at recovery of the microbiome. However, the precise types of Lactobacillus and other bacteria involved in BV remain unclear, and this has resulted in a failure to identify potential markers to predict clinic outcomes. In this study, we adopted a 16S rRNA gene full-length assembly sequencing technology for the taxonomy analysis and evaluation of vaginal microbiota before and after treatment with metronidazole. We additionally identified 96 and 189 novel 16S rRNA gene sequences in Lactobacillus and Prevotella species, respectively, in vaginal samples, which improves our understanding of the vaginal microbiota. Moreover, we found that the abundance of Lactobacillus iners and Prevotella bivia before treatment was associated with a lack of cure. These potential biomarkers will help to facilitate future studies aimed at improving BV treatment outcomes, optimize the vaginal microbiome, and reduce adverse sexual and reproductive outcomes.

Metagenomic next-generation sequencing: A promising tool for diagnosis and treatment of suspected pneumonia in rheumatic patients with acute respiratory failure: Retrospective cohort study.

Background: The effectiveness of metagenomic next-generation sequencing (mNGS) in respiratory pathogen detection and clinical decision-making in critically rheumatic patients remains largely unexplored. Methods: A single-center retrospective study of 58 rheumatic patients who were admitted to ICU due to suspected pneumonia with acute respiratory failure if they underwent both bronchoalveolar lavage fluid specimen mNGS and combined microbiological tests (CMTs) was conducted to compare their diagnostic performance, using clinical composite diagnosis as the gold standard. Treatment modifications based on mNGS results were also reviewed. Results: Forty-three patients were diagnosed with microbiologically confirmed pneumonia and 15 were considered as a non-infectious disease. mNGS outperformed CMTs in the accurate diagnosis of infectious and non-infectious lung infiltration (98.1% [57/58] vs. 87.9% [51/58], P = 0.031). A total of 94 causative pathogens were defined by the gold standard and 27 patients had polymicrobial pneumonia. The sensitivity of pathogen detection and complete concordance with the gold standard by mNGS exceeded those by CMTs (92.6% [87/94] vs. 76.6% [72/94], P < 0.001 and 72.1% [31/43] vs. 51.2% [22/43], P = 0.004, respectively). Moreover, 22 pathogens were detected only by mNGS and confirmed by orthogonal test. Accordingly, the etiological diagnosis changed in 19 cases, and the empirical treatment improved in 14 cases, including 8 cases of rescue treatment and 11 of antibiotics de-escalation. At the pathogen-type level, both methods were comparable for bacteria, but mNGS was advantageous to identify viruses (accuracy: 100% vs. 81%, P = 0.004). For Pneumocystis jirovecii detection, mNGS improved the sensitivity compared with Gomori's methenamine silver stain (91.7% vs. 4.2%, P < 0.001) and was higher than polymerase chain reaction (79.2%), but the difference was not significant (P = 0.289). In terms of Aspergillus, the better sensitivity with a combination of culture and galactomannan test than that with mNGS was found (100% vs. 66.7%, P = 0.033). Conclusions: mNGS has an excellent accuracy in etiological diagnosis and pathogen detection of suspected pneumonia in critically rheumatic patients, which has potential significance for clinical decision-making. Its superiority to different types of pathogens depends on the comprehensiveness of CMTs.

Epidemiology, Management, and Outcomes of Sepsis in ICUs among Countries of Differing National Wealth across Asia.

Rationale: Directly comparative data on sepsis epidemiology and sepsis bundle implementation in countries of differing national wealth remain sparse. Objectives: To evaluate across countries/regions of differing income status in Asia 1) the prevalence, causes, and outcomes of sepsis as a reason for ICU admission and 2) sepsis bundle (antibiotic administration, blood culture, and lactate measurement) compliance and its association with hospital mortality. Methods: A prospective point prevalence study was conducted among 386 adult ICUs from 22 Asian countries/regions. Adult ICU participants admitted for sepsis on four separate days (representing the seasons of 2019) were recruited. Measurements and Main Results: The overall prevalence of sepsis in ICUs was 22.4% (20.9%, 24.5%, and 21.3% in low-income countries/regions [LICs]/lower middle-income countries/regions [LMICs], upper middle-income countries/regions, and high-income countries/regions [HICs], respectively; P < 0.001). Patients were younger and had lower severity of illness in LICs/LMICs. Hospital mortality was 32.6% and marginally significantly higher in LICs/LMICs than HICs on multivariable generalized mixed model analysis (adjusted odds ratio, 1.84; 95% confidence interval, 1.00-3.37; P = 0.049). Sepsis bundle compliance was 21.5% at 1 hour (26.0%, 22.1%, and 16.2% in LICs/LMICs, upper middle-income countries/regions, and HICs, respectively; P < 0.001) and 36.6% at 3 hours (39.3%, 32.8%, and 38.5%, respectively; P = 0.001). Delaying antibiotic administration beyond 3 hours was the only element independently associated with increased mortality (adjusted odds ratio, 2.53; 95% confidence interval, 2.07-3.08; P < 0.001). Conclusions: Sepsis is a common cause of admission to Asian ICUs. Mortality remains high and is higher in LICs/LMICs after controlling for confounders. Sepsis bundle compliance remains low. Delaying antibiotic administration beyond 3 hours from diagnosis is associated with increased mortality. Clinical trial registered with www.ctri.nic.in (CTRI/2019/01/016898).

Research Progress on the Correlation Between Gardnerella Typing and Bacterial Vaginosis.

Bacterial vaginosis (BV) is the most common infectious disease of the reproductive tract in women of childbearing age. It often manifests as an imbalance in the vaginal microbiome, including a decrease in Lactobacillus and an increase in anaerobic bacteria. While Gardnerella spp. are considered a major cause of BV, they are also detected in the vaginal microbiome of healthy women. G. vaginalis was the only recognized species of Gardnerella until a recent study characterized three new species, G. leopoldii, G. piotii, and G. swidsinskii. This review describes the different types and genetic diversity of Gardnerella, as well as new findings on the correlation between different Gardnerella spp. and BV.

Correlation Analysis of Vaginal Microbiome Changes and Bacterial Vaginosis Plus Vulvovaginal Candidiasis Mixed Vaginitis Prognosis.

Mixed vaginitis is the result of the simultaneous presence of different pathogenic processes mediated by at least two types of vaginal pathogens. Among the various types of mixed vaginitis presentations, bacterial vaginosis (BV) plus vulvovaginal candidiasis (VVC) presents to be the most prevalent form. Mixed vaginitis affects the health of women of all ages worldwide. However, few studies have focused on clinical manifestations, pathogenesis, diagnostic criteria, or therapy of mixed vaginitis. We recruited 48 symptomatic patients with clinical diagnoses of VVC complicated with BV, they were treated with oral metronidazole combined with local clotrimazole and followed to assess the drug efficacy and vaginal microbiome alterations before and after treatment. The vaginal microbiome in BV+VVC mixed vaginitis patients was altered significantly after the combined drug treatment within a unique form different from a simple overlay mode of BV and VVC, the key bacteria including Gardnerella and Atopobium, Lactobacillus. The combined drug therapy for the mixed vaginitis in this study was effective and enhanced treatment for BV may be more favorable because of more difficulty in dealing with BV according to the treatment outcome. The abundance of Lactobacillus in patients with mixed vaginitis affects the recovery of the vaginal microbiome as well as the prognosis, and the abundance should be actively restored. This is the first study to investigate the composition, diversity, and other characteristics of the vaginal microbiome in patients with BV+VVC mixed vaginitis before and after drug treatment, our results provide clues to improving the cure rate and reducing recurrences.

Fixed dosing of kukoamine B in sepsis patients: Results from population pharmacokinetic modelling and simulation.

AIMS: To assess the appropriateness of the body weight or fixed dosing regimen, a population pharmacokinetic (PopPK) model of kukoamine B has been built in sepsis patients. METHODS: Plasma concentrations of kukoamine B and the covariates information were taken from 30 sepsis patients assigned into 0.06 mg/kg, 0.12 mg/kg and 0.24 mg/kg groups in a Phase IIa clinical trial. The PopPK model was built using a nonlinear mixed-effect (NLME) modelling approach. Based on the final model, PK profiles were respectively simulated 500 times applying the body weight and renal function information of 12 sepsis patients from the 0.24 mg/kg group on the body weight or the fixed dosing regimen. For each dosing regimen, PK profiles of 6000 virtual patients were obtained. Statistical analyses for Cmax and Cmin were performed. If the biases of Cmax and Cmin can all meet the criteria of ±15%, the fixed dosing regimen can substitute for the body weight dosing regimen. RESULTS: The PopPK model was successfully developed using the NLME approach. A bi-compartmental model was selected as the basic model. Renal function was identified as a statistically significant covariate of systemic clearance with the objective function value (OFV) decreasing 8.6, resulting in a 5.2% decrease in inter-individual variability (IIV) of systemic clearance. Body weight was not identified as a statistically significant covariate. Simulation results demonstrated two methods had a bias of 8.1% for Cmax , and 8.6% for Cmin . Furthermore, PK variability was lower on the fixed dosing regimen than the body weight regimen. CONCLUSIONS: Based on the simulation results, a fixed dosing regimen was recommended in the subsequent clinical trials.

A Retrospective Paired Comparison Between Untargeted Next Generation Sequencing and Conventional Microbiology Tests With Wisely Chosen Metagenomic Sequencing Positive Criteria.

Objectives: To evaluate the performance of metagenomic next generation sequencing (mNGS) using adequate criteria for the detection of pathogens in lower respiratory tract (LRT) samples with a paired comparison to conventional microbiology tests (CMT). Methods: One hundred sixty-seven patients were reviewed from four different intensive care units (ICUs) in mainland China during 2018 with both mNGS and CMT results of LRT samples available. The reads per million ratio (RPMsample/RPMnon-template-control ratio) and standardized strictly mapped reads number (SDSMRN) were the two criteria chosen for identifying positive pathogens reported from mNGS. A McNemar test was used for a paired comparison analysis between mNGS and CMT. Results: One hundred forty-nine cases were counted into the final analysis. The RPMsample/RPMNTC ratio criterion performed better with a higher accuracy for bacteria, fungi, and virus than SDSMRN criterion [bacteria (RPMsample/RPMNTC ratio vs. SDSMRN), 65.1 vs. 55.7%; fungi, 75.8 vs. 71.1%; DNA virus, 86.3 vs. 74.5%; RNA virus, 90.9 vs. 81.8%]. The mNGS was also superior in bacteria detection only if an SDSMRN ≥3 was used as a positive criterion with a paired comparison to culture [SDSMRN positive, 92/149 (61.7%); culture positive, 54/149 (36.2%); p < 0.001]; however, it was outperformed with significantly more fungi and DNA virus identification when choosing both criteria for positive outliers [fungi (RPMsample/RPMNTC ratio vs. SDSMRN vs. culture), 23.5 vs. 29.5 vs. 8.7%, p < 0.001; DNA virus (RPMsample/RPMNTC ratio vs. SDSMRN vs. PCR), 14.1 vs. 20.8 vs. 11.8%, p < 0.05]. Conclusions: Metagenomic next generation sequencing may contribute to revealing the LRT infection etiology in hospitalized groups of potential fungal infections and in situations with less access to the multiplex PCR of LRT samples from the laboratory by choosing a wise criterion like the RPMsample/RPMNTC ratio.

Feasibility and efficacy of modified fixed citrate concentration protocol using only commercial preparations in critically ill patients: a prospective cohort study with a historical control group.

BACKGROUND: The cumbersome program and the shortage of commercial solution hindered the regular application of regional citrate anticoagulation (RCA). It is urgent to simplify the protocol using only commercial preparations. The aim of this study was to explore the feasibility and efficacy of the modified protocol for continuous veno-venous hemofiltration (CVVH) in unselected critically ill patients. METHODS: A prospective cohort study was conducted in 66 patients who received a new protocol combining fixed citrate concentration with modified algorithm for supplements (i.e., fixed protocol), and compared the efficacy, safety and convenience for this group to a historical control group with a traditional protocol (n = 64), where citrate was titrated according to the circuit ionized calcium concentration (i.e., titrated protocol). The convenience was defined as the demand for monitoring test and dose adjustment of any supplement. RESULTS: The filter lifespan was 63.2 ± 16.1 h in the fixed group and 51.9 ± 17.7 h in the titrated group, respectively. Kaplan-Meier survival analysis demonstrated longer circuit lifetime for fixed group (log-rank, p = 0.026). The incidence of circuit clotting was lower in the fixed protocol (15.2% vs. 29.7% in the titrated protocol, p = 0.047). Moreover, compared with the titrated group, patients with fixed protocol had less demand for monitoring test and dose adjustment of any supplement (the number of times per person per day) (3.3 [IQR 2.3-4.5] vs. 5.7 [IQR 3.3-6.9], p = 0.001 and 1.9 [IQR 0.5-2.7] vs. 6.3 [IQR 4.2-7.9], p < 0.001; respectively). No new onset bleeding complications occurred in all patients. The overall incidence of suspected citrate accumulation was 4.6% and there was no difference between the two groups (p = 0.969), yet a lower rate of metabolic alkalosis was found in the fixed group (3.0% vs. 14.1%, p = 0.024). CONCLUSIONS: Our modified fixed citrate concentration protocol is feasible, safe and effective to enhance the circuit lifespan and the convenience of implementation while maintaining a similar safety when compared to the traditional protocol. Using only commercial preparations may be helpful for widespread application of RCA. TRIAL REGISTRATION: Clinicaltrials.gov. NCT02663960 . Registered 26 January 2016.

Metagenomic next-generation sequencing for the diagnosis of suspected pneumonia in immunocompromised patients.

OBJECTIVES: To evaluate the potential of metagenomic next-generation sequencing (mNGS), compared with that of comprehensive conventional microbiological tests (CMTs), of bronchoalveolar lavage fluid (BALF) as a front-line diagnostic for immunocompromised patients with suspected pneumonia. METHODS: Sixty critically ill immunocompromised patients undergoing both mNGS of BALF and CMTs for suspected pneumonia were retrospectively analysed. The diagnostic performance was compared between mNGS and CMTs, using the composite diagnosis as the reference standard. RESULTS: Forty-nine patients were diagnosed with microbiologically confirmed pneumonia, with 55% having polymicrobial infections. There was no significant difference in the overall diagnostic accuracy between mNGS and CMTs (61.7% vs 76.7%; P = 0.11). mNGS and CMTs had comparable diagnostic accuracy for bacterial and viral infections. Although mNGS identified more viral pneumonia, it had a much lower diagnostic accuracy for fungal infections (76.7% vs 99.2%; P < 0.001), mainly due to the low sensitivity for invasive pulmonary aspergillosis (45.5% vs 100%; P < 0.001). CONCLUSION: The overall diagnostic performance of BALF mNGS as a first-line diagnostic was similar to that of comprehensive CMTs, except in the case of a lack of consideration of potential pathogens or limited CMTs. The combination of mNGS and CMTs may be the best diagnostic strategy.

Etiologies and outcomes of rheumatology patients with acute respiratory failure requiring intensive care: a single-center medical records review study of 259 patients.

OBJECTIVE: The etiologies of acute respiratory failure in patients with systemic rheumatic diseases (SRDs) requiring intensive care remain unknown. This study was undertaken to investigate the etiologies and outcomes. METHODS: A medical records review study was performed of 259 adult SRDs patients with respiratory failure admitted to medical ICU across a 5-year period. The etiologies were classified as infection, SRD exacerbation, and undetermined. The factors associated with ICU mortality were identified with multivariate logistic regression analysis. RESULTS: The etiologies of respiratory failure included infection (n = 209, 80.7%), SRD exacerbation (n = 71, 27.4%), and undetermined (n = 21, 8.1%). The most common pathogen was Pneumocystis jirovecii (39.8%), followed by Aspergillus spp. (33.2%), and cytomegalovirus (23.2%). The ICU mortality rate was 59.8%. A high acute physiology and chronic health evaluation II score (OR 1.118, 95% CI 1.054 to 1.186, p < 0.001), a PaO2/FiO2 ratio < 100 mmHg (OR 3.918, 95% CI 2.199 to 6.892, p < 0.001), and a diagnosis of dermatomyositis/polymyositis (OR 4.898, 95% CI 1.949 to 12.309, p = 0.001), vasculitis (OR 3.007, 95% CI 1.237 to 7.309, p = 0.015), and Pneumocystis pneumonia (OR 2.345, 95% CI 1.168 to 4.705, p = 0.016) were associated with increased mortality. CONCLUSIONS: Opportunistic infections and SRD exacerbation were the most common etiologies of acute respiratory failure in patients with SRDs requiring ICU admission, with high ICU mortality. Development of a standard protocol for differential diagnosis in this population might help initiate definitive therapy and improve clinical outcome. Key Points • Infections, especially with opportunistic infections, were the leading cause of acute respiratory failure in critically ill rheumatology patients, with high mortality. • Severity of illness, certain types of rheumatic diseases, and opportunistic fungal infections were associated with increased mortality. • Using a comprehensive diagnostic workup might help to confirm the infective etiology and improve outcome.

[Predictive value of central venous-to-arterial carbon dioxide partial pressure difference for fluid responsiveness in septic shock patients: a prospective clinical study].

OBJECTIVE: To evaluate the accuracy of central venous-to-arterial carbon dioxide partial pressure difference (Pcv-aCO2) before and after rapid rehydration test (fluid challenge) in predicting the fluid responsiveness in patients with septic shock. METHODS: A prospective observation was conducted. Forty septic shock patients admitted to medical intensive care unit (ICU) of Peking Union Medical College Hospital from October 2015 to June 2017 were enrolled. All of the patients received fluid challenge in the presence of invasive hemodynamic monitoring. Heart rate (HR), blood pressure, cardiac index (CI), Pcv-aCO2 and other physiological variables were recorded at 10 minutes before and immediately after fluid challenge. Fluid responsiveness was defined as an increase in CI greater than 10% after fluid challenge, whereas fluid non-responsiveness was defined as no increase or increase in CI less than 10%. The correlation between Pcv-aCO2 and CI was explored by Pearson correlation analysis. Receiver operating characteristic (ROC) curves were established to evaluate the discriminatory abilities of baseline and the changes after fluid challenge in Pcv-aCO2 and other physiological variables to define the fluid responsiveness. The patients were separated into two groups according to the initial value of Pcv-aCO2. The cut-off value of 6 mmHg (1 mmHg = 0.133 kPa) was chosen according to previous studies. The discriminatory abilities of baseline and the change in Pcv-aCO2 (ΔPcv-aCO2) were assessed in each group. RESULTS: A total of 40 patients were finally included in this study. Twenty-two patients responded to the fluid challenge (responders). Eighteen patients were fluid non-responders. There was no significant difference in baseline physiological variable between the two groups. Fluid challenge could increase CI and blood pressure significantly, decrease HR notably and had no effect on Pcv-aCO2 in fluid responders. In non-responders, blood pressure was increased significantly and CI, HR, Pcv-aCO2 showed no change after fluid challenge. Pcv-aCO2 was comparable in responders and non-responders. In 40 patients, CI and Pcv-aCO2 was inversely correlated before fluid challenge (r = -0.391, P = 0.012) and the correlation between them weakened after fluid challenge (r = -0.301, P = 0.059). There was no significant correlation between the changes in CI and Pcv-aCO2 after fluid challenge (r = -0.164, P = 0.312). The baseline Pcv-aCO2 and ΔPcv-aCO2 could not discriminate between responders and non-responders, with the area under ROC curve (AUC) of 0.50 [95% confidence interval (95%CI) = 0.32-0.69] and 0.51 (95%CI = 0.33-0.70), respectively. HR and blood pressure before fluid challenge and their changes after fluid challenge showed very poor discriminative performances. Before fluid challenge, 16 patients had a Pcv-aCO2 > 6 mmHg. Their mean CI was significantly lower and Pcv-aCO2 was significantly higher than that in 24 patients whose Pcv-aCO2 ≤ 6 mmHg [n = 24; CI (mL×s-1×m-2): 48.3±11.7 vs. 65.0±18.3, P < 0.01; Pcv-aCO2 (mmHg): 8.4±1.9 vs. 2.9±2.8, P < 0.01]. Pcv-aCO2 was decreased significantly after fluid challenge in patients with an initial Pcv-aCO2 > 6 mmHg and their ΔPcv-aCO2 was notably different as compared with the patients whose baseline Pcv-aCO2 ≤ 6 mmHg (mmHg: -3.8±3.4 vs. 0.9±2.9, P < 0.01). 68.8% (11/16) patients responded to the fluid challenge in patients with an initial Pcv-aCO2 > 6 mmHg. The AUC of the baseline Pcv-aCO2 and ΔPcv-aCO2 to define fluid responsiveness was 0.85 (95%CI = 0.66-1.00) and 0.84 (95%CI = 0.63-1.00), respectively, and the positive predictive value was 1 when the cut-off value was 8.0 mmHg and -4.2 mmHg, respectively. 45.8% (11/24) patients responded to the fluid challenge in patients whose baseline Pcv-aCO2 ≤ 6 mmHg. There was no predictive value of baseline Pcv-aCO2 and ΔPcv-aCO2 on fluid responsiveness. CONCLUSIONS: Pcv-aCO2 and its change cannot serve as a surrogate of the change in cardiac output to define the response to fluid challenge in septic shock patients whose baseline Pcv-aCO2 ≤ 6 mmHg, while the predictive values of baseline Pcv-aCO2 and the change in Pcv-aCO2 are presented in patients with the initial value of Pcv-aCO2 > 6 mmHg. CLINICAL TRIAL REGISTRATION: Clinical Trials, NCT01941472.

Stress ulcer prophylaxis in intensive care unit patients receiving enteral nutrition: a systematic review and meta-analysis.

BACKGROUND: Pharmacologic stress ulcer prophylaxis (SUP) is recommended in critically ill patients with high risk of stress-related gastrointestinal (GI) bleeding. However, as to patients receiving enteral feeding, the preventive effect of SUP is not well-known. Therefore, we performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of pharmacologic SUP in enterally fed patients on stress-related GI bleeding and other clinical outcomes. METHODS: We searched PubMed, Embase, and the Cochrane database from inception through 30 Sep 2017. Eligible trials were RCTs comparing pharmacologic SUP to either placebo or no prophylaxis in enterally fed patients in the ICU. Results were expressed as risk ratio (RR) and mean difference (MD) with accompanying 95% confidence interval (CI). Heterogeneity, subgroup analysis, sensitivity analysis and publication bias were explored. RESULTS: Seven studies (n = 889 patients) were included. There was no statistically significant difference in GI bleeding (RR 0.80; 95% CI, 0.49 to 1.31, p = 0.37) between groups. This finding was confirmed by further subgroup analyses and sensitivity analysis. In addition, SUP had no effect on overall mortality (RR 1.21; 95% CI, 0.94 to 1.56, p = 0.14), Clostridium difficile infection (RR 0.89; 95% CI, 0.25 to 3.19, p = 0.86), length of stay in the ICU (MD 0.04 days; 95% CI, -0.79 to 0.87, p = 0.92), duration of mechanical ventilation (MD -0.38 days; 95% CI, -1.48 to 0.72, p = 0.50), but was associated with an increased risk of hospital-acquired pneumonia (RR 1.53; 95% CI, 1.04 to 2.27; p = 0.03). CONCLUSIONS: Our results suggested that in patients receiving enteral feeding, pharmacologic SUP is not beneficial and combined interventions may even increase the risk of nosocomial pneumonia.

Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells.

BACKGROUND: Pericytes are members of the tumor stroma; however, little is known about their origin, function, or interaction with other tumor components. Emerging evidence suggest that pericytes may regulate leukocyte transmigration. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with powerful inhibitory effects on T-cell-mediated antitumor reactivity. METHODS: We generated subcutaneous tumors in a genetic mouse model of pericyte deficiency (the pdgfb (ret/ret) mouse) and littermate control mice (n = 6-25). Gene expression profiles from 253 breast cancer patients (stage I-III) were evaluated for clinic-pathological parameters and survival using Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) based on a two-sided Wald test. RESULTS: We report that pericyte deficiency leads to increased transmigration of Gr1(+)/CD11b(+) cells in experimentally induced tumors. Pericyte deficiency produced defective tumor vasculature, resulting in a more hypoxic microenvironment promoting IL-6 upregulation in the malignant cells. Silencing IL-6 expression in tumor cells attenuated the observed differences in MDSC transmigration. Restoring the pericyte coverage in tumors abrogated the increased MDSC trafficking to pericyte-deficient tumors. MDSC accumulation in tumors led to increases in tumor growth and in circulating malignant cells. Finally, gene expression analysis from human breast cancer patients revealed increased expression of the human MDSC markers CD33 and S100A9 with concomitant decreased expression of pericyte genes and was associated with poor prognosis (HR = 1.88, 95% CI = 1.08 to 3.25, P = .03). CONCLUSIONS: Our data uncovers a novel paracrine interaction between tumor pericytes and inflammatory cells and delineates the cellular events resulting in the recruitment of MDSC to tumors. Furthermore, we propose for the first time a role for tumor pericytes in modulating the expression of immune mediators in malignant cells by promoting a hypoxic microenvironment.

In vivo cell tracking using PhOTO zebrafish.

By combining the strength of previously described in vivo cell tracking methodologies, we have recently generated a set of transgenic zebrafish lines, called "PhOTO (photoconvertible optical tracking of…)" zebrafish. PhOTO zebrafish lines are suitable for cell tracking during highly dynamic events, including gastrulation, tissue regeneration, tumorigenesis, and cancer/disease progression. Global monitoring of cell shape, cell interactions, e.g., cell intercalations, coordinated division, and cell dynamics are accomplished by using fluorescence imaging of nuclear and plasma membrane fluorescent protein labeling. The irreversible green-to-red photoconversion property of Dendra2 fusions enables noninvasive, specific and high-contrast selection of targeted cells of interest, which greatly simplifies cell tracking and segmentation in time and space. Here we demonstrate photoconversion and in vivo cell tracking using PhOTO zebrafish.