Efficacy and safety of intravenous combined with aerosolised polymyxin versus intravenous polymyxin alone in the treatment of multidrug-resistant gram-negative bacterial pneumonia: A systematic review and meta-analysis.

Background: Previous studies have questioned the efficacy and safety of intravenous combined with aerosolised (IV + AS) polymyxin versus intravenous (IV) polymyxin alone in the treatment of patients with multidrug-resistant gram-negative bacterial (MDR-GNB) pneumonia. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of IV + AS polymyxin in the treatment of MDR-GNB pneumonia. Methods: We identified all relevant studies by searching the PubMed, EMBASE and Cochrane library databases from their inception to May 31, 2022. All included studies were evaluated using the Newcastle Ottawa scale (NOS) checklist. The summary relative risk (RR) and 95% confidence interval (CI) were used to determine the outcome differences between the IV + AS and the IV groups. Subgroup analysis was performed based on population, polymyxin dose and kinds of polymyxin. Results: A total of 16 studies were included in the meta-analysis. The IV + AS group had lower mortality (RR = 0.86, 95% CI: 0.77-0.97, P = 0.01) than the IV group. Subgroup analysis revealed that IV + AS polymyxin could reduce mortality only when used in low doses. Simultaneously, the IV + AS group outperformed the IV group in terms of clinical response rate, clinical cure rate, microbiological eradication and duration of mechanical ventilation. The duration of hospitalisation and the incidence of nephrotoxicity did not differ significantly between the two groups. Conclusions: IV + AS polymyxin is beneficial in the treatment of MDR-GNB pneumonia. It could lower patient mortality and improve clinical and microbial outcomes without increasing the risk of nephrotoxicity. However, retrospective analysis in the majority of studies and heterogeneity between studies implies that our findings must be interpreted carefully.

Hydrocortisone Combined with Vitamin C and Thiamine in the Treatment of Sepsis/Septic Shock: A Systematic Review with Meta-Analysis and Trial Sequential Analysis.

BACKGROUND: This study explored the efficacy of hydrocortisone combined with vitamin C and thiamine (HVT) in the treatment of sepsis/septic shock. METHODS: PubMed, EMBASE and Web of Science were searched (establishment of the database to October 31, 2022). The meta-analysis included randomized controlled trials (RCTs); comparing the efficacy of HVT regimen and placebo in the treatment of sepsis/septic shock. The Cochrane Handbook for Systematic Reviews of Interventions was used to assess the risk of bias. The Review Manager 5.4 software was used for meta-analysis, and the relative risk (RR), mean difference (MD) and 95% confidence intervals (CI) were then determined. Trial sequential analysis (TSA) was then conducted. RESULTS: Eight RCTs with 1,572 patients were identified. Meta-analysis showed that HVT regimen did not reduce all-cause (RR=0.96, 95% CI: 0.83 - 1.11, P=0.60), hospital (RR=1.03, 95% CI: 0.83 - 1.27, P=0.80) or intensive care unit (ICU) mortalities (RR=1.05, 95% CI: 0.86 - 1.28, P=0.65). Furthermore, there was no significant difference in the change of sequential organ failure assessment score, length of ICU stay, length of hospital stay, duration of the use of vasopressors, incidence of acute kidney injury and ventilator-free days between HVT and control groups. TSA showed that more trials are needed to confirm the results. CONCLUSIONS: HVT regimen did not reduce the mortality of patients with sepsis/septic shock and was not associated with a significant improvement in outcomes. The TSA result showed that more RCTs with high quality and large sample sizes are needed to further confirm the results.

Efficacy and Safety of Glucocorticoid in the Treatment of Acute Respiratory Distress Syndrome caused by Covid-19: A Systematic Review and Meta-Analysis.

BACKGROUND: Glucocorticoids are often used to treat acute respiratory distress syndrome (ARDS) and novel coronavirus disease 2019 (COVID-19). However, the efficacy and safety of glucocorticoids in the treatment of ARDS caused by COVID-19 are still controversial; therefore, we conducted this meta-analysis of the literature on this topic. METHODS: Four databases (PubMed, EMBASE, Cochrane Library, and Web of Science) were searched from the establishment of the databases to August 16, 2023. Randomized controlled trials (RCTs) and cohort studies that compared glucocorticoid versus standard treatment for ARDS caused by COVID-19 were included. The Newcastle-Ottawa Scale (NOS) checklist and the Cochrane Handbook for Systematic Reviews of Interventions were used to evaluate the risk of bias. Review Manager 5.4 software and STATA 17.0 were used for meta-analy-sis, and the relative risk (RR), mean difference, and 95% confidence intervals (CIs) were then determined. Results: A total of 17 studies involving 8592 patients were evaluated, including 14 retrospective studies and 3 RCTs. Sixteen studies reported data on all-cause mortality. The results of the meta-analysis showed that glucocorticoids did not reduce all-cause (RR, 0.96; 95% CI 0.82-1.13, P = .62) or 28-day (RR, 1.01; 95% CI 0.78-1.32, P = .93) mortality. Subgroup analysis showed that only methylprednisolone reduced all-cause mortality. No matter whether glucocorticoid use was early or delayed, high-dose or low-dose, long-term or short-term, no regimen reduced all-cause mortality. Furthermore, there were no significant differences in length of intensive care unit (ICU) stay, length of hospital stay, hyperglycemia, and ventilator-associated pneumonia (VAP); how-ever, glucocorticoids increased the number of ventilator-free days. CONCLUSIONS: Although methylprednisolone may reduce all-cause mortality from ARDS caused by COVID-19, this effect was not found with other types of glucocorticoids. At the same time, glucocorticoid use was associ-ated with more ventilator-free days, without increasing the incidence of hyperglycemic events or VAP. Con-sidering that almost all of the included studies were retrospective cohort studies, more RCTs are needed to confirm these findings.

Chinese ICU physicians' knowledge of antibiotic pharmacokinetics/pharmacodynamics (PK/PD): a cross-sectional survey.

BACKGROUND: Patients with sepsis have a high mortality rate, accumulated evidences suggest that an optimal antibiotic administration strategy based on pharmacokinetics/pharmacodynamics (PK/PD) can improve the prognosis of septic patients. Therefore, we assessed Chinese intensive care unit (ICU) physicians' knowledge about PK/PD. METHODS: In December 2019, we designed a questionnaire focused on Chinese ICU physicians' knowledge about PK/PD and collected the questionnaires after 3 months. The questionnaire was distributed via e-mail and WeChat, and was distributed to ICU doctors in 31 administrative regions of China except Hong Kong, Macao and Taiwan. The passing score was corrected by the Angoff method, and the ICU physicians' knowledge about PK/PD was analysed accordingly. RESULTS: We received a total of 1,309 questionnaires and retained 1,240 valid questionnaires. The passing score was 90.8, and the overall pass rate was 56.94%. The pass rate for tertiary and secondary hospitals was 59.07% and 37.19%, respectively. ICU physicians with less than 5 years of work experience and resident physician accounted for the highest pass rate, while those with between 5 to 10 years of work experience and attending accounted for the lowest pass rate. The majority of participants in the Chinese Critical Care Certified Course (5C) were from Jiangsu and Henan provinces, and they had the highest average scores (125.8 and 126.5, respectively). For Beijing and Shanghai, the average score was only 79.4 and 90.9, respectively. CONCLUSIONS: Chinese ICU physicians' knowledge about PK/PD is unsatisfactory. Therefore, it is essential to strengthen ICU physicians' knowledge about PK/PD.

Umbilical Cord Mesenchymal Stem Cells Conditioned Medium Promotes Aß25-35 phagocytosis by Modulating Autophagy and Aß-Degrading Enzymes in BV2 Cells.

Mesenchymal stem cell (MSC) therapy is a promising prospect for the treatment of Alzheimer's disease (AD); however, the underlying mechanisms by which MSCs mediate positive effects are still unclear. We speculated that MSCs mediate microglial autophagy and enhance the clearance of Aß. To test this hypothesis, we cultured BV2 microglial cells with umbilical cord mesenchymal stem cells conditioned medium (ucMSCs-CM) in the presence or absence of Aß25-35 oligomers. We investigated BV2 cell proliferation, cell death, and Aß25-35 phagocytosis as well as protein expression levels of LC3, Beclin-1, p62, insulin-degrading enzyme (IDE), and neprilysin (Nep) with western blotting. The results showed that ucMSCs-CM inhibited the proliferation and decreased cell death of BV2 cells induced by Aß25-35. ucMSCs-CM also promoted the phagocytosis of Aß25-35 by BV2 cells and changed the expression of autophagy-related proteins LC3, Beclin-1, and p62. Treatment also upregulated the expression of Aß-degrading enzymes IDE and Nep. Furthermore, the culture medium in BV2 cells with Aß25-35 and ucMSCs-CM prevented neuronal cell SH-SY5Y from cell death compared to control medium without ucMSCs-CM. Altogether, these data suggested that ucMSCs-CM protect microglial and neuronal cells from Aß25-35-induced cell death and promote Aß phagocytosis by modulating autophagy and enhancing the expression of Aß-degrading enzymes in microglia.

Pharmacokinetic variations of tetramethylpyrazine phosphate after oral administration in hepatic precancerous mice and its hepatoprotective effects.

CONTEXT: Pharmacokinetics of drug may be altered by abnormal physiological functions in illness, which will affect its pharmacodynamic efficacy in turn. OBJECTIVE: To assess the preventive effects of tetramethylpyrazine (TMPZ) phosphate on hepatocarcinogenesis and its pharmacokinetic differentiations in model mice. METHODS: Diethylnitrosamine (DEN) was adopted to induce hepatic precancerous model in mice through intraperitoneal injection, and prevention efficacy of TMPZ at a dose of 162 mg/kg was examined by liver histological analysis and activities of serum marker enzymes. Pharmacokinetic variations of TMPZ between control and model mice were measured for single oral administration. RESULTS: DEN initiation led to a remarkable increase of serum marker enzymes, and abnormality such as bile canaliculi hyperplasia and presence of tumor cells were observed in liver histopathological examination in model mice, while the control ones revealed normal architecture. Oral treatment of TMPZ resulted in a marked reduction in serum marker enzymes and improvement in liver histopathology compared with model ones. In pharmacokinetic study, values of AUC and Tmax of TMPZ became significantly greater with increase of doses in both control and model mice, which elucidated the absorption was enhanced and delayed; meanwhile, its elimination was not affected markedly. When the mice were treated at same dose, the adsorption of TMPZ in model mice was greatly improved than that in control ones, while Tmax and MRT had no significant difference. CONCLUSION: TMPZ was partly effective to protect liver from carcinogenesis initiated by DEN, and hepatic insufficiency could change its pharmacokinetics.

[Discussion on existing problems of placebo acupuncture design based on acupuncture analgesia].

In the present article, the authors made an overview about the existing problems of placebo acupuncture design in accordance with the neurological basis of acupuncture analgesia. The neuron-segmental and systemic mechanisms initiated by local somesthetic stimuli at different intensities are involved in acupuncture analgesia. When the local pain locus and the stimulated point are in the same spinal segmental region, stimuli of either higher intensity or lower intensity may produce an obvious anaIgesia effect. If the stimulation site is far from the pain locus (in remote spinal segment region), only higher intensity stimulation works. From this viewpoint, the placebo acupuncture design in current clinical trials for pain treatment exists some unreasonable aspects. Both pain focus and intensity of acupuncture stimulation should be taken into consideration together. The optimal placebo acupuncture design for the treatment of pain conditions is that lower intensity acupuncture stimulation is given for longer distance between the pain origin locus and the stimulated acupoint.

[Thinking on controlled setting of plarebo acupuncture in clinical trial of acupuncture and moxibustion].

Differences and relations between effects of acupuncture therapy and sham acupuncture are systematically analyzed in this article through the influential factors of acupuncture effect. And it is held that sham acupuncture effect is not exactly equal to placebo effect. The effects of both acupuncture and sham acupuncture are composed by specific effects and non-specific effects, and the differences of non-specific effects between acupunc ture and sham acupuncture can be minimized furthest with blinding and randomized method. Therefore, the difference of acupuncture and sham acupuncture treatment rests with the degree of differences of the specific effects. Only when both of the specific effect of acupuncture and the effect of acupuncture are minimized, can it be applied as the ideal placebo control. Consequently when placebo acupunture are setted up, factors such as the body condition, site of stimulation and stimulation parameters which can influence the specific effect of acupuncture should be taken into consideration to produce the relatively minimum specific effect.

[Quality assessment of randomized controlled trials on wenxin granule for treatment of atrial fibrillation].

OBJECTIVE: To investigate the statement on randomized controlled trials on Wenxin granule for treatment of atrial fibrillation and to judge whether those trials could offer high quality evidence or not, thus improve design level and quality. METHOD: RCTs were searched from home and abroad about atrial fibrillation treated with Wenxin granule, which reported before October, 2010. Jadad scale and CONSORT statement were used. RESULT: There were 66 RCTs retrieved that met inclusion criteria. Using Jadad rating scale, only 2 literatures gain score 4 and 1 literature gains score 3, 54 literatures gain score 2, 7 literatures gain score 1, 2 literatures gain score 0. Only 2 literatures described random number table as the method of grouping. None of the RCTs was reported the allocation concealment. Only 1 literature was used blinding. Fifty-nine literatures were mentioned the lost to follow-up conditions. According to the CONSORT standards, only six literatures (9.1%) mentioned the method of generating the random sequence. Four literatures (6.1%) were quasi-random. Nineteen literatures (28.8%) had inclusion criteria. Six literatures (9.1%) had the follow-up record. Fifty one literatures (77.3%) described the adverse events. None had the estimation of the sample size, intention-to-treat analysis and stratified analysis. None had the ethical approval or informed consent. CONCLUSION: The quality of clinical trials of Wenxin granule in treating atrial fibrillation needs to be improved.