Genomic Insights into the First Emergence of blaNDM-5-Carrying Carbapenem-Resistant Salmonella enterica Serovar London Strain in China.

Carbapenem-resistant Salmonella enterica (S. enterica) pose a significant threat to public health, causing gastroenteritis and invasive infections. We report the first emergence of a carbapenem-resistant S. enterica serovar London strain, A132, carrying the blaNDM-5 gene in China. Whole-genome sequencing and bioinformatics analysis assigned A132 to be ST155, a multidrug-resistant clone frequently reported in China. The strain A132 exhibited resistance to multiple antibiotics, with 20 acquired antibiotic resistance genes (ARGs) identified, predominantly located on the IncFIB plasmid (pA132-1-NDM). Notably, the blaNDM-5 gene was located within an IS26 flanked-class 1 integron-ISCR1 complex, comprising two genetic cassettes. One cassette is the class 1 integron, which may facilitate the transmission of the entire complex, while the other is the blaNDM-5-containing ISCR1-IS26-flanked cassette, carrying multiple other ARGs. Genbank database search based on the blaNDM-5-carrying cassette identified a similar genetic context found in transmissible IncFIA plasmids from Escherichia coli (p91) and Enterobacter hormaechei (p388) with a shared host range, suggesting the potential for cross-species transmission of blaNDM-5. To our knowledge, this is the first reported case of Salmonella serovar London ST155 harboring blaNDM-5 gene. Phylogenetic analysis indicated a close relationship between A132 and eight S. London ST155 strains isolated from the same province. However, A132 differed by carrying the blaNDM-5 gene and four unique ARGs. Given the high transmissibility of the F-type plasmid harboring blaNDM-5 and 18 other ARGs, it is imperative to implement vigilant surveillance and adopt appropriate infection control measures to mitigate the threat to public health.

Monitoring the long-term spatiotemporal transmission dynamics and ecological surveillance of multidrug-resistant Salmonella enterica serovar Goldcoast: A multicenter genomic epidemiology study.

The emergence of multidrug-resistant Salmonella enterica serovar Goldcoast poses a significant threat to the effective treatment and control of salmonellosis within the ecological environment. Here, we conducted a genomic epidemiological study delineate the global dissemination scenarios of the multidrug-resistant S. Goldcoast originated from 11 countries for over 20 years. The population structure and evolutionary history of multidrug-resistant S. Goldcoast was investigated through phylogenomic and long-term spatiotemporal transmission dynamic analysis. ST358 and ST2529 are the predominant lineages of S. Goldcoast. Multidrug-resistant S. Goldcoast strains have mainly been identified in the ST358 lineage from human and the ST2529 lineage from livestock. ST358 S. Goldcoast was estimated to have emerged in the United Kingdom in 1969, and then spread to China, with both countries serve as centers for the global dissemination of the ST358 lineage. After its emergence and subsequent spread in Chinese clinical and environmental samples, occasional instances of this lineage have been reported in Canada, the United Kingdom, and Ireland. Clonal transmission of ST358 and ST2529 S. Goldcoast have occurred not only on an international and intercontinental scale but also among clinical, environmental and livestock samples. These data indicated that international circulation and local transmission of S. Goldcoast have occurred for over a decade. Continued surveillance of multidrug-resistant S. Goldcoast from a global "One Health" perspective is urgently needed to facilitate monitoring the spread of the antimicrobial resistant high-risk clones.

Protein Dynamics Mediated by Cardiolipin in Bacteria.

Bacterial proteins targeting the appropriate subcellular sites are the base for their proper function. Several studies have shown that the anionic phospholipid cardiolipin (CL), a conical lipid preferring negative membrane curvature, modulates the lipid bilayers' structure, which impacts the activity of their resident proteins. Due to the favor of negative membrane curvature, CL is not randomly distributed in the bacterial plasma membrane. In contrast, it gathers in particular parts of the cell membrane to form microdomains, in which many functional membrane proteins are accumulated and carry out diverse physiological processes of bacteria, such as cell division, metabolism, infection, and antibiotic residence. In addition, CL has a unique structure that carries two negative charges, which makes it play a pivotal role in protein assembly, interaction, and location. These characteristics of CL make it closely related to many crucial physiological functions of bacteria. Here, we have reviewed the mechanism of protein dynamics mediated by CL initiated on the bacterial membrane. Furthermore, we studied the effect of CL on bacterial infection and antibiotic residence. Finally, the CL-targeting therapeutic agents for antibacterial therapy are also examined.

The potential roles of galectin-3 in AKI and CKD.

Acute kidney injury (AKI) is a common condition with high morbidity and mortality, and is associated with the development and progression of chronic kidney disease (CKD). The beta-galactoside binding protein galectin-3 (Gal3), with its proinflammatory and profibrotic properties, has been implicated in the development of both AKI and CKD. Serum Gal3 levels are elevated in patients with AKI and CKD, and elevated Gal3 is associated with progression of CKD. In addition, Gal3 is associated with the incidence of AKI among critically ill patients, and blocking Gal3 in murine models of sepsis and ischemia-reperfusion injury results in significantly lower AKI incidence and mortality. Here we review the role of Gal3 in the pathophysiology of AKI and CKD, as well as the therapeutic potential of targeting Gal3.

The fluid management and hemodynamic characteristics of PiCCO employed on young children with severe hand, foot, and mouth disease-a retrospective study.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is an acute infectious disease caused by human enterovirus 71 (EV71), coxsackievirus, or echovirus, which is particularly common in preschool children. Severe HFMD is prone to cause pulmonary edema before progressing to respiratory and circulatory failure; thus hemodynamic monitoring and fluid management are important to the treatment process. METHODS: We did a review of young patients who had been successfully treated in our department for severe HFMD, which had been caused by EV71. A total of 20 patients met the inclusion criteria. Eight cases were monitored by the pulse indicator continuous cardiac output (PiCCO) technique, and fluid management was administered according to its parameters. With regard to the treatment with PiCCO monitoring, patients were divided into two groups: the PiCCO group (8 patients) and the control group (12 patients). The groups were then compared comprehensively to evaluate whether PiCCO monitoring could improve patients' clinical outcomes. RESULTS: After analysis, the findings informed that although PiCCO failed to shorten the length of ICU stay, reduce the days of vasoactive drug usage, or lower the number of cases which required mechanical ventilation, PiCCO did reduce the incidence of fluid overload (p = 0.085) and shorten the days of mechanical ventilation (p = 0.028). After effective treatment, PiCCO monitoring indicated that the cardiac index (CI) increased gradually(p < 0.0001), in contrast to their pulse (P, p < 0.0001), the extra vascular lung water index (EVLWI, p < 0.0001), the global end diastolic volume index (GEDVI, p = 0.0043), and the systemic vascular resistance index (SVRI, p < 0.0001), all of which decreased gradually. CONCLUSION: Our study discovered that PiCCO hemodynamic monitoring in young children with severe HFMD has some potential benefits, such as reducing fluid overload and the duration of mechanical ventilation. However, whether it can ameliorate the severity of the disease, reduce mortality, or prevent multiple organ dysfunction remain to be further investigated.

The efficacy of mesenchymal stromal cell-derived therapies for acute respiratory distress syndrome-a meta-analysis of preclinical trials.

BACKGROUND: The investigation of mesenchymal stromal cell (MSC)-conditioned medium or extracellular vesicles (exosomes or microvesicles) as a remedy for acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) has become a fast-growing field in recent years. Our purpose was to conduct a meta-analysis to investigate the efficacy of MSC-derived therapies (MDTs) for ALI/ARDS in animal models. METHODS: A meta-analysis of MDTs for ALI/ARDS in animal trials was performed. PubMed and EMBASE were searched to screen relevant preclinical trials with a predetermined search strategy. RESULTS: A total of 17 studies that compared MDT with the ALI control group were included in our study. The pooled result derived from the comparison of the two groups suggested that MDT could significantly reduce the lung injury score (standardized mean difference (SMD) = - 4.02, 95% CI [- 5.28, - 2.23], P < 0.0001) and improve animal survival (OR = - 6.45, 95% CI [2.78, 14.97], P < 0.0001). MDT mitigated the infiltration of neutrophils in alveoli (SMD = - 3.38, 95% CI [- 4.58, - 2.18], P < 0.00001). MDT also reduced the wet-dry weight ratio of the lung (SMD = - 2.34, 95% CI [- 3.42, - 1.26], P < 0.0001) and the total protein in BALF (SMD = - 2.23, 95% CI [- 3.07, - 1.40], P < 0.00001). Furthermore, MDT was found to downregulate proinflammatory mediators such as IL-1, IL-6 and TNF-a and to upregulate anti-inflammatory mediators such as IL-10. CONCLUSION: MDT reduces lung injury and improves survival in animal ARDS models since it can ameliorate lung permeability, decrease inflammatory cell infiltration, downregulate proinflammatory mediators, and upregulate anti-inflammatory mediators. However, more animal studies and human trials are needed for further investigation.

SARS-CoV-2: minireview and review of first case in Foshan, China.

The first case of #COVID19 in Foshan provides a reference for the treatment of severe #SARSCoV2 pneumonia https://bit.ly/3eD81qj.

Prognosis Risk of Urosepsis in Critical Care Medicine: A Prospective Observational Study.

This study aimed to investigate the clinical features of urosepsis and to raise awareness of this problem. Of the 112 sepsis patients enrolled, 36 were identified as having urosepsis. The bacteria involved in the infection leading to urosepsis included Escherichia coli, Proteus species, Enterococcus species, Klebsiella species, other Gram-positive cocci, and Pseudomonas aeruginosa. Although the organ/system dysfunction appeared earlier in the urosepsis patients than in the other sepsis patients (4.7 ± 2.4 versus 7.2 ± 4.5 hours, P < 0.001), the urosepsis patients presented with a better prognosis and lower 28-day mortality rate than the others (6% versus 37%). In the multivariate analysis, the type of sepsis (urosepsis, OR = 0.019, 95% CI = 0.001, 0.335, P = 0.007) and SOFA score (OR = 1.896, 95% CI = 1.012, 3.554, P = 0.046) remained significantly associated with the survival. The time of admission to the intensive care unit of 17 patients transferred from the Department of Urinary Surgery was significantly prolonged compared with those transferred from other departments (11.6 ± 7.3 versus 7.2 ± 4.9 hours, P < 0.05). In conclusion, urosepsis suggested a better prognosis, but attention needs to be paid in clinical practice, especially in urinary surgery.

[Clinical feature of severe hand, foot and mouth disease with acute pulmonary edema in pediatric patients].

OBJECTIVE: To explore the clinical feature of severe hand, foot and mouth disease (HFMD) in pediatric patients, and to observe the hemodynamic changes in those with acute pulmonary edema. METHODS: A prospective observation study was conducted. Thirty-five severe HFMD pediatric patients with acute pulmonary edema admitted to the intensive care unit (ICU) and Department of Pediatric of First People's Hospital of Foshan from May 2008 to September 2014 were enrolled. The clinical features were thoroughly investigated. Hemodynamic data were monitored by pulse-indicated continuous cardiac output (PiCCO) in 5 cases, and the changes in PiCCO parameters were observed at ICU admission (0 hour), and 24, 48, 96 hours after treatment. RESULTS: Thirty-five patients who met the diagnostic standard of severe HFMD were enrolled, including 22 male and 13 female, aged from 7 months to 4 years. Six patients were younger than 1 year, 13 1-2 years, 12 2-3 years, and 4 patients 3-4 years old. The most common time of occurrence of pulmonary edema was 3-4 days after the onset of the disease. Fever and central nervous system symptoms were found in all the patients, and examination of the cerebral spinal fluid (CSF) revealed non-bacterial inflammatory changes. PiCCO results showed a tendency of lowering of heart rate (HR), systemic vascular resistance index (SVRI), and extravascular lung water index (EVLWI) after the treatment, and the values obtained at 96 hours were significantly lower than those at 0 hour [HR (bpm): 119.0±14.7 vs. 200.8±19.7, SVRI (kPa×s×L(-1)×m(-2)): 148.9±14.6 vs. 209.6±58.7, EVLWI (mL/kg): 10.5±1.9 vs. 34.8±10.8, P<0.05 or P<0.01], global end-diastolic volume index (GEDVI) was also gradually decreased without significant differences among all the time points, together with a tendency of increase in stroke volume index (SI) and cardiac index (CI). The values of the parameters at 96 hours were significantly higher than those at 0 hour [SI (mL/m2): 38.5±6.5 vs. 17.4±2.8, CI (mL×s(-1)×m(-2)): 75.0±8.0 vs. 55.5±8.5, both P<0.01]. Left atrium was found to be enlarged, and left ventricular systolic function decreased in two patients by cardiac ultrasonic. Four out of 35 patients died, and functional disability of extremities was found in 1 patient. Other patients were cured and discharged without any sequelae. CONCLUSIONS: Severe HFMD complicated by acute pulmonary edema is a perilous condition in children, accompanied commonly by pathologic changes in central nervous system and systolic dysfunction of left ventricle. According to the results with PiCCO monitoring, HFMD patients suffering from acute pulmonary edema may be of cardiac origin in addition to neurogenic origin.

The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial.

INTRODUCTION: Severe sepsis is associated with a high mortality rate despite implementation of guideline recommendations. Adjunctive treatment may be efficient and require further investigation. In light of the crucial role of immunologic derangement in severe sepsis, thymosin alpha 1 (Tα1) is considered as a promising beneficial immunomodulatory drug. The trial is to evaluate whether Tα1 improves 28-day all-cause mortality rates and immunofunction in patients with severe sepsis. METHODS: We performed a multicenter randomized controlled trial in six tertiary, teaching hospitals in China between May 12, 2008 and Dec 22, 2010. Eligible patients admitted in ICU with severe sepsis were randomly allocated by a central randomization center to the control group or Tα1 group (1:1 ratio). The primary outcome was death from any cause and was assessed 28 days after enrollment. Secondary outcomes included dynamic changes of Sequential Organ Failure Assessment (SOFA) and monocyte human leukocyte antigen-DR (mHLA-DR) on day 0, 3, 7 in both groups. All analyses were done on an intention-to-treat basis. RESULTS: A total of 361 patients were allocated to either the control group (n = 180) or Tα1 (n = 181) group. The mortalities from any cause within 28 days in the Tα1 group and control group were 26.0% and 35.0% respectively with a marginal P value (nonstratified analysis, P = 0.062; log rank, P = 0.049); the relative risk of death in the Tα1 group as compared to the control group was 0.74 (95% CI 0.54 to 1.02). Greater improvement of mHLA-DR was observed in the Tα1 group on day 3 (mean difference in mHLA-DR changes between the two groups was 3.9%, 95% CI 0.2 to 7.6%, P = 0.037) and day 7 (mean difference in mHLA-DR changes between the two groups was 5.8%, 95% CI 1.0 to 10.5%, P = 0.017) than in the control group. No serious drug-related adverse event was recorded. CONCLUSIONS: The use of Tα1 therapy in combination with conventional medical therapies may be effective in improving clinical outcomes in a targeted population of severe sepsis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00711620.

[Immune and inflammation confusion in severe sepsis and effects of bi-immunomodulation therapy: a prospective, randomized, controlled clinical trial].

OBJECTIVE: To investigate the immune and inflammation confusion state in severe sepsis and the effects of two way immunomodulation therapy with continuous blood purification (CBP), thymosin alpha1, and combined therapy of CBP and thymosin alpha(1). METHODS: 91 Patients with severe sepsis aged > 18, with Marshall score>5. were randomly divided into 4 groups: CBP Group (n = 22) undergoing continuous renal replacement therapy (CRRT) or molecular adsorbents recirculating system (MARS) therapy once a day for 3 days in addition to classical Surviving Sepsis Campaign (SSC) therapy, Thymosin alpha(1) Group (n = 23) undergoing subcutaneous injection of thymosin alpha(1) 1.6 mg once a day for 7 days in addition to SSC therapy, Combined Therapy Group (n = 22) undergoing CBP combined with thymosin alpha(1) treatment in addition to SSC therapy, and SSC Group (treatment control group, n = 24) undergoing SSC therapy only. Peripheral blood samples were collected before treatment, and 3 and 7 days after the beginning of treatment (days 4 and 8) to detect the serum interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha. The levels of CD(14)(+) monocyte human leucocyte antigen (HLA)-DR and T lymphocytes were monitored. The mechanical ventilation time, ICU stay length, and mortality within 28 d and mortality within 90 d were observed. Ten healthy persons were used as healthy control group. RESULTS: Thirty-four of the 91 patients died within 28 d with a mortality of 77.4% (Death Group) and other 57 patients were put in Survival Group. The levels of serum IL-6, IL-10, and TNFalpha, and IL-6/IL-10 at different time points of both Death and Survival Groups were all significantly higher, and the HLA-DR level, and CD(3)(+), CD(4)(+), and CD(8)(+) T lymphocyte numbers at different time points of both Death and Survival Groups were all significantly lower than those of the healthy controls (P < 0.05 or < 0.01). The levels of serum IL-6, IL-6/IL-10, TNFalpha, HLA-DR, and CD(3)(+), CD(4)(+), and CD(8)(+) T lymphocyte at different time points of Death Group were all significantly higher than those of Survival Group (P < 0.05 or < 0.01). The CD(3)(+) T lymphocyte number on day 8 of Thymosin Group was significantly higher than that of SSC Group (all P < 0.05). The serum IL-6 and TNFalpha and IL-6/IL-10 were decreased, and HLA-DR, and CD(3)(+), CD(4)(+), and CD(8)(+) were increased significantly on day 8 in CBP and Combined Therapy Groups. The level of TNFalpha decreased, and the numbers of CD(3)(+) and CD(4)(+) T lymphocytes increased significantly on day 4 in Combined Therapy Group (P < 0.05 or P < 0.01). Compared with Thymosin Group, almost all the indexes of CBP and Combined Therapy Groups were improved, only the CD(3)(+) T lymphocyte level on day 4 increased and the IL-6/IL-10 ratio on day 8 was decreased significantly in Combined Therapy Group (both P < 0.05). Compared with those of SSC Group, the mechanical ventilation time, length of ICU stay within 28 days, and 28 days mortality and 90 days mortality of the 3 treatment groups were all decreased, and there were statistical differences in the length of ICU stay of CBP Group and in the mechanical ventilation time and length of ICU stay within 28 days of Combined Therapy Group (both P < 0.05). CONCLUSION: Systemic inflammatory response and immunodepression exist simultaneously in severe sepsis. Thymosin alpha(1) increases the cellular immunity, and CBP bi-modulates the immune turbulence, reduces the inflammatory mediators, and ameliorates the immune homeostasis. These 2 therapies also improve the clinical prognosis and the combination of both would be more effective.

[Effect of continuous blood purification and thymosin alpha1 on the cellular immunity in patients with severe sepsis: a prospective, randomized, controlled clinical trial].

OBJECTIVE: To discuss the effect of continuous blood purification (CBP), thymosin alpha1 and combined therapy on cellular immunity in patients with severe sepsis. METHODS: Ninety-one patients, age over 18 years, suffering from severe sepsis with Marshall score over 5, admitted to the intensive care unit (ICU) from June, 2004 to October, 2007, were randomly divided into four groups. The patients in control group (24 cases) were treated with classical Surviving Sepsis Campaign (SSC) therapy, those in CBP group (22 cases) were treated with continuous renal replacement therapy (CRRT) or molecular adsorbent recirculating system (MARS) in the first 3 days. The group of thymosin alpha1 (23 cases) were treated with thymosin alpha1, in a dose of 1.6 mg subcutaneous injection per day for 7 days. The patients in the group of combined therapy (22 cases) were treated with CBP and thymosin alpha1. All three treatment groups were treated with classical SSC therapy at the same time. Acute physiology and chronic health evaluation II (APACHE II) score and Marshall score were evaluated. CD14(+) monocyte human leucocyte antigen DR (HLA-DR) levels and the count of T lymphocyte were measured before treatment and 3 days and 7 days after the treatment. RESULTS: All 91 patients were included in the study. Compared with the control group, the 28-day mechanical ventilation (MV) time, length of ICU stay, 28-day mortality of three treatment groups were decreased. There was statistically significant difference in the length of ICU stay of the CBP group, and also the 28-day MV time, length of ICU stay of the group of combined therapy group (all P<0.05). Compared with the variables before treatment, Marshall scores were decreased significantly and levels of HLA-DR, CD3(+), CD4(+), CD8(+)T lymphocytes were increased significantly after 7-day treatment with thymosin alpha1 group (all P<0.05) . The above indexes and APACHE II scores were changed significantly as early as 3 days after treatment in CBP group and combined therapy group (P<0.05 or P<0.01). Compared with the variables at the same period in the control group, only CD3(+) T lymphocytes were increased significantly after 7-day treatment in thymosin alpha1 group (P<0.05), APACHE II scores and Marshall scores were decreased significantly , levels of HLA-DR and CD3(+), CD4(+), CD8(+) T lymphocytes were increased significantly after 7-day treatment in CBP group (all P<0.05). The above indexes were already changed significantly after 3-day treatment in the combined therapy group (P<0.05 or P<0.01). Compared with thymosin alpha1 group, all the indexes were improved but only level of CD3(+) T lymphocytes after 3-day treatment in the combined therapy group increased significantly (P<0.05). CONCLUSION: CBP and thymosin alpha1 could increase cellular immunity in patients with severe sepsis, promote recovery of organ function and improve prognosis. The effect of CBP appears earlier and more pronounced. Combined treatment can be more effective.