Anisodamine hydrobromide in the treatment of critically ill patients with septic shock: a multicenter randomized controlled trial.

BACKGROUND: Septic shock is the development of sepsis to refractory circulatory collapse and metabolic derangements, characterized by persistent hypotension and increased lactate levels. Anisodamine hydrobromide (Ani HBr) is a Chinese medicine used to improve blood flow in circulatory disorders. The purpose of this study was to determine the therapeutic efficacy of Ani HBr in the treatment of patients with septic shock. METHODS: This was a prospective, multicenter, randomized controlled trial focusing on patients with septic shock in 16 hospitals in China. Patients were randomly assigned in a 1:1 ratio to either the treatment group or the control group. The primary endpoint was 28-day mortality. The secondary outcomes included 7-day mortality, hospital mortality, hospital length of stay, vasopressor-free days within 7 days, etc. These indicators were measured and collected at 0, 6h, 24h, 48h, 72h and 7d after the diagnosis. RESULTS: Between September 2017 and March 2021, 404 subjects were enrolled. 203 subjects received Ani HBr and 201 subjects were assigned to the control group. The treated group showed lower 28-day mortality than the control group. Stratified analysis further showed significant differences in 28-day mortality between the two groups for patients with a high level of illness severity. We also observed significant differences in 7-day mortality, hospital mortality and some other clinical indicators between the two groups. CONCLUSION: Ani HBr might be an important adjuvant to conventional treatment to reduce 28-day mortality in patients with septic shock. A large-scale prospective randomized multicenter trial is warranted to confirm our results.

Base-Controlled Divergent Synthesis of Fluorine-Containing Benzo[4,5]imidazo[2,1-b][1,3]thiazines from 2-Mercaptobenzimidazoles and ß-CF3-1,3-Enynes.

A base-controlled divergent cyclization between 2-mercaptobenzimidazoles and ß-CF3-1,3-enynes providing either trifluoromethylated or fluorinated benzo[4,5]imidazo[2,1-b][1,3]thiazines has been developed. The ß-CF3-1,3-enyne, as a three-carbon synthon, underwent a 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU)-catalyzed tandem hydroamination/intramolecular hydrothiolation to give CF3-substituted 3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazine, whereas reaction with KOH afforded fluorinated 4H-benzo[4,5]imidazo[2,1-b][1,3]thiazine exclusively. In addition, the synthetic utility of this methodology was showcased through a variety of downstream derivatizations.

Sepsis Due to Pandoraea sputorum Infection After Multiple Trauma in a Non-Cystic Fibrosis Patient: A Case Report from Southeast China.

Pandoraea sputorum (P. sputorum) infection is of great concern as these gram-negative bacillus species are multidrug-resistant and usually isolated from the patients' respiratory tract suffering from cystic fibrosis (CF). A few cases of infection have also been reported in non-CF patients due to its rare pathogenic nature with unclear and overlapping clinical, biochemical, and microbiological characteristics with other species. Here, we report an unusual case of a 46-year-old non-CF female, who presented with multiple pelvic fractures, acute traumatic brain injury, multiple rib fractures, and multiple burns (18% of the total body surface area, II°) by the collapse of a brick kiln, suffered from P. sputorum sepsis due to wound infection. Pandoraea species were isolated both from her blood and wound secretion. Antibiotic susceptibility testing indicated susceptibility to imipenem, tetracyclines, sulfamethoxazole, and ampicillin/sulbactam but resistance to meropenem, quinolones, aminoglycosides, and other beta-lactams. 16S ribosomal RNA (rRNA) PCR assays and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) were used to confirm the bacteria as P. sputorum. After effective anti-infection of intravenous antibiotics (imipenem 1.0 Q8H with tigecycline 50 mg Q12H for 14 days), wound care, and other comprehensive treatment for two months, the patient improved and was discharged from the hospital eventually. After reviewing the literature, we observed that the susceptibility results of Pandoraea species were often multidrug-resistant and had a unique pattern of being resistant to meropenem but sensitive to imipenem. Biofilm formation, carbapenemase production, and unique gene procession differed from the environmental isolates could help explain its resistance. This case report highlights the potential virulence of Pandoraea species as a pathogen in patients with no underlying disease. Although they are often multi-resistant, imipenem can be a preferred treatment for Pandoraea species in the earliest identification steps.

Effect of Laser Quenching-Shock Peening Strengthening on the Microstructure and Mechanical Properties of Cr12MoV Steel.

The automobile covering parts mold is a key piece of equipment in the automobile industry, and its drawbead is the core element that affects the life of the mold and the quality of the parts made. Due to the complex structure of the mold cavity for covering parts, there exist differences between material flow characteristics, load conditions, stress strain, failure forms and so on in the surface of different parts of its drawbead and the different directions of the same part of the drawbead, thus putting forward new requirements for material strengthening. For the differentiated lose efficacy forms of the dangerous end faces of the tension bars, this study carried out research into the effect of laser quenching-shock peening strengthening (LQ-LSP) on the organization, plastic deformation resistance and wear resistance of Cr12MoV steel. It was shown that the microhardness (722.30 HV) and residual stress (-383.84 MPa) of the specimens were further enhanced after laser quenching-shock peening composite strengthening. The residual austenite content of the specimen was reduced to 0.8%, and the eutectic carbide distribution morphology was improved. After three rounds of laser composite peening, the specimens had the smallest displacement of the nanoindentation load-depth curve, which exhibited the greatest nanohardness (20.0 Pa) and modulus of elasticity (565.25 Pa), while reducing the coefficient of friction (0.61) and surface roughness (0.152 Ra). The smooth and flat surface of the specimen with shallow and narrow plow grooves improved the resistance of Cr12MoV steel to plastic deformation and wear.

Accuracy and Safety of Robot-Assisted versus Fluoroscopy-Guided Posterior C1 Lateral Mass and C2 Pedicle Screw Internal Fixation for Atlantoaxial Dislocation: A Preliminary Study.

Objective: To compare the accuracy, efficiency, and safety of robotic assistance (RA) and conventional fluoroscopy guidance for the placement of C1 lateral mass and C2 pedicle screws in posterior atlantoaxial fusion. Methods: The data of patients who underwent posterior C1-C2 screw fixation (Goel-Harm's technique) in our hospital from August 2014 to March 2021 were retrospectively evaluated, including 14 cases under fluoroscopic guidance and 11 cases under RA. The hospital records, radiographic results, surgical data, and follow-up records were reviewed. Accuracy of screw placement was assessed using the Gertzbein and Robbins scale, and clinical outcomes were evaluated by Japanese Orthopedic Association (JOA) score, visual analogue scale (VAS), modified MacNab criteria, and postoperative complications. Results: Baseline characteristics of both groups were similar. The mean estimated blood loss in the fluoroscopic guidance and RA groups was 205.7 ± 80.3 mL and 120.9 ± 31.9 mL, respectively (p = 0.03). The mean surgical duration was 34 min longer with RA compared to that performed with free-hand (FH) method (p = 0.15). In addition, lower intraoperative radiation exposure was detected in the RA group (12.4 ± 1.4 mGy/screw) versus the FH (19.9 ± 2.1 mGy/screw) group (p = 0.01). The proportion of "clinically acceptable" screws (graded 0 and I) was higher in the RA group (93.2%) than that in the FH group (87.5%, p = 0.04). There was no significant difference in the increase of JOA score and decrease of VAS score between the two surgical procedures. Furthermore, there were no significant differences in overall clinical outcome between the two groups and no neurovascular complications associated with screw insertion. Conclusions: RA is a safe and potentially more accurate alternative to the conventional fluoroscopic-guided FH technique for posterior atlantoaxial internal fixation.

Meta-analysis of the association between new hypoglycemic agents and digestive diseases.

BACKGROUND: New hypoglycemic agents include sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide 1 receptor agonists (GLP1RAs), and dipeptidyl peptidase-4 inhibitors (DPP4is). The association between each class of these new hypoglycemic drugs and the risks of various digestive system diseases is unknown. We aimed to explore this relationship by performing a meta-analysis. METHODS: We included large randomized trials of SGLT2is, GLP1RAs, and DPP4is. Outcomes of interest were 91 kinds of digestive diseases including 75 kinds of gastrointestinal disorders and 16 kinds of hepatobiliary disorders. Meta-analysis was done to generate pooled risk ratio (RR) and 95% confidence interval (CI). Subgroup analysis was conducted according to 3 different drug classes. RESULTS: We included 21 large trials in this meta-analysis. Compared with placebo, GLP1RAs were associated with the higher risks of gastric ulcer hemorrhage (RR 2.68, 95% CI 1.07-6.68; Pdrug = .035; I2 = 0), pancreatitis (RR 1.48, 95% CI 1.02-2.15; Pdrug = .041; I2 = 0), cholangitis acute (RR 5.96, 95% CI 1.04-34.08; Pdrug = .045; I2 = 0), and cholecystitis acute (RR 1.52, 95% CI 1.08-2.15; Pdrug = .017; I2 = 1.5%), but were not significantly associated with the occurrences of the other 87 kinds of digestive diseases (Pdrug ranged from .064 to .999). SGLT2is versus placebo were not significantly associated with the occurrences of 91 kinds of digestive diseases (Pdrug ranged from .077 to .995). DPP4is versus placebo were not significantly associated with the occurrences of 91 kinds of digestive diseases (Pdrug ranged from .085 to .999). CONCLUSIONS: Neither SGLT2is nor DPP4is are associated with the occurrences of various kinds of digestive diseases, whereas GLP1RAs are associated with the higher risks of 4 kinds of digestive diseases, namely, gastric ulcer hemorrhage, pancreatitis, cholangitis acute, and cholecystitis acute. These findings seem to suggest that GLP1RAs are not applicable for patients at high risk of 4 specific digestive diseases, whereas SGLT2is and DPP4is are safe for patients susceptible to digestive diseases. However, our findings require to be further verified by future studies with sufficient statistical power.

Meta-regression analysis of the efficacy of alendronate for prevention of glucocorticoid-induced fractures.

BACKGROUND: What affects the efficacy of alendronate for prevention of glucocorticoid-induced (GI) fractures remains unclear. We aimed to explore the factors affecting alendronate's efficacy, and further identify subgroup effects of alendronate in preventing GI fractures. METHODS: We searched 3 databases. Random-effects meta-analysis was conducted to synthesize risk ratio (RR) and 95% confidence interval (CI) for each endpoint. Meta-regression analysis was used to explore sources of heterogeneity, and subgroup analysis was used to address heterogeneity and evaluate subgroup effects. We detected publication bias using funnel plots and Egger tests. RESULTS: We included 13 papers from 12 unique studies involving 46431 participants. Glucocorticoid (GC) dosage (P = .053) and proportion of previous vertebral fracture (PVF) (P = .047) were probably 2 sources of heterogeneity in meta-analysis for vertebral fractures, while GC duration (P = .020) was probably 1 for nonvertebral fractures. Alendronate reduced vertebral fractures in the high dosage subgroup (RR 0.61, 95% CI 0.44-0.86), but didn't in the low dosage subgroup (RR 1.56, 95% CI 0.20-12.02). Alendronate reduced vertebral fractures (RR 0.53, 95% CI 0.40-0.68) in the subgroup of PVF proportion <5%, but didn't (RR 0.76, 95% CI 0.42-1.37) in the subgroup of this proportion ≥5%. Alendronate reduced nonvertebral and hip fractures, whether in primary or in secondary prevention subgroup. CONCLUSIONS: The findings in our study support that alendronate is used for the primary and secondary prevention of GI fractures, but do not support that alendronate is recommended as a first-line agent for patients receiving a low dose of GCs or patients with PVF.

GLP-1RAs and SGLT2is Reduce Cardiovascular Events Independent of Reductions of Systolic Blood Pressure and Body Weight: A Meta-Analysis with Meta-Regression.

INTRODUCTION: The impact of reduction of systolic blood pressure or body weight on reduction of cardiovascular events during the treatment with glucagon-like peptide 1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter 2 inhibitors (SGLT2is) for type 2 diabetes is unclear. METHODS: We searched Embase and PubMed. We performed meta-analysis using hazard ratio (HR) and 95% confidence interval (CI) as effect size stratified by drug class on six endpoints of interest, which were major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), cardiovascular death (CVD), myocardial infarction (MI), stroke, and all-cause death (ACD). We performed meta-regression to assess the difference between GLP-1RAs and SGLT2is, and the impact of reduction of systolic blood pressure or body weight on reduction of cardiovascular events. RESULTS: We included 11 randomized trials. Compared with placebo, SGLT2is reduced HHF by 32% (HR 0.68, 95% CI 0.60-0.76) whereas GLP-1RAs reduced HHF by only 9% (HR 0.91, 95% CI 0.83-0.99). The benefit from SGLT2is on HHF was significantly greater than that from GLP-1RAs (Psubgroup = 0.004). GLP-1RAs reduced stroke by 16% (HR 0.84, 95% CI 0.76-0.93) whereas SGLT2is did not reduce stroke (HR 0.96, 95% CI 0.82-1.12). GLP-1RAs and SGLT2is similarly reduced MACE by 12%, CVD by 15%, MI by 9%, and ACD by 13%. The effects of systolic blood pressure reduction and body weight reduction on the logarithms of HRs of GLP-1RAs or SGLT2is vs. placebo as for reducing six endpoints of interest were not statistically significant (ß ranged from - 0.145 to 0.269, and P ranged from 0.211 to 0.941). CONCLUSIONS: GLP-1RAs and SGLT2is lead to similar benefits on MACE, CVD, MI, and ACD in adults with type 2 diabetes. The benefit from SGLT2is on HHF is greater than that from GLP-1RAs, while GLP-1RAs vs. placebo significantly reduce stroke whereas SGLT2is do not. The two drug classes reduce cardiovascular events independent of reductions of systolic blood pressure and body weight.

SGLT2 inhibitors for prevention of cardiorenal events in people with type 2 diabetes without cardiorenal disease: A meta-analysis of large randomized trials and cohort studies.

To investigate whether sodium glucose cotransporter 2 inhibitors (SGLT2is) can reduce important cardiorenal endpoints in type 2 diabetic adults without established cardiovascular disease (ECD), in those without heart failure (HF), and in those without chronic kidney disease (CKD). We searched PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and clinicaltrials.gov. Event-driven randomized controlled trials (RCTs) and cohort studies were included. We conducted random-effects meta-analysis, respectively based on RCTs and cohort studies, on eight cardiorenal endpoints in three type 2 diabetic subgroups. Thirteen large studies were included. Meta-analysis of RCTs showed the high quality evidences: compared with placebo, SGLT2is significantly reduced the risk of major adverse cardiovascular events, cardiovascular death or hospitalization for HF, and progression of CKD in type 2 diabetic adults without ECD [HRs (95 % CIs): 0.88 (0.82, 0.94), 0.76 (0.70, 0.82), and 0.59 (0.52, 0.66), respectively; risk differences (95 % CIs): -1.6 (-2.4, -0.8), -2.6 (-3.3, -2.0), and -2.4 (-2.8, -2.0) per 1000 patient-years, respectively], in those without HF [HRs (95 % CIs): 0.89 (0.82, 0.95), 0.74 (0.67, 0.81), and 0.61 (0.55, 0.67), respectively; risk differences (95 % CIs): -1.7 (-2.9, -0.8), -5.8 (-7.3, -4.2), and -2.3 (-2.6, -1.9) per 1000 patient-years, respectively], and in those without CKD [HRs (95 % CIs): 0.88 (0.82, 0.94), 0.77 (0.71, 0.83), and 0.63 (0.57, 0.70), respectively; risk differences (95 % CIs): -2.4 (-3.6, -1.2), -6.1 (-7.6, -4.5), and -2.2 (-2.6, -1.8) per 1000 patient-years, respectively]. Meta-analysis of cohort studies also showed the benefits of SGLT2is on the three composite outcomes in the three diabetic subgroups. SGLT2is also significantly reduced some other cardiorenal endpoints in these diabetic subgroups. SGLT2is can significantly reduce important cardiorenal events in type 2 diabetic adults without ECD, in those without HF, and in those without CKD; which supports SGLT2is used in these diabetic subpopulations to prevent cardiorenal events.