A Novel Oral GyrB/ParE Dual Binding Inhibitor Effective against Multidrug-Resistant Neisseria gonorrhoeae and Other High-Threat Pathogens.

Drug-resistant Neisseria gonorrhoeae is a serious global health concern. New drugs are needed that can overcome existing drug resistance and limit the development of new resistances. Here, we describe the small molecule tricyclic pyrimidoindole JSF-2414 [8-(6-fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)oxy)-9H-pyrimido[4,5-b]indol-4-yl)-2-oxa-8-azaspiro[4.5]decan-3-yl)methanol], which was developed to target both ATP-binding regions of DNA gyrase (GyrB) and topoisomerase (ParE). JSF-2414 displays potent activity against N. gonorrhoeae, including drug-resistant strains. A phosphate pro-drug, JSF-2659, was developed to facilitate oral dosing. In two different animal models of Neisseria gonorrhoeae vaginal infection, JSF-2659 was highly efficacious in reducing microbial burdens to the limit of detection. The parent molecule also showed potent in vitro activity against high-threat Gram-positive organisms, and JSF-2659 was shown in a deep tissue model of vancomycin-resistant Staphylococcus aureus (VRSA) and a model of Clostridioides difficile-induced colitis to be highly efficacious and protective. JSF-2659 is a novel preclinical drug candidate against high-threat multidrug resistant organisms with low potential to develop new resistance.

Dynamic compression locking system versus multiple cannulated compression screw for the treatment of femoral neck fractures: a comparative study.

BACKGROUND: Femoral neck fractures are one of the problems in clinical treatment. The prognosis is uncertain. Currently, No internal fixation method is superior to other internal fixation methods in the treatment of femoral neck fractures. Therefore, the internal fixation system needs to be further explored. The aim of this study was to compare clinical outcomes of femoral neck dynamic compression locking system (DCLS) and multiple cannulated compression screws(MCCS) in the treatment of femoral neck fractures. METHODS: A prospective analysis of 54 cases of femoral neck fractures treated with either a DCLS (n = 28) or MCCS (n = 26) was conducted between December 2015 and November 2017 in authors' hospitals. The perioperative and postoperative parameters of the two groups were recorded and evaluated. RESULTS: Fifty-four patients were followed up for 24-47 months. The etiology was caused by a fall. There was no significant difference in follow-up time, operation time, incision length, surgical blood loss, the incidence of perioperative and postoperative healing complications, and mobility in the two groups (all P > 0.05). The Harris score, fracture healing time, femoral neck shortening, partial weight-bearing time and complete weight-bearing time were significantly better in the DCLS group than in the MCCS group (all P < 0.05). The fracture healing rate in the DCLS group was higher than that in the MCCS group. CONCLUSIONS: The DCLS and MCCS might be equally effective in terms of operation time, incision length, surgical blood loss, the incidence of perioperative and postoperative healing complications, and mobility in the treatment of femoral neck fractures. However, the DCLS is superior to the MCCS in Harris score, fracture healing time, femoral neck shortening, weight-bearing time and fracture healing rate. So, DCLS deserves further study.

The clinical application of a novel method of internal fixation for femoral neck fractures-dynamic locking compression system.

BACKGROUND: Femoral neck fractures are the commonly encountered injury in orthopedic practice and result in significant morbidity and mortality. Currently, how to treat femoral neck fractures safely and effectively is still a challenge. The objective of this study is to evaluate the efficiency of dynamic compression locking system for femoral neck fractures. METHODS: This is a retrospective study conducted from May 2015 to October 2016. The study included 36 patients suffering from femoral neck fractures who underwent closed reduction and were fixed using dynamic compression locking system. All surgeries were performed by the same surgeon. The study was conducted by telephone and on-site follow-up. The Garden classification and anatomical site classification were categorized for all patients. We assessed radiographic outcomes of union, femoral neck shortening, screw back-out, and femoral head avascular necrosis. We also evaluated functional outcome using the Harris hip score. Other outcomes included the length of surgery, duration of hospital stay, injury to surgery time, intraoperative hemorrhage, time to clinical bone union, and other fracture complications. RESULTS: All patients were followed up 12 to 29 months with an average of 21.58 ± 5.41 months. All cases were caused by falls including 17 males and 19 females with an average age of 65.33 ± 9.30 years old ranging from 53 to 82 years old. Among them, injury to surgery time ranged between 1 and 4 days with an average of 2.58 ± 1.05 days. Duration of hospital stay was 8 to 21 days with an average of 15.33 ± 3.71 days. Intraoperative hemorrhage was 40 to 80 ml with an average of 61.67 ± 12.31 ml. Operation time was from 35 to 80 min with average of 50.25 ± 11.77 min. According to Garden classification, 9 cases (25%) were type II and 27 cases (75%) were type III. According to the anatomical site classification, 8 cases (22.2%) were subcapital femoral neck fractures, 19 cases (52.8%) trans-cervical, and 9 cases (25%) basi-cervical. At present, the follow-up has not found the fracture complications of femoral head avascular necrosis, fracture nonunion, and re-fracture. All patients achieved solid bone union. The mean time of clinical bone union was 3 to 4 months. Among all patients, there were only 3 cases of femoral neck shortening < 5 mm and 1 case of screw back-out = 4 mm. For Harris scoring, average Harris scale at the end of the follow-up was 93.42 ± 3.95 ranging from 85 to 98. There were 32 cases of excellent function scores on the Harris scale and 4 cases of good function scores on the Harris scale. Therefore, the excellent and good rate of Harris hip scores was 100%. CONCLUSIONS: Femoral neck dynamic compression locking system for femoral neck fractures in elderly patients can provide effective stability and reduce complications and revision rates.

Diagnosis related group grouping study of senile cataract patients based on E-CHAID algorithm.

AIM: To figure out the contributed factors of the hospitalization expenses of senile cataract patients (HECP) and build up an area-specified senile cataract diagnosis related group (DRG) of Shanghai thereby formulating the reference range of HECP and providing scientific basis for the fair use and supervision of the health care insurance fund. METHODS: The data was collected from the first page of the medical records of 22 097 hospitalized patients from tertiary hospitals in Shanghai from 2010 to 2012 whose major diagnosis were senile cataract. Firstly, we analyzed the influence factors of HECP using univariate and multivariate analysis. DRG grouping was conducted according to the exhaustive Chi-squared automatic interaction detector (E-CHAID) model, using HECP as target variable. Finally we evaluated the grouping results using non-parametric test such as Kruskal-Wallis H test, RIV, CV, etc. RESULTS: The 6 DRGs were established as well as criterion of HECP, using age, sex, type of surgery and whether complications/comorbidities occurred as the key variables of classification node of senile cataract cases. CONCLUSION: The grouping of senile cataract cases based on E-CHAID algorithm is reasonable. And the criterion of HECP based on DRG can provide a feasible way of management in the fair use and supervision of medical insurance fund.

A Novel Small-Molecule Inhibitor of the Mycobacterium tuberculosis Demethylmenaquinone Methyltransferase MenG Is Bactericidal to Both Growing and Nutritionally Deprived Persister Cells.

Active tuberculosis (TB) and latent Mycobacterium tuberculosis infection both require lengthy treatments to achieve durable cures. This problem has partly been attributable to the existence of nonreplicating M. tuberculosis "persisters" that are difficult to kill using conventional anti-TB treatments. Compounds that target the respiratory pathway have the potential to kill both replicating and persistent M. tuberculosis and shorten TB treatment, as this pathway is essential in both metabolic states. We developed a novel respiratory pathway-specific whole-cell screen to identify new respiration inhibitors. This screen identified the biphenyl amide GSK1733953A (DG70) as a likely respiration inhibitor. DG70 inhibited both clinical drug-susceptible and drug-resistant M. tuberculosis strains. Whole-genome sequencing of DG70-resistant colonies identified mutations in menG (rv0558), which is responsible for the final step in menaquinone biosynthesis and required for respiration. Overexpression of menG from wild-type and DG70-resistant isolates increased the DG70 MIC by 4× and 8× to 30×, respectively. Radiolabeling and high-resolution mass spectrometry studies confirmed that DG70 inhibited the final step in menaquinone biosynthesis. DG70 also inhibited oxygen utilization and ATP biosynthesis, which was reversed by external menaquinone supplementation. DG70 was bactericidal in actively replicating cultures and in a nutritionally deprived persistence model. DG70 was synergistic with the first-line TB drugs isoniazid, rifampin, and the respiratory inhibitor bedaquiline. The combination of DG70 and isoniazid completely sterilized cultures in the persistence model by day 10. These results suggest that MenG is a good therapeutic target and that compounds targeting MenG along with standard TB therapy have the potential to shorten TB treatment duration.IMPORTANCE This study shows that MenG, which is responsible for the last enzymatic step in menaquinone biosynthesis, may be a good drug target for improving TB treatments. We describe the first small-molecule inhibitor (DG70) of Mycobacterium tuberculosis MenG and show that DG70 has characteristics that are highly desirable for a new antitubercular agent, including bactericidality against both actively growing and nonreplicating mycobacteria and synergy with several first-line drugs that are currently used to treat TB.

[Clinical features of four atypical pediatric cases of endemic typhus with pneumonia].

OBJECTIVE: To analyze clinical manifestations, treatment and prognosis of 4 cases with endemic typhus. METHOD: The clinical data of four endemic typhus patients in prognosis were retrospectively analyzed. These four atypical cases of endemic typhus with pneumonia were treated in our department from October 2011 to March 2012. They were all male, with an age range of 15 months to 7 years. The four patients had long history, mild respiratory symptom and no improvement was found after treatment with cephalosporins. There were no evidences of bacterial, viral, or fungal infections and we thought they might have infection with other pathogen. Three were from rural areas. Routine blood tests, Weil-Felix reaction, blood smear (Giemsa staining) , and indirect immunofluorescence assay were performed. RESULT: Blood smear and IFA tests showed evidences for endemic typhus. The clinical presentations were atypical, the patients had no headache, but all had fever, rash, and pneumonia of varying severity. None of the patients had a severe cough, but bronchial casts were observed in one case. Recurrent fever was reported in three cases. Physical examinations showed no eschars, but one patient had a subconjunctival hemorrhage, and one had skin scratches, cervical lymphadenopathy, pleural effusion, pericardial effusion, and cardiac dilatation. Two patients had remarkably increased peripheral blood leukocyte counts; both these patients also had high alanine aminotransferase (ALT) levels and one had a high C-reactive protein (CRP) level. Weil-Felix testing was negative or the OX19 titer was low. The peripheral blood smear (Giemsa stain) showed intracellular pathogens in all four cases. After combined therapy with doxycycline and macrolide antibiotics, all four patients recovered well. CONCLUSION: The endemic typhus children often come from rural areas. The clinical presentations were atypical, they usually have no headache, but have fever (often Periodic fever) , rash, and pneumonia of varying severity in these four cases. Combined therapy with doxycycline and macrolide antibiotics was effective in all four patients.