The main protease (M^pro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent M^pro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent M^pro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent M^pro inhibitors with desirable properties have been developed based on available crystal structures of M^pro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^pro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent M^pro inhibitors are also discussed.

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R₁₀L₄ was endowed with significant inhibitory activity towards wild-type HIV-1 (EC_50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC₅₀ = 0.017 μmol/L, SI = 13,055), E138K (EC₅₀ = 0.017 μmol/L, SI = 13,123) and Y181C (EC₅₀ = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R₁₀L₄ was characterized with significantly reduced cytotoxicity (CC₅₀ = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R₁₀L₄ and HIV-1 RT. Additionally, R₁₀L₄ presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.

Neonatal seizures are the most common clinical manifestations of critically ill neonates and often suggest serious diseases and complicated etiologies. The precise diagnosis of this disease can optimize the use of anti-seizure medication, reduce hospital costs, and improve the long-term neurodevelopmental outcomes. Currently, a few artificial intelligence-assisted diagnosis and treatment systems have been developed for neonatal seizures, but there is still a lack of high-level evidence for the diagnosis and treatment value in the real world. Based on an artificial intelligence-assisted diagnosis and treatment systems that has been developed for neonatal seizures, this study plans to recruit 370 neonates at a high risk of seizures from 6 neonatal intensive care units (NICUs) in China, in order to evaluate the effect of the system on the diagnosis, treatment, and prognosis of neonatal seizures in neonates with different gestational ages in the NICU. In this study, a diagnostic study protocol is used to evaluate the diagnostic value of the system, and a randomized parallel-controlled trial is designed to evaluate the effect of the system on the treatment and prognosis of neonates at a high risk of seizures. This multicenter prospective study will provide high-level evidence for the clinical application of artificial intelligence-assisted diagnosis and treatment systems for neonatal seizures in the real world.
Artificial Intelligence ; Electroencephalography/methods* ; Epilepsy/diagnosis* ; Humans ; Infant, Newborn ; Infant, Newborn, Diseases/diagnosis* ; Intensive Care Units, Neonatal ; Multicenter Studies as Topic ; Prospective Studies ; Randomized Controlled Trials as Topic ; Seizures/drug therapy*

Objective: To summarize the application of temporalis muscle flap in the salvage nasopharyngectomy for advanced recurrent nasopharyngeal carcinoma (rNPC), and to provide guidance for the repair of extensive skull base defects in salvage rNPC. Methods: A total of 54 patients with the application of temporalis muscle flap in the salvage nasopharyngectomy for advanced rNPC were retrospectively analyzed, including 42 males and 12 females, aging from 29 to 71 years. There were 36 patients with rT3 and 18 patients with rT4. The surgical methods of temporalis muscle flap repair were summarized. The general situation, survival time and postoperative complications of patients were recorded, and the advantages and disadvantages of temporalis muscle flap were discussed. Results: The temporal muscle flap could completely cover the defect area of nasopharynx and skull base, without the need for other autologous repair materials. The follow-up period was 2 to 28 months. The survival rate of temporalis flap was 98.1% (53/54). The 1-year overall survival rate was 84.5% while 1-year progression-free survival rate was 49.0%. None of the patients had facial nerve injury. Three patients (5.6%) had necrosis of the cranial membrane required surgical intervention and four patients (7.4%) required a chonoplasty due to severe chonostril stenosis or chonostril atresia. Eleven cases (20.4%) had mouth opening restriction, chewing weakness, dysphagia and other eating difficulties. Conclusions: Temporalis muscle flap is an alternative flap for the salvage nasopharyngectomy for advanced rNPC. Temporal muscle flap shows high survival rate and wide coverage, but the surgeon should apprehend the possible complications and reduce the occurrence of them.
Humans ; Male ; Female ; Nasopharyngeal Carcinoma ; Retrospective Studies ; Surgical Flaps ; Nasopharyngeal Neoplasms/pathology* ; Muscles/pathology*

Objective: To evaluate the efficiency of internal carotid artery (ICA) embolization technology in endoscopic salvage surgery for recurrent nasopharyngeal carcinoma (rNPC) invading the ICA. Methods: From January 2016 to March 2021, 83 patients with rNPC who invaded the ICA and underwent endoscopic extended nasopharyngectomy were retrospectively collected from the Eye & ENT Hospital in Fudan University, including 60 males and 23 females. The age of the patients ranged from 27 to 77 years. The standard of ICA invasion was that the distance from the lesion to the ICA on enhanced MRI was ≤ 1.8 mm. The clinical characteristics, ICA management strategy and survival prognosis of patients were analyzed, and the effectiveness of ICA embolization was evaluated. Kaplan-Meier method was used to calculate the survival rate and Log-rank test was used to compare the difference. Results: In 83 patients with rNPC, there were 13 patients with rT2, 38 patients with rT3, 32 patients with rT4, and 16 patients had lymph node metastasis. A total of 37 patients (44.6%) underwent ICA coil embolization before surgery, of which 2 cases underwent external carotid-middle cerebral artery artery bypass grafting and ICA embolization due to positive balloon occlusion test (BOT). Patients with positive surgical margin accounted for 24.1% (20/83). Among them, patients with rT4 and patients without ICA embolization had a higher positive rate of surgical margin (P value was 0.001, 0.043, respectively). The 3-year overall survival (OS) and progression free survival (PFS) rate of all patients was 46.5% and 26.7%, respectively. In addition, the 3-year OS and PFS of patients with ICA embolization was significantly higher than those without ICA embolization, respectively (69.1% vs 27.8%, P=0.003; 33.9% vs 18.9%, P=0.018). Only 2 patients (2/37, 5.4%) had cerebral infarction complications after coil embolization of the affected ICA due to negative BOT. Conclusion: Preoperative ICA embolization can be used to treat patients with rNPC invading the ICA, improve the total removal rate and survival rate of patients, which is an effective salvage treatment.
Humans ; Male ; Female ; Adult ; Middle Aged ; Aged ; Nasopharyngeal Carcinoma ; Salvage Therapy ; Retrospective Studies ; Carotid Artery, Internal ; Neoplasm Recurrence, Local/surgery* ; Nasopharyngeal Neoplasms/pathology*

OBJECTIVE: To evaluate the early and mid-term clinical results of medial parapatellar soft tissue overlapping suture in total knee arthroplasty for treatment of severe osteoarthritis combined with permanent patellar dislocation. METHODS: We retrospectively analyzed the data of 12 patients (12 knees) diagnosed with severe knee osteoarthritis combined with permanent patellar dislocation undergoing total knee arthroplasty with medial parapatellar soft tissue overlapping suture. Knee Society Score (KSS), University of California Los Angeles (UCLA) activity-level rating, Visual Analog Scale (VAS) pain score, and knee range of motion of the patients were assessed before and 2 years after the surgery. Anteroposterior and lateral radiographs of the knee joint, full-length standing radiographs of the lower limbs and patellar axial radiographs were evaluated. RESULTS: The mean Knee Society Score of the patients increased from 34.2±11.1 before surgery to 73.5±6.3 at two years after the surgery (P < 0.001). The UCLA activity-level rating increased from an average of 3.8 ± 0.8 before surgery to 5.8 ± 0.6 at two years postoperatively (P=0.003). The mean VAS pain score decreased from 42.8±6.0 before surgery to 20.1±3.7 (P < 0.001) and the range of motion of the knee joint increased from 74.6±8.9 degrees to 97.5±4.5 degrees at two years (P < 0.001). The radiographs showed no signs of subluxation or dislocation of the patella in all the patients. CONCLUSIONS Medial parapatellar soft tissue overlapping suture in total knee arthroplasty can achieve good early and mid-term clinical results for treatment of severe osteoarthritis combined with permanent patellar dislocation.
Arthroplasty, Replacement, Knee/methods* ; Humans ; Osteoarthritis, Knee/surgery* ; Patella/surgery* ; Retrospective Studies ; Sutures

OBJECTIVE: To study the distribution and drug resistance of pathogens causing periprosthetic infections after hip and knee arthroplasty, and to formulate prevention and treatment strategies for drug-resistant bacteria. METHODS: The data of 146 cases of periprosthetic infection after primary hip and knee arthroplasty from 2010 to 2015 were collected, including 111 cases of periprosthetic infection after hip arthroplasty and 35 cases of periprosthetic infection after knee arthroplasty. The culture positive rate, pathogenic bacteria composition and drug resistance rate were counted over the years, and the change trend of pathogen distribution and drug resistance was analyzed. RESULTS: One hundredand eight strains of pathogenic bacteria were detected in 146 cases, and the positive rate of culture was 73.97%. Gram positive bacteria accounted for 55.48%, Staphylococcus epidermidis and Staphylococcus aureus accounted for 25.34% and 15.07% respectively. Gram negative bacteria accounted for 13.01%, including Enterobacter cloacae, Pseudomonas aeruginosa and Escherichia coli. There were 4 cases of Mycobacterium tuberculosis infection and mixed infection. The results of culture over the years showed that the constituent ratio of Gram positive bacteria had an increasing trend, fluctuating from 39.13% to 76.47%. The results of drug sensitivity showed that the pathogens were highly resistant to β-lactams, quinolones, clindamycin and gentamicin, and the drug resistance rate was increasing, but it was still sensitive to rifampicin, nitrofurantoin, tigecycline, linezolid and vancomycin. CONCLUSION Gram positive bacteria are the main pathogens of periprosthetic infection, and the proportion is increasing gradually.The pathogens have high resistance to many kinds of antibiotics, and the resistance rate is still increasing. To strengthen the monitoring of the distribution and drug resistance of pathogenic bacteria is helpful to grasp its change trend and formulate targeted prevention and control strategies.
Anti-Bacterial Agents/therapeutic use* ; Arthroplasty, Replacement, Knee/adverse effects* ; Drug Resistance ; Drug Resistance, Bacterial ; Gram-Positive Bacteria ; Microbial Sensitivity Tests ; Retrospective Studies

BACKGROUND: Although a variety of risk factors of pneumonia after clipping or coiling of the aneurysm (post-operative pneumonia [POP]) in patients with aneurysmal subarachnoid hemorrhage (aSAH) have been studied, the predictive model of POP after aSAH has still not been well established. Thus, the aim of this study was to assess the feasibility of using admission neutrophil to lymphocyte ratio (NLR) to predict the occurrence of POP in aSAH patients. METHODS: We evaluated 711 aSAH patients who were enrolled in a prospective observational study and collected admission blood cell counts data. We analyzed available demographics and baseline variables for these patients and analyzed the correlation of these factors with POP using Cox regression. After screening out the prognosis-related factors, the predictive value of these factors for POP was further assessed. RESULTS: POP occurred in 219 patients (30.4%) in this cohort. Patients with POP had significantly higher NLR than those without (14.11 ± 8.90 vs. 8.80 ± 5.82, P < 0.001). Multivariate analysis revealed that NLR remained a significant factor independently associated with POP following aSAH after adjusting for possible confounding factors, including the age, World Federation of Neurosurgical Societies (WFNS) grade, endovascular treatment, and ventilator use. And the predictive value of NLR was significantly increased after WFNS grade was combined with NLR (NLR vs. WFNS grade × NLR, P = 0.011). CONCLUSIONS Regardless of good or poor WNFS grade, patients having NLR >10 had significantly worse POP survival rate than patients having NLR ≤10. NLR at admission might be helpful as a predictor of POP in aSAH patients.
Humans ; Lymphocytes ; Neutrophils ; Pneumonia/etiology* ; Prognosis ; Subarachnoid Hemorrhage ; Treatment Outcome

In this report, a series of novel piperidine-substituted thiophene[3,2-]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead . The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure-activity relationship and molecular docking were also investigated. Furthermore, exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound holds great promise as a potential drug candidate for the treatment of HIV-1 infection.

OBJECTIVE: By recording the treatment events of implantable cardioverter defibrillator(ICD) in patients with ejection fraction reduced heart failure(HFrEF), to analyze the difference in primary and secondary prevention patients. METHODS: A single center retrospective study was conducted. HFrEF patients with ICD or cardiac resynchronization therapy with cardioverter defibrillator(CRT-D) implanted in Peking Union Medical College Hospital from January 2006 to December 2017 were enrolled in our study. Basic clinical data was collected and ICD treatment events were recorded during follow-up. The appropriate treatment events were identified according to electrocardiogram recorded by ICD. The ICD treatment events of primary and secondary prevention patients were analyzed. RESULTS: 1) A total of 145 patients with HFrEF implanted with ICD or CRT-D were enrolled, 103 primary prevention patients and 42 secondary prevention patients. Primary prevention patients had longer left ventricular end-systolic diameter(LVESD) and lower left ventricular ejection fraction(LVEF) than secondary prevention patients. 2) Multivariate competitive risk regression analysis showed that secondary prevention patients and male patients had higher risk of receiving appropriate treatment and appropriate shock therapy. 3) K-M curve and Log-Rank test showed that there was no significant difference in the risk of inappropriate treatment between primary and secondary prevention patients. The main cause of inappropriate treatment was atrial flutter or atrial fibrillation. CONCLUSION: 1) Primary prevention patients have lower risk of receiving appropriate treatment and appropriate shock therapy than secondary prevention patients; 2) There is no significant difference between primary and secondary prevention patients in the risk of inappropriate treatment. The main cause of inappropriate treatment events is atrial flutter or atrial fibrillation.