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.

Hyperkalemia is one of the common ion metabolism disorders in clinical practice. Hyperkalemia is defined as serum potassium higher than 5.0 mmol/L according to the guidelines at home and abroad. Acute severe hyperkalemia can cause serious consequences, such as flaccid paralysis, fatal arrhythmia, and even cardiac arrest. The use of renin-angiotensin- aldosterone system inhibitors, β-blockers and diuretics, low-sodium and high-potassium diets, and the presence of related comorbidities increase the occurrence of hyperkalemia. Hyperkalemia risk exist in all clinical departments, but there is a lack of a standardization in the management of multi- department cooperation in hospital. Therefore, a number of domestic nephrology and cardiology department experts have discussed a management model for multi-department cooperation in hyperkalemia, formulating the management standard on hospital evaluation, early warning, diagnosis and treatment, and process. This can promote each department to more effectively participate in nosocomial hyperkalemia diagnosis and treatment, as well as the long-term management of chronic hyperkalemia, improving the quality of hyperkalemia management in hospital.

COVID-19 epidemic continues to spread around the world till these days, and it is urgent to develop more safe and effective new drugs. Due to the limited P3 biosafety laboratories for directly screening inhibitors of virulent viruses with high infectivity, it is necessary to develop rapid and efficient screening methods for viral proteases and other related targets. The main protease (M^pro), which plays a key role in the replication cycle of SARS-CoV-2, is highly conserved and has no homologous proteases in humans, making it an ideal target for drug development. From two different levels, namely, molecular level and cellular level, this paper summarizes the reported screening methods of SARS-CoV-2 M^pro inhibitors through a variety of representative examples, expecting to provide references for further development of SARS-CoV-2 M^pro inhibitors.

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.

As a common protease with high similarity among coronavirus species, the main protease (M^pro) of SARS-CoV-2 is responsible for the catalytic hydrolysis of viral precursor proteins into functional proteins, which is essential for coronavirus replication and is one of the ideal targets for the development of broad-spectrum antiviral drugs. This paper reviews the main protease inhibitors of SARS-CoV-2, including their molecular structures, potencies and drug-like profiles, binding modes and structure-activity relationships, etc.

This study evaluated the scientific nature and effectiveness of iterative optimization of prevention and control measures for local outbreaks caused by the BA.2 and BA.5.2 COVID-19 strains in Fujian Province in 2022,to provide a scientif-ic basis for responding to future new or recurrent respiratory infectious diseases.According to the theory of infectious disease dynamics,relevant information regarding the local epidemic situation caused by the BA.2 sub-type Omicron virus strain in March 2022 and BA.5.2 sub-type Omicron virus strain in October 2022 in Fujian Province was collected.The susceptible exposed infectious removed(SEIAR)model of COVID-19 infection with a latent period and asymptomatic infected persons was used to analyze the transmission dynam-ics of two local epidemic situations,and evaluate the preven-tion and control effects.The incubation period of the BA.2 epidemic was 3 days(1～9 days),the intergenerational inter-val was 3 days(1～5 days),and the initial Rt was 3.0(95％CI:2.7～3.3).The incubation period of the BA.5.2 epidemic was 2 days(1～6 days),the intergenerational interval was 1 day(0～2 days),and the initial R,was 1.9(95％CI:1.7～2.1).The fittingresults for the BA.2 and BA.5.2 epidemics were good,and no statistical difference was observed between the predic-ted and actual numbers of cases(x2BA.2=31.53,x2BA.5.2=27.88,P＞0.05).If an emergency response had not been initiated,the BA.2 epidemic would have continued to spread andpeak on April 7th,with an estimated 638 035 cases.The BA.5.2 epidemic would have rapidly spread,reaching a peak on November 14th,with an estimated 685 940 cases.If one incubation period were detected early,the scale of the BA.2 epidemic would have decreased by 25.73％;if two incubation periods were detected early,the scale would have decreased by 79.56％,and if one incubation period had been delayed,the scale would have expanded by 13.72％.If one incubation period had been detected early in the BA.5.2 epidemic,the scale would have decreased by 35.04％;if two incubation periods had been detected early,the scale would have decreased by 92.47％;and if one incubation period had been delayed,the scale would have increased by 19.75％.The guiding ideology,and the prevention and control measures for handling two local epidemics were optimized and iterated.Our study indicated that implementing the"four early"measures ef-fectively decreased the scale of the epidemic,and earlier detection was associated with more significant control effects.This study provides valuable information for the prevention and control of new or recurrent respiratory infectious diseases.

Objective:To explore the optimal keV value of the virtual monoenergetic image (VMI) for displaying the osteosarcoma by using the dual-layer spectral detector CT and to evaluate its application value in determining the extent of intramedullary invasion of osteosarcoma.Methods:From August 2021 to August 2022, 57 patients with conventional osteosarcoma of long bone confirmed by biopsy in Beijing Jishuitan Hospital, Capital Medical University were retrospectively analyzed. All patients completed dual-layer spectral CT enhanced examination before limb salvage surgery, and tumor segment resection specimens were obtained after surgery. Conventional 120 kVp image and VMI of 40, 50, 60, 70 and 80 keV were obtained by spectral CT examination, and the CT values of tumors, image noise were measured and the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the corresponding images were calculated. The objective evaluation among the six groups of images were assessed with the Friedman test, and then determined the optimal keV value. The maximum distance between the intramedullary boundary of osteosarcoma and the adjacent articular surfaces was measured on the best keV VMI and the tumor segment resection specimens. The Wilcoxon signed rank test was used to find the differences and the Spearman correlation analysis was used to evaluate the correlation between the distance measured from the best keV VMI and the specimens.Results:There were significant differences in CT value, image noise, SNR and CNR between 40-80 keV VMI and 120 kVp conventional CT images ( P<0.05). The CT value, SNR and CNR of 40 and 50 keV VMI were better than 120 kVp ( P<0.001). The 50 keV VMI was chosen as the best keV VMI to measure the intramedullary extent of osteosarcoma. The distance measured from 50 keV VMI was 103.9 (80.4, 131.4) mm, while the distance measured from specimens was 113.5 (94.0, 142.0) mm, and the difference was statistically significant ( Z=-5.76, P<0.001). The 50 keV VMI measurements in 51 patients were smaller than the gross specimens, which underestimated the tumor intramedullary extent, with the difference was 11.1 (6.6, 13.8) mm. The Spearman correlation analysis demonstrated a high positive correlation of distance measured on gross specimens with the 50 keV VMI ( r s=0.960, P<0.001). Conclusions:Dual-layer spectral detector CT with 50 keV VMI is the best image to show the limb osteosarcoma. Compared with gross specimens, the distance measured from CT underestimated the intramedullary invasion range of limb osteosarcoma about 10 mm, but the two show a good correlation.

OBJECTIVE: To explore the characteristics and clinical phenotypes of rheumatoid arthritis (RA) and provide the basis for further understanding, interventions and outcomes of this disease. METHODS: RA patients attended at Peking University People's Hospital from 2018 to 2021 were enrolled in the study. Data collection included demographic data, the sites and numbers of joints involved, extra-articular manifestations (EAM), comorbidities and laboratory variables. Statistical and bioinformatical analysis was performed to establish clinical subtypes by clustering analysis based on the type of joint involved, EAM involvement and other autoimmune diseases overlapped. The characteristics of each subtype were analyzed. RESULTS: A total of 411 patients with RA were enrolled. The mean age was (48.84±15.17) years, and 346 (84.2%) were females. The patients were classified into 4 subtypes: small joint subtype (74, 18.0%), total joint subtype (154, 37.5%), systemic subtype (100, 24.3%), and overlapping subtype (83, 20.2%). The small joint subtype had no medium or large joint involvement, and 35.1% had systemic involvement. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels and platelet count (PLT) were lower than those in other subtypes, and the rates of positive rheumatoid factors (RF-IgA and RF-IgG) were significantly higher in the small joint subtype. The total joint subtype had both large and small joint involvement but no systemic involvement. The rate of morning stiffness and positive antinuclear antibodies (ANA) in this subtype were lower than those in other subtypes. In the systemic subtype, interstitial lung disease and secondary Sjögren syndrome were the most common systemic involvements, with prominent levels of disease activity score 28-joint count (DAS28-ESR and DAS28-CRP). The overlapping subtype was commonly combined with Hashimoto's thyroiditis or primary Sjögren syndrome. Female in the overlapping subtype was more common than in other subtypes. This subtype was characterized by hyperglobulinemia, hypocomplementemia and high rate of positive ANA, especially spotting type. CONCLUSION Based on the clinical features, RA patients could be classified into 4 subtypes: small joint subtype, total joint subtype, systemic subtype, and overlapping subtype. Each subtype had its own clinical characteristics. They help for further understanding and a more individualized treatment strategy of RA.
Female ; Male ; Humans ; Cross-Sectional Studies ; Sjogren's Syndrome ; Rheumatoid Factor ; Arthritis, Rheumatoid ; Blood Sedimentation ; Phenotype

Malocclusion is one of the three most common oral diseases reported by World Health Organization(WHO). In China, its incidence rate is rising. Malocclusion seriously affects the dental and maxillofacial function, facial appearance and growth development of nearly 260 million children in China, and what is more, it affects their physical and mental health development. Malocclusion occurrence is related to genetic and environmental factors. Early treatment of malocclusion can create a good dental and maxillofacial development environment, correct abnormal growth and control the adverse effects of abnormal genetic factors. It can effectively reduce the prevalence of children's malocclusion and enhance their physical and mental health. This is an urgent need from the economic perspective of our society, so it has great practical and social significance. Experts from the project group "standard diagnose and treatment protocols for early orthodontic intervention of malocclusions of children" which initiated by China National Health Institute of Hospital Administration wrote the "China Experts' Consensus on Preventive and Interceptive Orthodontic Treatments of Malocclusions of Children", which aims to guide and popularize the clinical practice, improve the clinical theory and practice level, and accelerate the disciplinary development of early treatment of children's malocclusion in China. The consensus elaborates the harmfulness of malocclusion and the necessity of early treatment, and brings up the principles and fundamental contents. Based on the law of dental and maxillofacial development, this paper puts forward the guiding suggestions of preventive and interceptive treatments in different stages of dental development ranging from fetus to early permanent dentition. It is a systematic project to promote and standardize the early treatment of malocclusion. Through scientific and comprehensive stratified clinical practice and professional training, the clinical system of early treatment of malocclusion in China will eventually be perfected, so as to comprehensively care for children's dental and maxillofacial health, and improve their oral and physical health in China.
Child ; China/epidemiology* ; Consensus ; Dental Care ; Humans ; Malocclusion/prevention & control* ; Orthodontics, Interceptive

OBJECTIVE: To observe the clinical effect of high suspension and low incision (HSLI) surgery on mixed haemorrhoids, compared with Milligan-Morgan haemorrhoidectomy. METHODS: A multi-centre, randomized, single-blind, non-inferiority clinical trial was performed. Participants with mixed haemorrhoids from Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing Rectum Hospital, Air Force Medical Center of People's Liberation Army of China, and Puyang Hospital of Traditional Chinese Medicine were enrolled from September 2016 to March 2018. By using a blocked randomization scheme, participants were assigned to two groups. The experimental group was treated with HSLI, while the control group was treated with Milligan-Morgan haemorrhoidectomy. The primary outcome was the clinical effect evaluated at 12 weeks after operation. The secondary outcomes included the number of haemorrhoids treated during the operation, pain scores, use of analgesics, postoperative oedema, wound healing, incidence of anal stenosis, anorectal manometry after operation, as well as surgical duration, length of stay and total hospitalization expenses. A safety evaluation was also conducted. RESULTS: In total, 246 eligible participants were enrolled, with 123 cases in each group. There was no significant difference in the clinical effect between the two groups (100.00% vs. 99.19%, P>0.05). Compared with the control group, the number of external haemorrhoids treated during the operation and the pain scores after operation were significantly reduced in the experimental group (P<0.05 or P<0.01); the patient number with wound healing at 2 weeks after operation and the functional length of anal canal at 12 weeks after operation were significantly increased in the experimental group (P<0.05). There was no significant difference in the incidence of anal stenosis, the numbers of patients using analgesics and patients with postoperative oedema between the two groups after operation (P>0.05). The surgical duration and length of stay in the experimental group were significantly longer than those in the control group, and the total hospitalization expense was significantly higher than that in the control group (all P<0.05). No adverse events were reported in either group during the whole trial or follow-up period. CONCLUSION HSLI had the advantages of preserving the skin of anal canal completely, alleviating postsurgical pain and promoting rapid recovery after operation. (Registration No. ChiCTR1900022883).