The proteolysis targeting chimeras (PROTACs) technology has been rapidly developed since its birth in 2001, attracting rapidly growing attention of scientific institutes and pharmaceutical companies. At present, a variety of small molecule PROTACs have entered the clinical trial. However, as small molecule PROTACs flourish, non-small molecule PROTACs (NSM-PROTACs) such as peptide PROTACs, nucleic acid PROTACs and antibody PROTACs have also advanced considerably over recent years, exhibiting the unique characters beyond the small molecule PROTACs. Here, we briefly introduce the types of NSM-PROTACs, describe the advantages of NSM-PROTACs, and summarize the development of NSM-PROTACs so far in detail. We hope this article could not only provide useful insights into NSM-PROTACs, but also expand the research interest of NSM-PROTACs.

OBJECTIVE：To observe the effects of Compound danshen drip ping pills on the prevention of contrast-induced nephropathy（CIN）after percutaneous coronary intervention （PCI）and its influence on clinical prognosis. METHODS ：From Jan. to Jun. 2020，240 patients with coronary heart disease receiving PCI in Tianjin Chest Hospital were randomly divided into control group（120 cases）and Danshen dripping pills group （120 cases）according to random number table. The patients in both groups were injected with Lippaclitanol injection 1-5 mL slowly through radial or femoral artery sheath ，and intravenous hydration was performed before and after PCI ；Danshen dripping pills group was additionally given Compound danshen dripping pills 270 mg orally for a long term ，three times a day ，three days before and after PCI ，on the basis of the control group. The levels of renal function indexes [serum creatinine （Scr），blood urea nitrogen （BUN），cystatin C （Cys-C），creatinine clearance rate （Ccr）]， inflammatory reaction indexes [high sensitivity C-reactive protein （hs-CRP）， interleukin-6 （IL-6）] and oxidative stress index [malondialdehyde （MDA）] were observed in 2 groups before and 72 hours after PCI. The occurrence of CIN in 2 groups was recorded 3 days after PCI therapy ；the occurrence of major cardiovascular adverse events was also observed during 1-year follow-up period. RESULTS ：Before treatment ，there was no significant difference in serum renal function indexes ，inflammatory reaction indexes and oxidative stress index between 2 groups（P＞0.05）. Seventy-two hours after PCI ，serum levels of Scr ，BUN， Cys-C，hs-CRP，IL-6 and MDA were increased significantly in 2 groups than before treatment ，while the Ccr were decreased significantly；those indexes of Danshen dripping pills group were significantly better than those of control group （P＜ 0.05）. The incidence of CIN in Danshen dripping pills group was 4.2％ after treatment ， and total incidence of major cardiovascular adverse events was 13.3％ during follow-up period，which were sign ificantly lower than 13.3％ and 27.5％ of control group （P＜0.05）. CONCLUSIONS ：Compound danshen dripping pills may have a certain effect on the prevention of CIN in coronary heart disease patients after PCI ，and can reduce the incidence of major cardiovascular adverse events.

Humans ; Lung ; Pneumoconiosis/diagnostic imaging* ; Radiography ; Tomography, X-Ray Computed

Objective:To analyze the incidence and epidemiological characteristics of traumatic spinal cord injury in China in 2018.Methods:Multi-stage stratified cluster sampling was used to randomly select hospitals capable of treating patients with spinal cord injury from 3 regions，9 provinces and 27 cities in China to retrospectively investigate eligible patients with traumatic spinal cord injury admitted in 2018. National and regional incidence rates were calculated. The data of cause of injury，injury level，severity of injury，segment and type of fracture，complications，death and other data were collected by medical record questionnaire，and analyzed according to geographical region，age and gender.Results:Medical records of 4，134 patients were included in this study，with a male-to-female ratio of 2.99∶1. The incidence of traumatic spinal cord injury in China in 2018 was 50.484 / 1 million （95% CI 50.122-50.846）. The highest incidence in the Eastern region was 53.791 / 1 million （95% CI 53.217-54.365）. In the whole country，the main causes of injury were high falls （29.58%），as well as in the Western region （40.68%），while the main causes of injury in the Eastern and Central regions were traffic injuries （31.22%，30.10%）. The main injury level was cervical spinal cord in the whole country （64.49%），and the proportion of cervical spinal cord injury in the Central region was the highest （74.68%），and the proportion of lumbosacral spinal cord injury in the Western region was the highest （32.30%）. The highest proportion of degree of injury was incomplete quadriplegia （55.20%），and the distribution pattern was the same in each region. A total of 65.87% of the patients were complicated with fracture or dislocation，77.95% in the Western region and only 54.77% in the Central region. In the whole country，the head was the main combined injury （37.87%），as well as in the Eastern and Central regions，while the proportion of chest combined injury in the Western region was the highest （38.57%）. A total of 32.90% of the patients were complicated with respiratory complications. There were 23 patients （0.56%） died in hospital，of which 17（73.91%） died of respiratory dysfunction. Conclusions:The Eastern region of China has a high incidence of traumatic spinal cord injury. Other epidemiological features include high fall as the main cause of injury cervical spinal cord injury as the main injury level，incomplete quadriplegia as the main degree of injury，head as the main combined injury，and respiratory complications as the main complication.

Objective To assess the quantitative impact of the application of high-throughput sequencing worldwide on clinical virology.Methods The following records from 2000 to 2018 were collected from National Center for Biotechnology Information:The number of complete genome of virus records per year;the number of virus discovery articles per year;the number of virus quasi-species articles per year;the number of viral infection gene signature articles per year.The method of interrupted time series was applied to analyze the trends of those records.Results Since the sequencing centers worldwide began to transit from the Sanger sequencing to the high-throughput sequencing technology in 2008,the annual value of records mentioned above increased by 3.755,2.760,6.195 and 3.885 times respectively.The long-term trends of change of each record are as follows:the number of complete genome of virus records increased by 1639.991 per year (P＜0.001);the number of virus discovery articles increased by 83.091 per year (P＜0.001);the number of virus quasi-species articles increased by 2.509 per year (P＜ 0.001);the number of viral infection gene signature articles increased by 30.836 per year (P＜ 0.001).Conclusions In 2008,the sequencing centers worldwide began to apply high-throughput sequencing technology which led to continuous decrease of the cost for sequencing.It result ed in not only increasingly enriched applications in clinical virology but also a long-term positive impact on the advance of clinical virology.

Objective:To analyze the clinical data of 203 discharged patients with corona virus disease 2019(COVID-19), and to investigate the predictors for the severe cases.Methods:Confirmed COVID-19 cases hospitalized at Zhongnan Hospital of Wuhan University from January 1 to February 1, 2020 were consecutively enrolled, who were divided into severe group and non-severe group.The clinical data of enrolled patients were collected and the clinical manifestations, laboratory results, imaging, treatments and prognosis of patients in the two groups were analyzed. Mann-Whitney U rank sum test and chi-square test were used for statistical analysis. Results:A total of 203 discharged patients with COVID-19 were enrolled. The common clinical manifestations included fever (89.2%, 181/203), dry cough (60.1%, 122/203), chest distress (35.5%, 72/203), shortness of breath(29.1%, 59/203)and myalgia or arthralgia (26.6%, 54/203). The time from disease onset to hospital admission was 5.8 days (1.0 to 20.0 days). Among 203 enrolled patients, 107(52.7%) were divided into severe group and 96(47.3%) were non-severe group. The age in severe group was 60 years (23 to 91 years), which was significantly older than non-severe group (47 years (20 to 86 years)), the difference was statistically significant ( Z=-6.12, P<0.01). There were 63.6%(68/107) patients in severe group with at least one underlying disease, which was significantly more than non-severe group (20.8% (20/96)), the difference was statistically significant ( χ2=37.60, P<0.01). The proportions of patients with increased white blood cells, decreased lymphocytes and albumin, elevated alanine aminotransferase, aspartate aminotransferase, creatinine, lactic acid dehydrogenase, creatine kinase, fasting blood glucose, D-dimer, erythrocyte sedimentation rate, C-reactive protein, interleukin-6, and procalcitonin in severe group were all higher. On admission, 172 patients (84.7%) had bilateral patchy shadows or ground glass opacity in the lungs on chest imaging study, 20(9.9%) presented pleural effusion. Fifty-five cases (27.1%) showed progressions of lung lesions on computed tomography (CT) rescan at an average interval of five days. Among 203 patients, 123(60.6%) were given oxygen therapy upon admission, 107(52.7%) were given short-term glucocorticoid therapy, and 131(64.5%) received antiviral therapy; and 26(12.8%) died. The hospital stay was 11.0 days (1.0 to 45.0 days). Conclusions:Fever is the most common symptoms in COVID-19 patients.Elderly and patients with underlying diseases are risk factors for progression to severe cases. The elderly patients should be strengthened early monitoring, paid attention to the control of underlying diseases, and reduce the occurrence of critical diseases.

Objective To study the constituents of urinary stones in patients in Zhejiang,and analyze the composition difference between patients from northern Zhejiang province and southern Zhejiang province.Methods From October 2012 to October 2018,clinical data of 4 423 urinary stone patients treated in Sir Run Run Shaw Hospital,the Second Affiliated Hospital of Wenzhou Medical University,and Huzhou First People's Hospital was retrospectively analyzed.Infrared spectrum was used to analyze urinary calculi constituents.Among 4 423 patients,there were 3 041 males and 1 382 females,male to female ratio was 2.2∶ 1,and the mean age was (51.2 ±16.5) years.There were 2 974 northern Zhejiang patients and 1 449 southern Zhejiang patients.High incidence age group was 41-60 years [48.2％ (2 136/4 423)].The distribution characteristics of urinary calculi constituents in different groups of sex,age,and region were analyzed.Results Among the 4 423 cases,the mixed urinary stones were dominant in the urinary calculus [73.1％ (3 235/4 423)],in which,the most component was the calcium oxalate monohydrate + calcium oxalate dehydrate + carbonated apatite [36.2％ (1 604/4 423)];among the pure stones,the most component was the calcium oxalate monohydrate [16.3 ％ (719/4 423)].Carbonated apatite stones [70.1％ (970/1 382) vs.61.0％ (1 856/3 041),P ＜0.05] and magnesium ammonium phosphate stones [12.7％ (176/1 382) vs.4.9％ (150/3 041),P ＜ 0.05] were both more prevalent in females than males,but uric acid stones[10.6％ (325/3 041) vs.5.8％ (81/1 382),P ＜0.05] were more common in males than females.The proportions of calcium oxalate stones[90.6％ (961/1 060) vs.76.2％ (935/1 227),P ＜0.05],carbonated apatite stones [77.6％ (823/1 060) vs.50.7％ (623/1 227),P ＜ 0.05],and magnesium ammonium phosphate stones[9.1％ (97/1 060) vs.6.5％ (80/1 227),P ＜0.05] of 0-40 years group were all higher than ＞ 60 years group,however,uric acid stones were more frequent in ＞ 60 years group [3.5％ (38/1 060) vs.17.0％ (209/1 227),P ＜ 0.05].The proportion of calcium oxalate stones in southern Zhejiang was lower than northern Zhejiang [79.0％ (1 145/1 449) vs.89.4％ (2 661/ 2 974),P ＜ 0.05].However,carbonated apatite stones [71.5％ (1 037/1 449) vs.60.1％ (1 789/2 974),P ＜ 0.05],magnesium ammonium phosphate stones [15.1％ (220/1 449) vs.3.5％ (106/ 2 974),P ＜ 0.05],and uric acid stones [10.7％ (156/1 449) vs.8.4％ (250/2 974),P ＜ 0.05] were more prevalent in southern Zhejiang than northern Zhejiang.Conclusions The distribution of constituents of urinary stones in Zhejiang was different in genders,age,and regions.Carbonated apatite stones and magnesium ammonium phosphate stones were more prevalent in females and young people,and uric acid stones were more common in males and old people.Calcium oxalate stones were more common in youths.Moreover,calcium oxalate stones were more frequent in northern Zhejiang,and carbonated apatite stones,magnesium ammonium phosphate stones and uric acid stones were common in southern Zhejiang.

Interrupted time-series (ITS) is a quasi-experimental design which evaluates the effectiveness of an intervention based on time-series outcome variables. Compared with the single group of ITS, the two groups of ITS can better control the influence of pre-interventional confounding factors and evaluate the effectiveness of the intervention. This paper summarizes the principles and statistical methods of two groups of ITS by an example of evaluating vaccine effect on the incidence of a disease in two cities. The regression model is fitted by Prais-Winsten method and Newey-West method and the results are explained and compared in detail. When the intervention is performed with other confounding interventions at the same time, the two groups of ITS can be more effective to balance the existing trends before the intervention, and evaluate the effectiveness of intervention. The method of two groups of ITS has important practical significance, providing new insights in program evaluation.

AIM: To study the effect of G-protein-coupled receptor kinase 5 (GRK5) on the activation of astrocytesin the brain cortex of newborn Wistar rats .METHODS: GRK5 gene was silenced in the model of rat brain cortexastrocytes in vitro for 24 h.N-acetylcysteine (NAC), which is a known inhibitor of NF-κB, was added into the culture mediumaccording to gene silencing for 24 h.The expression levels of GFAP and caspase-3 were detected by the method of immunofluorescence,and the mRNA levels of NF-κB, TNF-α, IL-1βand iNOS were determined by real-time PCR.Moreover,the activity of SOD and concentrations of TNF -αand NO were measured.RESULTS: GRK5 gene silencing increasedthe expression of NF-κB at mRNA and protein levels obviously (P <0.01), and the mRNA levels of IL-1βand iNOS increasedsynchronously (P <0.01).Furthermore, caspase-3-positive cells in GRK5 siRNA group were increased comparedwith control siRNA group (P <0.01).Treatment with NAC obviously reduced the activity of NF -κB and weakened theeffects induced by GRK5 siRNA (P <0.05).CONCLUSION: GRK5 siRNA increases NF-κB activity and induces the activationof astrocytes.

Objective The purpose of this study was to analyze the distribution,temporal and spatial clustering characteristics and changes of severe hand,foot,and mouth disease (HFMD) in order to provide evidence-based decision making strategy for control and prevention of severe HFMD cases.Methods Severe HFMD cares were extracted from the National Diseases Reporting System of Chinese Center for Disease Control and Prevention (CDC) between 2008 and 2013.Definition and clinical diagnostic criteria of severe HFMD cases were set up by China CDC in the Hand,Foot,and Mouth Disease Control and Prevention Guideline,version 2010.Spatial scan unit was under the district/county of 2 900 in mainland China with temporal scan unit as month and time span as from May 2008 to August 2013.Kulldorff scan statistics was applied and analyses were conducted by SaTScanTM 9.1.Mapping and visualizing the results were carried out with ArcGIS 10.0.Results Data related to the monitoring program on severe HFMD from 2008 to 2013 demonstrated that above 96％ of the severe HFMD cases occurred under 5 years old,mostly males,with the ratio of males to females as 1.73-1.80 and over 84％ of the children were ‘scattered'.Results from SaTScan illustrated that the temporal and spatial clustering existed among severe HFMD cases.The temporal dimension of severe HFMD was from May to July each year.Spatial dimension was located in south-east coastal area and middle-east area.With respect to the changes of temporal and spatial clustering phenomena,Class 1 clustering area was located in south-east coastal region in 2008 and in middle-east region in 2009 and was shifting to the west from middle-east region in 2010.It moved to the north-east from middle-east region in 2011 and to the north-west and south-west from middle-east region in 2012.Class 1 clustering area covered districts/countries from 18 provinces in 2012.The same pattem of Class 1 clustering area was observed as in the previous year-2013,but with less districts/countries from the 13 provinces.Conclusion Temporal and spatial clustering areas of severe HFMD were presented in this report,and the yearly changing pattern of the clustering areas was noted.Findings from this study provided evidence-based data to the decision-making authorities so as to prevent deaths from severe HFMD cases under reasonable prevention and control strategies.