PI3Kγ and PI3Kδ have important regulatory roles in the immune system, and targeting these two subtypes helps to reshape the tumor microenvironment. PI3Kγ and PI3Kδ are potential targets for tumor immunotherapy. In this study, a series of new pyrazolopyrimidine derivatives were designed and synthesized on the basis of our previously reported PI3K inhibitors, resulting in the discovery of compound 16l as a potent and selective PI3Kγ/δ dual inhibitor. Compound 16l demonstrated strong biochemical potencies against PI3Kγ and PI3Kδ with IC₅₀ values of 0.11 and 0.79 nmol·L^-1. In cell-based assays, it potently inhibited the PI3Kγ and PI3Kδ mediated Akt S473 phosphorylation with EC₅₀ values of 3 and 7 nmol·L^-1. In vivo, compound 16l exhibited acceptable pharmacokinetic properties in Sprague-Dawley (SD) rats and suppressed the tumor growth in a MC38 syngeneic mouse model. The animal experiments were approved by the Animal Ethics Committee of Hefei Institutes of Physical Science, Chinese Academy of Sciences (approval number: DWLL-2000-06). In addition, no appreciable human ether-a-go-go-related gene (hERG) inhibition was observed for compound 16l even at 30 μmol·L^-1. These results suggested that compound 16l might be a potential research tool for studying the PI3Kγ/δ mediated signaling pathways.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective: To analyze the difference of application methods and effects of local flap in small and medium-sized defects of different aesthetic subunits of nose, in order to provide reference for clinical work. Methods: A retrospective analysis was made on 59 patients with external nasal masses and scars who underwent surgical treatment in the Department of Aesthetic Plastic Surgery of the Affiliated Hospital of Qingdao University from July 1, 2021 to January 30, 2022, including 27 females and 32 males, aged 15 to 69 years. Using Likert scale, the repair methods and effects of local flap for nasal soft tissue defects were evaluated and summarized from three aspects of texture, flatness and scar concealment. GraphPad Prism 5.0 software was used for data statistics and analysis. Results: The use of skin flaps to repair small and medium-sized areas of the nose could achieve satisfactory results. For patients with different subunits, in terms of skin flatness and scar concealment degree in the operation area, patients' satisfaction with the dorsal and lateral nasal areas was higher than that of the alar and tip areas, respectively (F=6.40, P=0.001; F=10.57, P<0.001). For patients with different skin flap repair methods, the satisfaction of patients with Z-plasty and Dufourmentel skin flap was higher than that of other skin flap repair methods (F=4.38, P=0.002), and the satisfaction of patients with Dufourmentel skin flap was the highest in the degree of scar concealment (F=2.57, P=0.038). Conclusions: In the small and medium-sized defects of the nose, the use of multiple local flaps can achieve good cosmetic effects and functional recovery. The operator should select the appropriate flap repair method according to the characteristics of different aesthetic subunits of the nose.

Objective: To quantitatively assess the pulmonary vasculature using non-contrast computed tomography (CT) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) pre- and post-treatment and correlate CT-based parameters with right heart catheterization (RHC) hemodynamic and clinical parameters. Materials and Methods: A total of 30 patients with CTEPH (mean age, 57.9 years; 53% female) who received multimodal treatment, including riociguat for ≥ 16 weeks with or without balloon pulmonary angioplasty and underwent both noncontrast CT for pulmonary vasculature analysis and RHC pre- and post-treatment were included. The radiographic analysis included subpleural perfusion parameters, including blood volume in small vessels with a cross-sectional area ≤ 5 mm 2 (BV5) and total blood vessel volume (TBV) in the lungs. The RHC parameters included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index (CI). Clinical parameters included the World Health Organization (WHO) functional class and 6-minute walking distance (6MWD). Results: The number, area, and density of the subpleural small vessels increased after treatment by 35.7% (P < 0.001), 13.3% (P = 0.028), and 39.3% (P < 0.001), respectively. The blood volume shifted from larger to smaller vessels, as indicated by an 11.3% increase in the BV5/TBV ratio (P = 0.042). The BV5/TBV ratio was negatively correlated with PVR (r = -0.26; P = 0.035) and positively correlated with CI (r = 0.33; P = 0.009). The percent change across treatment in the BV5/TBV ratio correlated with the percent change in mPAP (r = -0.56; P = 0.001), PVR (r = -0.64; P < 0.001), and CI (r = 0.28; P = 0.049).Furthermore, the BV5/TBV ratio was inversely associated with the WHO functional classes I–IV (P = 0.004) and positively associated with 6MWD (P = 0.013). Conclusion Non-contrast CT measures could quantitatively assess changes in the pulmonary vasculature in response to treatment and were correlated with hemodynamic and clinical parameters.

Objective: To observe the effects of acupoints, cone numbers and durations of moxibustion with different moxibustion methods on skin surface and inside temperature, and to provide references for the clinical standardization of moxibustion amount. Methods: The 42 big-ear white rabbits were divided into 6 groups according to the random number table method, a 1-cone direct moxibustion group, a 2-cone direct moxibustion group, a 3-cone direct moxibustion group, a 1-cone herbal cake-partitioned moxibustion group, a 2-cone herbal cake-partitioned moxibustion group, and a 3-cone herbal cake-partitioned moxibustion group, with 7 rabbits in each group. Shenque (CV 8), Shenshu (BL 23) and Zusanli (ST 36) were used in each group, but the moxibustion methods, cone numbers and durations of moxibustion were different. Rabbits in each group received moxibustion once every other day for 5 times in total. During the intervention, a thermoelectricity coupled probe and a temperature recorder were used to record the real-time acupoint skin temperature and the temperature at different time points, so as to observe, analyze and process the real-time changes in the temperature difference between the surface and inside of acupoint skin. Results: For herbal cake-partitioned moxibustion, the best temperature for cone changing was (46.38±0.51) ℃ when the highest surface temperature was (49.20±0.52) ℃; the multi-factor comparison of acupoint × cone number × time and acupoint × moxibustion method × time showed that time × acupoint, time × moxibustion method and cone number × acupoint had interactive effects (all P<0.05). Comparing skin temperature differences between different cone numbers at the same acupoint, Shenque (CV 8) on the 1st and the 5th days, Shenshu (BL 23) on the 3rd and the 7th days, Zusanli (ST 36) on the 1st and the 9th days of experiment showed statistically significant differences (all P<0.05). The skin temperature comparison of different moxibustion methods at the same acupoint all had statistical differences (all P<0.05), except for Shenque (CV 8) before moxibustion, Shenshu (BL 23) before moxibustion and on the 5th day; Zusanli (ST 36) only showed statistical differences on the 5th and 7th days (both P<0.05). The skin temperature differences of different acupoints after moxibustion in the 1-cone, 2-cone and 3-cone groups were statistically different (all P<0.05); direct moxibustion and herbal cake-partitioned moxibustion at different acupoints were all statistically different (all P<0.05). Conclusion: Cone changing temperature under the same specifications of herbal cake-partitioned moxibustion was confirmed. Temperature difference between surface and inside of different acupoint skin at the same maximum temperature was significantly different due to the cone numbers and moxibustion methods, which showed the highest at Shenshu (BL 23), the second at Shenque (CV 8), and the lowest at Zusanli (ST 36). The influence of acupoint factor should be considered to determine the quantitative indicators of moxibustion.

Objective: Several COVID-19 patients have overlapping comorbidities. The independent role of each component contributing to the risk of COVID-19 is unknown, and how some non-cardiometabolic comorbidities affect the risk of COVID-19 remains unclear. Methods: A retrospective follow-up design was adopted. A total of 1,160 laboratory-confirmed patients were enrolled from nine provinces in China. Data on comorbidities were obtained from the patients' medical records. Multivariable logistic regression models were used to estimate the odds ratio ( Results: Overall, 158 (13.6%) patients were diagnosed with severe illness and 32 (2.7%) had unfavorable outcomes. Hypertension (2.87, 1.30-6.32), type 2 diabetes (T2DM) (3.57, 2.32-5.49), cardiovascular disease (CVD) (3.78, 1.81-7.89), fatty liver disease (7.53, 1.96-28.96), hyperlipidemia (2.15, 1.26-3.67), other lung diseases (6.00, 3.01-11.96), and electrolyte imbalance (10.40, 3.00-26.10) were independently linked to increased odds of being severely ill. T2DM (6.07, 2.89-12.75), CVD (8.47, 6.03-11.89), and electrolyte imbalance (19.44, 11.47-32.96) were also strong predictors of unfavorable outcomes. Women with comorbidities were more likely to have severe disease on admission (5.46, 3.25-9.19), while men with comorbidities were more likely to have unfavorable treatment outcomes (6.58, 1.46-29.64) within two weeks. Conclusion Besides hypertension, diabetes, and CVD, fatty liver disease, hyperlipidemia, other lung diseases, and electrolyte imbalance were independent risk factors for COVID-19 severity and poor treatment outcome. Women with comorbidities were more likely to have severe disease, while men with comorbidities were more likely to have unfavorable treatment outcomes.
Adult ; Aged ; COVID-19/virology* ; China/epidemiology* ; Comorbidity ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Severity of Illness Index ; Treatment Outcome

Objective: To investigate the incidence of chromosome polymorphisms and their influence on semen quality and sperm DNA integrity in male patients receiving in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). METHODS: We retrospectively analyzed the chromosomal karyotypes and the types and incidence rate of chromosome polymorphisms in 2 370 male patients undergoing IVF/ICSI between June 2016 and June 2018. We classified the patients into groups A (with variation in the secondary constriction region in the autosomal long arm), B (with variation in the short arm of the D/G group chromosomes), C (with interbrachial inversion of chromosome 9) and D (with Y chromosome polymorphisms), and compared the semen parameters and sperm DNA fragmentation indexes (DFI) between the patients with chromosome polymorphisms and those with normal chromosomes. RESULTS: Totally, 154 (6.50%) of the patients undergoing IVF/ICSI were found with chromosome polymorphisms, including 34 cases of secondary constriction variation in the long arm of the autosome (1.43% ［34/2 370］, 22.08% ［34/154］), 82 cases of short arm polymorphisms of the D/G group chromosomes (3.46% ［82/2 370］, 53.25% ［82/154］), 26 cases of interbrachial inversion of chromosome 9 (1.10% ［26/2 370］, 16.88% ［26/154］), 10 cases of Y chromosome polymorphisms (0.42% ［10/2 370］, 6.50% ［10/154］), and 2 cases of mixed chromosome polymorphisms (0.08% ［2/2 370］, 1.42% ［2/154］). The total sperm count was lower in group D than in the other polymorphism groups and the normal chromosome group, but with no statistically significant difference among the five groups (P > 0.05). The sperm progressive motility was also lower in group D than in the other five groups, with statistically significant difference from group B (27.5 ± 13.5 vs. 41.5 ± 21.1, P = 0.027), but not from the other groups (P > 0.05). No statistically significant difference was observed in the sperm DFI between the polymorphism groups and the normal chromosome group (P > 0.05), or among the polymorphism groups (P > 0.05). The proportion of normal semen was lower in group D than in the other four groups, but with no statistically significant difference among the five groups (P > 0.05). The incidence rate of asthenospermia was higher in group D than in the other four groups, but with no statistically significant difference among the five groups (P > 0.05), and so was that of oligoasthenospermia, with statistically significant difference from the normal chromosome group (30.0% vs 8.0%, P = 0.041), but not from the other polymorphism groups (P > 0.05). CONCLUSIONS Short arm polymorphisms of the D/G group chromosomes are the most common type of chromosome polymorphisms in male patients undergoing IVF/ICSI. Polymorphisms of the Y chromosome have a negative effect on semen quality, while those of the other chromosomes do not significantly affect semen quality and sperm DNA integrity.

In this review, the authors summarized the drugs in treatment of the age-related macular degeneration (AMD or ARMD), including the pathogenesis of the age-related macular degeneration at home and abroad, dosage forms used in the treatment, and the drugs research and development directions in the future. AMD disease is the third largest blinding diseases all over the world, with an incidence of 6.62%. The dosage form of the traditional medicine is mostly oral formulations, playing a role in body, while the newly dosage form is topical drug delivery formulation. Traditional Chinese medicine (TCM) has certain advantages in the treatment of AMD disease and the development of topical drug delivery preparations with newly preparation technologies would have a very bright prospect in the future.

The aim of this study is to investigate the epidemic condition of water-related diseases in the eastern route of South-to-North Water Diversion Project (SNWDP).All data were extracted from published literatures in Chinese about water-related diseases in the eastern route of SNWDP.Pooled analysis was used to explore geographical distribution and epidemiology of the disease.A total of 325 articles about water-related diseases were retrieved during 1953 to 2013,and 209 articles were included in this study.Pooling analysis showed that Shandong Province had the largest number of cases for water-related diseases,following by Jiangsu,Hebei,Tianjin,and Anhui.The numbers of cases were relative small before 1960s according to epidemic curve,and the curve peaked in the 1970s,and decreased after the 1980s.A total of 1 383 834 cases of bacillary dysentery was reported,accounting for 84％ of all water-related diseases on these regions of SNWDP,and followed by hepatitis A,hepatitis E,Japanese encephalitis,typhoid and paratyphoid fever and hemorrhagic fever with renal syndrome.Other reported diseases displayed scatter condition and a small numbers of cases.The prevalence of water-related diseases is sporadic and a trend of decline along the regions of the eastern route of SNWDP.