Disrupted bone morphogenetic protein type 2 receptor (BMPR2) signaling in endothelial cells drives pulmonary arterial hypertension (PAH). However, targeted recovery of this signaling pathway by lipid nanoparticles (LNPs) has not been explored as a therapy. Here, we employed Design of Experiments to optimize the delivery efficiency of LNPs targeting pulmonary endothelial cells developed by our laboratory, resulting in a remarkable 35-fold increase in a simplified three-component formulation without helper lipids. Administration of BMPR2 mRNA LNPs effectively reversed established PAH in two experimental rat models (monocrotaline or SU5416-hypoxia) by reversing pulmonary vascular remodeling. Specifically, BMPR2 mRNA LNPs replenished the expression of BMPR2 protein and subsequently activated downstream pathways, as confirmed by elevated levels of p-SMAD1/5/9 and ID1 proteins. The relief of pulmonary arterial occlusion was demonstrated by thinned pulmonary arterial media and decreased proportion of full muscularized vessels. Alleviation of right ventricular hypertrophy was indicated by declined Fulton index, the cross-sectional area of right ventricular cardiomyocytes as well as collagen deposition. Effective recovery of right ventricular function was evidenced by increased pulmonary artery flow acceleration time/pulmonary artery flow ejection time ratio. These findings underscore the potential of restoring BMPR2 signaling through pulmonary endothelial cell-specific LNPs for treating PAH.

ObjectiveTo explore the clinical effectiveness and safety of stick-point sinew-soothing and bone-setting manipulation for scapulohumeral periarthritis. MethodsUsing prospective randomised controlled trial method， 60 cases of patients with scapulohumeral periarthritis were collected and randomly divided into 30 cases each in control group and trial group. Both groups of patients were orally treated with celecoxib， on the basis of which the control group was treated with traditional bonesetting manipulation once every other day for 14 days， while the trial group was treated with stick-point sinew-soothing and bone-setting manipulation once every 3~5 days for 14 days. Both groups were treated for 2 courses. The main observation indexes were pain visual analogue scale （VAS） score and shoulder pain and dysfunction index （SPADI）， which were evaluated once before treatment and after 2 and 4 weeks of treatment. The secondary effectiveness indicators included the university of California at Los Angeles shoulder rating scale （UCLA）， traditional Chinese medicine syndrome score （including symptom scores as joint pain， pain in a fixed place， activity limitation， local stiffness）， and serum interleukin （IL-6） and tumour necrosis factor α （TNF-α） levels before and after the treatment， in order to evaluate the clinical effectiveness， and to record the adverse reactions that occurred in the process of diagnosis and treatment. ResultsCompared with the groups before treatment， the pain VAS score， SPADI and scores of joint pain， pain with a fixed place， activity limitation and local stiffness were lower， UCLA score was higher， and serum IL-6 and TNF-α levels were lower at 4 weeks of treatment in the two groups （P＜0.05）. When comparing the two groups between the groups at 2 and 4 weeks of treatment， the pain VAS score， SPADI and TCM scores of each symptom in the study group were lower than those in the control group， the UCLA score was higher than those in the control group （P＜0.01）， and the serum IL-6 and TNF-α levels were lower than those in the control group at 4 weeks of treatment （P＜0.01）. The clinical effectiveness rate of the study group was 66.67%， which was significantly higher than that of the control group， which was 40.00% （P = 0.038）. No adverse reactions were seen in both groups during the study. ConclusionCompared with the traditional massage manipulation， the treatment of scapulohumeral periarthritis with stick-point sinew-soothing and bone-setting manipulation has more advantages in relieving pain symptoms， reducing inflammatory reaction， and promoting the recovery of shoulder joint function.

Objective To investigate the expression and prognostic value of serum receptor for advanced glycation end products(RAGE)and CXC-chemokine ligand 16(CXCL16)in patients with sepsis complicated with acute respiratory distress syndrome(ARDS).Methods A total of 234 patients with sepsis diagnosed and treated in a hospital from January 2019 to January 2022 were selected as the study subjects,and were divided into 82 patients with sepsis complicated with ARDS(ARDS group)and 152 patients with sepsis without ARDS(non-ARDS group)according to whether the subjects were complicated with ARDS.ARDS group was divided into survival group(n=50)and death group(n=32)according to the survival status within 28 days of admission.Another 60 healthy subjects who underwent physical examination in the same period were se-lected as the control group.Serum RAGE and CXCL16 levels were detected by enzyme-linked immunosorbent assay.Pearson correlation analysis of serum RAGE and CXCL16 levels with sequential organ failure assess-ment(SOFA)score,acute physiology and chronic health evaluation Ⅱ(APACHE Ⅱ)score and oxygenation index in patients with sepsis and ARDS.Multivariate Logistic regression analysis of prognostic factors of sep-sis complicated with ARDS.The predictive value of serum RAGE and CXCL16 on the prognosis of sepsis complicated with ARDS patients was analyzed by receiver operating characteristic curve.Results The serum RAGE and CXCL16 levels in ARDS group were higher than those in non-ARDS group and control group,and the serum RAGE and CXCL16 levels in non-ARDS group were higher than those in control group,the differ-ence was statistically significant(P＜0.05).Compared with the survival group,the mechanical ventilation time,intensive care unit stay time,procalcitonin,SOFA score,APACHE Ⅱ score,serum RAGE,CXCL16 lev-els were higher in the death group,and the oxygenation index was lower,with statistical significance(all P＜0.05).The serum RAGE level in patients with sepsis complicated with ARDS was positively correlated with SOFA score and APACHE Ⅱ score(r=0.603,0.671,P＜0.05).Serum CXCL16 levels were positively corre-lated with SOFA score and APACHE Ⅱ score(r=0.655,0.707,P＜0.05).Serum RAGE and CXCL16 were negatively correlated with oxygenation index(r=-0.712,-0.683,P＜0.05).Multi-factor Logistics regres-sion analysis showed that serum RAGE and CXCL16 were independent risk factors for death within 28 days of admission in patients with sepsis complicated with ARDS.The area under the curve(AUC)of combined de-tection of serum RAGE and CXCL16 for predicting death within 28 days of admission in patients with sepsis complicated with ARDS was 0.882,which was higher than that of single index detection of serum RAGE and CXCL16,and the difference was statistically significant(Z=4.450,4.906,P＜0.05).Conclusion The com-bined detection of serum RAGE and CXCL16 is helpful to evaluate the clinical prognosis of sepsis complicated with ARDS patients.

Objective To investigate the value of 4D-CTA combined with SDF-1a/CXCR4 signaling pathway in evaluating the risk of intracranial aneurysm rupture.Methods Fifty patients with unruptured intracranial posterior communicating aneurysms and 50 patients with ruptured intracranial posterior communicating aneurysms were divided into unruptured group 1 and ruptured group 1.All patients underwent 4D-CTA examination and serumSDF-1alevel was detected.Non-ruptured group 1 was followed up for 12 months(After conservative treatment),on this basis,patients with ruptured posterior communicating aneurysms were included in ruptured group 2,and patients with unruptured posterior communicating aneurysms were included in non-ruptured group 2.Results The AUC values of Wn,AR,L,SR,SDF-1a and their combinations in diagnosing ruptured intracranial posterior communicating aneurysms were all greater than 0.70.The AUC values of Wn,AR,L,SR,SDF-1a and their combinations in predicting ruptured intracranial posterior communicating aneurysms in ruptured group 2 were all greater than 0.70.Conclusion 4D-CTA combined with SDF-1acan effectively distinguish ruptured intracranial posterior communicating aneurysms and predict the risk of rupture.

A patient with osteomyelitis who developed a rash after previous treatment with vancomycin was admitted to the hospital due to a recurrence of osteomyelitis.After admission,the orthopedic doctor intended to perform a"calcium sulfate vancomycin implantation surgery"on him.Clinical pharmacist identified the patient's previous rash reaction as red man syndrome(RMS)rather than genuine drug allergy.At the same time,in response to the clinical doubt of whether patients with previous RMS can undergo"calcium sulfate vancomycin implantation surgery",clinical pharmacists reviewed and analyzed the literature,and suggested that the surgery can continue under close monitoring.The patient did not experience RMS or allergic reactions after surgery,and the condition improved.In this paper,the clinical pharmacists started with the identification of RMS and rapid allergic reactions,reviewed the literature on the local use of vancomycin and the risk of RMS,and provide suggestions for subsequent treatment,and also provide references for clinical safe drug use and treatment of similar diseases.

Objective:To explore the significance of multiple frequency bioelectrical impedance analysis (MFBIA) in the combined surgical treatment of breast cancer-related lymphedema (BCRL).Methods:A retrospective analysis was conducted on the clinical data of 30 patients with unilateral postoperative BCRL. The patients recieved staged liposuction and lymphaticovenular anastomosis (LVA) from April to October 2021 at the Department of Lymphatic Surgery in Beijing Shijitan Hospital, Capital Medical University. After LVA surgery, patients were followed-up by telephone and other means, and asked to come to the hospital at 1 year and 2 years, respectively. The circumference of each part of the upper limbs, the length of forearm and arm were measured, and the limb volume was calculated. MFBIA were also performed to record limb bioelectrical impedance, extracellular water(ECW), and extracellular water ratios (ECW/TBW). SPSS 21.0 was used for statistical analysis. Clinical data of the patients were analysed by One-way Repeated Measurement Anova to examine the changes in volume of the affected arms before and after surgery and the changes in values collected by MFBIA. Subsequently, differences in the volumes and values of MFBIA of the affected arms before and after surgery, and the ratios of the above were analysed by paired t-test to compare each pair, then followed by Pearson correlation test. P<0.05 was considered statistically significant. Results:After liposuction, the volume differences of affected and healthy arms were reduced from 1 147 ml ± 484 ml before surgery to 261 ml ± 304 ml after surgery, which achieved a significant reduction with statistical significance ( P<0.05). However, there were no significant changes in ECW or bioelectrical impedance at various frequencies (1-1 000 K) ( P>0.05). After LVA, the differences in volume of the affected and healthy arms further decreased to 17 ml±264 ml with statistical significance compared to that before surgery ( P<0.05), ECW decreased from 1.115 L ± 0.207 L to 0.937 L ± 0.164 L with statistical significance ( P<0.05), ECW/TBW decreased from 0.412 ± 0.008 to 0.405 ± 0.007 with statistical significance ( P<0.05), and the bioelectrical impedance at various frequencies was significantly increased with statistical significance ( P<0.05). After LVA, the difference in arm volume was positively correlated with the difference in ECW (correlation coefficient 0.602, P<0.05), positively correlated with the difference in Rate of ECW (correlation coefficient 0.560, P<0.05), and negatively correlated with the ratios of impedance at various frequencies (correlation coefficients 0.529-0.545, P<0.05). Conclusion:In the staged surgical treatment of BCRL, with the application of MFBIA, it is found that lymphatic liposuction removes the pathological adipose tissue of an arm, hence significantly reduces the volume of the affected arm. However, lymphatic stasis remains unrelieved, therefore without a significant reduction in arm oedema. After the second-stage LVA, the improvement of lymphatic return leads to the relief of arm oedema, and the volume of the affected arm approaches to that of the healthy side. MFBIA can be used for assessment of arm oedema.

Objective:To investigate the characteristics and diagnostic methods for the patients with primary lymphedema and interstitial lung disease, as well as the efficacy of thoracic duct or right lymphatic duct plasty.Methods:A retrospective study was performed on 13 patients who were treated for primary lymphedema in the Department of Lymphatic Surgery, Beijing Shijitan Hospital, Capital Medical University, from January 2018 to December 2022. All patients were confirmed with interstitial lung disease by high-resolution CT (HRCT) and then underwent thoracic duct or right lymphatic duct plasty surgery. The 13 patients in this study were 7 males and 6 females aged 7.3 (0.7-30.0) years old. Primary lymphedema was the first manifestation in all patients, with an average morbidity age at 1.0 (0-11.0) years old. The average time from the onset of lymphedema to the confirmed interstitial lung disease was 6.3 (0.3-19.0) years. All patients underwent thoracic duct or right lymphatic duct plasty for improvement of the lymphatic flow. In addition, 9 cases (69.2%) received a direct lymphangiography (DLG). In which, 4 cases (44.4%) received further treatment of ligation of the reflux branches, and 1 (11.1%) had the treatment plans changed, because a chylous reflux into the lung through a bronchomediastinal trunk was found from DLG, therefore a ligation of the abnormal reflux branches was performed and a life-long strict low-fat diet was required. Postoperative follow-ups for evaluation of the improvements of lymphedema and pulmonary lymphatic flow were carried out by visit of outpatient clinic or via telephone interviews.Results:All patients recovered well after surgery with an average follow-up time of 47.5 (19.0-68.0) months. Lymphedema was stable in 2 cases (15.4%) and relieved in 11 cases (84.6%). Ten cases (76.9%) had completed the postoperative HRCT reviews and 9 (90.0%) were found with significant improvement in the interstitial lung disease.Conclusion:The interstitial lung disease found during the examination of patients with primary lymphedema can be explained with a lymphatic flow disorder. DLG can identify the cause and make to guide the treatment. Thoracic duct or right lymphatic duct plasty can effectively improve both of the symptom of lymphedema and interstitial lung disease.

Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its in vivo instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of α/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability (t _1/2 > 14 days) compared to t _1/2 (<1 day) of GLP-1 in the blood plasma and in vivo. These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment. Additionally, our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.

Objective:To investigate the cerebral blood flow autoregulation and cerebrovascular reactivity in patients with cerebral small vessel disease (SVD) and depression.Methods:Eighty patients who were treated in Dalian Municipal Central Hospital Affiliated with Dalian University of Technology from May 2020 to may 2021 were selected and divided into observation group and control group according to the existence of depression. Transcranial Doppler sonography combined with standing and lying position test, breath holding test and breath exchange test were used to observe the "w" wave slope, the "w" wave slope, the "w" wave velocity and the "w" wave velocity cerebral blood flow velocity difference, breath holding index, pulsation index (PI) change rate before and after breath holding, resistance index (RI) change rate before and after breath holding, mean velocity (Vm), PI, RI change rate before and after breath exchange. The correlation between depression score and blood flow index was analyzed.Results:There were 38 and 29 patients occurred "w" wave in the control group and observation group respectively, and the rate were 95.0% (38/40) and 72.5% (29/40) respectively ( χ2 = 7.44, P = 0.006). The slope of "w" descending branch of Vm and the slope of "w" ascending branch of Vm in the observation group were smaller than those of the control group respectively: (1.26 ± 0.23) cm/s vs. (2.45 ± 1.00) cm/s, (1.38 ± 0.71) cm/s vs. (2.56 ± 0.77) cm/s, the difference of which had statistical meanings ( P<0.05). The difference of cerebral blood flow velocity of Vm after different positions in the observation group was higher than that in the control group significantly: (7.20 ± 3.07) cm/s vs. (2.93 ± 1.46) cm/s ( P<0.05). The breath holding index PI change rate, RI change rate before and after breath holding test in the observation group were lower than those in the control group statistically: (0.88 ± 0.33)% vs. (1.49 ± 0.27)%, (14.42 ± 9.31)% vs. (21.51 ± 8.79)%, (11.07 ± 1.70)% vs. (15.31 ± 6.73)% ( P<0.05). The change rates of Vm, PI and RI in the observation group before and after ventilation were lower than those in the control group ( P<0.05). There was a negative correlation between depression score and "w" wave slope (Vm), breath holding index, Vm change rate before and after ventilation, and a positive correlation between depression score and cerebral blood flow velocity difference (Vm) in supine and upright position with statistical meanings ( P<0.05). Conclusions:Depression could lead to the decline of cerebral blood flow autoregulation and cerebrovascular reactivity in patients with SVD. And with the aggravation of depression, the decline of cerebral blood flow autoregulation and cerebrovascular reactivity in patients with SVD is more serious.

Objective:To analyze the independent diagnostic indicators and their diagnostic values for pulmonary tuberculosis complicated with pulmonary embolism.Methods:A total of 34 cases of pulmonary tuberculosis complicated with pulmonary embolism treated in Huzhou Central Hospital from March 2014 to September 2021 were enrolled. And 136 patients with simple pulmonary tuberculosis who were hospitalized during the same period were collected with a ratio of 1∶4 according to the principle of age and gender matching. The general conditions, clinical symptoms, comorbidities and laboratory indicators of the patients were retrospectively analyzed. The univariate analysis was performed using independent samples t test, Mann-Whitney U test and chi-square test. Binary logistic regression was used to analyze the related diagnostic factors for pulmonary embolism in pulmonary tuberculosis patients, and the combined factors were constructed by transforming the model equation, and the receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value and evaluate its diagnostic value. Results:The univariate analysis showed that patients with pulmonary tuberculosis complicated with pulmonary embolism had higher ratio of chest tightness (67.6%(23/34) vs 22.1%(30/136)), syncope (23.5%(8/34) vs 0.7%(1/136)), fever (55.9%(19/34) vs 36.0%(49/136)), hemostatic drug use (100.0%(34/34) vs 13.2%(18/136)), history of venous thrombosis (8.8%(3/34) vs 0.7%(1/136)), atrial fibrillation (11.8%(4/34) vs 2.2%(3/136)) and D-dimer levels (4.090 0(1.035 0, 10.790 0) mg/L vs 0.850 0(0.432 5, 2.145 0) mg/L) than those of simple pulmonary tuberculosis patients, and the differences were all statistically significant ( χ2=26.35, 28.19, 4.47, 96.44, 7.75, 6.30 and Z=-4.65, respectively; all P<0.050). The arterial partial pressure of oxygen (PaO 2)(61.90(52.95, 73.00) mmHg vs 82.00 (75.00, 87.00) mmHg, 1 mmHg=0.133 kPa) and albumin ((28.83±4.98) g/L vs (32.76±5.65) g/L) of patients with pulmonary tuberculosis complicated with pulmonary embolism were lower than those of simple pulmonary tuberculosis patients, and the differences were both statistically significant ( Z=-5.21 and t=3.71, respectively, both P<0.001). Binary regression analysis showed that chest tightness (odds ratio ( OR)=3.494, 95%confidence interval ( CI) 1.208 to 10.100, P=0.021), D-dimer ( OR=1.285, 95% CI 1.079 to 1.530, P=0.005) and PaO 2( OR=0.931, 95% CI 0.895 to 0.970, P=0.001) were the independent diagnostic indicators for pulmonary embolism in pulmonary tuberculosis patients. The areas under the ROC curve of chest tightness, D-dimer, PaO 2, and the combination of the three indicators (the combination factor) were 0.728, 0.758, 0.834, and 0.890, respectively. The optimal cut-off value of the combination factor was -3.1, with the sensitivity of 0.824 and the specificity of 0.824. Conclusions:Chest tightness, increased D-dimer and decreased PaO 2 are independent diagnostic indicators for pulmonary embolism in pulmonary tuberculosis patients. It is recommended to perform pulmonary artery computed tomography angiography promptly when the combination factor is higher than -3.1 to determine whether the patient is complicated by pulmonary embolism.