Objective Heart failure(HF)complicated by acute kidney injury(AKI)significantly impacts patient outcomes,and it is crucial to make early predictions of short-term mortality.This study is focused on developing an interpretable machine learning model to enhance early prediction accuracy in such clinical scenarios.Methods This retrospective cohort study utilized data from the Medical Information Mart for Intensive Care Ⅳ(MIMIC-Ⅳ,version 2.0)database.Data from the first 24 hours after admission to the ICU were extracted and divided into a training set(70％)and a validation set(30％).We utilized the SHapley Additive exPlanation(SHAP)method to interpret the workings of an extreme gradient boosting(XGBoost)model and identify key prognostic factors.The XGBoost model's predictive ability was evaluated against three other machine learning models using the area under the curve(AUC)metric,and its interpretation was enhanced using the SHAP method.Results The study included 8 028 patients with HF complicated by AKI.The XGBoost model outperformed the other models,achieving an AUC of 0.93(95％confidence interval[CI]:0.78-0.94;accuracy=0.89),while neural network model showed the worst performance(AUC=0.79,95％CI:0.77-0.82;accuracy=0.82).Decision curve analysis showed the superior net benefit of the XGBoost model within the 9％to 60％threshold probabilities.SHAP analysis was performed to identify the top 20 predictors,with age(mean SHAP value 1.29)and Glasgow Coma Scale score(mean SHAP value 1.24)emerging as significant factors.Conclusions Our interpretable model offers an enhanced ability to predict mortality risk in HF patients with AKI in ICUs.This model can be used to assist in formulating effective treatment plans and optimizing resource allocation.

Objective Sepsis-induced acute respiratory distress syndrome(ARDS)is an independent risk factor for mortality in critically ill septic patients.However,effective therapeutic targets are still unavailable due to the lack of understanding of its unclear pathogenesis.With increasing understanding in the roles of circulating histones and endothelial dysfunction in sepsis,we aimed to investigate the mechanism of histone-induced endothelial dysfunction leading to sepsis-induced ARDS and to provide experimental support for histone-targeted treatment of sepsis-induced ARDS.Methods First of all,in vitro experiments were conducted.Human umbilical vein endothelial cells(HUVEC)were stimulated with gradient concentrations of histones to explore for the optimal stimulation concentration in vitro.Then,HUVEC were exposed to histones at an optimal concentration with or without resatorvid(TAK-242),a selective inhibitor of Toll-like receptor 4(TLR4),for 24 hours for modeling.The cells were divided into 4 groups:1)the blank control group,2)the blank control+TAK-242 intervention group,3)the histone stimulation group,and 4)the histone+TAK-242 intervention group.HUVEC apoptosis was determined by flow cytometry,VE-Cadherin expression in endothelial cells was determined by Western blot,and the integrity of adhesion connections between endothelial cells was evaluated with confocal fluorescence microscopic images.Male C57BL/6 mice aged 6-8 weeks and weighing 22-25 g were used for the in vivo experiment.Then,the mice were given cecal ligation and puncture(CLP)as well as histone injection at 50 mg/kg via the tail vein for sepsis modeling.The experimental animals were divided into 6 groups:1)the blank control group,2)the blank control+TAK-242 intervention group,3)the CLP model group,4)the CLP+TAK-242 intervention group,5)the histone model group,and 6)the histone+TAK-242 intervention group.After 24 h,the concentrations of serum interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)were determined using ELISA kits.Western blot was performed to determine the expression of vascular endothelial(VE)-cadherin in the lung tissue.Hematoxylin and eosin(HE)staining was performed to observe the pathological changes in the lung tissue of the mice.Evans Blue was injected via the tail vein 30 min before the mice were sacrificed.Lung tissue was collected after the mice were sacrificed.Then,the concentrations of Evans blue dye per unit mass in the lung tissue from mice of different groups were evaluated,the rates of pulmonary endothelial leakage were calculated,and the integrity of the pulmonary endothelial barrier was evaluated.Results The results of the in vitro experiment showed that,compared with those of the control group,HUVEC apoptosis was significantly increased under histone stimulation(P＜0.05),the expression of VE-cadherin was decreased(P＜0.05),and the integrity of adherens junctions between endothelial cells was damaged.TAK-242 can significantly inhibit histone-induced HUVEC apoptosis and VE-cadherin expression reduction and maintain the integrity of adherens junctions between endothelial cells.According to the findings from the in vivo experiments,in mice with CLP-induced and histone-induced sepsis,TAK-242 effectively alleviated the increase in serum concentrations of IL-6 and TNF-α,reduced the downregulation of VE-cadherin expression in the lung tissue(P＜0.05),decreased endothelial permeability of the lung vessels,and improved pathological injury in the lung tissue.Conclusion By binding to TLR-4,histone decreases VE-cadherin expression on the surface of vascular endothelial cells,disrupts the integrity of intercellular adherens junctions,and triggers pathological damage to lung tissue.Using TLR-4 inhibitors can prevent sepsis-induced ARDS in histone-induced sepsis.

Uremic pruritus,a severe complication in patients with chronic kidney disease,is associated with a high prevalence.It can cause depression and sleep disorders,and seriously affect the quality of life and the social relations of patients.Recently,there is growing evidence showing that κ-opioid receptor agonists,including nalfurafine,difelikefalin,and nalbuphine,can effectively and safely reduce itching symptoms in patients with refractory uremic pruritus.Herein,we reviewed the epidemiology,pathogenesis,clinical symptoms,and treatment strategies of uremic pruritus,and summarized in detail the progress in clinical research on the use of κ-opioid receptor agonists,including nalfurafine,difelikefalin,and nalbuphine,in the management of patients with uremic pruritus.

ObjectiveTo review the ancient and modern literature of Huanglian Ejiaotang and learn about the historical evolution and clinical application， thereby providing a theoretical basis for the modern application of the classical prescription. MethodLiterature in the Chinese Medical Classics Database was retrieved with "Huanglian Ejiaotang" as the keyword. In China National Knowledge Infrastructure （CNKI） and PubMed， "Huanglian Ejiaotang" in Chinese and English was used as the keyword to retrieve literature. The items and modern clinical application studies related to the prescription， medicine， dosage， syndrome， and treatment of Huanglian Ejiaotang were selected and recorded. The inclusion and exclusion criteria were used to screen out literature. The information about the dynasty， book title， function， and indication was integrated to understand the history， evolution， and clinical application of Huanglian Ejiaotang. ResultFinally， 89 ancient books were included with 111 items. Huanglian Ejiaotang was initially recorded in ZHANG Zhongjing's Treatise on Cold Damage and Miscellaneous Diseases in the Han dynasty. It was composed of five herbs， namely Coptidis Rhizoma， Scutellariae Radix， Paeoniae Radix Alba， Asini Corii Colla， and egg yolk. With the change of historical dynasties， the composition， origin basis， dosage， and preparation method of Huanglian Ejiaotang all changed， but the changes in the processing were not obvious， which was basically consistent with Treatise on Cold Damage and Miscellaneous Diseases. In addition， 48 studies were included to analyze the clinical application of Huanglian Ejiaotang， which was mainly used for insomnia， anxiety， depression， diabetes， and so on. ConclusionAccording to the ancient and modern literature， the origin basis， dosage， processing， decoction， administration， and other content of Huanglian Ejiaotang are consistent with Treatise on Cold Damage and Miscellaneous Diseases. The present clinical application has expanded the usage scale of the ancient record， which promotes the innovation and development of the classic prescription and provides references for later research， development， and accurate application.

Three-dimensional printing is a technology that prints the products layer-by-layer, in which materials are deposited according to the digital model designed by computer aided design (CAD) software. This technology has competitive advantages regarding product design complexity, product personalization, and on-demand manufacturing. The emergence of 3D technology provides innovative strategies and new ways to develop novel drug delivery systems. This review summarizes the application of 3D printing technologies in the pharmaceutical field, with an emphasis on the advantages of 3D printing technologies for achieving rapid drug delivery, personalized drug delivery, compound drug delivery and customized drug delivery. In addition, this article illustrates the limitations and challenges of 3D printing technologies in the field of pharmaceutical formulation development.

Objective: To explore the imaging characteristics of large vestibular aqueduct syndrome (LVAS) patients and their relationship with the acoustically evoked short latency negative response (ANSR), so as to provide reference for the diagnosis of LVAS. Methods: Clinical data of 174 patients(334 ears) with LVAS diagnosed and treated by the Department of Otorhinolaryngology Head and Neck Surgery of the First Affiliated Hospital of Guangxi Medical University, from October 2009 to December 2017 were retrospectively analyzed, including 117 males and 57 females, aged from 5 months to 47 years old, with the median age of 4 years and 4 months. ABR and imaging data of patients were collected. Midpoint diameter and the outlet diameter of the vestibular aqueduct were measured on CT images, the midpoint diameter of the intraosseous parts and the extraosseous parts of enlarged endolymphatic sac(EES) were measured on MRI images. The correlation between the above measurements was analyzed by Pearson test using SPSS 17.0. According to whether ASNR was detected in ABR, the above data were divided into two groups, and the differences of the above imaging measurements were compared by the Independent-Sample Test. Results: The average midpoint diameter of the vestibular aqueduct was (1.87±0.58) mm (±s, the following was the same), and the outlet diameter was (3.07±0.99) mm on CT; the average midpoint diameter of the intraosseous parts in enlarged endolymphatic sac(EES) was (2.39±1.37) mm, and the extraosseous parts was (2.50±2.18) mm on MRI. There was a correlation between the four measurements (P<0.05), among which the midpoint diameter of vestibular aqueduct was strongly positively correlated with the outlet diameter (r=0.760), and the remaining pairs were weakly correlated. ASNR was detected in 241 ears (72.16%,241/334) and undetected in 93 ears (27.84%, 93/334) of the 334 ears with LVAS. Midpoint diameter and the outlet diameter of the vestibular aqueduct in no ASNR group were smaller than the ASNR group, and the difference was statistically significant (t value was 2.814 and 2.754, P<0.05). There was no significant difference in the midpoint diameter of the intraosseous parts and the extraosseous parts of enlarged endolymphatic sac between the two groups, and the difference was no statistically significant(t value was 0.101 and 0.683, P>0.05). Conclusions There is a strong positive correlation between the midpoint diameter of vestibular aqueduct and the outlet diameter in LVAS patients. There is a certain correlation between the size of vestibular aqueduct and the size of endolymphatic sac. The smaller the diameter of vestibular aqueduct, the lower the occurrence rate of ASNR.

Objective To investigate the preoperative localizaion diagnosis and surgical strategies of primary hyperparathyroidism (pHPT).Methods The clinical data of pHPT patients who underwent initial parathyroid surgery at the Peking Union Medical College Hospital from Jan.2009 to Apr.2017 were retrospectively analyzed to explore preoperative localization and surgical options.Results There were a total of 902 surgical cases included in the study with 674 women and 228 men.All had preoperative parathyroid ultrasonography (US) (sensitivity 97.18％,positive predictive value (PPV) 98.40％) and 99Tcm-sestamibi (MIBI) scan (sensitivity 94.24％,PPV 98.00％).The combination of US and MIBI scan had a sensitivity of 92.39％ and PPV of 97.37％.MIBI scan showed negative results in 51 cases.We found that male patients with cystic lesions were more likely related to negative MIBI scan (P＜0.05).Among 89 patients with negative MIBI and/or US,39 received neck CT,17 received positron emission tomography (PET)/CT,and 9 received ultrasound-guided biopsy for further localization.800 patients (88.69％) underwent minimally invasive parathyroid surgery (MIP) with anesthesia of cervical plexus block.656 patients (72.72％) had normal parathyroid hormone (PTH) level on the first post-operative day,140 patients (15.52％) had postoperative hypocalcaemia and 234 patients (25.94％) presented hypocalcaemic symptoms within 3 days after operation,which could be relieved by intravenous calcium or continuous medicine taken by mouth.During the follow-up of the 800 MIP patients,4 had recurrence and one patient was not cured.Conclusions Parathyroid US and MIBI scan are of good value in localizaion diagnosis.Neck CT or PET/CT should be used as supplementary approaches in patients with negative US and/or MIBI scan.MIP with anesthesia of cervical plexus block is simple and feasiable for pHPT cases with accurate localization.

Objective To summarize the strategy of sequential parathyroidectomy for secondary hyperparathyroidism.Methods Between January 2009 and December 2017,32 patients with secondary hyperparathyroidism underwent parathyroidectomy in Department of General Surgery,Peking Union Medical College Hospital.There were 11 male and 21 female patients with a mean age of 51.3 years.Eleven of them underwent bilateral neck exploration under general anesthesia,while the rest of them underwent sequential parathyroidectomy.For the patients with sequential parathyroidectomy,a unilateral neck exploration was performed in the initial operation under cervical plexus blocking anesthesia.Second operation for contralateral parathyroid lesions was performed if the serum intact parathyroid hormone (iPTH) was still higher than 1 000 ng/L or related symptoms were not relieved significantly 6 months later after initial surgery.Fisher exact test was used to compare the date between the 2 groups.Results In the bilateral exploration group,the serum iPTH level gradually exceeded above 1 000 ng/L in 5 patients during followup,and reoperation were performed in 3 patients of them.In the group with sequential parathyroidectomy,the serum iPTH level after initial operation exceeded above 1 000 ng/L in 15 patients.Eleven of them underwent contralateral parathyroidectomy,which decreases the serum iPTH levels to less than 1 000 ng/L in 10 patients.Compared with the sequential parathyroidectomy group (1/11),more patients needed to be treated in the intensive care unit after operation in bilateral exploration group (6/11),although the difference was statistically insignificant (P=0.063).Conclusions Sequential parathyroidectomy strategy is feasible for the secondary hyperparathyroidism with severe complications.Prospective controlled observation with large sample size is needed to confirm its effect.

Objective To summarize the strategy of sequential parathyroidectomy for secondary hyperparathyroidism.Methods Between January 2009 and December 2017,32 patients with secondary hyperparathyroidism underwent parathyroidectomy in Department of General Surgery,Peking Union Medical College Hospital.There were 11 male and 21 female patients with a mean age of 51.3 years.Eleven of them underwent bilateral neck exploration under general anesthesia,while the rest of them underwent sequential parathyroidectomy.For the patients with sequential parathyroidectomy,a unilateral neck exploration was performed in the initial operation under cervical plexus blocking anesthesia.Second operation for contralateral parathyroid lesions was performed if the serum intact parathyroid hormone (iPTH) was still higher than 1 000 ng/L or related symptoms were not relieved significantly 6 months later after initial surgery.Fisher exact test was used to compare the date between the 2 groups.Results In the bilateral exploration group,the serum iPTH level gradually exceeded above 1 000 ng/L in 5 patients during followup,and reoperation were performed in 3 patients of them.In the group with sequential parathyroidectomy,the serum iPTH level after initial operation exceeded above 1 000 ng/L in 15 patients.Eleven of them underwent contralateral parathyroidectomy,which decreases the serum iPTH levels to less than 1 000 ng/L in 10 patients.Compared with the sequential parathyroidectomy group (1/11),more patients needed to be treated in the intensive care unit after operation in bilateral exploration group (6/11),although the difference was statistically insignificant (P=0.063).Conclusions Sequential parathyroidectomy strategy is feasible for the secondary hyperparathyroidism with severe complications.Prospective controlled observation with large sample size is needed to confirm its effect.

Objective: To discuss the diagnosis, preoperative imaging and surgical technique of patients who underwent reoperation for persistent hyperparathyroidism. Methods: A prospective database about primary hyperparathyroidism in Department of General Surgery, Peking Union Medical College Hospital was searched for the patients who underwent reoperation for persistent hyperparathyroidism from January 2009 to December 2016. The information about the initial operation, preoperative imaging study and result of reoperations were collected and reviewed. A total of 58 patients underwent reoperation for hyperparathyroidism. Eleven of these patients were referred to this institute for reoperation after missing single parathyroid lesion in the initial parathyroidectomy. Nine patients were female, and the mean patient age at reoperation was 54.9 years. Results: For this group, the accuracy of ultrasound neck scan and sestamibi scintigraphy was 10/11 in identifying diseased parathyroid gland before reoperation. Combined with enhanced CT and SPECT, all parathyroid lesions were localized before reoperations. With general anesthesia or cervical plexus block, all diseased parathyroid glands were removed in the reoperations. No signs of hyperparathyroidism appeared during follow-up. Conclusions The initial surgery for primary hyperparathyroidism should be performed in experienced center to avoid reoperations. Combining preoperative localization and cervical exploration will help to increase the success rate of reoperation.