Diabetic kidney disease (DKD) with increasing global prevalence lacks effective therapeutic targets to halt or reverse its progression. Therapeutic targets supported by causal genetic evidence are more likely to succeed in randomized clinical trials. In this study, we integrated large-scale plasma proteomics, genetic-driven causal inference, and experimental validation to identify prioritized targets for DKD using the UK Biobank (UKB) and FinnGen cohorts. Among 2844 diabetic patients (528 with DKD), we identified 37 targets significantly associated with incident DKD, supported by both observational and causal evidence. Of these, 22% (8/37) of the potential targets are currently under investigation for DKD or other diseases. Our prospective study confirmed that higher levels of three prioritized targets-insulin-like growth factor binding protein 4 (IGFBP4), family with sequence similarity 3 member C (FAM3C), and prostaglandin D2 synthase (PTGDS)-were associated with a 4.35, 3.51, and 3.57-fold increased likelihood of developing DKD, respectively. In addition, population-level protein-altering variants (PAVs) analysis and in vitro experiments cross-validated FAM3C and IGFBP4 as potential new target candidates for DKD, through the classic NLR family pyrin domain containing 3 (NLRP3)-caspase-1-gasdermin D (GSDMD) apoptotic axis. Our results demonstrate that integrating omics data mining with causal inference may be a promising strategy for prioritizing therapeutic targets.

The analysis of ammonia nitrogen in real water samples is challenging due to matrix interferences and difficulties for rapid on-site analysis.On the basis of the standard method,i.e.water quality-determination of ammonia nitrogen-salicylic acid spectrophotometry(HJ 536-2009),a simple device for online detecting ammonia nitrogen was developed using a sequential injection analysis(SIA)system in this work.The ammonia nitrogen transformation system,color reaction system,and detection system were built in compatible with the SIA system,respectively.In particular,the detection system was assembled by employing light-emitting diode as the light source,photodiode as the detector,and polyvinylchloride tube as the cuvette,thus significantly reducing the volume,energy consumption and fabricating cost of the detection system.As a result,the accurate analysis of ammonia nitrogen in complex water samples was achieved.A quantitative detection of ammonia nitrogen in water sample was obtained in 12 min,along with linear range extending to 1000 μmol/L,precisions(Relative standard deviation,RSD)of 4.3%(C=10 μmol/L,n=7)and 4.2%(C=500 μmol/L,n=7),and limit of detection(LOD)of 0.65 μmol/L(S/N=3,n=7).The results of interfering experiments showed that the detection of ammonia nitrogen by the developed device was not interfered by the common coexisting ions and components,therefore the environmental water could be directly analyzed,such as reservoir water,domestic sewage,sea water and leachate of waste landfill.The analytical results were consistent with those obtained by the environmental protection standard method(Water quality determination of ammonia nitrogen-salicylic acid spectrophotometry,HJ 536-2009).In addition,the spiking recoveries were in the range of 92.3%-98.1%,further confirming the accuracy and practicality of the developed device.

This case report presents an adolescent patient with type 3 pseudotumor associated with vascular hemophilia (von willebrand disease, VWD) of the femur. The patient experienced weakness and pain in the right knee joint for two months following physical activity, with no apparent history of trauma. Genetic testing identified two compound heterozygous mutations in the von willebrand factor (VWF) gene, consistent with a diagnosis of "VWD type 3". Laboratory results revealed a Factor VIII activity of 2.8%, a negative Factor VIII inhibitor test, VWF activity of 1%, and VWF antigen levels below 3%. The desmopressin infusion test (1 hours and 4 hours) showed VWF levels of less than 1%. Imaging studies revealed an osteolytic lesion in the right distal femoral epiphysis, characterized by discontinuous cortical resorption in the anterior femur, thinning of the medial, lateral, and posterior cortex, prominent sclerotic bands, and extension of the tumor into the distal femoral epiphysis without periosteal reaction. After multidisciplinary consultation, the diagnosis of VWD type 3 pseudotumor of the femur was confirmed. The patient had no history of coagulation factor supplementation and no significant knee trauma. Preoperatively, the VWF level was maintained above 80% with cryoprecipitate infusion. The lesion was surgically debrided, followed by bone grafting with autologous fibula and allograft bone. Postoperative follow-up at 5 months showed good recovery of knee function. Pseudotumor is a rare but serious manifestation of inherited bleeding disorders, predominantly observed in hemophiliacs. Skeletal muscle system pseudotumor in VWD is exceptionally rare, with previous reports limited to the maxilla and mandible. MRI is crucial for the diagnosis of hemophilic pseudotumor, with characteristic findings of peripheral enhancement without central enhancement on enhanced scans. Surgery remains the preferred and effective treatment, with adequate perioperative preparation being essential for success. In this case, a multidisciplinary approach was critical in developing a personalized treatment plan, contributing significantly to the patient's positive outcome.

Objectives: To construct a nomogram for prediction of intrahepatic cholangiocarcinoma (ICC) lymph node metastasis based on inflammation-related markers,and to conduct its clinical verification. Methods: Clinical and pathological data of 858 ICC patients who underwent radical resection were retrospectively collected at 10 domestic tertiary hospitals in China from January 2010 to December 2018. Among the 508 patients who underwent lymph node dissection,207 cases had complete variable clinical data for constructing the nomogram,including 84 males,123 females,109 patients≥60 years old,98 patients<60 years old and 69 patients were pathologically diagnosed with positive lymph nodes after surgery. Receiver operating characteristic curve was drawn to calculate the accuracy of preoperative imaging examinations to determine lymph node status,and the difference in overall survival time was compared by Log-rank test. Partial regression squares and statistically significant preoperative variables were screened by backward stepwise regression analysis. R software was applied to construct a nomogram,clinical decision curve and clinical influence curve,and Bootstrap method was used for internal verification. Moreover,retrospectively collecting clinical information of 107 ICC patients with intraoperative lymph node dissection admitted to 9 tertiary hospitals in China from January 2019 to June 2021 was for external verification to verify the accuracy of the nomogram. 80 patients with complete clinical data but without lymph node dissection were divided into lymph node metastasis high-risk group and low-risk group according to the score of the nomogram among the 858 patients. Log-rank test was used to compare the overall survival of patients with or without lymph node metastasis diagnosed by pathology. Results: The area under the curve of preoperative imaging examinations for lymph node status assessment of 440 patients was 0.615,with a false negative rate of 62.8% (113/180) and a false positive rate of 14.2% (37/260). The median survival time of 207 patients used to construct a nomogram with positive or negative postoperative pathological lymph node metastases was 18.5 months and 27.1 months,respectively (P<0.05). Five variables related to lymph node metastasis were screened out by backward stepwise regression analysis,which were combined calculi,neutrophil/lymphocyte ratio,albumin,liver capsule invasion and systemic immune inflammation index,according to which a nomogram was constructed with concordance index(C-index) of 0.737 (95%CI: 0.667 to 0.806). The C-index of external verification was 0.674 (95%CI:0.569 to 0.779). The calibration prediction curve was in good agreement with the reference curve. The results of the clinical decision curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.32,the maximum net benefit could be obtained by 0.11,and the cost/benefit ratio was 1∶2. The results of clinical influence curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.6,the probability of correctly predicting lymph node metastasis could reach more than 90%. There was no significant difference in overall survival time between patients with high/low risk of lymph node metastasis assessed by the nomogram and those with pathologically confirmed lymph node metastasis or without lymph node metastasis (Log-rank test:P=0.082 and 0.510,respectively). Conclusion: The prediction accuracy of preoperative nomogram for ICC lymph node metastasis based on inflammation-related markers is satisfactory,which can be used as a supplementary method for preoperative diagnosis of lymph node metastasis and is helpful for clinicians to make personalized decision of lymph node dissection for patients with ICC.

Objective: To understand the basic characteristics of previously reported patients with hepatitis C and analyze the related factors affecting their antiviral treatment. Methods: A convenient sampling method was adopted. Patients who had been previously diagnosed with hepatitis C in the Wenshan Prefecture of Yunnan Province and Xuzhou City of Jiangsu Province were contacted by telephone for an interview study. The Andersen health service utilization behavior model and related literature were used to design the research framework for antiviral treatment in previously reported hepatitis C patients. A step-by-step multivariate regression analysis was used in previously reported hepatitis C patients treated with antiviral therapy. Results: A total of 483 hepatitis C patients, aged 51.73 ± 12.06 years, were investigated. The proportion of male, agricultural occupants who were registered permanent residents, farmers and migrant workers was 65.24%, 67.49%, and 58.18%, respectively. Han ethnicity (70.81%), married (77.02%), and junior high school and below educational level (82.61%) were the main ones. Multivariate logistic regression analysis results showed that married patients with hepatitis C (OR = 3.19, 95% CI: 1.93-5.25, compared with unmarried, divorced, and widowed patients) with high school education or above (OR = 2.54, 95% CI: 1.54-4.20, compared with patients with junior high school education or below) were more likely to receive antiviral treatment in the predisposition module. Patients with severe self-perceived hepatitis C in the need factor module (compared with patients with mild self-perceived disease, OR = 3.36, 95% CI: 2.09-5.40) were more likely to receive treatment. In the competency module, the family's per capita monthly income was more than 1,000 yuan (compared with patients with per capita monthly income below 1,000 yuan, OR = 1.59, 95% CI: 1.02-2.47), and the patients had a high level of awareness of hepatitis C knowledge (compared with patients with a low level of knowledge, OR = 1.54, 95% CI: 1.01-2.35), and the family members who knew the patient's infection status (compared with patients with an unknown infection status, OR = 4.59, 95% CI: 2.24-9.39) were more likely to receive antiviral treatment. Conclusion: Different income, educational, and marital statuses are related to antiviral treatment behavior in hepatitis C patients. Family support of hepatitis C patients receiving hepatitis C-related knowledge and their families knowing the infection status is more important in promoting the antiviral treatment of patients, suggesting that in the future, we should further strengthen the hepatitis C knowledge of hepatitis C patients, especially the family support of hepatitis C patients' families in treatment.
Humans ; Male ; Antiviral Agents/therapeutic use* ; China ; Hepatitis C/drug therapy* ; Hepacivirus ; Logistic Models

Child, Preschool ; Humans ; Infant ; Airway Obstruction/complications* ; Laryngostenosis/surgery* ; Tracheostomy

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Based on our findings, neuropilin 1 (NRP1), a receptor of SARS-CoV-2, was significantly elevated in cerebral cortex post infection, accompanied by active immune response releasing inflammatory factors and signal transmission among tissues, which enhanced infection of the central nervous system (CNS) in a positive feedback way, leading to viral encephalitis. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.
Animals ; COVID-19/genetics* ; Macaca mulatta ; SARS-CoV-2/genetics* ; Transcriptome

: Objective: To explore the feasibility and preliminary technical experience of the double-tract reconstruction combined with π-shaped esophagojejunal anastomosis after total laparoscopic proximal gastrectomy (TLPG) in the treatment of adenocarcinoma of esophagogastric junction (AEG). Methods: A descriptive case series study method was used. Clinical data of 12 AEG patients who underwent the double-tract reconstruction combined with π-shaped esophagojejunal anastomosis after TLPG from January 2021 to June 2021 at the Department of General Surgery, First Medical Center, PLA General Hospital were retrospectively analyzed. Among the 12 patients, the median tumor diameter was 2.0 (1.5-2.9) cm, and the pathological stage was T1-3N0-3aM0. All the patients routinely underwent TLPG and D2 lymph node dissection with double-tract reconstruction combined with π-shaped esophagojejunal anastomosis: (1) Double-tract reconstruction combined with π-shaped esophagojejunal anastomosis: mesentery 25 cm away from the Trevor ligament was treated, and an incision of about 1 cm was made on the mesenteric border of the intestinal wall and the right wall of the esophagus, two arms of the linear cutting closure were inserted, and esophagojejunal side-to-side anastomosis was performed. A linear stapler was used to cut off the lower edge of the anastomosis and close the common opening to complete the esophagojejunal π-shaped anastomosis. (2) Side-to-side gastrojejunostomy anastomosis: an incision of about 1 cm was made at the jejunum to mesenteric border and at the greater curvature of the remnant stomach 15 cm from the esophagojejunostomy, and a linear stapler was inserted to complete the gastrojejunostomy side-to-side anastomosis. (3) Side-to-side jejunojejunal anastomosis: an incision of about 1 cm was made at the proximal and distal jejunum to the mesangial border 40 cm from the esophagojejunostomy, and two arms of the linear stapler were inserted respectively to complete the side-to-side jejunojejunal anastomosis. A midline incision about 4-6 cm in the upper abdomen was conducted to take out the specimen, and an abdominal drainage tube was placed, then layer-by-layer abdominal closure was performed. INDICATIONS: (1) adenocarcinoma of esophagogastric junction (Seiwert type II-III) was diagnosed by endoscopy and pathological examination; (2) ability to preserve at least 1/2 of the distal stomach after R0 resection of proximal stomach was evaluated preoperatively. CONTRAINDICATIONS: (1) evaluation indicated distant metastasis of tumor or invasion of other organs; (2) short abdominal esophagus or existence of diaphragmatic hiatal hernia was assessed during the operation; (3) mesentery was too short or the tension was too high; (4) existence of severe comorbidities before surgery; (5) only palliative surgery was required in preoperative evaluation; (6) poor nutritional status. MAIN OUTCOME MEASURES operation time, intraoperative blood loss, postoperative complications, time to first flatus and time to start liquid diet, postoperative hospital stay, operation cost, etc. Continuous variables that conformed to normal distribution were presented as mean ± standard deviation, and those that did not conform to normal distribution were presented as median (Q1,Q3). Results: All the patients successfully completed TLPG with double-tract reconstruction combined with π-shaped esophagojejunal anastomosis, and postoperative pathology showed that no cancer cells were found on the upper incision margin. The operation time was (247.9±62.4) minutes, the median intraoperative blood loss was 100.0 (62.5, 100.0) ml, no intraoperative blood transfusion was required, the incision length was (4.9±1.0) cm, and the operation cost was (55.5±0.7) thousand yuan. The median time to start liquid diet was 1.0 (1.0, 2.0) days, and the mean time to flatus was (3.1±0.9) days. All the patients were discharged uneventfully. Only 1 patient developed postoperative paralytic ileus and infectious pneumonia with Clavien-Dindo classification of grade II. The patient recovered after conservative treatment. There was no surgery-related death. The postoperative hospital stay was (8.3±2.1) days. Conclusion: The double-tract reconstruction combined with π-shaped esophagojejunal anastomosis after TLPG is safe and feasible, which can minimize surgical trauma and accelerate postoperative recovery.
Adenocarcinoma/surgery* ; Anastomosis, Surgical/methods* ; Blood Loss, Surgical ; Esophagogastric Junction/surgery* ; Flatulence ; Gastrectomy/methods* ; Humans ; Laparoscopy ; Retrospective Studies ; Stomach Neoplasms/surgery*

Optimal vision and ergonomics are essential factors contributing to the achievement of good results during microsurgery. The three-dimensional (3D) digital image microscope system with a better 3D depth of field can release strain on the surgeon's neck and back, which can improve outcomes in microsurgery. We report a randomized prospective study of vasoepididymostomy and vasovasostomy using a 3D digital image microscope system (3D-DIM) in rats. A total of 16 adult male rats were randomly divided into two groups of 8 each: the standard operating microscope (SOM) group and the 3D-DIM group. The outcomes measured included the operative time, real-time postoperative mechanical patency, and anastomosis leakage. Furthermore, a user-friendly microscope score was designed to evaluate the ergonomic design and equipment characteristics of the microscope. There were no differences in operative time between the two groups. The real-time postoperative mechanical patency rates were 100.0% for both groups. The percentage of vasoepididymostomy anastomosis leakage was 16.7% in the SOM group and 25.0% in the 3D-DIM group; however, no vasovasostomy anastomosis leakage was found in either group. In terms of the ergonomic design, the 3D-DIM group obtained better scores based on the surgeon's feelings; in terms of the equipment characteristics, the 3D-DIM group had lower scores for clarity and higher scores for flexibility and adaptivity. Based on our randomized prospective study in a rat model, we believe that the 3D-DIM can improve surgeon comfort without compromising outcomes in male infertility reconstructive microsurgery, so the 3D-DIM might be widely used in the future.

Non-obstructive azoospermia (NOA), which is defined as the absence of spermatozoa in the ejaculate secondary to impaired spermatogenesis within the testis, may be caused by a variety of etiologies, including varicocele-induced testicular damage, cryptorchidism, prior testicular torsion, post-pubertal mumps orchitis, gonadotoxic effects from medications, genetic abnormalities, chemotherapy/radiation, and other unknown causes currently classified as idiopathic (Cocuzza et al., 2013). The microdissection testicular sperm extraction (micro-TESE) technique involves a meticulous microsurgical exploration of the testicular parenchyma to identify and selectively extract larger seminiferous tubules that carry a higher probability of complete spermatogenesis (Schlegel, 1999). The Cornell group evaluated the efficacy of micro-TESE in 152 NOA patients with an associated history of cryptorchidism. In their series, spermatozoa were successfully retrieved in 116/181 attempts (64%), and the resulting pregnancy rate was 50% with a delivery rate of 38% (Dabaja and Schlegel, 2013). Franco et al. (2016) described a stepwise micro-TESE approach in NOA patients, which was considered to reduce the cost, time, and effort associated with the surgery. Alrabeeah et al. (2016) further reported that a mini-incision micro-TESE, carried through a 1-cm equatorial testicular incision, can be useful for micro-TESE candidates, particularly in patients with cryptozoospermia. We conducted a retrospective study of 20 consecutive NOA patients with a history of orchidopexy from May 2015 to March 2017.
Adult ; Azoospermia/surgery* ; Humans ; Male ; Microdissection/methods* ; Middle Aged ; Orchiopexy ; Retrospective Studies ; Sperm Retrieval