SARS-CoV-2 and male infertility: from short- to long-term impacts.

PURPOSE: The coronavirus 2019 (COVID-19) pandemic-caused by a new type of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-has posed severe impacts on public health worldwide and has resulted in a total of > 6 million deaths. Notably, male patients developed more complications and had mortality rates ~ 77% higher than those of female patients. The extensive expression of the SARS-CoV-2 receptor and related proteins in the male reproductive tract and the association of serum testosterone levels with viral entry and infection have brought attention to COVID-19's effects on male fertility. METHODS: The peer-reviewed articles and reviews were obtained by searching for the keywords SARS-CoV-2, COVID-19, endocrine, spermatogenesis, epididymis, prostate, and vaccine in the databases of PubMed, Web of Science and Google Scholar from 2020-2022. RESULTS: This review summarizes the effects of COVID-19 on the male reproductive system and investigates the impact of various types of SARS-CoV-2 vaccines on male reproductive health. We also present the underlying mechanisms by which SARS-CoV-2 affects male reproduction and discuss the potentially harmful effects of asymptomatic infections, as well as the long-term impact of COVID-19 on male reproductive health. CONCLUSION: COVID-19 disrupted the HPG axis, which had negative impacts on spermatogenesis and the epididymis, albeit further investigations need to be performed. The development of vaccines against various SARS-CoV-2 variations is important to lower infection rates and long-term COVID risks.

[Bioinformatics analysis of primary biliary cholangitis key genes and molecular mechanisms].

Objective: To extract the differentially expressed key genes of primary biliary cholangitis (PBC) using bioinformatics methods, so as to provide information for further study into the mechanism. Methods: The GSE119600 dataset was downloaded from the GEO database to obtain differentially expressed genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for differentially expressed genes. Protein-protein interaction (PPI) network reconstruction, Cytoscape software visualization, and core gene screening were performed. The area under the receiver operating characteristic curve (ROC AUC) was used to assess the diagnostic effectiveness of genes and plot the pROC software package. The x-Cell software was used to calculate the enrichment score of 34 immune cells in each sample. Finally, four key genes (PSMA4, PSMA1, PSMB1, and PSMA3) were selected. Blood samples were analyzed using the qPCR method. Results:: A total of 373 immune-related differentially expressed genes were identified. Eight genes (PSMC6, PSMB2, PSMB1, PSMA3, PSMA4, PSMA1, PSMD7, and PSMB5) were screened from the 178 nodes and 596 edges as hub genes of the PPI network, which were significantly related to amino acid metabolism, hematopoietic stem cell differentiation, cell cycle, and immune processes. PSMA4, PSMA1, PSMB1, and PSMA3 were defined as immunological biomarkers for PBC with an AUC value of the ROC curve > 0.7. Immunoinfiltrating cell analysis showed that the proportion of eosinophils was significantly higher in PBC patients compared to the control group, whereas the proportion of CD4+ memory T cells, plasma cells, Th2 cells, and cDC cells was significantly lower in PBC patients than the control group. Plasma cells were associated with all four immunological biomarkers. Seven PBC patients and seven healthy subjects were selected for peripheral blood qPCR validation, which demonstrates that PSMB1, PSMA3, PSMA1, and PSMA4 levels were significantly lower in PBC patients than healthy subjects, with a statistically significant difference. Conclusion:: Bioinformatics screened eight key genes, of which four were key immunological markers and may serve as a basis for clinical diagnosis and mechanism exploration.

[Clinical study of digital six-axis external fixation frame based on CT data for tibiofibular fractures].

Objective: To investigate the clinical effect of applying the digital six-axis external fixation frame based on CT data in the treatment of tibiofibular fractures. Methods: The clinical data of 43 patients with tibiofibular fractures treated by the self-developed digital six-axis external fixation frame based on CT data at Integrated Orthopedic Department of Traditional Chinese Medicine (TCM) and Western Medicine,HongHui Hospital from January 2018 to January 2021 were retrospective analysis.There were 27 males and 16 females,aged (36.0±9.4) years(range:25 to 50 years).AO classification:15 cases of 42A,11 cases of 42B, and 17 cases of 42C.There were 7 open fractures and Gustilo fracture classification:2 cases of type Ⅰ,4 cases of type Ⅱ,and 1 case of type Ⅲ.The two or three plane rings were connected with six connecting rods to form a complete six-axis external fixation frame,and the distal and proximal fracture blocks were connected to the distal and proximal rings by fixation pins,and the lengths of the six connecting rods needed to be adjusted were calculated by using the supporting software according to the CT data after surgery,and then the lengths of the connecting rods were adjusted one by one to complete the reduction of the fracture. The reduction accuracy of this six-axis external fixation brace was evaluated by measuring postoperative radiographs; postoperative recovery and complications were collected,the time of brace removal was recorded,and the function of the affected limb was evaluated according to the Johner-Wruhs score at the final follow-up. Results: Postoperative radiographs showed that all patients achieved satisfactory reduction with lateral displacement(M(IQR)) of 2.3(2.5) mm (range:0.3 to 7.3 mm),anteroposterior displacement of 2.1 (2.4) mm (range:0.3 to 5.7 mm),anteroposterior angulation of 2.5(2.4)°(range:0 to 5°),internal and external angulation of 2.1(1.5)°(range:0 to 4°), and no significant internal or external rotational deformity was detected on the exterior.On the second postoperative day,all patients were able to walk with partial weight-bearing on crutches. All 43 patients were followed up for more than 6 months,with a follow-up period of (33.3±7.3) weeks (range:24 to 42 weeks).The external fixation frame was removed after the fracture healed.The external frame was removed at 20(3)weeks (range:18 to 25 weeks) postoperatively. Up to the final follow up, no secondary fracture occurred in any of them.The Johner-Wruhs score of the affected limb at the last follow-up was excellent in 39 cases and good in 4 cases. Conclusion: The digital six-axis external fixator based on CT data for tibiofibular fractures has the advantages of precise reduction,firm fixation,simple operation,rapid fracture healing,and minimal trauma, which is a minimally invasive method for treating tibiofibular fractures,especially suitable for patients with poor skin and soft tissue conditions such as open injuries.

Comprehensive evaluation of genetic variants using chromosomal microarray analysis and exome sequencing in fetuses with congenital heart defect.

OBJECTIVE: To evaluate comprehensively, using chromosomal microarray analysis (CMA) and exome sequencing (ES), the prevalence of chromosomal abnormalities and sequence variants in unselected fetuses with congenital heart defect (CHD) and to evaluate the potential diagnostic yields of CMA and ES for different CHD subgroups. METHODS: This was a study of 360 unselected singleton fetuses with CHD detected by echocardiography, referred to our department for genetic testing between February 2018 and December 2019. We performed CMA, as a routine test for aneuploidy and copy number variations (CNV), and then, in cases without aneuploidy or pathogenic CNV on CMA, we performed ES. RESULTS: Overall, positive genetic diagnoses were made in 84 (23.3%) fetuses: chromosomal abnormalities were detected by CMA in 60 (16.7%) and sequence variants were detected by ES in a further 24 (6.7%) cases. The detection rate of pathogenic and likely pathogenic genetic variants in fetuses with non-isolated CHD (32/83, 38.6%) was significantly higher than that in fetuses with isolated CHD (52/277, 18.8%) (P < 0.001), this difference being due mainly to the difference in frequency of aneuploidy between the two groups. The prevalence of a genetic defect was highest in fetuses with an atrioventricular septal defect (36.8%), ventricular septal defect with or without atrial septal defect (28.4%), conotruncal defect (22.2%) or right ventricular outflow tract obstruction (20.0%). We also identified two novel missense mutations (c.2447G>C, p.Arg816Pro; c.1171C>T, p.Arg391Cys) and a new phenotype caused by variants in PLD1. CONCLUSIONS: Chromosomal abnormalities were identified in 16.7% and sequence variants in a further 6.7% of fetuses with CHD. ES should be offered to all pregnant women with a CHD fetus without chromosomal abnormality or pathogenic CNV identified by CMA, regardless of whether the CHD is isolated. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

[Early reduction of serum RANTES can predict HBsAg clearance in patients with chronic hepatitis B treated with nucleos(t)ide analogues combined with peginterferon alpha].

Objective: To observe the dynamic changes of serum RANTES during the treatment with nucleos(t)ide analogues combined with pegylated interferon alpha (peginterferon-α), and further analyze the predictive effect of RANTES on HBsAg clearance in patients with chronic hepatitis B. Methods: 98 cases of chronic hepatitis B with quantitative HBsAg < 3 000 IU/ml and HBV DNA < 20 IU/ml after≥1 year NAs treatment were enrolled. Among them, 26 cases continued to receive NAs monotherapy, 72 cases received NAs combined with pegylated interferon alpha therapy. The changes in RANTES during treatment were observed. The receiver operating characteristic curve was used to analyze the early changes of RANTES to predict the HBsAg clearance during 48 weeks. Results: During 48 weeks, 15 cases (20.83%) had achieved HBsAg clearance in combination group, while no patient had achieved HBsAg clearance in NAs group. The overall serum RANTES level had decreased from baseline in NAs and combination group. At week 48, in the combination group, the serum RANTES level was decreased more significantly in patients with HBsAg clearance than patients without. Further analysis showed that, in combination group, HBsAg clearance rate of patients with serum RANTES decreased at week 12 and 24 was higher than patients with elevated (29.17% vs. 4.17%, P = 0.014; 28.00% vs. 4.55%, P = 0.052), and quantitative HBsAg reduction was larger significantly [(1.49 ± 1.26) log(10)IU/ml vs. (0.73 ± 0.81) log(10)IU/ml, P = 0.017; (1.54 ± 1.27) log(10)IU/ml vs. (0.57 ± 0.56) log(10)IU/ml, P = 0.004]. Receiver operating characteristic curve analysis showed that the baseline quantitative HBsAg and the reduction in quantitative HBsAg and serum RANTES during the early period were predictors of HBsAg clearance after 48-week combination therapy. Furthermore, the combination of baseline quantitative HBsAg and 12 - or 24-week reduction of serum RANTES were better predictors of HBsAg clearance than that of baseline quantitative HBsAg combined with HBsAg decrease at week 12 or 24. The area under the receiver operating characteristic curve of the former was 0.925 and 0.939, while that of the latter was 0.909 and 0.929, respectively. Conclusion: Early reduction of serum RANTES at week 12 and 24 can predict HBsAg loss in CHB patients receiving addition of peginterferon-α to ongoing NAs Therapy, so serum RANTES could be one of the key immunological markers for predicting HBsAg clearance.

[Safety and efficacy of transcatheter tricuspid valve replacement with LuX-Valve in patients with severe tricuspid regurgitation].

Objectives: To evaluate the safety and efficacy of LuX-Valve on the treatment of severe tricuspid regurgitation (TR). Methods: This is a prospective observational study. From September 2018 to March 2019, 12 patients with severe TR, who were not suitable for surgery, received LuX-Valve implantation in Changhai Hospital. LuX-Valve was implanted under general anesthesia and the guidance of transesophageal echocardiography and X-ray fluoroscopy. Access to the tricuspid valve was achieved via a minimally invasive thoracotomy and transatrial approach. Main endpoints were surgery success and device success. Surgery success was defined as successful implanting the device and withdrawing the delivery system, positioning the valve correctly and stably without severe or life-threatening adverse events. Device success was defined as satisfied valve function (TR severity reduction ≥ 2 grades, tricuspid gradient ≤ 6 mmHg (1 mmHg=0.133 kPa)), absence of malposition, valve failure and reintervention, major adverse events including device related mortality, embolization, conduction system disturbances and new onset shunt across ventricular septum at day 30 post implantation. Results: A total of 12 patients with severe to torrential TR were included in this study. The age was (68.5±6.9) years and 7 were female. All patients had typical right heart failure symptoms. Procedural success was achieved in all cases, there was no intraprocedural mortality or transfer to open surgery. TR significantly improved after LuX-Valve implantation (none/trivial in 8 patients, mild in 3 patients and moderate in 1 patient). The average device time was (9.2±4.2) minutes. Intensive care unit duration was 3.0 (2.0, 4.8) days. One patient died at postoperative day 18 due to non-surgery and device reasons. Transthoracic echocardiography at 30 days after operation showed that TR was significantly reduced (none/trivial in 8 patients, mild in 2 patients and moderate in 1 patient) and device success was achieved in 11 cases. All survived patients experienced a significant improvement in life quality with significantly improvement in New York Heart Association (NYHA) classification (Ⅰ and Ⅱ: 6/11 post operation vs. 0/11 before operation, P=0.012) and there were no device related complications in this patient cohort. Conclusions: LuX-Valve implantation is feasible, safe and effective for the treatment of patients with severe TR.

Systematic analysis of copy-number variations associated with early pregnancy loss.

OBJECTIVES: Embryonic numerical and structural chromosomal abnormalities are the most common cause of early pregnancy loss. However, the role of submicroscopic copy-number variations (CNVs) in early pregnancy loss is unclear, and little is known about the critical regions and candidate genes for miscarriage, because of the large size of structural chromosomal abnormalities. The aim of this study was to identify potential miscarriage-associated submicroscopic CNVs and critical regions of large CNVs as well as candidate genes for miscarriage. METHODS: Over a 5-year period, 5180 fresh miscarriage specimens were investigated using quantitative fluorescent polymerase chain reaction/CNV sequencing or chromosomal microarray analysis. Statistically significant submicroscopic CNVs were identified by comparing the frequency of recurrent submicroscopic CNVs between cases and a published control cohort. Furthermore, genes within critical regions of miscarriage-associated CNVs were prioritized by integrating the Residual Variation Intolerance Score and the human gene expression dataset for identification of potential miscarriage candidate genes. RESULTS: Results without significant maternal-cell contamination were obtained in 5003 of the 5180 (96.6%) cases. Clinically significant chromosomal abnormalities were identified in 59.1% (2955/5003) of these cases. Three recurrent submicroscopic CNVs (microdeletions in 22q11.21, 2q37.3 and 9p24.3p24.2) were significantly more frequent in miscarriage cases, and were considered to be associated with miscarriage. Moreover, 44 critical regions of large CNVs were observed, including 14 deletions and 30 duplications. There were 309 genes identified as potential miscarriage candidate genes through gene-prioritization analysis. CONCLUSIONS: We identified potential miscarriage candidate CNVs and genes. These data demonstrate the importance of CNVs in the etiology of miscarriage and highlight the importance of ongoing analysis of CNVs in the study of miscarriage. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

[Application of a new type of angle-adjustable osteotomy guide in closing wedge distal femoral osteotomy].

Objective: To explore the feasibility of fast and accurate osteotomy using a new angle adjustable osteotomy guide (AAOG) in closing wedge distal femoral osteotomy(CWDFO). Methods: The clinical data of 14 patients (17 knees) with valgus knee treated with CWDFO at Department of Integrated Chinese and Western Medicine Orthopedics, Honghui Hospital, Xi'an Jiaotong University from January 2018 to July 2019 were analyzed retrospectively. There were 3 males and 11 females, aging (41.4±16.4) years (range: 18 to 56 years). The body mass index was (23.5±3.5) kg/m(2) (range: 18.1 to 28.9 kg/m(2)). The guide pins were placed with the assistance of the self-designed AAOG. Before the surgery, Solidworks software was used to calculate the correction angle and the osteotomy radius accurately. The osteotomy guide was adjusted according to these two parameters. During the surgery, the adjusted osteotomy guide was placed to the surface of bone closely and the guide pins were drilled into the bone through the guide holes. The position of the guide pins was confirmed under fluoroscopy. The osteotomy was finished under guide of pins and fixed with Tomofix plate (Synthes). The times and duration of placement of the guide pins, the times of X-ray examination, the planned and actual thickness of the osteotomy wedge, the top and bottom area of the osteotomy wedge, the posterior distal femoral angle(PDFA), the correction of the weight line, and the American Knee Society Score(AKSS) and Tegner scores were collected and compared by paired t test or Kruskal-Wallis non-parametric test. Healing time after osteotomy and complications were recorded. Results: The guide pins were successfully placed once in 10 knees, adjusted once in 5 knees and twice in 2 knees. The time spent in placing all the 6 pins was 82.4 seconds (range: 51 to 125 seconds), and the times of X-ray examination was 1.5 times (range: 1 to 5 times). The top and bottom areas of the osteotomy wedge were (5.52±0.52)cm(2) and (5.36±0.49)cm(2). PDFA was (85.2±2.6)° preoperatively and (85.5±1.4)° postoperatively (t=-0.401, P>0.05). The thickness of the osteotomy was (11.3±1.9)mm according to the preoperative plan, and the actual thickness was (8.1±1.7)mm. All the patients were followed up for 6 months after surgery and AKSS and Tegner scores improved significantly (all P<0.05). The correction of the weight lines was within the ideal range. Fractures of the hinge point occurred in 3 knees. All of the osseous healing without complications. Conclusion: The new osteotomy guide helps to place the guide pins rapidly and precisely according to the preoperative planning, which should be widely used in clinical applications with promising outcomes.

[Efficacy and peripheral immunity analysis of allogeneic natural killer cells therapy in patients with hepatocellular carcinoma].

OBJECTIVE: To evaluate the safety and efficacy of allogeneic natural killer (NK) cells in the treatment of primary hepatocellular carcinoma (HCC), and to elucidate the mechanism of NK cells therapy. METHODS: Twenty-one patients with primary HCC treated with allogeneic NK cells at the Fifth Medical Center of the PLA General Hospital were followed up for 1 year. Peripheral blood mononuclear cells (PBMCs) were isolated from patient-related donors and cultured in vitro for 15 days and infused to the patients in two consecutive days. Clinical data and laboratory data were collected and analyzed, including survival, clinical features, imaging changes, hematology, immunology, and biochemical indicators to evaluate the safety and efficacy of allogeneic NK cell therapy. The changes of peripheral blood lymphocyte subsets after treatment were also analyzed to explore the possible anti-tumor mechanisms. RESULTS: (1) Of the 21 patients with primary HCC, 11 patients were treated once, 5 patients were treated twice, and 5 patients were treated 3 times. After allogeneic NK cells infusion, 10 patients had fever, 1 patient had slight hepatalgia and 1 patient had slight headache, no other adverse events occurred including acute and chronic graft-versus-host disease (GVHD). They resolved spontaneously within 8 hours without other treatment. (2) The total disease control rate was 76.2% during one-year follow-up. Among them, the patients with Barcelona clinic liver cancer (BCLC) stage A had a disease control rate of 100%, stable disease (SD) in 10 cases; BCLC stage B patients had a disease control rate of 60%, partial response (PR) in 1 case, and SD 2 in cases; BCLC stage C patients had a disease control rate of 50%, complete response (CR) in 1 case, and 2 cases of PR. (3) The frequencies of NK cells and CD8+ T cells in peripheral blood were significantly lower than that before at 24 hours after treatment, and the frequencies of CD4+ T cells and CD4/CD8 were significantly higher than the baseline. CONCLUSION: Allogeneic NK cells have good safety and efficacy in the treatment of primary HCC. The anti-tumor effect of the allogeneic NK cells may play an important role in the activation of the patient's natural immune system and delay disease progression, suggesting that allogeneic NK cells combined with sorafenib may be a very effective treatment for advanced HCC, and further large-sample multicenter randomized controlled clinical trials are needed to validate this result.

Clinical application of targeted next-generation sequencing in fetuses with congenital heart defect.

OBJECTIVES: To assess the value of targeted next-generation sequencing (NGS) in prenatal diagnosis of congenital heart defects (CHD) and to investigate the genetic etiology of prenatal CHD. METHODS: Forty-four fetuses with CHD, normal molecular karyotype and negative chromosomal microarray results underwent targeted NGS. Fetal genomic DNA was extracted directly from amniotic fluid cells in each prenatal case. A customized targeted-NGS panel of 77 CHD-associated genes was designed to detect variants in the coding regions and the splicing sites of these genes. The detected variants were classified as pathogenic, likely pathogenic, of uncertain significance, likely benign or benign, following the guidelines recommended by the American College of Medical Genetics and Genomics. RESULTS: The detection rates of targeted NGS for pathogenic and likely pathogenic variations were 13.6% (6/44) and 2.3% (1/44), respectively. The turnaround time of the test was 3 weeks. The six pathogenic variations were identified on the genes CHD7 (CHARGE syndrome), CITED2 (tetralogy of Fallot, ventricular septal defect and atrial septal defect), ZFPM2 (tetralogy of Fallot), MYH6 (atrial septal defect, familial isolated dilated cardiomyopathy) and, in two cases, KMT2D (Kabuki syndrome). The likely pathogenic variation was detected on JAG1, which is associated with tetralogy of Fallot and Alagille syndrome. Sanger sequencing in the fetuses and their parents indicated that all seven mutations were de novo. Variations of uncertain significance were detected in 79.5% of cases. CONCLUSIONS: Targeted NGS in fetuses with isolated and non-isolated CHD achieved a high diagnostic yield in our cohort, with an acceptable turnaround time for the prenatal setting. Our results have important implications for clinical management and genetic counseling. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

[Predictor measures on CT for hematoma expansion following acute intracerebral hemorrhage].

OBJECTIVE: To evaluate the worth of solid predictors in acute intracerebral hematoma(ICH) expansions in computer tomography images. METHODS: A total of 105 patients with acute ICH in The Second Affiliated Hospital of Soochow University during January 2012 to February 2015 were enrolled. CT plain scan, CTA within 6 hours since the symptoms and CT plain scan recheck within 24 hours were executed. Hematoma location, initial volume of hematoma, shape of hematoma, "spot sign" , UHG speed were analyzed with single factor and binary Logistic regression between the patients with and without hematoma expansion. RESULTS: There were 30 cases with hematoma expansion and 75 cases with no hematoma expansion in 105 patients. In single factor comparisons, hematoma location(χ(2) =13.125, P<0.05), hematoma shape(χ(2) =23.987, P<0.05), spot sign(χ(2) =25.846, P<0.05), UHG speed(χ(2) =20.328, P<0.05) and the initial hematoma volume(t=-3.183, P<0.05) between the hematoma expansions and the non-hematoma expansions made significant differences. In binary Logistic regression, hematoma shape(irregular (P=0.033) and cleavage(P=0.009)), spot sign(P=0.000) and UHG speed(P=0.040) had significant differences between the two groups. ROC curve areas of hematoma shape, spot sign and UHG speed were 0.776(95%CI 0.682-0.870), 0.740(95%CI 0.625-0.855) and 0.720(95% CI 0.604-0.836). The high specificities of hematoma shape(84%), spot sign (88%)and UHG speed(84%)revealed their great reliabilities with equal sensitivity (60%). CONCLUSION: Hematoma shape, spot sign and UHG speed are solid predictors of hematoma expansion among which spot sign has promising specificity, hematoma shape and UHG speed are more convenient to be observed.

[Multiposition spiral suture of the lower uterine segment: a new technique to control the intraoperative bleeding of pernicious placenta previa].

Objective: To explore the efficacy and safety of multiposition spiral suture of the lower uterine segment, a new technique to control the intraoperative bleeding of pernicious placenta previa(PPP). Methods: From May 2014 to May 2015, 38 patients were diagnosed PPP in Tongji Hospital and cesarean sections were performed. After removing the placenta, multiposition spiral suture was used when massive bleeding occurred, and bilateral descending branches of uterine artery ligation was conducted when necessary. Results: 18 of the 38 PPP patients(47%,18/38)were diagnosed placenta accreta. The average cervical canal length of 38 PPP patients was(3.1±0.6)cm. There were 12 cases(32%, 12/38)with 4 regions sutured, 23 cases(61%, 23/38)with 2-3 regions sutured and 3 cases(8%, 3/38)with only posterior wall area sutured. Twelve cases(32%, 12/38)underwent uterine artery ligation, 3 cases(8%, 3/38)underwent uterine artery ligation and COOK balloon. None of them was postpartum hemorrhage or performing internal iliac artery embolization. Two patients received hysterectomy. The average blood loss in the operation was(1 696± 1 397)ml. In 16(42%,16/38)patients, the blood loss exceeded 1 500 ml, and the heaviest one was 4 500 ml. Three patients had haematuria in the first 3 days after the operation. No complication was found in 6 months after the operation. Conclusions: The multiposition spiral suture technique is a simple, safe and effective way to control the massive bleeding in the cesarean section of PPP patients. It is also beneficial for the recovery of the uterus.

A novel protocol allowing oral delivery of a protein complement inhibitor that subsequently targets to inflamed colon mucosa and ameliorates murine colitis.

While there is evidence of a pathogenic role for complement in inflammatory bowel disease, there is also evidence for a protective role that relates to host defence and protection from endotoxaemia. There is thus concern regarding the use of systemic complement inhibition as a therapeutic strategy. Local delivery of a complement inhibitor to the colon by oral administration would ameliorate such concerns, but while formulations exist for oral delivery of low molecular weight drugs to the colon, they have not been used successfully for oral delivery of proteins. We describe a novel pellet formulation consisting of cross-linked dextran coated with an acrylic co-polymer that protects the complement inhibitor CR2-Crry from destruction in the gastrointestinal tract. CR2-Crry containing pellets administered by gavage, were characterized using a therapeutic protocol in a mouse model of dextran sulphate sodium (DSS)-induced colitis. Oral treatment of established colitis over a 5-day period significantly reduced mucosal inflammation and injury, with similar therapeutic benefit whether or not the proton pump inhibitor, omeprazole, was co-administered. Reduction in injury was associated with the targeting of CR2-Crry to the mucosal surface and reduced local complement activation. Treatment had no effect on systemic complement activity. This novel method for oral delivery of a targeted protein complement inhibitor will reduce systemic effects, thereby decreasing the risk of opportunistic infection, as well as lowering the required dose and treatment cost and improving patient compliance. Furthermore, the novel delivery system described here may provide similar benefits for administration of other protein-based drugs, such as anti-tumour necrosis factor-α antibodies.

The incidence of surgical site infections in China.

Surgical site infections (SSIs) are a common type of healthcare-associated infection. We performed a literature review to demonstrate the incidence of SSIs in mainland China based on studies since 2010. We included 231 eligible studies with ≥30 postoperative patients, comprising 14 providing overall SSI data regardless of surgical sites and 217 reporting SSIs for a specific site. We found that the overall SSI incidence was 2.91% (median; interquartile range: 1.05%, 4.57%) or 3.18% (pooled; 95% confidence interval: 1.85%, 4.51%) and the SSI incidence varied remarkably according to the surgical site between the lowest (median, 1.00%; pooled, 1.69%) in thyroid surgeries and the highest (median, 14.89%; pooled, 12.54%) in colorectal procedures. We uncovered that Enterobacterales and staphylococci were the most common types of micro-organisms associated with SSIs after various abdominal surgeries and cardiac or neurological procedures, respectively. We identified two, nine, and five studies addressing the impact of SSIs on mortality, the length of stay (LOS) in hospital, and additional healthcare-related economic burden, respectively, all of which demonstrated increased mortality, prolonged LOS, and elevated medical costs associated with SSIs among affected patients. Our findings illustrate that SSIs remain a relatively common, serious threat to patient safety in China, requiring more action. To tackle SSIs, we propose to establish a nationwide network for SSI surveillance using unified criteria with the aid of informatic techniques and to tailor and implement countermeasures based on local data and observation. We highlight that the impact of SSIs in China warrants further study.

High leptin level and leptin receptor Lys656Asn variant are risk factors for preeclampsia.

The aim of this study was to investigate the relationship between the leptin receptor (LEPR) polymorphism/serum leptin level and preeclampsia. The prevalence of a single nucleotide polymorphism in the LEPR gene exon 14 at -656 and the serum leptin concentrations in 97 preeclamptic pregnant mothers were compared to those of 110 healthy controls. The Lys656Asn genotype and Lys656Asn + Asn656Asn frequencies in the LEPR gene were significantly more prevalent in preeclampsia mothers than in controls (P < 0.05). The serum leptin levels of preeclampsia cases were significantly higher than those of controls. In addition, there were higher serum leptin levels in individuals with the GC + CC genotype both in the total cohort and in women with preeclampsia than in those with the GG genotype. Our findings suggest that the Lys656Asn polymorphism is a functional variant in the LEPR, which can affect the interaction of leptin and its receptor. Furthermore, high leptin level and the LEPR variant are risk factors for preeclampsia in Chinese women.

Cdk5 targets active Src for ubiquitin-dependent degradation by phosphorylating Src(S75).

The non-receptor tyrosine kinase Src is a critical regulator of cytoskeletal contraction, cell adhesion, and migration. In normal cells, Src activity is stringently controlled by Csk-dependent phosphorylation of Src(Y530), and by Cullin-5-dependent ubiquitinylation, which affects active Src(pY419) exclusively, leading to its degradation by the proteosome. Previous work has shown that Src activity is also limited by Cdk5, a proline-directed kinase, which has been shown to phosphorylate Src(S75). Here we show that this phosphorylation promotes the ubiquitin-dependent degradation of Src, thus restricting the availability of active Src. We demonstrate that Src(S75) phosphorylation occurs in vivo in epithelial cells, and like ubiquitinylation, is associated only with active Src. Preventing Cdk5-dependent phosphorylation of Src(S75), by site-specific mutation of S75 or by Cdk5 inhibition or suppression, increases Src(Y419) phosphorylation and kinase activity, resulting in Src-dependent cytoskeletal changes. In transfected cells, ubiquitinylation of Src(S75A) is about 35% that of wild-type Src-V5, and its half-life is approximately 2.5-fold greater. Cdk5 suppression leads to a comparable decrease in the ubiquitinylation of endogenous Src and a similar increase in Src stability. Together, these findings demonstrate that Cdk5-dependent phosphorylation of Src(S75) is a physiologically significant mechanism of regulating intracellular Src activity.

Development of a dynamic food chain model for assessment of the radiological impact from radioactive releases to the aquatic environment.

The software tool POSEIDON-R was developed for modelling the concentration of radionuclides in water and sediments as well as uptake and fate in the aquatic environment and marine organisms. The software has been actively advanced in the aftermath of the Fukushima Dai-ichi accident. This includes development of an uptake model for the benthic food chain, a kinetic-allometric compartment model for fish and recent advancements for the application of 3H. This work will focus on the food chain model development and its extension to key artificial radionuclides in radioecology such as 3H. Subsequently, the model will be applied to assess the radiological dose for marine biota from 3H, 90Sr, 131I, 134Cs and 137Cs released during and after the Fukushima Dai-ichi accident. The simulation results for 3H, 90Sr, 131I, 134Cs and 137Cs obtained from the coastal box (4-4 km) located at the discharge area of the Fukushima Dai-ichi NPP, and the surrounding regional box (15-30 km) are compared with measurements. The predictions are by and large consistent with experimental findings, although good validation for 3H, 90Sr and 131I is challenging due to lack of data. On the basis of the model predictions a dose assessment for pelagic and benthic fish is carried out. Maximum absorbed dose rates in the coastal box and the regional box are respectively 6000 and 50 µGy d-1 and are found in the pelagic non-piscivorous fish. Dose rates exceeding ICRP's derived consideration levels of 1 mGy d-1 are only found in the direct vicinity of the release and shortly after the accident. During the post-accidental phase absorbed dose rates consistently fall to levels where no deleterious effects to the marine biota are expected. The results also demonstrate the prolonged dose rate from 134Cs and 137Cs, particularly for benthic organisms, due to caesium's affinity with sediment, re-entry of caesium from the sediment into the food chain and external exposure from its high energetic gamma emissions. Uptake of non-organic tritium (HTO) and organically bound tritium (OBT) is modelled and shows some accumulation of OBT in the marine organism. However, dose rates from tritium, even during the accident, are low.

[Association between tooth missing and non-alcoholic fatty liver disease].

Objective: To evaluate the association between the number of teeth missed and the prevalence of non-alcoholic fatty liver disease (NAFLD) in adults. Methods: A cross-sectional study was carried out in 26 983 adults from Tianjin Chronic Low-grade Systemic Inflammation and Health Cohort Study. The number of teeth missed (excluding third molars) was recorded and classified into four categories: 0, 1-, 3- and ≥6. NAFLD was diagnosed by at least two liver ultrasonography examinations. Adjusted multivariable logistic regression analysis was used to access the association between the number of missed teeth and NAFLD in adults. Results: The overall prevalence of NAFLD was 7 270 and the number of the subjects with at least one tooth missed was 9 667. The multivariable-adjusted ORs (95%CI) of NAFLD across the categories of tooth missing (0, 1-, 3- and ≥6) were as follows: 1.00, 1.04 (0.93-1.15), 1.08 (0.93-1.26) and 1.38 (1.09-1.76) (trend test P=0.030) in males; 1.00, 0.96 (0.82-1.12), 1.11 (0.91-1.35) and 1.22 (0.90-1.64) (trend test P=0.450) in females. Conclusion: The number of missed teeth was positively associated with a higher prevalence rate of NAFLD in males with over 6 teeth missed, but not in females.