Rationale and design for a pragmatic randomized trial to assess gene-based prescribing for SSRIs in the treatment of depression.

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

Pharmacogenetic testing in primary care could bolster depression treatment: A value proposition.

Pharmacogenetic testing could reduce the time to identify a safe and effective medication for depression; however, it is underutilized in practice. Major depression constitutes the most common mental disorder in the US, and while antidepressant therapy can help, the current trial -and error approach can require patients to endure multiple medication trials before finding one that is effective. Tailoring the fit of pharmacogenetic testing with prescribers' needs across a variety of settings could help to establish a generalizable value proposition to improve likelihood of adoption. We conducted a study to explore the value proposition for health systems using pharmacogenetic testing for mental health medications through prescribers' real-world experiences using implementation science concepts and systematic interviews with prescribers and administrators from four health care systems. To identify a value proposition, we organized the themes according to the Triple Aim framework, a leading framework for health care policy which asserts that high-value care should focus on three key metrics: (1) better health care quality and (2) population-level outcomes with (3) reduced per capita costs. Primary care providers whom we interviewed said that they value pharmacogenetic testing because it would provide more information about medications that they can prescribe, expanding their ability to identify medications that best-fit patients and reducing their reliance on referrals to specialists; they said that this capacity would help meet patients' needs for access to mental health care through primary care. At the same time, prescribers expressed differing views about how pharmacogenetic testing can help with quality of care and whether their views about out-of-pocket cost would prevent them from offering it. Thus, implementation should focus on integrating pharmacogenetic testing into primary care and using strategies to support prescribers' interactions with patients.

Identifying protected areas in biodiversity hotspots at risk from climate and human-induced compound events for conserving threatened species.

Anthropogenic pressure in areas of biodiversity importance erodes the integrity of the ecosystems they harbour, making features of biodiversity less buffered against extreme climatic events. We define the combination of these disturbances as compound events. We assessed compound event risk in protected areas (PAs) applying a spatial framework guided by criteria and quantitative thresholds associated with exposure to cyclones, drought, and intense human pressure. This assessment was used in a relational matrix to classify PAs with different risk of compound event occurrence. We identified PAs of higher conservation concern by quantifying the extent of human pressure in their surrounding landscape while harbouring large numbers of threatened vertebrate species. Of the 39,694 PAs assessed, very high risk of compound events was determined for 6965 PAs (17.5 %) related to cyclones and human pressure (mainly island hotspots), 6367 PAs (16 %) related to droughts and human pressure (island and continental hotspots), and 2031 PAs (5 %) to cyclones, drought and human pressure (mainly in island hotspots). From the subset of 2031 PAs assessed at very high risk, we identified 239 PAs of higher conservation concern distributed predominantly in the Caribbean Islands, Japan, North America Coastal Plain, Philippines, and Southwest Australia. Our work highlights PAs in the biodiversity hotspots where high risk of compound event occurrence poses a greater threat to species. We encourage researchers to adapt and apply this framework across other globally significant sites for conserving biodiversity to identify high risk-prone areas, and prevent further biodiversity decline.

Mouse model of Graves' orbitopathy induced by the immunization with TSHR A and IGF-1R α subunit gene.

PURPOSE: The study aimed to establish a mouse model of Graves' disease (GD) with Graves' orbitopathy (GO; GD + GO) that can represent the clinical disease characteristics. METHODS: A eukaryotic expression plasmid of insulin-like growth factor 1 receptor (IGF-1R) α subunit (pcDNA3.1/IGF-1Rα) and a thyrotropin receptor (TSHR) A subunit plasmid (pcDNA3.1/TSHR-289) were injected in female BALB/c mice followed by immediate electroporation to induce a GD + GO model. Grouping was performed according to the frequency of injection (2- to 4-week intervals) and type of injected plasmids: T: pcDNA3.1/TSHR-289( +), I: pcDNA3.1/IGF-1Rα( +), or co-injection T + I: pcDNA3.1/TSHR-289( +) and pcDNA3.1/IGF-1Rα( +). Serum TSH, T4, TSAb, TSBAb, body weight, and blood glucose levels were evaluated. Thyroid 99mTcO4- imaging and retrobulbar magnetic resonance imaging (MRI) were performed, and bilateral eye muscle volumes were measured. Immunohistochemistry and hematoxylin-eosin staining were performed on the relevant tissues, and semi-quantitative analysis was performed. RESULTS: A total of 60% of mice (3/5, one mouse died) in the T group developed GD + GO. In the T + I group, 83.3% of mice (5/6) developed GD + GO. Mice in the I group did not develop GD. Compared with the control group, serum T4, TSAb, and TSBAb of the mice in the GD + GO model groups were increased to varying degrees (P < 0.05), and serum TSH and body weight were significantly lower compared to the control group (P < 0.05). The thyroid uptake capacity of 99mTcO4- and the volume of eye muscle of mice in the GD + GO group were significantly higher compared to the control group (P < 0.05). The thyroid and retrobulbar muscles of these mice showed varying inflammatory infiltration and interstitial muscle edema. The severity of GD + GO in the co-injection group was not related to injection frequency; however, GD and ocular signs in co-injection mice were more severe compared to the T group. CONCLUSIONS: We successfully induced a GD + GO mouse model by a repeated co-injection of pcDNA3.1/IGF-1Rα and pcDNA3.1/TSHR-289 plasmids. Injection of pcDNA3.1/IGF-1Rα alone failed to induce GD. Co-injection of two plasmids induced more severe GD + GO than pcDNA3.1/TSHR-289( +) alone.

Quantitative evaluation of bronchoalveolar lavage for the treatment of Severe mycoplasma pneumoniae pneumonia in children-A new complementary index: Bronchial Insufflation Sign Score.

OBJECTIVE: The aim of this study was to investigate the value of Broncoplasma Insufflation Sign in lung ultrasound signs in assessing the efficacy of bronchoalveolar lavage in Severe mycoplasma pneumoniae pneumonia in children. METHODS: Forty-seven children with Severe mycoplasma pneumoniae pneumonia were treated with medication and bronchial lavage. Laboratory and imaging results were collected, and lung ultrasonography was performed before bronchoalveolar lavage and 1, 3, and 7 days after lavage to record changes in Bronchial Insufflation Sign and changes in the extent of solid lung lesions. Factors affecting the effectiveness of bronchoalveolar lavage were analyzed using logistic regression and other factors. RESULTS: Bronchial Insufflation Sign Score and the extent of lung solid lesions were the factors affecting the effectiveness of bronchoalveolar lavage treatment. The smaller the area of lung solid lesions and the higher the Bronchial Insufflation Sign Score, the more effective the results of bronchoalveolar lavage treatment were, and the difference was statistically significant, with a difference of p < 0.05. The Bronchial Insufflation Sign Score had the highest sensitivity and specificity for the prediction of the efficacy of bronchoalveolar lavage treatment in the first 7 days after the treatment. CONCLUSION: Bronchial Insufflation Sign Score combined with the extent of solid lung lesions can assess the efficacy of bronchoalveolar lavage in the treatment of Severe mycoplasma pneumoniae pneumonia in children; lung ultrasound is a timely and effective means of assessing the efficacy of bronchoalveolar lavage.

[Porphyromonas gingivalis outer membrane vesicles activate Toll-like receptor 2 to promote osteoclast differentiation by carrying lipopolysaccharide].

Objective: To investigate the effects of Porphyromonas gingivalis derived outer membrane vesicles (Pg OMV) on osteoclast differentiation of macrophages and its underlying mechanisms. Methods: The morphology and the size distribution of Pg OMV were analyzed by transmission electron microscopy and nanoparticle tracing analysis, respectively. The osteoclast precursors were treated with 1, 3 and 10 mg/L Pg OMV (1, 3 and 10 mg/L OMV treatment group) or phosphate buffer solution (PBS)(control group). The formation of osteoclasts was analyzed by tartrate-resistant acid phosphase (TRAP) staining and F-actin staining and real-time quantitative PCR (RT-qPCR) were used to detect the expression of Fos and matrix metallopeptidase 9 (MMP9). Polymyxin B (PMB) was used to block lipopolysaccharide (LPS) and then Pg OMV was used to treat osteoclast precursor (PMB-OMV treatment group), and OMV treatment group was used as control. TRAP and F-actin staining were used to observe the formation of osteoclasts and actin rings. The effect of Pg OMV on the expression of Toll-like receptor (TLR) 2 and TLR4 in preosteoclasts was detected by Western blotting. The osteoclast precursors were pretreated with 10, 50, 100 and 200 µmol/L C29, an inhibitor of TLR2, and then treated with Pg OMV(OMV+10, 50, 100 and 200 µmol/L C29 treatment group) and OMV treatment group without C29 pretreatment was control. TRAP and F-actin staining were used to observe the formation of osteoclasts and actin rings. The osteoclast precursor cells were treated with OMV (OMV treatment group) and OMV incubated with PMB (PMB-OMV treatment group) and the expression of TLR2 in osteoclast precursor was detected by Western blotting. Results: Pg OMV showed classical vesicular structures, and the average particle size of Pg OMV were 179.2 nm. A large number of actin rings were observed in the 3 and 10 mg/L OMV treatment groups. The percentages of TRAP-positive osteoclast area in 3 mg/L OMV treatment group [(22.6±2.1)%] and 10 mg/L OMV treatment group [(32.0±2.3)%] were significantly increased compared with control group [(4.9±0.5)%] (P<0.001). Compared with the control group (1.000±0.029), the mRNA relative expression of Fos in 3 mg/L OMV treatment group (1.491±0.114) and 10 mg/L OMV treatment group (1.726±0.254) was significantly increased (P=0.013, P=0.001). Compared with the control group (1.007±0.148), the mRNA relative expression of MMP9 in the group of 10 mg/L OMV (2.232±0.097) was significantly increased (P<0.001). Actin ring formation was less in PMB-OMV treatment groups than in OMV treatment groups. The proportion of TRAP-positive osteoclasts area [(14.8±3.8)%] in PMB-OMV treatment group was significantly lower than OMV treatment group [(31.5±6.7) %] (P=0.004). The relative expression of TLR2 in OMV treatment group (1.359±0.134) was significantly higher than that in the control group (1.000±0.000) (t=4.62, P=0.044). Compared with the OMV treatment group [(29.4±1.7)%], 50, 100 and 200 µmol/L C29 significantly decreased the formation of osteoclasts [(24.0±1.7)%, (18.5±2.1)%, (9.1±1.3) %] (P=0.026, P<0.001, P<0.001). TLR2 protein expression in PMB-OMV group (0.780±0.046) was significantly lower than that in OMV group (1.000±0.000)(t=8.32, P=0.001). Conclusions: Pg OMV can promote osteoclast differentiation by carrying LPS, TLR2 plays an important role in Pg OMV mediated osteoclast differentiation.

[Effect of preemptive analgesia with ibuprofen on postoperative pain after mandibular third molar extraction: a randomized controlled trial].

Objective: To evaluate the impact of preemptive analgesia with ibuprofen on postoperative pain following the extraction of impacted mandibular third molars in a Chinese population, aiming to provide a clinical reference for its application. Methods: This multicenter, randomized, double-blind, placebo-controlled parallel-group trial was conducted from April 2022 to October 2023 at the Capital Medical University School of Stomatology (40 cases), Beijing TianTan Hospital, Capital Medical University (22 cases), and Beijing Chao-Yang Hospital, Capital Medical University (20 cases). It included 82 patients with impacted mandibular third molars, with 41 in the ibuprofen group and 41 in the control group. Participants in the ibuprofen group received 300 mg of sustained-release ibuprofen capsules orally 15 min before surgery, while the control group received a placebo. Both groups were instructed to take sustained-release ibuprofen capsules as planned for 3 days post-surgery. Pain intensity was measured using the numerical rating scale at 30 min, 4 h, 6 h, 8 h, 24 h, 48 h, and 72 h after surgery, and the use of additional analgesic medication was recorded during days 4 to 6 postoperatively. Results: All 82 patients completed the study according to the protocol. No adverse events such as nausea, vomiting, or allergies were reported in either group during the trial. The ibuprofen group exhibited significantly lower pain scores at 4 h [2.0 (1.0, 4.0) vs. 4.0 (3.0, 5.0)] (Z=-3.73, P<0.001), 6 h [2.0 (1.0, 4.0) vs. 5.0(2.5, 6.0)] (Z=-3.38, P<0.001), and 8 h [2.0 (1.0, 4.0) vs. 5.0 (2.0, 6.0)] (Z=-2.11, P=0.035) postoperatively compared to the control group. There were no statistically significant differences in pain scores between the groups at 30 min, 24 h, 48 h, and 72 h postoperatively (P>0.05). Additionally, 11 out of 41 patients (26.8%) in the ibuprofen group and 23 out of 41 patients (56.1%) in the control group required extra analgesic medication between days 4 and 6 post-surgery, with the ibuprofen group taking significantly fewer additional pills [0.0 (0.0, 1.0) vs. 1.0 (0.0, 3.0)] (Z=-2.81, P=0.005). Conclusions: A pain management regimen involving 300 mg of oral sustained-release ibuprofen capsules administered 15 minutes before surgery and continued for 3 d postoperatively effectively reduces pain levels and the total amount of analgesic medication used after the extraction of impacted mandibular third molars. Considering its efficacy, safety, and cost-effectiveness, ibuprofen is recommended as a first-line drug for perioperative pain management, enhancing patient comfort during diagnosis and treatment in a feasible manner.

[Parecoxib sodium down-regulates CXCL8-CXCR1/2 to improve inflammatory microenvironment and promote patient recovery following laparoscopic radical resection of rectal cancer].

OBJECTIVE: To study the effect of parecoxib sodium on tumor microenvironment in patients undergoing laparoscopic radical resection of rectal cancer. METHODS: Sixty patients undergoing laparoscopic surgery for radical rectal cancer resection were randomized into test group and control group (n=30). The patients in test control group received intravenous injections of 40 mg parecoxib sodium at the time of anesthesia induction, immediately after and at 12 h after the surgery, and those in the control group were injected with an equal volume of physiological saline at the same time points. Plasma levels of IL-6, TNF-α, and CXCL8 of the patients were measured using ELISA, and expressions of CXCL8, CXCR1, and CXCR2 in the peripheral blood mononuclear cells (PBMCs) were detected with Western blotting. Postoperative VAS scores and gastrointestinal reactions and disease regression at 6 months after the operation were recorded. RESULTS: Compared with the control patients, the patients in the test group showed significantly reduced plasma levels of IL-6, TNF-α, and CXCL8 (P < 0.05) and milder elevations of CXCL8, CXCR1, and CXCR2 proteins in PBMCs (P < 0.05) with significantly lower VAS scores at 12 h and 24 h after the operation (P < 0.05) and lower postoperative incidence of adverse gastrointestinal reactions (P < 0.05). At 6 months after the operation, the number of patients with metastasis or tumor recurrence was significantly smaller in the test group than in the control group (P>0.05). CONCLUSION: Parecoxib sodium can improve the inflammatory microenvironment to promote patient recovery after laparoscopic radical resection of rectal cancer possibly through a mechanism that down-regulates CXCL8-CXCR1/2 expressions in the PBMCs.

The causal association between body fat distribution and risk of abdominal wall hernia: a two-sample Mendelian randomization study.

PURPOSE: Obesity and a high body mass index (BMI) are considered as risk factors for abdominal wall hernia (AWH). However, anthropometric measures of body fat distribution (BFD) seem to be better indicators in the hernia field. This Mendelian randomization analysis aimed to generate more robust evidence for the impact of waist circumstance (WC), body, trunk, arm, and leg fat percentages (BFP, TFP, AFP, LFP) on AWH. METHODS: A univariable MR design was employed and the summary statistics allowing for assessment were obtained from the genome-wide association studies (GWASs). An inverse variance weighted (IVW) method was applied as the primary analysis, and the odds ratio value was used to evaluate the causal relationship between BFD and AWH. RESULTS: None of the MR-Egger regression intercepts deviated from null, indicating no evidence of horizontal pleiotropy (p > 0.05). The Cochran Q test showed heterogeneity between the genetic IVs for WC (p = 0.005; p = 0.005), TFP (p < 0.001; p < 0.001), AFP-L (p = 0.016; p = 0.015), LFP-R (p = 0.012; p = 0.009), and LFP-L (p < 0.001; p < 0.001). Taking the IVW random-effects model as gold standard, each standard deviation increment in genetically determined WC, BFP, TFP, AFP-R, AFP-L, LFP-R, and LFP-L raised the risk of AWH by 70.9%, 70.7%, 56.5%, 69.7%, 78.3%, 87.7%, and 72.5%, respectively. CONCLUSIONS: This study proves the causal relationship between AWH and BFD, attracting more attention from BMI to BFD. It provides evidence-based medical evidence that healthy figure management can prevent AWH.

Total iron binding capacity: an independent predictor of prognosis for pulmonary arterial hypertension in systemic lupus erythematosus.

OBJECTIVE: To investigate the role of parameters of iron metabolism in systemic lupus erythematosus (SLE) patients with pulmonary arterial hypertension (PAH). METHOD: This was a prospective observational study recruiting patients diagnosed with systemic lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH). Patients with other factors that might lead to PAH were excluded from the study. All patients were assessed for PAH every 1-3 months and were followed up for 6 months. The primary outcome was considered improved if the grade of risk stratification declined at the endpoint; otherwise, it was considered unimproved. RESULTS: In total, 29 patients with SLE-PAH were included in this study. The mean of serum ferritin was higher than normal, and total iron binding capacity (TIBC) decreased in 48% of patients. Correlation analyses showed that serum iron (SI) was negatively correlated with World Health Organization functional class (WHO-FC) (r = -0.409, p = 0.028), and positively correlated with Six-Minute Walk Test distance (6MWD) (r = 0.427, p = 0.021) and tricuspid annular plane systolic excursion (TAPSE) (r = 0.388, p = 0.037). Primary outcomes improved in 12 patients at the endpoint, and univariate logistic regression analyses indicated that TIBC was associated with improved primary outcomes in patients with SLE-PAH (odds ratio 12.00, 95% confidence interval 1.90-75.72). CONCLUSION: SI was negatively correlated with WHO-FC, and positively correlated with 6MWD and TAPSE. Furthermore, TIBC was associated with improved outcomes of patients with SLE-PAH, which could be an independent predictor of prognosis. Further research is needed to verify the findings.

The top 100 most-cited papers in incisional hernia: a bibliometric analysis from 2003 to 2023.

PURPOSE: Incisional hernia (IH) is one of the most common complications after abdominal surgeries and may bring great suffering to patients. This study aims to evaluate the global trends in IH research from 2003 to 2023 and visualize the frontiers using bibliometric analysis. METHODS: The literature search was conducted on the Web of Science for IH studies published from 2003 to 2023 and sorted by citation frequency. The top 100 most-cited articles were analyzed by the annual publication number, prolific countries and institutions, influential author and journal, and the number of citations through descriptive statistics and visualization. RESULTS: The top paper was cited 1075 times and the median number of citations was 146. All studies were published between 2003 and 2019 and the most prolific year was 2003 with 14 articles. Jeekel J and Rosen M were regarded as the most productive authors with ten articles each and acquired 2738 and 2391 citations, respectively. The top three institutions with the most productive articles were Erasmus Mc, Carolinas Med Ctr, and Univ Utah, while the top three countries were the United States, Netherlands and Germany. The most frequent keyword was "incisional hernia" with 55 occurrences, followed by "mesh repair", "randomized controlled trial", and "polypropylene". CONCLUSION: The 100 most-cited papers related to IH were published predominantly by USA and European countries, with randomized controlled trial (RCT) and observational study designs, addressing topics related to risk factors, complications, mesh repair, and mesh components.

Risk factors for incisional hernia after gastrointestinal surgeries in non-tumor patients.

PURPOSE: Incisional hernia (IH) is a common secondary ventral hernia after abdominal incisions and there is still little reliable evidence to predict and prevent IH. This study aimed to estimate risk factors of its incidence, especially concentrating on blood results. METHODS: 96 patients received midline laparotomy for gastrointestinal benign diseases and suffered from IH were enrolled in the IH group. A control group of 192 patients were randomly selected from patients underwent midline laparotomy for gastrointestinal benign diseases without IH. RESULTS: Patients in the IH group exhibited higher age (P < 0.001), BMI (P < 0.001), hernia history (P = 0.001) and laparotomy history (P < 0.001). Rate of coronary heart disease (P = 0.046), hypertension (P < 0.001), diabetes (P = 0.008), incisional infection (P = 0.004) and emergency surgery (P = 0.041) were also higher in the IH group. Patients with IH had lower levels of Hb (P = 0.002), TP (P = 0.013), ALB (P < 0.001), A/G (P = 0.019), PA (P < 0.001), HDL-C (P = 0.008) and ApoA1 (P = 0.005). Meanwhile, patients in the control group bore lower levels of LDH (P = 0.008), GLU (P = 0.007), BUN (P = 0.048), UA (P = 0.021), TG (P = 0.011), TG/HDL-C (P = 0.002), TC/HDL-C (P = 0.013), ApoB/ApoA1 (P = 0.001) and Lp(a) (P = 0.001). A multivariate logistic regression revealed that high BMI, laparotomy history, incisional infection, decreased PA, elevated levels of UA, Lp(a) and ApoB/ApoA1 were independent risk factors of IH. CONCLUSION: This is the first study to reveal the relationship between IH and serum biochemical levels, and give a prediction through the nomograph model. These results will help surgeons identify high-risk patients, and take measures to prevent IH during the perioperative period.

[Quantitative analysis of differential proteins in renal tissues of rats with chronic intermittent hypoxic exposure based on TMT and PRM technology].

OBJECTIVE: To screen the differentially expressed proteins in the kidneys of rats exposed to chronic intermittent hypoxia (CIH) based on TMT-PRM technology to identify the potential biomarkers of renal injuries induced by CIH. METHODS: Twenty SD rats were randomized into two groups (n=10) and exposed to CIH or normoxia. After 12 weeks of exposure, the kidneys of the rats were collected for observing pathological changes. The renal proteins were extracted, enzymatically digested and labelled with TMT, and LC-MS/MS was used to identify the proteins. The data were processed using Proteome Discoverer2.4 for bioinformatic analysis of the differentially expressed proteins. PRM technology was used to verify the expression of the candidate proteins. RESULTS: CIH induced obvious renal injury in the rats, manifested by irregular glomerulus and swelling of the epithelial cells of the renal tubules. A total of 31 differentially expressed proteins were identified in CIH rats, including 22 up-regulated and 9 down-regulated proteins. Enrichment analysis of GO function and KEGG pathway analysis showed that the differentially expressed proteins participated mainly in the biological processes of cell adhesion, hypoxic stress, and calcium ions and were involved in the PPAR, AMPK, and metabolic pathways. In PRM quantitative analysis, 3 proteins, namely P07379 (PCK1), P19132 (Fth1) and Q5XI79 (Ndufaf7), showed results consistent with those of TMT-quantitative proteomic analysis. CONCLUSION: Thirty-one differentially expressed proteins were identified in the renal tissues of rats with CIH exposure, and among them P07379 (PCK1), P19132 (Fth1), and Q5XI79 (Ndufaf7) may be the key proteins closely related to the renal injury in induced by CIH.

Knockdown of Long Noncoding RNA CCAT2 Suppresses Malignant Phenotype in Human Laryngeal Squamous Cell Carcinoma.

This study aimed to explore the biological role and mechanism underlying the effects of colon cancer-associated transcript 2 (CCAT2), a long noncoding RNA (lncRNA) in human laryngeal squamous cell carcinoma (LSCC). CCAT2 expression levels in clinical LSCC samples and TU-212 cell line were evaluated by quantitative real-time PCR. The correlation of CCAT2 expression level with clinical-pathological characteristics of patients and their prognosis was analyzed. The functional role of CCAT2 in human LSCC was assessed by Cell Counting Kit-8, Transwell assay, flow cytometric analysis, and LSCC xenograft experiment in vivo. The expression of potential targeted proteins was detected by Western blotting and immunohistochemistry. We found that expression of CCAT2 was significantly elevated in LSCC tissues and TU-212 cells (p<0.05). Survival analysis showed that LSCC patients with high expression of CCAT2 had a shorter 5-year overall survival rate than those with low expression (p<0.05). In addition, CCAT2 silencing with short hairpin RNA significantly decreased the proliferative and invasive potential of TU-212 cells (p<0.05) and promoted their apoptosis. In Nude mice, CCAT2 knockdown suppressed the growth of tumor and decreased its volume and weight in comparison with the controls (p<0.05). In TU-212 cells, CCAT2 silencing with short hairpin RNA significantly down-regulated the expression of ß-catenin and CDK8 (p<0.05). Thus, knockdown of CCAT2 suppresses proliferation and invasion of the cells and inhibits Wnt/ß-catenin signaling pathway in LSCC, which indicates novel therapeutic targets and prognostic indicators in patients with LSCC.

Author Correction: Linkage and association of novel DRD2 variants to the comorbidity of type 2 diabetes and depression.

Correction to: Eur Rev Med Pharmacol Sci 2022; 26 (22): 8370-8375-DOI: 10.26355/eurrev_202211_30372-PMID: 36459020-published online on November 20, 2022. • In Amin, Wu, Postolache, and Gragnoli (2022), the originally published Figure 1 inadvertently included an error in the markers. The authors have submitted a corrected version, which is shown here. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/30372.

[Comprehensive assessment of mismatch repair and microsatellite instability status in molecular classification of endometrial carcinoma].

Objective: To explore the concordance and causes of different mismatch repair (MMR) and microsatellite instability (MSI) detection results in endometrial carcinoma (EC) molecular typing. Methods: A total of 214 EC patients diagnosed from January 2021 to April 2023 were selected at the Department of Pathology, Peking University Third Hospital. The immunohistochemistry (IHC) results of MMR protein were reviewed. Tumor specific somatic mutations, MMR germline mutations, microsatellite scores and tumor mutation burden (TMB) were detected by next-generation sequencing (NGS) with multi-gene panel. Methylation-specific PCR was used to detect the methylation status of MLH1 gene promoter in cases with deficient MLH1 protein expression. In cases with discrepant results between MMR-IHC and MSI-NGS, the MSI status was detected again by PCR (MSI-PCR), and the molecular typing was determined by combining the results of TMB and MLH1 gene promoter methylation. Results: (1) In this study, there were 22 cases of POLE gene mutation subtype, 55 cases of mismatch repair deficient (MMR-d) subtype, 29 cases of p53 abnormal subtype, and 108 cases of no specific molecular profile (NSMP). The median age at diagnosis of MMR-d subtype (54 years old) and the proportion of aggressive histological types (40.0%, 22/55) were higher than those of NSMP subtype [50 years old and 12.0% (13/108) respectively; all P<0.05]. (2) Among 214 patients, MMR-IHC test showed that 153 patients were mismatch repair proficient (MMR-p), 49 patients were MMR-d, and 12 patients were difficult to evaluate directly. MSI-NGS showed that 164 patients were microsatellite stable (MSS; equal to MMR-p), 48 patients were high microsatellite instability (MSI-H; equal to MMR-d), and 2 patients had no MSI-NGS results because the effective sequencing depth did not meet the quality control. The overall concordance between MMR-IHC and MSI-NGS was 94.3% (200/212). All the 12 discrepant cases were MMR-d or subclonal loss of MMR protein by IHC, but MSS by NGS. Among them, 10 cases were loss or subclonal loss of MLH1 and (or) PMS2 protein. Three discrepant cases were classified as POLE gene mutation subtype. In the remaining 9 cases, 5 cases and 3 cases were confirmed as MSI-H and low microsatellite instability (MSI-L) respectively by MSI-PCR, 6 cases were detected as MLH1 gene promoter methylation and 7 cases demonstrated high TMB (>10 mutations/Mb). These 9 cases were classified as MMR-d EC. (3) Lynch syndrome was diagnosed in 27.3% (15/55) of all 55 MMR-d EC cases, and the TMB of EC with MSH2 and (or) MSH6 protein loss or associated with Lynch syndrome [(71.0±26.2) and (71.5±20.1) mutations/Mb respectively] were significantly higher than those of EC with MLH1 and (or) PMS2 loss or sporadic MMR-d EC [(38.2±19.1) and (41.9±24.3) mutations/Mb respectively, all P<0.01]. The top 10 most frequently mutated genes in MMR-d EC were PTEN (85.5%, 47/55), ARID1A (80.0%, 44/55), PIK3CA (69.1%, 38/55), KMT2B (60.0%, 33/55), CTCF (45.5%, 25/55), RNF43 (40.0%, 22/55), KRAS (36.4%, 20/55), CREBBP (34.5%, 19/55), LRP1B (32.7%, 18/55) and BRCA2 (32.7%, 18/55). Concurrent PTEN, ARID1A and PIK3CA gene mutations were found in 50.9% (28/55) of MMR-d EC patients. Conclusions: The concordance of MMR-IHC and MSI-NGS in EC is relatively high.The discordance in a few MMR-d EC are mostly found in cases with MLH1 and (or) PMS2 protein loss or MMR protein subclonal staining caused by MLH1 gene promoter hypermethylation. In order to provide accurate molecular typing for EC patients, MLH1 gene methylation, MSI-PCR, MMR gene germline mutation and TMB should be combined to comprehensively evaluate MMR and MSI status.

[Surgical management for the perforation of digestive tract with intraabdominal infection].

Perforation of digestive tract with intra-abdominal infection is one of the common causes of emergency surgery. After the resection with intestine, primary anastomosis or stoma remains a subject of debate. With the continuous improvement of surgical technology and the need to improve patients' quality of life, primary anastomosis is supposed to be the most ideal surgery. However, the rate of stoma is still high due to concerns about postoperative anastomotic leakage. This paper summarizes the surgical treatment of intra-abdominal infection caused by gastrointestinal perforation in recent years, and discuss the best operation plan according to the perforation location and etiology. We also discuss a variety of treatment methods for the prevention of anastomotic leakage (perioperative management, gastrointestinal anastomosis, enteric lavage decompression and other techniques) to improve the primary anastomosis, improve the quality of life of patients and reduce the medical burden.

Novel implication of the prolactin (PRL) gene in the comorbidity of type 2 diabetes and depression.

OBJECTIVE: The prolactin (PRL) system plays important behavioral, social, and metabolic roles, such as mediating social bonding and insulin secretion. Inherited dysfunction of the PRL pathway-related genes is associated with psychopathology and insulin resistance. We have previously suggested that the PRL system might be implicated in the comorbidity of psychiatric (depression) and type 2 diabetes (T2D) owing to the pleiotropy of PRL pathway-related genes. To our knowledge, no PRL variants have so far been reported in patients with either major depressive disorder (MDD) and/or T2D. PATIENTS AND METHODS: In this study, we analyzed 6 variants within the PRL gene and tested them for the presence of parametric linkage and/or linkage disequilibrium (LD, i.e., linkage and association) with familial MDD, T2D, and their comorbidity. RESULTS: We found, for the first time, that the PRL gene and its novel risk variants are linked to and in LD (i.e., linkage and association) with familial MDD, T2D, and MDD-T2D comorbidity. CONCLUSIONS: PRL might play a key role in mental-metabolic comorbidity and can be considered a novel gene in MDD and T2D.