Search

Objective: In this paper, we present a comprehensive overview of our experience in establishing and leading distinct extracorporeal cardiopulmonary resuscitation (ECPR)-related teams to independently handle ECPR in the early stages in the emergency department. Methods: A retrospective analysis was conducted on the clinical data of 29 patients who underwent ECPR treatment in the emergency room between May 2018 and April 2022. A control group, consisting of 10 patients treated between May 2018 and September 2019 was managed using a standard rescue coordination mode. The 19 patients who received ECPR between October 2019 and April 2022 were treated by members of the department's 24-h extracorporeal life support team. We compared the implementation and operational challenges faced by the two groups, including item preparation, circuit setup, and ECPR initiation times, among other factors. Results: Gender, age, cardiac arrest risk factors, and other baseline data did not significantly differ between the two groups. Extracorporeal membrane oxygenation (ECMO) pipeline prefilling time (from 35.27±10.34 to 13.46±5.32), ECPR establishment time (from 62.35±29.61 to 30.98±13.41), and item preparation time (from 16.42±9.78 to 3.19±1.49) all considerably decreased when compared to the control group. The rate of return of spontaneous circulation recovery rose from 37.50 % to 77.78 % (P

Schwannoma (syn. neurilemoma, neuroschwannoma) is a benign tumor derived from nerve sheath cells (Schwann cells), which is the most common type of peripheral neurogenic tumors. In this case, a patient with papillary thyroid carcinoma on the left side was found to have a predominantly cystic nodule in the ipsilateral neck level 4 by ultrasonography (US), which mistook for ipsilateral cervical lymph node metastasis and was later found to be a vagal nerve sheath tumor by surgery. The article reviews the pathology, imaging findings and differential diagnosis of schwannomas. A meticulous evaluation and comprehensive differential diagnosis are pivotal to reach correct diagnosis.

Introduction: This study aimed to compare the efficacy and safety of docetaxel + trastuzumab + pertuzumab and docetaxel + carboplatin + trastuzumab + pertuzumab for treating HER2-positive breast cancer. Method: HER2-positive breast cancer from patients diagnosed between January 2020 and September 2022 were included in this retrospective study. Docetaxel + trastuzumab + pertuzumab or docetaxel + carboplatin + trastuzumab + pertuzumab was selected as the neoadjuvant regimen. The primary endpoint was a complete pathological remission rate. Secondary endpoints were toxicity during neoadjuvant treatment, adjustment of the neoadjuvant therapy scheme, and adjuvant medication. Result: A total of 81 patients were included in this study (38 in the docetaxel + carboplatin + trastuzumab + pertuzumab treatment group and 43 in the docetaxel + trastuzumab + pertuzumab group). The complete pathological remission rates in the docetaxel + carboplatin + trastuzumab + pertuzumab and docetaxel + trastuzumab + pertuzumab groups were 44.7% (95% confidence interval: 30.2%-60.3%) and 51.2% (95% confidence interval: 36.8%-65.4%), respectively. The incidence of grade 3 or higher toxicity in the docetaxel + carboplatin + trastuzumab + pertuzumab group was significantly higher than that in the docetaxel + trastuzumab + pertuzumab group (68.4% vs 39.5%, P = .009). Neutropenia and asthenia were the most common grade 3 or higher toxicities. The incidence of neoadjuvant scheme adjustment was significantly higher in the docetaxel + carboplatin + trastuzumab + pertuzumab group than in the docetaxel + trastuzumab + pertuzumab group (26.3% vs 7.0%, P = .039). The proportion of patients who received

Purpose This study aims to determine the optimal cut-off value of Ki-67 to better predict the recurrence of early low-risk endometrial cancer (EC). Methods Seven hundred and forty-eight patients diagnosed with low-risk EC from West China Second Hospital of Sichuan University and the First Affiliated Hospital of Chongqing Medical University were retrospectively analyzed. The receiver operating characteristic curve (ROC) and Youden index were used to calculate the optimal cut-off value of Ki-67 expression. The clinicopathological indexes between two groups divided by cut-off value of Ki-67 were compared. The univariate and multivariate regression analyses were performed to investigate risk factors connected to the recurrence of early low-risk EC. The survival analysis was shown in Kaplan–Meier curve. Result Thirty-three patients were detected with tumor recurrence after primary surgery (4.4%); 33% was the optimal cut-off value of the Ki-67 index. A high Ki-67 was significantly associated with age ( P = .002), myometrial invasion ( P < .001), and the expression of P53 ( P = .007). The multivariate regression analysis verified that Ki67 ≥ 33% was an independent prognostic factor for predicting recurrence. The recurrence-free survival (RFS) and the overall survival (OS) in high Ki-67 group was significantly lower than that in low Ki-67 group ( P < .001 and P = .029, respectively). The prognostic values of ER, PR, and P53 in combination with Ki-67 were superior to each single predictor. Conclusions The optimal cut-off value of Ki-67 for predicting recurrence is 33%, which quantitatively defines the specific value of Ki-67 that causes high-risk recurrence in early low-risk EC.

Background: The aim of lymph node dissection for melanoma patients is to prevent metastasis. However, this procedure is accompanied by a long-term and impaired life-quality complication called extremity lymphedema. This condition involves long-term lower limb swelling, which causes discomfort and impaired function, and affects patients both physically and psychologically. Herein, we conducted a retrospective cohort study at a single center to investigate the risk factors associated with lower extremity lymphedema after inguinal lymphadenectomy. Materials and Methods: We identified 136 inguinal lymphadenectomy melanoma patients treated between January 2010 and January 2021. The patients' demographic, clinical, and pathological data and postoperative outcomes were collected by electronic medical record review and patient follow-up. The patients' postoperative outcomes were defined as lower extremity swelling and lower extremity lymphedema. Univariate and multivariate analyses were used to determine the independent predictors of lower extremity lymphedema. Results: The follow-up results from 85 melanoma patients who underwent inguinal lymphadenectomy were analyzed. Multivariate logistic regression analysis showed that number of lymph nodes removed≥10 was the significant risk factor for postoperative lower extremity lymphedema (odds ratio = 6.468, P = .042, 95% confidence interval: 1.069 to 39.147). Moreover, 8 (100%) patients in the lower extremity lymphedema group and 32 (53.3%) patients in the normal group were female, which indicated that female patients might be more susceptible to postoperative lower extremity lymphedema (P = .012). Conclusion: Our study found that number of inguinal lymph nodes removed ≥10 was associated with a significantly higher incidence of lower extremity lymphedema with a 6.5-fold increased risk in melanoma patients. Also, female patients were more likely to develop lower extremity lymphedema after inguinal lymphadenectomy.

Gas therapy is a new therapeutic method that has been developed in recent years and shows great clinical prospects for the treatment of tumours and cardiovascular, nerve, and immune system diseases. Therapeutic gases, including oxygen, hydrogen, nitric oxide, hydrogen sulfide, xenon, and other bioactive gases are involved in modulating cell signaling pathways and have important physiological functions with substantial therapeutic potential. However, their precise delivery remains a major challenge. Recently, researchers began to use ultrasound to trigger microbubbles that have encapsulated these gases for intravenous administration. This not only enhances the contrast of ultrasound imaging, but also precisely releases gases in the targeted area using ultrasound-targeted microbubble destruction. This article reviews the latest advances in the use of microbubbles to load therapeutic gases for the treatment of diseases.

As an emerging technology, radiomics has shown potential values in the field of healthcare. CT/MRI was preferred in previous radiomics researches because its images are easy to be standardized. And only until recently, an increasing number of studies focusing on the application of ultrasound radiomics in predicting molecular subtypes, identifying of malignant lesions, reactions to neoadjuvant chemotherapy, and axillary lymph node metastasis of breast cancer have been published. The purpose of this review is to summarize the steps of radiomics used in the field of breast cancer. In conclusion, ultrasound radiomics is a promising technology in diagnosing and monitoring breast cancer and further assisting physicians in patient management.

Background Effective means for early diagnosis are imperative to reduce death rate of non-small cell lung cancer (NSCLC) patients. We aimed to find out high-performance serologic markers to distinguish early-stage NSCLC patients from benign pulmonary nodule patients and healthy controls (HC). Cystatin-SN (CST1) is an active cysteine protease inhibitor of the CST superfamily, involving in the processes of inflammation and tumorigenesis. This is the first exploration of the diagnostic and prognostic values of serum CST1 in NSCLC. Methods We analyzed the transcriptome data from The Cancer Genome Atlas and the Gene Expression Omnibus database, screened biomarkers for NSCLC, and verified the candidate markers via the ONCOMINE database. Then, we performed ELISA, western blotting, and immunohistochemistry analysis to detect the expression levels of CST1 in NSCLC cell lines, tumor tissues, and serum samples of clinical cohorts. Results We identified 3 up-regulated secreted protein-encoding genes, validated the expression levels of CST1 in NSCLC tumor tissues and cell lines, and found that serum CST1 levels of NSCLC (4289 ± 2405 pg/mL) were significantly higher than those of PBN patients (1558 ± 441 pg/mL, P < .0001) and healthy controls (1529 ± 416 pg/mL, P < .0001). The AUC of the combination of CST1, Cytokeratin 19 fragment (Cyfra21-1), and Carcinoembryonic antigen (CEA) for distinguishing early-stage NSCLC from PBN/HC was as high as .914/0.925. Furthermore, our results suggested that the NSCLC patient with low serum CST1 level had a better survival rate. Conclusions Serum CST1 may serve as a novel diagnostic marker for differentiating early-stage NSCLC from PBN and HC, and could be used as a prognosis predictor in NSCLC patients.

Purpose: The objective of this retrospective study is to evaluate the efficacy and safety of hypofractionated simultaneous integrated boost radiotherapy for early breast cancer patients undergoing breast-conserving surgery. Methods: A total of 185 women with early breast cancer undergoing breast-conserving surgery were retrospectively divided into hypofractionated simultaneous integrated boost group and conventional fractionation group. Hypofractionated simultaneous integrated boost included 104 patients and the dose of whole-breast radiation reached 42.56 Gy in 16 fractions and simultaneously tumor bed boost to 48 Gy in 16 fractions, which course of radiotherapy was 22 days. The 81 patients of the conventional fractionation group received whole breast radiation to 50 Gy in 25 fractions and followed by tumor bed boost to 10 Gy in 5 fractions, which course of radiotherapy was 40 days. Clinical information including patients’ characteristics, skin toxicity, myelosuppression, radiation pneumonia, and cosmetic effects was recorded to analyze the influence of age, chemotherapy, position, and breast volume on the results of radiotherapy. Results: Hypofractionated simultaneous integrated boost group had no case of recurrence after a median follow-up of 25.6 months (9-47 months)) as compared with 2 after a median follow-up of 33.4 months (25-45 months) in the conventional fractionation group. The 2 groups had similar results in skin toxicity, cosmetic outcomes, and radiation pneumonia. In terms of myelosuppression, grade 1, grade 2, and grade 3 of myelosuppression in the hypofractionated simultaneous integrated boost group accounted for 16.7%, 12.3%, and 3.5% as compared with 30.0%, 21.1%, and 12.3% of the conventional fractionation group, respectively ( P = .000). Conclusions: HF-SIB RT is a considerable option in patients after breast-conserving surgery with a lower degree of myelosuppression and shorter treatment time.

Background : Recently, accumulating evidence confirmed that up-frameshift protein 1 (UPF1) was aberrantly expressed in various cancers. However, the molecular mechanism mediated by UPF1 underlying colorectal carcinogenesis remains unclear. Method : Immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction analysis were used to determine the expression level of UPF1 in colorectal cancer (CRC) tissues. CCK-8, EdU, transwell assay, and flow cytometry were performed to investigate the biological significance of UPF1. Epithelial–mesenchymal transition (EMT) and apoptosis associated markers were detected by western blotting. Results : We found that UPF1 expression was upregulated in CRC tissues and cell lines. Clinical analysis revealed that high UPF1 expression was positively correlated with advanced stage, lymph node metastasis and shorter survival. Knockdown of UPF1 suppressed cell proliferation and cell cycle progression. Functionally, UPF1 promotes tumor metastasis by inducing epithelial to mesenchymal transition. Further investigations revealed that knockdown of UPF1 promoted apoptosis through triggering DNA damage. Conclusions : Taken together, this research revealed that UPF1 plays an oncogenic role in CRC via regulating EMT and apoptosis and may be a potential therapeutic target for CRC.

Background: 5-fluorouracil (5-FU) is a widely used drug for cancer treatment, but its effect and underlying mechanisms on osteosarcoma (OS) cells remain unclear. Methods: U2OS and MG63 cells were treated with 0, 50, 100, and 500 μM 5-FU. MTS and flow cytometry were used to examine the effect of 5-FU on cell viability and apoptosis, respectively. Circular RNA (circRNA) expression was detected using RNA sequencing and quantitative real-time PCR (qPCR). Differentially expressed circRNAs were further subjected to the Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analysis to predict their functions. A circRNA–miRNA–mRNA interaction network was generated to analyze the regulatory networks of 5-FU–induced differentially expressed circRNAs. Western blotting (WB) was used to verify the protein in the downstream of circRNAs. Results: 5-FU inhibited the cell viability of the MG63 cells in a concentration-dependent manner. The most significant effect was observed in the cells treated with 500 μM 5-FU. Apoptosis was also increased in the MG63 cells after 500 μM 5-FU treatment for 3 days. RNA sequencing results showed that 183 differentially expressed circRNAs (172 upregulated and 11 downregulated) in 5-FU–treated cells. KEGG and GO analysis showed that the differentially expressed circRNAs were primarily enriched in proliferation-, apoptosis-, and metabolism-related functions. qPCR was used to verify the most upregulated and downregulated circRNAs. The circRNA–miRNA–mRNA interaction network showed that these 8 circRNAs had a sizable regulatory network that links a series of genes involved in tumor suppression. Conclusion: 5-FU treatment resulted in the differentially expressed circRNAs that were proliferation- and apoptosis-associated and were involved in the 5-FU–induced inhibition of tumor proliferation in OS cells.

We performed a pairwise and network meta-analysis to compare pathological complete response (pCR) among neoadjuvant chemotherapy in patients with triple-negative breast cancer. We searched PubMed for randomized clinical trials between January 1, 2000 and December 1, 2020. Abstracts from meetings were also searched. A frequentist random-effect model was applied to compare pCR and toxicities. The P-score was used to rank treatment effects. Nineteen trials with 16 treatments and 7794 patients were included. On the basis of SoC, the addition of carboplatin (OR = 1.82, 95% CI, 1.24 to 2.68, P < .01) and the addition of checkpoint inhibitors (OR = 1.69, 95% CI, 1.23 to 2.32, P < .01) increased pCR in pairwise meta-analysis; compared with paclitaxel, nab-paclitaxel did not improve pCR rates (OR = 1.81, 95% CI, .80 to 4.12, P = .16). The anthracycline-sparing regimen led to similar pCR compared with the anthracycline-containing regimen (OR = 1.50, 95% CI, .82 to 2.76, P = .19). In network meta-analysis, the addition of carboplatin plus a PD-1 inhibitor (pembrolizumab), carboplatin plus bevacizumab, and carboplatin plus veliparib ranked as the top three treatments for achieving pCR, with corresponding P-scores of .91, .84, and .72, respectively. Among patients with homologous recombination deficiency, the addition of carboplatin (OR = 1.31, 95% CI, .69 to 2.50, P = .41) or carboplatin plus PARP inhibitors (OR = 1.19, 95% CI, .58 to 2.47, P = .63) did not increase pCR. For triple-negative breast cancer, combining carboplatin with taxane-anthracycline-containing neoadjuvant chemotherapy could be the standard of care, and the combination containing checkpoint inhibitor is promising. However, their role in long-term oncologic outcome remains to be determined.

Objective To investigate the safety and efficacy of regional citrate anticoagulation (RCA) on elderly patients at high risk of bleeding after continuous renal replacement therapy (CRRT). Methods A total of 31 patients at high risk of bleeding who received CRRT in the intensive care unit were collected. The patients were divided into RCA group (n = 17) and no anticoagulation group (NA, n = 14) according to whether RCA was used or not. The levels of creatinine (Cr), blood urea nitrogen (BUN), prothrombin time (PT), activated partial thromboplastin time (APTT), total calcium (tCa), ionized calcium ion (iCa 2+ ), sodium ion (Na + ), bicarbonate ion (HCO 3 − ), tCa/iCa 2+ ratio, and pH were observed after treatment. The filter use time, number of filters used, filter obstruction events, clinical outcomes, and safety evaluation indexes were compared post-treatment. Results After treatment, serum Cr and BUN levels, APTT and PT levels in the RCA group were significantly lower than the NA group. The tCa, iCa 2+ , HCO 3 − , tCa/iCa 2+ , and pH were within the normal range after RCA treatment while Na + levels saw a significant increase. In the RCA group, the filter using time was significantly longer, with significantly reduced numbers of filter use within 72 h and filter disorder events. Additionally, patients in the RCA group showed significant recovery of renal function and a significant reduction in bleeding events and in-hospital mortality. Conclusion RCA treatment significantly improves clinical outcome of patients at high risk of bleeding after CRRT, safely and effectively prolongs the filter life and avoids coagulation incidences.

Objective: Our objective is to assess whether the outcome of intrahepatic unresectable or ablative hepatocellular carcinoma (HCC) could be improved by supplemental transarterial chemoembolization (TACE) following initial treatment of TACE with 3-dimensional conformal radiotherapy (3DCRT), compared to TACE followed by 3DCRT alone. Methods: We retrospectively analyzed intrahepatic unresectable or ablative HCC patients who underwent TACE, followed by 3DCRT with or without additional TACE, from June 2010 to December 2016 at our institution. Survival was assessed using the Kaplan-Meier method and compared with the log-rank test. Cox regression analyses were used to identify factors that influenced prognosis. Toxicity profiles were evaluated using CTCAE 4.0. Results: 27 patients received TACE with 3DCRT (TR group) and 11 received additional TACE following TACE and 3DCRT (sandwich group), respectively. The median intrahepatic progression-free survival (IPFS), progression-free survival (PFS), and overall survival (OS) in the TR group and sandwich group were 5.4 months vs. 17 months (P = 0.018), 5.4 months vs. 17 months (P = 0.008), and 13.5 months vs. 29.2 months (P = 0.011), respectively. Multivariate Cox regression demonstrated that TACE followed by radiotherapy alone had a shorter IPFS (HR: 2.516, 95% CI (1.136-5.570), P = 0.023) and PFS (HR: 2.637, 95% CI (1.182-5.880), P = 0.018) compared with the sandwich treatment. Hepatitis B virus reactivation occurred in 1 patient in the sandwich group. Myleosuppresion was considered a grade 3/4 adverse event. Conclusion: Unresectable or ablative HCC patients possibly benefit from the combination of TACE and 3DCRT followed by additional TACE therapy, compared with TACE followed by 3DCRT alone.

We do not know the clinical and prognostic factors that influence the survival of patients with gastric signet ring cell carcinoma (SRC). Therefore, a retrospective review was undertaken of 219 patients with SRC who had undergone gastrectomy between January 2009 and December 2012 in our hospital. Patient age, sex, TNM stage, vessel carcinoma embolus, perineural invasion, tumor site and operation type, postoperative chemotherapy, and five-year overall survival were recorded and evaluated. In our study, 93 cases (42.5%) were signet ring cell carcinoma only, and 126 cases (57.5%) were signet ring cell carcinoma coexisting with other components (such as adenocarcinoma or mucus adenocarcinoma). Eighty-three patients were female, 136 were male, 46 occurred at the gastroesophageal junction (21.0%), 63 at the fundus/body (28.8%), 80 were antrum/pylorus (36.5%), and 30 were whole stomach (13.7%). The prognosis of gastric antrum/ pylorus cancer was the best (P < 0.05). There were 133 patients (60.7%) with stage III, and the single factor analysis showed that the earlier the stage, the better the prognosis. The overall five-year survival rate was 30.1% in all patients. One-hundred and 41 patients (64.4%) received D2 radical surgery, 64 (29.2%) received D1 radical operation, and 14 (6.4%) received palliative resection, and the patients who received D2 had the best overall survival (P < 0.05). The survival time of the paclitaxel-based regimen in postoperative adjuvant chemotherapy tended to be prolonged. There was no statistical difference in overall survival between the percentage of signet-ring cells and sex. In summary, age, tumor stage, and surgical resection combined with D2 lymphadenectomy were independent prognostic factors for SRC. Adjuvant chemotherapy with a paclitaxel-based regimen may improve the survival of patients with SRC.

Background: Although the landmark INT-0116 trial and National Comprehensive Cancer Network (NCCN) guidelines recommended pT3-4Nx gastric cancer (GC) patients to receive chemoradiotherapy, the role of radiotherapy has not been distinguished from chemoradiotherapy. Methods: GC with behavior of metastasis-indolent in lymph node (MILN) being confirmed with more than 15 examined LNs after gastrectomy were identified using the Surveillance, Epidemiology and End Result (SEER) database. The cancer-specific survival (CSS) of subgroups for radiotherapy, chemotherapy, chemoradiotherapy and non-adjuvant-treatment were compared. Propensity score matching (PSM) was performed between radiotherapy and non-radiotherapy subgroups to further distinguish the role of radiotherapy from chemoradiotherapy. Cox regression was performed to identify whether radiotherapy or chemotherapy could independently improve prognosis. Results: We identified 690 MILN GC patients in SEER database. 5-year CSS was 71.9% in radiotherapy subgroup and 75.1% in non-radiotherapy subgroup(HR = 1.013, 95% CI = 0.714-1.438, p = 0.940), 75.6% in chemotherapy subgroup and 68.5% in non-chemotherapy subgroup(HR = 0.616, 95% CI = 0.430-0.884, p = 0.008), 52.5% in radiotherapy-alone subgroup and 71.9% in non-adjuvant treatment group (HR = 1.604, 95% CI = 0.575-4.471, p = 0.360), 72.9% in chemoradiotherapy subgroup and 79.5% in chemotherapy-alone subgroup (HR = 1.365, 95% CI = 0.859-2.172, p = 0.185), respectively. Further, PSM markedly improved balance of variables between radiotherapy subgroup and non-radiotherapy subgroup. After PSM, the role of the variables of radiotherapy and chemotherapy in contributing to improving CSS are consistent with that before PSM. Cox regression showed chemotherapy, tumor size, tumor invasiveness and Lauren classification were independent prognostic factors, but not including radiotherapy. Conclusions: Chemoradiotherapy confers superior prognosis to MILN GC patients compared with surgery alone might only be attributed to chemotherapy rather than radiotherapy.

Background: Many hospitals require all operative specimens be sent to pathologists for routine examination. Although previous studies indicate this practice increases medical cost, it remains unclear whether it alters patient management and whether it is cost-effective.Questions/purposes: We therefore (1) determined the rate of discordance between clinical and histologic examinations of routine operative specimens during elective primary arthroplasties, (2) determined the cost of routine histologic screening, and (3) estimated its cost-effectiveness in terms of cost per quality-adjusted life year gained, as compared with gross examination or no examination.Methods: We retrospectively reviewed medical records of 1247 patients who underwent 1363 routine elective primary total joint arthroplasties between January 18, 2006 and March 15, 2010. We compared preoperative, postoperative, and histologic diagnoses for each patient and categorized them into three classes: concordant (clinical and histologic diagnoses agreed), discrepant (diagnoses differed but with no resultant change in treatment), and discordant (diagnoses differed with resultant change in treatment). Medicare reimbursements were determined through the pathology department's administrative office.Results: In 1363 cases, 1335 (97.9%) clinical and histologic diagnoses were concordant, 28 (2.1%) were discrepant, and none were discordant. Total reimbursement for routine pathological examination was $139,532, or $102.37 per specimen. The average cost to identify each discrepant case was $4983.29. Routine histologic examination did not alter patient management, and there was no direct gain in quality-adjusted life years.Conclusions: Our observations show routine histologic examinations of routine operative specimens during elective primary arthroplasties increase medical cost but rarely alter patient management and are not cost-effective.Level Of Evidence: Level I, economic and decision analyses. See Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Purpose: To analyze nationwide pre-operative gonioscopy utilization patterns for various glaucoma surgeries and laser surgeries over time using the IRIS ® Registry (Intelligent Research in Sight)., Design: Retrospective cohort study., Participants: All adults who underwent a glaucoma surgery or laser surgery between January 1, 2014 and April 14, 2023., Methods: The first glaucoma procedure from the first eye of each patient was recorded as the index event and time was measured between the most recent pre-operative gonioscopy date to the index event. Baseline demographics, pre-operative clinical characteristics, glaucoma diagnosis, procedure type, and type of subspecialist performing the procedure were collected., Main Outcome Measures: Primary outcomes were the percentage of patients who had gonioscopy before a glaucoma procedure (1) at any prior visit and (2) within 1 year prior to the procedure. Secondary outcomes were the baseline factors that were associated with higher gonioscopy utilization at any prior visit using multivariable logistic regression., Results: The study included 1.1 million patients (mean age 69.5±12.0 years). A majority had an in-office laser surgery (71.9%), while 16.2% had microinvasive glaucoma surgeries (MIGS), 6.5% had a trabeculectomy or tube (traditional), and 4.6% had other glaucoma surgeries. Pre-operative gonioscopy was identified in 64.7% of patients, and 85.0% of those were within 1 year of the index event.In multivariable models, Asian (OR 1.16, 95%CI 1.13-1.18, P <0.001) and Black (OR 1.13, 95%CI 1.12-1.15, P <0.001) racial and ethnic groups were associated with higher odds of gonioscopy compared to White groups. When compared to traditional surgery, MIGS were associated with lower utilization (OR 0.69, 95%CI 0.68-0.71, P <0.001), but in-clinic laser surgeries were not ( P =0.231). Glaucoma subspecialists were more likely to perform pre-operative gonioscopy compared to non-glaucoma subspecialists (OR 2.65, 95%CI 2.62-2.69, P <0.001)., Conclusions: Pre-operative gonioscopy use and/or coding is lower than expected, given current guidelines. Among glaucoma procedures, ab interno MIGS were associated with lower pre-operative gonioscopy utilization., Competing Interests: Additional Declarations: The authors declare no competing interests.

Purpose: To describe effects of sustained-release steroid delivery devices on intraocular pressure (IOP) in eyes with glaucoma drainage devices (GDD)., Methods: Retrospective case series of eyes with steroid implants (dexamethasone or fluocinolone acetonide) and prior GDD (Ahmed, Baerveldt) without uveitis. Outcomes included IOP, IOP rise, central foveal thickness (CFT), and IOP medications., Results: We included 14 eyes (14 patients, 38% male, 94% pseudophakic). Mean age at steroid implantation was 64 ± 12 years. Baerveldt (64%) was more common than Ahmed (36%). Tubes were in the anterior chamber (57.1%), sulcus (28.6%), and pars plana (14.3%). Ozurdex (93%) was more common than Yutiq (7%). Mean IOP was 13.5 ± 3.4 mmHg pre-implant, 11.8 ± 3.7 mmHg at month 1, 13.3 ± 3.6 mmHg at month 3 (p=0.35), and 11.3 ± 3.8 mmHg at 1 year (p=0.032). Mean antihypertensive medications was unchanged at month 3 (p = 1.0), and -0.36 medications at last follow-up (p = 0.35). Mean CFT change was -204 ± 158 μm (p = 0.001). There were no cases of endophthalmitis., Conclusions: Intravitreal steroid implants were safe and effective for the treatment of post-surgical CME in patients with pre-existing GDD. There was no increase in IOP and no increase in antihypertensive drops.

Neurotransmitter release is triggered in microseconds by Ca 2+ -binding to the Synaptotagmin-1 C 2 -domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca 2+ -sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 C 2 B domain to SNARE complexes through a "primary interface" comprising two regions (I and II). The Synaptotagmin-1 Ca 2+ -binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers, or helping bridge the membranes, but SNARE complex binding through the primary interface orients the Ca 2+ -binding loops away from the fusion site, hindering these putative activities. To clarify this paradox, we have used NMR and fluorescence spectroscopy. NMR experiments reveal that binding of C 2 B domain arginines to SNARE acidic residues at region II remains after disruption of region I, and that a mutation that impairs spontaneous and Ca 2+ -triggered neurotransmitter release enhances binding through region I. Moreover, fluorescence assays show that Ca 2+ does not induce dissociation of Synaptotagmin-1 from membrane-anchored SNARE complex but causes reorientation of the C 2 B domain. Based on these results and electrophysiological data described by Toulme et al. (https://doi.org/10.1073/pnas.2409636121), we propose that upon Ca 2+ binding the Synaptotagmin-1 C 2 B domain reorients on the membrane and dissociates from the SNAREs at region I but not region II, acting remotely as a lever that pulls the SNARE complex and facilitates linker zippering or other SNARE structural changes required for fast membrane fusion., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: NDR1/HIN1-like (NHL) genes play crucial roles in Psa resistance. Kiwifruit canker, caused by Pseudomonas syringae pv. Actinidiae (Psa) infection is one of the most serious diseases affecting the kiwifruit industry. However, the key NHL has not yet been identified in kiwifruit., Results: In this study, we conducted a genome-wide identification of NHL family in kiwifruit (Actinidia eriantha). A total of 33 AeNHLs were divided into five domain-conserved subfamilies, which were mainly assigned into phytohormones and defense responses. The expression of AeNHL genes was analyzed to identify key genes in response to Psa, and we found AeNHL17 was highly expressed upon Psa inoculation. Transgenic tobacco overexpressing AeNHL17 presented higher resistance to Psa than wild-type (WT) tobacco, implying a key role for AeNHL17 in Psa resistance. Finally, we carried out a stable genetic transformation of kiwifruit (A. chinensis), which is sensitive to Psa, and found that the overexpression of AeNHL17 increased resistance to infection. AeNHL17-silenced plants exhibited larger disease lesions than control plants., Conclusions: Our findings revealed the function of AaNHL17 in Psa resistance, providing new data regarding the functional analysis of the NHL gene family in kiwifruit., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Aims: This study applied exercise stress echocardiography (ESE) to identify risk factors associated with exercise intolerance in patients with chronic coronary syndrome (CCS)., Methods and Results: 90 CCS patients underwent a cardiopulmonary exercise test and ESE, assessing exercise capacity, left ventricular systolic and diastolic function, and systolic reserve. The patients were divided into two groups according to the percentage of predicted oxygen consumption (VO 2 ) at peak (≥85%, normal exercise tolerance group; <85%, exercise intolerant group). The left ventricular ejection fraction, average mitral valve S', and left ventricular global longitudinal strain were lower in the exercise intolerant group than in the normal group, but no significant differences were observed in myocardial work parameters at rest. The average mitral valve E/e', EDVi/E/e', and proportion of abnormal diastolic function at the peak were higher in the exercise intolerant group than in the normal group. Moreover, the Δ SVi and flow reserve were lower, but the Δ average mitral valve E/e' was higher in the exercise-intolerant group. From univariate and multivariate logistic regression analysis, only peak EDVi/E/e' and Δ SVi correlated independently with exercise intolerance in CCS patients. With cutoff values of 8.64 ml/m 2 for peak EDVi/E/e' and 12.17 ml/m 2 for Δ SVi, the combination of these factors had an area under the receiver operating characteristic curve of 0.906 (95% confidence interval, 0.820-0.960) for the prediction of exercise intolerance in CCS patients., Conclusion: Hemodynamic changes during exercise in CCS patients were effectively evaluated using ESE. An elevated peak EDVi/E/e' and a decreased Δ SVi are independent risk factors for exercise intolerance in patients with CCS., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could potentially create a conflict of interest., (© 2024 Zhu, Tian, Guo, Lin, Cai, Qin, Ding and Lv.)

Objective: To investigate the clinical characteristics of heterotopic cervical pregnancy (HCP). Methods: A retrospective analysis was conducted based on the general clinical data, assisted reproductive technology (ART) data, diagnosis and treatment data, and pregnancy outcomes of 17 patients diagnosed with HCP who received ART at the Reproductive Medicine Center of Peking University Third Hospital from January 2011 to April 2022. Results: The age of 17 HCP patients was (34.2±1.5) years, all of whom occurred after the application of ART; Among them, 11 cases had a history of uterine cavity operation. All 17 patients had vaginal bleeding, with only 1 case accompanied by abdominal pain. The gestational age at the diagnosis of HCP was [6 +2 (5 +2 -6 +4 )] weeks. Two patients underwent conservative observation and were closely followed up. Both of them had intrauterine pregnancy until full-term and underwent cesarean section; One patient underwent ultrasound-guided cervical pregnancy reduction surgery, resulting in miscarriage due to premature rupture of membranes at 18 +1 weeks of intrauterine pregnancy; One patient underwent ultrasound-guided cervical pregnancy reduction surgery, followed by uterine artery embolization, hysteroscopy, removal of cervical pregnancy lesions, and curettage due to excessive bleeding; One patient underwent uterine artery embolization, hysteroscopy, cervical pregnancy lesion clearance, and curettage due to excessive vaginal bleeding; One patient underwent hysteroscopy examination, cervical pregnancy lesion removal surgery, and uterine curettage due to embryo arrest during intrauterine pregnancy; 11 cases underwent ultrasound-guided cervical pregnancy lesion clearance surgery, all of which resulted in live births. Among the 13 delivery patients, 4 cases were premature and 9 cases were full-term; 5 cases of vaginal delivery and 8 cases of cesarean section. Conclusions: The most common clinical manifestation of HCP is vaginal bleeding. Ultrasound guided cervical pregnancy lesion clearance surgery is safe and feasible, and with good pregnancy outcomes.

Background: Helicobacter pylori (HP), the most common pathogenic microorganism in the stomach, can induce inflammatory reactions in the gastric mucosa, causing chronic gastritis and even gastric cancer. HP infection affects over 4.4 billion people globally, with a worldwide infection rate of up to 50%. The multidrug resistance of HP poses a serious challenge to eradication. It has been de-monstrated that compared to bismuth quadruple therapy, Qingre Huashi decoction (QHD) combined with triple therapy exhibits comparable eradication rates but with a lower incidence of adverse reactions; in addition, QHD can directly inhibit and kill HP in vitro., Aim: To explore the effect and mechanism of QHD on clinically multidrug-resistant and strong biofilm-forming HP., Methods: In this study, 12 HP strains were isolated in vitro after biopsy during gastroscopy of HP-infected patients. In vitro , the minimum inhibitory concentration (MIC) values for clinical HP strains and biofilm quantification were determined through the E-test method and crystal violet staining, respectively. The most robust biofilm-forming strain of HP was selected, and QHD was evaluated for its inhibitory and bactericidal effects on the strain with strong biofilm formation. This assessment was performed using agar dilution, E-test, killing dynamics, and transmission electron microscopy (TEM). The study also explored the impact of QHD on antibiotic resistance in these HP strains with strong biofilm formation. Crystalline violet method, scanning electron microscopy, laser confocal scanning microscopy, and (p)ppGpp chromatographic identification were employed to evaluate the effect of QHD on biofilm in strong biofilm-forming HP strains. The effect of QHD on biofilm and efflux pump-related gene expression was evaluated by quantitative polymerase chain reaction. Non-targeted metabolomics with UHPLC-MS/MS was used to identify potential metabolic pathways and biomarkers which were different between the NC and QHD groups., Results: HP could form biofilms of different degrees in vitro , and the intensity of formation was associated with the drug resistance of the strain. QHD had strong bacteriostatic and bactericidal effects on HP, with MICs of 32-64 mg/mL. QHD could inhibit the biofilm formation of the strong biofilm-forming HP strains, disrupt the biofilm structure, lower the accumulation of (p)ppGpp, decrease the expression of biofilm-related genes including LuxS , Spot , glup (HP1174), NapA , and CagE , and reduce the expression of efflux pump-related genes such as HP0605, HP0971, HP1327 , and HP1489 . Based on metabolomic analysis, QHD induced oxidative stress in HP, enhanced metabolism, and potentially inhibited relevant signaling pathways by upregulating adenosine monophosphate (AMP), thereby affecting HP growth, metabolism, and protein synthesis., Conclusion: QHD exerts bacteriostatic and bactericidal effects on HP, and reduces HP drug resistance by inhibiting HP biofilm formation, destroying its biofilm structure, inhibiting the expression of biofilm-related genes and efflux pump-related genes, enhancing HP metabolism, and activating AMP in HP., Competing Interests: Conflict-of-interest statement: All the authors declare that they have no competing interest to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Neurotransmitter release is triggered in microseconds by Ca 2+ -binding to the Synaptotagmin-1 C 2 domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca 2+ -sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 C 2 B domain to SNARE complexes through a 'primary interface' comprising two regions (I and II). The Synaptotagmin-1 Ca 2+ -binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers or helping bridge the membranes, but SNARE complex binding orients the Ca 2+ -binding loops away from the fusion site, hindering these putative activities. Molecular dynamics simulations now suggest that Synaptotagmin-1 C 2 domains near the site of fusion hinder SNARE action, providing an explanation for this paradox and arguing against previous models of Sytnaptotagmin-1 action. NMR experiments reveal that binding of C 2 B domain arginines to SNARE acidic residues at region II remains after disruption of region I. These results and fluorescence resonance energy transfer assays, together with previous data, suggest that Ca 2+ causes reorientation of the C 2 B domain on the membrane and dissociation from the SNAREs at region I but not region II. Based on these results and molecular modeling, we propose that Synaptotagmin-1 acts as a lever that pulls the SNARE complex when Ca 2+ causes reorientation of the C 2 B domain, facilitating linker zippering and fast membrane fusion. This hypothesis is supported by the electrophysiological data described in the accompanying paper., Competing Interests: Declaration of interests The authors declare no competing interests.

Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

The SNAP receptor (SNARE) proteins syntaxin-1, SNAP-25, and synaptobrevin mediate neurotransmitter release by forming tight SNARE complexes that fuse synaptic vesicles with the plasma membranes in microseconds. Membrane fusion is generally explained by the action of proteins on macroscopic membrane properties such as curvature, elastic modulus, and tension, and a widespread model envisions that the SNARE motifs, juxtamembrane linkers, and C-terminal transmembrane regions of synaptobrevin and syntaxin-1 form continuous helices that act mechanically as semirigid rods, squeezing the membranes together as they assemble ("zipper") from the N to the C termini. However, the mechanism underlying fast SNARE-induced membrane fusion remains unknown. We have used all-atom molecular dynamics simulations to investigate this mechanism. Our results need to be interpreted with caution because of the limited number and length of the simulations, but they suggest a model of membrane fusion that has a natural physicochemical basis, emphasizes local molecular events over general membrane properties, and explains extensive experimental data. In this model, the central event that initiates fast (microsecond scale) membrane fusion occurs when the SNARE helices zipper into the juxtamembrane linkers which, together with the adjacent transmembrane regions, promote encounters of acyl chains from both bilayers at the polar interface. The resulting hydrophobic nucleus rapidly expands into stalk-like structures that gradually progress to form a fusion pore, aided by the SNARE transmembrane regions and without clearly discernible intermediates. The propensity of polyunsaturated lipids to participate in encounters that initiate fusion suggests that these lipids may be important for the high speed of neurotransmitter release., Competing Interests: Competing interests statement:The authors declare no competing interest.

Competing Interests: The authors declare that they have no conflicts of interest to disclose.

Protein fibril self-assembly is a universal transition implicated in neurodegenerative diseases. Although fibril structure/growth are well characterized, fibril nucleation is poorly understood. Here, we use a computational-experimental approach to resolve fibril nucleation. We show that monomer hairpin content quantified from molecular dynamics simulations is predictive of experimental fibril formation kinetics across a tau motif mutant library. Hairpin trimers are predicted to be fibril transition states; one hairpin spontaneously converts into the cross-beta conformation, templating subsequent fibril growth. We designed a disulfide-linked dimer mimicking the transition state that catalyzes fibril formation, measured by ThT fluorescence and TEM, of wild-type motif - which does not normally fibrillize. A dimer compatible with extended conformations but not the transition-state fails to nucleate fibril at any concentration. Tau repeat domain simulations show how long-range interactions sequester this motif in a mutation-dependent manner. This work implies that different fibril morphologies could arise from disease-dependent hairpin seeding from different loci., (© 2024. The Author(s).)

In 2017, four independent publications described the glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as receptor for the growth differentiation factor 15 (GDF15, also MIC-1, NAG-1) with an expression exclusively in the mice brainstem area postrema (AP) and nucleus tractus solitarii (NTS) where it mediates effects of GDF15 on reduction of food intake and body weight. GDF15 is a cell stress cytokine with a widespread expression and pleiotropic effects, which both seem to be in contrast to the reported highly specialized localization of its receptor. This discrepancy prompts us to re-evaluate the expression pattern of GFRAL in the brain and peripheral tissues of mice. In this detailed immunohistochemical study, we provide evidence for a more widespread distribution of this receptor. Apart from the AP/NTS region, GFRAL-immunoreactivity was found in the prefrontal cortex, hippocampus, nucleus arcuatus and peripheral tissues including liver, small intestine, fat, kidney and muscle tissues. This widespread receptor expression, not taken into consideration so far, may explain the multiple effects of GDF-15 that are not yet assigned to GFRAL. Furthermore, our results could be relevant for the development of novel pharmacological therapies for physical and mental disorders related to body image and food intake, such as eating disorders, cachexia and obesity.

To automate the discovery of new scientific and engineering principles, artificial intelligence must distill explicit rules from experimental data. This has proven difficult because existing methods typically search through the enormous space of possible functions. Here we introduce deep distilling, a machine learning method that does not perform searches but instead learns from data using symbolic essence neural networks and then losslessly condenses the network parameters into a concise algorithm written in computer code. This distilled code, which can contain loops and nested logic, is equivalent to the neural network but is human-comprehensible and orders-of-magnitude more compact. On arithmetic, vision and optimization tasks, the distilled code is capable of out-of-distribution systematic generalization to solve cases orders-of-magnitude larger and more complex than the training data. The distilled algorithms can sometimes outperform human-designed algorithms, demonstrating that deep distilling is able to discover generalizable principles complementary to human expertise., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To investigate the clinical characteristics, treatments and fertility recovery of rudimentary horn pregnancy (RHP). Methods: The clinical data of 12 cases with RHP diagnosed and treated in Peking University Third Hospital from January 1, 2010 to December 31, 2022 were retrospectively analyzed. Clinical informations, diagnosis and treatments of RHP and the pregnancy status after surgery were analyzed. Results: The median age of 12 RHP patients was 29 years (range: 24-37 years). Eight cases of pregnancy in residual horn of uterus occurred in type Ⅰ residual horn of uterus, 4 cases occurred in type Ⅱ residual horn of uterus; among which 5 cases were misdiagnosed by ultrasound before surgery. All patients underwent excision of residual horn of uterus and affected salpingectomy. After surgery, 9 patients expected future pregnancy, and 3 cases of natural pregnancy, 2 cases of successful pregnancy through assisted reproductive technology. Four pregnancies resulted in live birth with cesarean section, and 1 case resulted in spontaneous abortion during the first trimester of pregnancy. No uterine rupture or ectopic pregnancy occurred in subsequent pregnancies. Conclusions: Ultrasonography could aid early diagnosis of RHP while misdiagnosis occurred in certain cases. Thus, a comprehensive judgment and decision ought to be made based on medical history, physical examination and assisted examination. Surgical exploration is necessary for diagnosis and treatment of RHP. For infertile patients, assisted reproductive technology should be applied when necessary. Caution to prevent the occurrence of pregnancy complications such as uterine rupture, and application of cesarean section to terminate pregnancy are recommended.

Chinese patent medicine preparations containing Epimedii Folium and Psoraleae Fructus have been associated with the occurrence of idiosyncratic drug-induced liver injury(IDILI). However, the specific toxic biomarkers and mechanisms underlying these effects remain unclear. This study aimed to comprehensively assess the impact of bavachin and epimedin B, two principal consti-tuents found in Psoraleae Fructus and Epimedii Folium, on an IDILI model induced by tumor necrosis factor-α(TNF-α) treatment, both in vitro and in vivo. To evaluate the extent of liver injury, various parameters were assessed. Lactate dehydrogenase(LDH) release in the cell culture supernatant, as well as the levels of alanine aminotransferase(ALT) and aspartate transaminase(AST) in mouse plasma were measured. Additionally, histological analysis employing hematoxylin-eosin staining was performed to observe liver tissue changes indicative of the severity of liver injury. Furthermore, a pseudo-targeted metabolomics approach was employed, followed by multivariate analysis, to identify differential metabolites. These identified metabolites were subsequently subjected to Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis. The results showed that at the cellular level, after 2 hours of TNF-α stimulation, bavachin significantly increased the release of LDH in HepG2 cells compared to the normal group and the group treated alone; after the combination of bavachin and epimedin B, the release of LDH further significantly increased on the original basis. Similarly, although the individual or combination treatments of bavachin and epimedin B did not induce liver injury in normal mice, the combination of both drugs induced marked liver injury in TNF-α treated mice, leading to a significant elevation in plasma AST and ALT levels and substantial infiltration of inflammatory immune cells in the liver tissue. Pseudo-targeted metabolomics analysis identified seven common differential metabolites. Among these, D-glucosamine-6-phosphate, N1-methyl-2-pyridone-5-carboxamide, 17beta-nitro-5a-androstane, irisolidone-7-O-glucuronide, and N-(1-deoxy-1-fructosyl) valine emerged as potential biomarkers, with an area under the curve(AUC) exceeding 0.9. Furthermore, our results suggest that the metabolism of nicotinic acid and nicotinamide, as well as the linoleic acid metabolic pathway, may play pivotal roles in bavachin and epimedin B-induced IDILI. In conclusion, within an immune-stressed environment mediated by TNF-α, bavachin and epimedin B appear to induce IDILI through disruptions in metabolic processes.

In July 2022, the World Health Organization announced monkeypox as a public health emergency of international concern (PHEIC), and over 85,000 global cases have been reported currently. However, preventive and therapeutic treatments for the monkeypox virus (MPXV) remain limited. MPXV mRNA cap N7 methyltransferase (MTase) is composed of two subunits (E1 C-terminal domain (E1 CTD ) and E12) which are essential for the replication of MPXV. Here, we solved a 2.16 Å crystal structure of E12. We also docked the D1 CTD of the vaccinia virus (VACV) corresponding to the E1 CTD in MPXV with E12 and found critical residues at their interface. These residues were further used for drug screening. After virtual screening, the top 347 compounds were screened out and a list of top 20 potential MPXV E12 inhibitors were discovered, including Rutin, Quercitrin, Epigallocatechin, Rosuvastatin, 5-hydroxy-L-Tryptophan, and Deferasirox, etc., which were potential E12 inhibitors. Taking the advantage of the previously unrecognized special structure of MPXV MTase composing of E1 CTD and E12 heterodimer, we screened for inhibitors targeting MTase for the first time based on the interface between the heterodimer of MPXV MTase. Our study may provide insights into the development of anti-MPXV drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The aims of the study were first to explore the adaptive leisure activities of classified nursing model from the perspective of nurse-patient interactive care, and to explore its impact on the physical and mental health of patients with colon cancer., Methods: From September 2017 to March 2022 as the observation time node, 82 patients with colon cancer who met the established inclusion and exclusion criteria were regarded as the research objects through the random number table as the grouping tool. The two groups of patients were named as the research group and the control group, with 41 patients in each group. The control group implemented routine nursing measures, and the research group implemented classified nursing mode and adaptive leisure activity mode. The two groups of patients received 4 weeks of nursing intervention. With the help of self-rating anxiety scale, self-rating depression scale, self-care ability evaluation scale and health status survey brief form, the two groups of patients were compared before intervention and at the end of the 4th week after intervention., Results: After the intervention, the anxiety score (t = 6.656, p < 0.001) and depression score (t = 4.851, p < 0.001) of the research group were lower than those of the control group, and the difference was statistically significant. After the intervention, the self-concept (t = 4.845, p < 0.001), self-responsibility (t = 6.071, p < 0.001), self-care skills (t = 3.341, p < 0.001), health knowledge (t = 3.698, p < 0.001) and total score (t = 9.246, p < 0.001) of the research group were higher than those of the control group, and the difference was statistically significant. After the intervention, physical functioning (t = 8.141, p < 0.001), bodily pain (t = 6.083, p < 0.001), general health (t = 9.424, p < 0.001), role-physical (t = 8.057, p < 0.001), role-emotional (t = 13.252, p < 0.001), mental health (t = 12.565, p < 0.001), social functioning (t = 10.813, p < 0.001) and vitality score (t = 12.890, p < 0.001) of the research group were higher than those of the control group, with significant differences., Conclusion: Interactive care through adaptive leisure nursing improves mental well-being, self-management, and psychosocial functioning in elderly colon cancer patients, promoting overall health., (© 2023. The Author(s).)

Between January 2015 and October 2022, 38 patients with culture-confirmed melioidosis were identified in the Kowloon West (KW) Region, Hong Kong. Notably, 30 of them were clustered in the Sham Shui Po (SSP) district, which covers an estimated area of 2.5 km 2 . Between August and October 2022, 18 patients were identified in this district after heavy rainfall and typhoons. The sudden upsurge in cases prompted an environmental investigation, which involved collecting 20 air samples and 72 soil samples from residential areas near the patients. A viable isolate of Burkholderia pseudomallei was obtained from an air sample collected at a building site five days after a typhoon. B. pseudomallei DNA was also detected in 21 soil samples collected from the building site and adjacent gardening areas using full-length 16S rRNA gene sequencing, suggesting that B. psuedomallei is widely distributed in the soil environment surrounding the district. Core genome-multilocus sequence typing showed that the air sample isolate was phylogenetically clustered with the outbreak isolates in KW Region. Multispectral satellite imagery revealed a continuous reduction in vegetation region in SSP district by 162,255 m 2 from 2016 to 2022, supporting the hypothesis of inhalation of aerosols from the contaminated soil as the transmission route of melioidosis during extreme weather events. This is because the bacteria in unvegetated soil are more easily spread by winds. In consistent with inhalational melioidosis, 24 (63.2%) patients had pneumonia. Clinicians should be aware of melioidosis during typhoon season and initiate appropriate investigation and treatment for patients with compatible symptoms.

Prcis: Participant surveys taken after using tablet-based and smart visual function analyzer (SVFA) perimetry tests suggest that patients may prefer novel perimetry tests over traditional visual field machines., Purpose: Compare patient experience using the IMOvifa SVFA and the tablet-based Melbourne Rapid Fields visual field (VF) tests to the Humphrey Field 24-2 Swedish Interactive Threshold Algorithm Standard., Patients and Methods: Prospective observational cohort study on adult participants with diagnoses of glaucoma suspect, ocular hypertension, or glaucoma. Participants attended 2 study visits ~3 months apart. During the first visit, participants were trained to use the 2 novel perimeters, took 1 test on both new devices and the Humphrey Field Analyzer, then were surveyed. Participants received tablets and performed weekly tablet VF tests at home between study visits. At the final study visit, participants re-took the VF tests and completed the same surveys., Results: Eighty-one participants were surveyed twice. At the baseline survey, participants preferred the SVFA (71.7%) and tablet tests (69.2%) over the Humphrey VF. Most were willing to perform weekly monitoring at home on the SVFA (69.1%) and tablet (75.4%). Participants generally had a "very good" overall experience when testing on the SVFA (71.6%) and tablet (90.1%). At the final visit, fewer participants were willing to test on the tablet daily (23.5% to 9.9%; P = 0.02 for change) and more were willing to test monthly (18.5% to 33.3%; P = 0.03 for change)., Conclusion: Users reported a preference for novel VF devices. Overall participant experience using these devices was positive, supporting the feasibility of home monitoring of VFs from an experience perspective., Competing Interests: Disclosure: D.S.F. receives research support from Genentech Inc. and has received speaking honoraria and travel expenses from Thea Pharmaceuticals. D.S.C. is employed by Genentech Inc. T.E. receives research support from Genentech Inc. The remaining authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Allostery, the transfer of information between distant parts of a macromolecule, is a fundamental feature of protein function and regulation. However, allosteric mechanisms are usually not explained by protein structure, requiring information on correlated fluctuations uniquely accessible to molecular simulation. Existing work to extract allosteric pathways from molecular dynamics simulations has focused on thermodynamic correlations. Here, we show how kinetic correlations encode complementary information essential to explain observed variations in allosteric regulation. We applied kinetic and thermodynamic correlation analysis on atomistic simulations of H, K, and NRas isoforms in the apo, GTP, and GDP-bound states of Ras protein, with and without complexing to its downstream effector, Raf. We show that switch I and switch II are the primary components of thermodynamic and kinetic allosteric networks, consistent with the key roles of these two motifs. These networks connect the switches to an allosteric loop recently discovered from a crystal structure of HRas. This allosteric loop is inactive in KRas, but is coupled to the hydrolysis arm switch II in NRas and HRas. We find that the mechanism in the latter two isoforms are thermodynamic and kinetic, respectively. Binding of Raf-RBD further activates thermodynamic allostery in HRas and KRas but has limited effect on NRas. These results indicate that kinetic and thermodynamic correlations are both needed to explain protein function and allostery. These two distinct channels of allosteric regulation, and their combinatorial variability, may explain how subtle mutational differences can lead to diverse regulatory profiles among enzymatic proteins., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) restricts human immunodeficiency virus type 1 (HIV-1) infection by reducing the intracellular dNTP pool. We have shown that SAMHD1 suppresses nuclear factor kappa-B activation and type I interferon (IFN-I) induction by viral infection and inflammatory stimuli. However, the mechanism by which SAMHD1 inhibits IFN-I remains unclear. Here, we show that SAMHD1 inhibits IFN-I activation induced by the mitochondrial antiviral-signaling protein (MAVS). SAMHD1 interacted with MAVS and suppressed MAVS aggregation in response to Sendai virus infection in human monocytic THP-1 cells. This resulted in increased phosphorylation of TANK binding kinase 1 (TBK1), inhibitor of nuclear factor kappa-B kinase epsilon (IKKε), and IFN regulatory factor 3 (IRF3). SAMHD1 suppressed IFN-I activation induced by IKKε and prevented IRF7 binding to the kinase domain of IKKε. We found that SAMHD1 interaction with the inhibitory domain (ID) of IRF7 (IRF7-ID) was necessary and sufficient for SAMHD1 suppression of IRF7-mediated IFN-I activation in HEK293T cells. Computational docking and molecular dynamics simulations revealed possible binding sites between IRF7-ID and full-length SAMHD1. Individual substitution of F411, E416, or V460 in IRF7-ID significantly reduced IRF7 transactivation activity and SAMHD1 binding. Furthermore, we investigated the role of SAMHD1 inhibition of IRF7-mediated IFN-I induction during HIV-1 infection. We found that THP-1 cells lacking IRF7 expression had reduced HIV-1 infection and viral transcription compared to control cells, indicating a positive role of IRF7 in HIV-1 infection. Our findings suggest that SAMHD1 suppresses IFN-I induction through the MAVS, IKKε, and IRF7 signaling axis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Prcis: This retrospective case series of patients with open angle glaucoma and prior trabeculectomy or tube shunt surgery found that selective laser trabeculoplasty (SLT) resulted in significant intraocular pressure (IOP) reductions in the intermediate follow-up period in select cases., Purpose: The purpose of this study was to assess the IOP-lowering effect and tolerability of SLT after prior trabeculectomy or tube shunt surgery., Materials and Methods: Open angle glaucoma patients at Wills Eye Hospital who previously underwent incisional glaucoma surgery and subsequently received SLT between 2013 and 2018 were included, along with an age-matched control group. Baseline characteristics, procedural data, and post-SLT data were recorded at 1, 3, 6, 12 months, and most recent visit. The primary success of SLT treatment was defined as IOP reduction of 20% or greater without the use of additional glaucoma medications compared to pre-SLT IOP. Secondary success was defined as IOP reduction ≥20% with the use of additional glaucoma medications compared to pre-SLT IOP., Results: There were 45 eyes in the study group and 45 eyes in the control group. In the study group, IOP decreased from a baseline of 19.5±4.7 mm Hg on 2.2±1.2 medications to 16.7±5.2 mm Hg ( P =0.002) on 2.2±1.1 glaucoma medications ( P =0.57). In the control group, IOP decreased from 19.5±4.2 mm Hg on 2.4±1.0 medications to 16.4±5.2 mm Hg ( P =0.003) on 2.1±1.3 medications ( P =0.36). There was no difference in IOP reduction or change in number of glaucoma medications after SLT at any postoperative visit between the 2 groups ( P ≥0.12 for all). Primary success rates at 12 months were 24.4% for the control group and 26.7% for the prior incisional glaucoma surgery group with no significant difference between the groups ( P =0.92). There were no persistent complications after SLT treatment in either group., Conclusion: SLT may effectively lower IOP in patients with open angle glaucoma who have had previous incisional glaucoma surgery and should be considered in select cases., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Kazachstania aerobia and Kazachstania servazzii can affect wine aroma by increasing acetate ester concentrations, most remarkably phenylethyl acetate and isoamyl acetate. The genetic basis of this is unknown, there being little to no sequence data available on the genome architecture. We report for the first time the near-complete genome sequence of the two species using long-read (PacBio) sequencing ( K. aerobia 20 contigs, one scaffold; and K. servazzii 22 contigs, one scaffold). The annotated genomes of K. aerobia (12.5 Mb) and K. servazzii (12.3 Mb) were compared to Saccharomyces cerevisiae genomes (laboratory strain S288C and wine strain EC1118). Whilst a comparison of the two Kazachstania spp. genomes revealed few differences between them, divergence was evident in relation to the genes involved in ester biosynthesis, for which gene duplications or absences were apparent. The annotations of these genomes are valuable resources for future research into the evolutionary biology of Kazachstania and other yeast species (comparative genomics) as well as understanding the metabolic processes associated with alcoholic fermentation and the production of secondary 'aromatic' metabolites (transcriptomics, proteomics and metabolomics).

Proteins can aggregate into disordered aggregates or ordered assemblies such as amyloid fibrils. These two distinct phases serve differing roles in function and disease. How protein sequence determines the preferred phase is unknown. Here we establish a statistical mechanical disorder-to-order transition condition for compact polymer aggregates, including proteins. The theory produces a simple universal equation determining the favored phase as a function of temperature, polymer length, and interaction energy variance. We show that the sequence-dependent energy variance is efficiently calculated using atomistic simulations, so that the theory has no adjustable parameters. The equation accurately predicts experimental length-dependent crystallization temperatures of synthetic polymers. The equation also predicts that all protein sequences that aggregate will also favor ordering. Consequently, energy must be expended to maintain the steady-state disordered phase if it is not kinetically metastable on physiological timescales. More broadly, the theory suggests that aggregates of organic polymers will generally tend to order on habitable planets., (© 2022 Wiley Periodicals LLC.)