iTRAQ-based proteomic study on monocyte cell model discovered an association of LAMP2 downregulation with HIV-1 latency.

BACKGROUND: Patients with immunodeficiency virus-1 (HIV-1) infection are challenging to be cured completely due to the existence of HIV-1 latency reservoirs. However, the knowledge of the mechanisms and biomarkers associated with HIV-1 latency is limited. Therefore, identifying proteins related to HIV-1 latency could provide new insights into the underlying mechanisms of HIV-1 latency, and ultimately contribute to the eradication of HIV reservoirs. METHODS: An Isobaric Tags for Relative and Absolute Quantification (iTRAQ)-labeled subcellular proteomic study was performed on an HIV-1 latently infected cell model (U1, a HIV-1-integrated U937 cell line) and its control (U937). Differentially expressed proteins (DEPs) were analyzed using STRING-DB. Selected DEPs were further evaluated by western blotting and multiple reaction monitoring technology in both cell model and patient-derived cluster of differentiation 4 (CD4)+ T cells. Finally, we investigated the relationship between a specific DEP lysosome-associated membrane glycoprotein 2 (LAMP2) and HIV-1 reactivation by panobinostat or lysosome regulation by a lysosomotropic agent hydroxychloroquine in U1 and U937 cells. RESULTS: In total, 110 DEPs were identified in U1 cells comparing to U937 control cells. Bioinformatics analysis suggested associations of the altered proteins with the immune response and endosomal/lysosomal pathway. LAMP2, leukocyte surface antigen CD47, CD55, and ITGA6 were downregulated in HIV-1 latent cells. Downregulated LAMP2 was further confirmed in resting CD4+ T cells from patients with latent HIV-1 infection. Furthermore, both HIV-1 reactivation by panobinostat and stimulation with hydroxychloroquine upregulated LAMP2 expression. CONCLUSIONS: Our results indicated the involvement of the endosomal/lysosomal pathway in HIV-1 latency in macrophage cell model. The down-modulation of LAMP2 was associated with HIV latency, and the restoration of LAMP2 expression accompanied the transition of viral latency to active infection. This study provides new insights into the mechanism of HIV-1 latency and potential strategies for eradicating HIV-1 reservoirs by targeting LAMP2 expression.

Long-term trends and risk factors of tracheostomy and decannulation in patients with cervical spinal cord Injury.

STUDY DESIGN: Retrospective study. OBJECTIVES: To investigate the risk factors of tracheostomy and decannulation after cervical spinal cord injury (CSCI) and their epidemiological changes over the past 8 years in Beijing Bo'ai Hospital, China Rehabilitation Research Center (CRRC), China. SETTING: Beijing Bo'ai Hospital, CRRC. METHODS: We reviewed 8 years of patient data (2013.1.1 to 2020.12.31) at CRRC, focusing on those hospitalized and diagnosed with CSCI. We analyzed changes in demographic and clinical data's trends. Logistic regression analysis was used to determine factors impacting tracheostomy and decannulation. RESULTS: Finally, 1641 CSCI patients met the inclusion criteria. Over the past 8 years, the proportion of tracheostomized patients with CSCI was 16.3%, and the proportion of successfully decannulated of tracheostomized patients with TCSCI was 77.9%. We found that Traumatic (OR = 1.8, 95% CI = 1.06, 3.22; p = 0.046), Motor level of injury (C5-C8) (OR = 0.32, 95% CI = -1.91,-0.34; p = 0.005), AIS = A/B/C (OR = 22.7/11.1/4.2, 95% CI = 12.16,42.26/5.74,21.56/2.23,7.89; p < 0.001/p < 0.001/p < 0.001), age > 56 (OR = 1.6, 95% CI = 1.04, 2.32; p = 0.031) were the risk factors for tracheostomy. By analyzing the risk factors of decannulation failure in tracheostomized patients with TCSCI through multivariable logistic regression, statistically significant differences were found in age > 45 (OR = 4.1, 95% CI = 1.44, 11.81; p = 0.008), complete injury (OR = 2.7, 95% CI = 1.26, 5.95; p = 0.011), facet dislocation (OR = 2.8, 95% CI = 1.13,7.07; p = 0.027). CONCLUSIONS: Recent years have witnessed shifts in the epidemiological characteristics of CSCI. Identifying the factors influencing tracheostomy and decannulation in CSCI can aid in improving patient prognosis.

Effect of neuromuscular electrical stimulation in critically ill adults with mechanical ventilation: a systematic review and network meta-analysis.

BACKGROUND: Neuromuscular electrical stimulation (NMES) is widely used as a rehabilitation methods to restore muscle mass and function in prolonged immobilization individuals. However, its effect in mechanically ventilated patients to improve clinical outcomes remains unclear. METHODS: A comprehensive search was conducted using PubMed, Embase, Web of Science, PEDro, and the Cochrane Library from their inception until December 24th, 2023. The search targeted randomized controlled trials (RCTs) comparing NMES with physical therapy (PT) or usual ICU care (CG), for improving clinical outcomes in mechanically ventilated patients. We performed a network meta-analysis utilizing Stata version 14.0 and R 4.3.1. RESULTS: We included 23 RCTs comprising 1312 mechanically ventilated adults. The treatments analyzed were NMES, PT, NMES combined with PT (NMES+PT), and CG. Network meta-analyses revealed that NMES or NMES+PT significantly improved extubation success rate compared to CG, with ORs of 1.85 (95% CI: 1.11, 3.08) and 5.89 (95% CI: 1.77, 19.65), respectively. Additionally, NMES exhibited a slight decrease in extubation success rate compared with NMES+PT, with OR of 0.31 (95% CI: 0.11, 0.93). Nevertheless, neither NMES nor NMES+PT showed any significant improvement in ICU length of stay (LOS), ventilation duration, or mortality when compared with PT or CG. NMES+PT emerged as the most effective strategy for all considered clinical outcomes according to the ranking probabilities. The evidence quality ranged from "low" to "very low" in this network meta-analysis. CONCLUSIONS: NMES appears to be a straightforward and safe modality for critically ill, mechanically ventilated patients. When combined with PT, it significantly improved the extubation success rate against standard ICU care and NMES alone, and showed a better ranking over PT or NMES alone for clinical outcomes. Therefore, NMES combined with PT may be a superior rehabilitation strategy for this patient group.

Silencing geranylgeranyltransferase I inhibits the migration and invasion of salivary adenoid cystic carcinoma through RhoA/ROCK1/MLC signaling and suppresses proliferation through cell cycle regulation.

Geranylgeranyltransferase type I (GGTase-I) significantly affects Rho proteins, such that the malignant progression of several cancers may be induced. Nevertheless, the effect and underlying mechanism of GGTase-I in the malignant progression of salivary adenoid cystic carcinoma (SACC) remain unclear. This study primarily aimed to investigate the role and mechanism of GGTase-I in mediating the malignant progression of SACC. The level of GGTase-I gene in cells was stably knocked down by short hairpin RNA-EGFP-lentivirus. The effects of GGTase-I silencing on the migration, invasion, and spread of cells were examined, the messenger RNA levels of GGTase-I and RhoA genes of SACC cells after GGTase-I knockdown were determined, and the protein levels of RhoA and RhoA membrane of SACC cells were analyzed. Moreover, the potential underlying mechanism of silencing GGTase-I on the above-mentioned aspects in SACC cells was assessed by examining the protein expression of ROCK1, MLC, p-MLC, E-cadherin, Vimentin, MMP2, and MMP9. Furthermore, the underlying mechanism of SACC cells proliferation was investigated through the analysis of the expression of cyclinD1, MYC, E2F1, and p21CIP1/WAF1 . Besides, the change of RhoA level in SACC tissues compared with normal paracancer tissues was demonstrated through quantitative reverse-transcription polymerase chain reaction and western blot experiments. Next, the effect after GGTase-I silencing was assessed through the subcutaneous tumorigenicity assay. As indicated by the result of this study, the silencing of GGTase-I significantly reduced the malignant progression of tumors in vivo while decreasing the migration, invasion, and proliferation of SACC cells and RhoA membrane, Vimentin, ROCK1, p-MLC, MMP2, MMP9, MYC, E2F1, and CyclinD1 expression. However, the protein expression of E-cadherin and p21CIP1/WAF1 was notably upregulated. Subsequently, no significant transform of RhoA and MLC proteins was identified. Furthermore, RhoA expression in SACC tissues was significantly higher than that in paracancerous tissues. As revealed by the results of this study, GGTase-I shows a correlation with the proliferation of SACC through the regulation of cell cycle and may take on vital significance in the migration and invasion of SACC by regulating RhoA/ROCK1/MLC signaling pathway. GGTase-I is expected to serve as a novel exploration site of SACC.

Clear cell sarcoma in the post-molar area: Report of an ultra-rare case and literature review of oral clear cell sarcoma.

BACKGROUND: Clear cell sarcoma of soft tissue is an exceptionally rare sarcoma. It is even rarer in the oral cavity. To our knowledge, this case is the first reported clear cell sarcoma involving the post-molar area. Pathologically, clear cell sarcoma has low mitotic activity, rare nuclear pleomorphism, and necrosis. Its biological behavior is often underestimated by morphology. It is a highly aggressive tumor. CASE REPORT: A 39-year-old female presented with an asymptomatic mass in the post-molar area. It was mistaken for a benign or low-grade malignant tumor based on frozen incisional biopsy samples. The surgical resection sample was tested by NGS, which detected a rare EWSR1::CREB1 in clear cell sarcoma. The final diagnosis was made by combining morphological, immunohistochemical, and molecular test results. The patient did not receive any adjuvant therapy after surgery and no recurrence of the disease was detected at 8 months of follow-up. CONCLUSION: The study highlights that mild histological manifestation in the oral cavity should be considered the possibility of CCS affecting young patients. Careful histological investigation, sufficient immunohistochemical staining, and molecular tests are essential to the diagnosis.

Development of a prognostic model for anoikis and identifies hub genes in hepatocellular carcinoma.

Considering the high fatality of hepatocellular carcinoma (HCC), current prognostic systems are insufficient to accurately forecast HCC patients' outcomes. In our study, nine anoikis­related genes (PTRH2, ITGAV, ANXA5, BIRC5, BDNF, BSG, DAP3, SKP2, and EGF) were determined to establish a risk scoring model using LASSO regression, which could be validated in ICGC dataset. Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curve analysis confirmed the risk score possessed an accurate predictive value for the prognosis of HCC patients. The high-risk group showed a higher infiltration of aDCs, macrophages, T-follicular helper cells, and Th2 cells. Besides, PD-L1 was significantly higher in the high-risk group compared to the low-risk group. Several anoikis­related genes, such as ANX5, ITGAV, BDNF and SKP2, were associated with drug sensitivity in HCC. Finally, we identified BIRC5 and SKP2 as hub genes among the nine model genes using WGCNA analysis. BIRC5 and SKP2 were over-expressed in HCC tissues, and their over-expression was associated with poor prognosis, no matter in our cohort by immunohistochemical staining or in the TCGA cohort by mRNA-Seq. In our cohort, BIRC5 expression was highly associated with the T stage, pathologic stage, histologic grade and AFP of HCC patients. In general, our anoikis-related risk model can enhance the ability to predict the survival outcomes of HCC patients and provide a feasible therapeutic strategy for immunotherapy and drug resistance in HCC. BIRC5 and SKP2 are hub genes of anoikis­related genes in HCC.

Development and Validation of Prognostic Nomograms for Lung Squamous Cell Carcinoma With Brain Metastasis in Patients Aged 45 Years or Older: A Population-Based Study.

PURPOSE: We aimed to establish nomograms to predict the survival in patients aged ≥45  years with lung squamous cell carcinoma and brain metastasis. METHODS: We collected patients diagnosed as lung squamous cell carcinoma with brain metastasis aged ≥45 years between 2010 and 2019 from the Surveillance, Epidemiology, and End Results database. Prognostic factors were determined by the univariate and multivariate Cox regression analysis, and then the nomogram was constructed to predict cancer-specific survival and overall survival. Nomograms were evaluated by decision curve analysis, the area under the receiver operating characteristic curve, calibration plot, concordance index, and risk group stratification. RESULTS: In total, 2437 patients were included, with 1706 and 731 in the cohorts of training and validation, respectively. The age, N stage, T stage, liver metastasis, chemotherapy, bone metastasis, along with radiotherapy were significant in predicting the survival, and adopted for the establishment of nomograms. In the training and validation sets, the concordance index were .713(95%CI:0.699-.728) & .700(95%CI:0.677-.722) in predicting cancer-specific survival and .715(95%CI:0.701-.729) & .712(95%CI:0.690-.735) in predicting overall survival, respectively. Besides, the area under the receiver operating characteristic curve for predicting cancer-specific survival and overall survival in the training set were all >.7 at 1-, 2-, and 3- years. Calibration plots proved the survival predicted by nomograms were consistent with the actual values. decision curve analysis revealed better clinical validity of the nomogram in predicting cancer-specific survival and overall survival at 1-year than TNM staging. Patients were stratified into the high-/low-risk groups according to the optimal cutoff value of 100.21 for cancer-specific survival and 91.98 for overall survival. A web-based probability calculator was constructed finally. CONCLUSION: Two nomograms were developed for the prognostic prediction of lung squamous cell carcinoma patients with brain metastasis aged ≥45 years, providing guidance for decision-making in clinical practice.

M2e-specific antibodies protect against influenza PR8 virus in an isotype and route dependent manner.

The ectodomain of influenza matrix protein 2 (M2e) is a promising target for the development of universal prophylactic and therapeutic agents against influenza viruses of different subtypes. We constructed three M2e-specific monoclonal antibody variants, M2A1-1 (IgG1), M2A1-2a (IgG2a), M2A1-2b (IgG2b), which have the same Fab region targeting the M2e epitope but different isotypes, and compared their protective efficacy in influenza PR8-infected mice. We found that anti-M2e antibodies provided protection against influenza virus in a subtype-dependent manner, with the IgG2a variant providing significantly better protection with lower virus titers and milder lung injury than IgG1 and IgG2b isotypes. Additionally, we observed that the protective efficacy was dependent on the administration routes, with intranasal administration of antibody providing better protection than intraperitoneal administration. The timing of administration was also critical in determining the protective efficacy; while all the antibody isotypes provided protection when administered before influenza challenge, only IgG2a provided minimal protection when the antibodies were administered after virus challenge. These results provide valuable information for optimizing the therapeutics usage of M2e-based antibodies and furthering the development of M2e-based universal influenza vaccines.

Comparison of High Flow Nasal Therapy with Non-Invasive Ventilation and Conventional Oxygen Therapy for Acute Hypercapnic Respiratory Failure: A Meta-Analysis of Randomized Controlled Trials.

Purpose: We aimed to evaluate whether high flow nasal cannula (HFNC) is an effective and safe method for adult patients with acute hypercapnic respiratory failure (AHRF). Methods: We searched the Cochrane Library, Embase, and PubMed databases from inception to August 2022 to obtain randomized controlled trials (RCTs) that compared HFNC with conventional oxygen treatment (COT) or non-invasive ventilation (NIV) in patients with AHRF, and then performed a meta-analysis. Results: A total of ten parallel RCTs with 1265 individuals were identified. Of them, two studies compared HFNC with COT and eight studies compared HFNC with NIV. In terms of intubation rate, mortality, and arterial blood gas (ABG) improvement, HFNC showed comparable effects to NIV and COT. However, HFNC was more comfortable (mean difference [MD] -1.87, 95% confidence interval [CI] =-2.59, -1.15, P <0.00001, I2 =0%) and resulted in fewer adverse events (odds ratio [OR] 0.12, 95% CI=0.06, 0.28, P<0.00001, I2 = 0%), compared with NIV. In comparison to NIV, HFNC could significantly lower heart rate (HR) (MD -4.66, 95% CI=-6.82, -2.50, P <0.0001, I2 =0%), respiratory rate (RR) (MD -1.17, 95% CI=-2.03, -0.31, P =0.008, I2 =0%), and hospital stay length (MD -0.80, 95% CI=-1.44, -0.16, P =0.01, I2 =0%). NIV showed a decreased frequency in the treatment crossover rate, compared with HFNC in patients with pH<7.30 (OR 5.78, 95% CI=1.50, 22.31, P = 0.01, I2: not applicable). Contrary to COT, HFNC could considerably reduce the need for NIV (OR 0.57, 95% CI=0.35, 0.91, P=0.02, I2=0%). Conclusion: HFNC was effective and safe in patients with AHRF. However, in patients with pH <7.30, HFNC may result in a higher incidence of treatment crossover, compared with NIV. Compared to COT, HFNC may decrease the need for NIV in patients with compensated hypercapnia.

Development and validation of nomograms to predict early death in non-small cell lung cancer patients with brain metastasis: a retrospective study in the SEER database.

Background: Throughout the course of non-small cell lung cancer (NSCLC), a lot of patients would develop brain metastasis (BM) associated with the poor prognosis and high rate of mortality. However, there have been few models to predict early death (ED) from NSCLC patients with BM. We aimed to develop nomograms to predict ED in NSCLC patients with BM. Methods: The NSCLC patients with BM between 2010 and 2015 were selected from the Surveillance, Epidemiology, and End Result (SEER) database. Our inclusion criteria were as follows: (I) patients were pathologically diagnosed as NSCLC; (II) patients who suffered from BM. The patients were randomly divided into 2 cohorts at the ratio of 7:3, for training and validation cohorts, respectively. The univariate and multivariate logistic regression methods were managed to identify risk factors for ED in NSCLC patients with BM. Two nomograms were established and validated by calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). The follow-up data included survival months, causes of death, vital status. Death that occurred within 3 months of initial diagnosis is defined as ED and the endpoints were all-cause ED and cancer-specific ED. Results: A total of 4,920 NSCLC patients with BM were included and randomly divided into 2 cohorts (7:3), including the training (n=3,444) and validation (n=1,476) cohorts. The independent prognostic factors for all-cause ED and cancer-specific ED included age, sex, race, tumor size, histology, T stage, N stage, grade, surgical operation, radiotherapy, chemotherapy, bone metastasis, and liver metastasis. All these variables were used to establish the nomograms. In the nomograms of all-cause and cancer-specific ED, the areas under the ROC curves were 0.813 (95% CI: 0.799-0.837) and 0.808 (95% CI: 0.791-0.830) for the training dataset as well as 0.835 (95% CI: 0.805-0.862) and 0.824 (95% CI: 0.790-0.849) for the validation dataset, respectively. Besides, the calibration curves proved that the predicted ED was consistent with the actual value. DCA suggested a good clinical application. Conclusions: The nomograms can be used to predict the specific probability of a patient's death, which aids in treatment decisions and focused care, as well as in physician-patient communication.

Comparison of early and late postoperative outcomes between chordal reconstruction and quadrangular resection in patients with posterior mitral valve prolapse: a single-center retrospective study.

BACKGROUND: To compare the early and late postoperative outcomes of chordal reconstruction (CR) and quadrangular resection (QR) in patients with posterior mitral valve prolapse (PMPL). METHODS: Between January 2008 and December 2018, 305 patients with PMPL who underwent mitral valve plasty (MVP) were included in this retrospective analysis. The CR and QR procedures were performed in 169 patients (CR group) and 136 patients (QR group), respectively. Early and late postoperative outcomes were compared between the groups. RESULTS: Follow-up was complete in 96.4% (294/305) of patients, with a mean follow-up of 81.2 ± 30.4 months. No 30-day mortality was observed in any of the patients. The success rate of the mitral valve repair was similar in both groups (99.4% vs. 98.5%, P = 0.850). The incidence of early postoperative hemolysis was lower in the CR group than in the QR group (0.00% vs. 3.0%, P = 0.024). Postoperative left ventricular end-diastolic diameter (LVEDD) decreased more significantly in the CR group than in the QR group at 3 months (8.15 [1.30,12.65] vs. 3.25 [- 0.05, 8.75] mm, P < 0.001). During follow-up, the overall survival rates were 95.1% and 94.6% in the CR and QR groups, respectively. The incidence of reoperation for moderate or severe mitral regurgitation (MR) was similar in both groups (4.3% vs.5.4%, P = 0.653), but the time interval between the initial operation and reoperation was shorter in the QR group than in the CR group (84.3 ± 36.1 vs. 120.9 ± 27.6 months, P = 0.026). The LVEDD enlargement was more significant in the QR group than in the CR group (4.5 [3.6, 4.5] vs. 2.4 [1.3, 2.8] mm, P < 0.001). CONCLUSION: CR and QR are effective techniques for patients with PMPL. Both techniques resulted in a low incidence of recurrent MR. However, CR can reduce early postoperative hemolysis and LVEDD more significantly. During the long-term follow-up, reoperations due to recurrent MR were performed at a longer interval after the initial operation. LVEDD expansion was better avoided in the CR group.

Rare renal cell carcinoma with haemangioblastoma-like features and leiomyomatous stroma: report of a unique case with TSC2 and SETD2 variations.

BACKGROUND: Renal cell carcinoma (RCC) with haemangioblastoma-like characteristics is a type of RCC reported in recent years. RCC with (angio) leiomyomatous stroma (RCCLMS) was included as a provisional entity of the 2016 World Health Organization (WHO) classification. RCC with haemangioblastoma-like characteristics and leiomyomatous stroma is extremely rare. This is the first report of a rare tumour harbouring TSC2 and SETD2 variations. CASE PRESENTATION: The patient was a 38-year-old woman who presented with discomfort in the area of her right kidney. Ultrasound and enhanced CT showed a right renal mass, and clear cell renal cell carcinoma (CCRCC) was suspected; hence, robot-assisted laparoscopic nephron-sparing partial nephrectomy was performed. Gross examination revealed a well-circumscribed tumour measuring 2.0 cm × 1 cm × 0.7 cm under the renal capsule adjacent to the stripping edge that was greyish yellow and greyish red in colour. Histologic examination showed that the tumour consisted of three different structures: a CCRCC-like region, a haemangioblastoma-like region, and a focal leiomyomatous stroma component. Based on immunohistochemistry, the CCRCC-like region was diffusely strongly positive for AE1/AE3, vimentin, CAIX, PAX8, PAX2, CK7, and CAM5.2, partly positive for HNF1α, and negative for CD10, α-inhibin, NSE, S-100, CD34, and TFE3. The haemangioblastoma-like area was diffusely positive for vimentin, CAIX; partly positive for PAX8, PAX2, α-inhibin, and S-100; mostly positive for NSE; and slightly positive for HNF1α; the CD34 staining highlighted the complex capillary network. The Ki67 index was approximately 1-2% in the two above areas, and the leiomyomatous stroma was strongly positive for SMA. The whole-exon sequencing (WES) showed TSC2 and SETD2 variations. There was no progression after 18 months of follow-up. CONCLUSION: We report for the first time a unique case of RCC with haemangioblastoma-like features and leiomyomatous stroma accompanied by rare molecular abnormalities. Whether this is a new tumour entity or a variant of clear cell carcinoma remains to be determined. The biological behaviour and clinical characteristics need to be further examined.

Cervical cancer screening in high-altitude areas in China: A large cross-section study of 25,173 women in northern Tibet.

Background: Cervical cancer has become a worldwide concern owing to its high incidence and mortality rates. To date, high-altitude areas of Tibet have not benefited from any large-scale cervical cancer screening programs. Therefore, we initiated a screening program to investigate the prevalence of human papilloma virus (HPV) and HPV genotype distribution to reveal cervical cancer and its precursor which lead to morbidity among women in the city of Nagqu in northern Tib3et. Methods: A total of 25,173 women were recruited to undergo HPV genotype tests between June and December 2019. Women infected with HPV 16 and/or 18 underwent colposcopy and histological examination. Women with other high-risk HPV type (hr-HPV) underwent cytological tests to determine whether to conduct further colposcopy and histological examination for diagnosis. HPV prevalence was calculated in the total population and further stratified according to various parameters, such as age group, area location (altitude level), and single or mixed infection status. The HPV genotype distribution was also investigated accordingly. Cervical lesions revealed by further colposcopic findings were also analyzed; high-grade and malignant lesion morbidities were calculated in total and in each county. Most data were collected and analyzed using descriptive and consistency check statistical methods, and a risk factor investigation for HPV infection was performed using logistic regression models. Results: The total HPV infection rate among women in Nagqu was 13.42%. Of the 25,173 women in the study, 999 (3.97%) were HPV 16/18 positive, 2,379 (9.45%) were other hr-HPV-positive, and 21,795 (86.58%) were HPV-negative. The five most common HPV genotypes, accounting for more than 60% of all HPV infections in Nagqu people, were HPV 16, 58, 31, 18, and 52. Tibetan women younger than 20 years and older than 60 years were the two age groups with the highest rates of HPV infection, 26.7% and 19.8%, respectively. Among the HPV-positive women, 2,656 (78.33%) were infected with a single strain and 732 (21.67%) were infected with multiple strains (more than two genotypes). HPV prevalence increased in high-altitude areas (positive rate highest in Nyima with an altitude of 5,000 m, 23.9%) and decreased in relatively low-altitude areas (positive rate lowest in Lhari with an altitude of 4,000 m, 6.6%). Multiple analyses showed that age, parity, age at first delivery, and altitude of residence were independent factors facilitating HPV infection in Tibetan women. High-grade and malignant cervical lesions revealed by histological findings were different among living locations, with the highest rates in Xainza, Baingoin, and Nyainrong, these being 2.019%, 1.820%, and 1.116%, respectively, among women in these areas. Conclusion: Our survey provides an overall perspective on HPV genotype infection and cervical lesions in women in northern Tibet. The data not only provide useful information for the treatment of cervical lesions but also has great value in terms of the primary and secondary prevention measures that can be taken for women living in these regions. Clinical Trial Registration: www.chictr.org.cn, indentifier ChiCTR2000035061.

Diagnostic Value of Multimodal Magnetic Resonance Imaging in Discriminating Between Metastatic and Non-Metastatic Pelvic Lymph Nodes in Cervical Cancer.

Background: The status of pelvic lymph node (PLN) metastasis affects treatment and prognosis plans in patients with cervical cancer. However, it is hard to be diagnosed in clinical practice. Purpose: The present study aimed to evaluate the diagnostic value of multimodal magnetic resonance imaging (MRI) in discriminating between metastatic and non-metastatic pelvic lymph nodes (PLNs) in cervical cancer. Methods: This retrospective study analyzed MRIs of 209 PLNs in 25 women with pathologically proven cervical cancer. All PLNs had been assessed by pre-treatment multimodal MRIs, and their status was finally confirmed by histopathology. In conventional MRI, lymph node characteristics were compared between metastatic and non-metastatic PLNs. Signal intensity, time-intensity curve (TIC) patterns minimal and mean apparent diffusion coefficients (ADC) were compared between them in DWI. In DCE-MRI, quantitative (Ktrans, Kep and Ve) analyses were performed on DCE-MRI sequences, and their predictive values were analyzed by ROC curves. Results: Of 209 PLNs, 22 (10.53%) were metastases and 187 (89.47%) were non-metastases at histopathologic examination. Considering a comparison of lymph node characteristics, the short axis size, the long axis size, and the boundary differed significantly between the two groups (P<0.05).The differences in ADCmin, TIC types, Ktrans and Ve between metastatic and non-metastatic PLNs were significant as well (P<0.05). The good diagnostic performance of multimodal MRI was shown in discriminating between metastatic and non-metastatic PLNs, with the sensitivity of 85.0% (17/20), specificity of 97.3% (184/189), and accuracy of 96.2% (201/209). ROC analyses showed that the diagnostic accuracy of ADCmin, Ktrans and Ve for discriminating between metastatic and non-metastatic PLNs in cervical cancer was 83.7%, 91.4%, and 92.4% with the cut-off values of 0.72 × 10-3mm2/s, 0.52 min-1, and 0.53 min-1, respectively. Conclusion: Multimodal MRI showed good diagnostic performance in determining PLN status in cervical cancer.

Effects of Inspiratory Muscle Training and High-Intensity Interval Training on Lung Function and Respiratory Muscle Function in Asthma.

BACKGROUND: Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. Although inspiratory muscle training (IMT) and high-intensity interval training (HIIT) are beneficial for patients with asthma, controversies persist. Therefore, we aimed to investigate the effects of IMT and HIIT on lung function and respiratory muscle function of subjects with asthma. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library databases up to May 2021. Inclusion criteria were randomized controlled trials (RCTs) of subjects with asthma who received either IMT or HIIT. The outcome measures were changes in lung function and respiratory muscle function. RESULTS: A total of 13 RCTs (10 in IMT and 3 in HIIT) were included, with a total of 598 subjects. The meta-analysis showed a significantly improved FEV1 of the expected value (FEV1%pred) (mean difference [MD] 4.49% [95% CI 2.31-6.67], P < .001; I2 = 13%), FVC of the expected value (FVC % pred) (MD 5.72% [95% CI 3.56-7.88], P < .001; I2 = 0%), FEV1/FVC % (MD 5.01% [95% CI 2.45-7.58], P < .001; I2 = 25%), FVC (L) (MD 0.21 L [95% CI 0.03-0.40], P = .02; I2 = 0%), maximum inspiratory pressure (PImax) (MD 27.62 cm H2O [95% CI 6.50-48.74], P = .01; I2 = 96%), and PImax (%pred) (MD 27.35% [95% CI 6.94-47.76], P = .009; I2 = 83.5%) in the IMT group. There was no statistical significance in maximum expiratory pressure. CONCLUSIONS: IMT improved pulmonary function (FEV1%pred, FVC) and inspiratory muscle strength in subjects with stable asthma. Due to the small number of RCT studies included and the limited outcome measures involving HIIT, we were unable to draw conclusions about whether HIIT was beneficial in this meta-analysis. Moreover, clinical heterogeneity exists in different areas such as population and training programs; the above conclusions still need to be confirmed in future studies.

Effects of Tung Oil Composite Regenerating Agent on Rheological Properties and Microstructures of Reclaimed Asphalt Binder.

The single light oil regenerating agent has certain limitations on the performance recovery of aged asphalt. In this study, tung oil, dioctyl phthalate (DOP), C9 petroleum resin, and organic montmorillonite (OMMT) were used to prepare the composite regenerating agent, and its optimal mix proportion was determined by the orthogonal experimental design. The rheological properties and anti-aging performance of reclaimed asphalt were studied by the dynamic shear rheometer (DSR) and bending beam rheometer (BBR); and the Fourier transform infrared (FTIR) spectrometer, gel permeation chromatography (GPC), and scanning electron microscope (SEM) were adopted to explore its microstructure, morphology, and mechanism of action. The results show that with the addition of tung oil composite regenerating agent, the rheological properties of aged asphalt can be effectively recovered, even better than that of base asphalt. By using the complex modulus aging index (CMAI) and phase angle aging index (PMAI) it is found that the anti-aging performance of reclaimed asphalt is better than that of base asphalt. With the optimal content of the tung oil composite regenerating agent, the contents of characteristic functional groups and macromolecular asphaltenes in the aged asphalt can be reduced, indicating that the composite regenerating agent is beneficial to the dispersion and dissolution of polar substances in the aged asphalt. After aging, a large number of wrinkles appear on the surface of the asphalt. However, the addition of the tung oil composite regenerating agent can make the asphalt surface smooth, which indicates that the tung oil composite regenerating agent can restore the microstructure and morphology of aged asphalt to a certain extent.

Effect of exercise-based pulmonary rehabilitation in patients with bronchiectasis: A meta-analysis.

OBJECTIVE: We aimed to assess the effectiveness of exercise training in patients with bronchiectasis in terms of exercise capacity, pulmonary function, and quality of life. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) examining pulmonary rehabilitation to treat bronchiectasis, and the search timeline was from inception through November 2020. Two researchers independently screened the literature, extracted data, evaluated the risk of bias in the included studies, and used Review Manager 5.3 software to perform the meta-analysis. The primary outcomes were incremental shuttle walk distance (ISWD) and 6-minute walk distance (6-MWD) at 8 weeks. The secondary outcomes were forced expiratory volume in 1 second (FEV1), St. George's Respiratory Questionnaire (SGRQ) score, and Leicester Cough Questionnaire (LCQ) score at 8 weeks. RESULTS: A total of five RCTs with a total of 198 patients were included. A pooled analysis showed that improvements in ISWD (mean difference [MD] = 92.47 m, 95% confidence interval [CI] 49.87, 135.08; P < 0.0001), 6-MWD (MD = 31.01 m, 95% CI 1.60, 60.42; P = 0.04), and FEV1 (MD = 0.08 L, 95% CI 0.04, 0.12; P = 0.0002) in the pulmonary rehabilitation group were more marked than in the control group. There was no significant difference between the two groups in terms of the improvement in SGRQ and LCQ scores. CONCLUSIONS: Pulmonary rehabilitation improves exercise capacity and pulmonary function (specifically FEV1) in patients with bronchiectasis. However, due to limitations in the number and quality of current studies, the above conclusions need to be verified in future research.

Novel sarbecovirus bispecific neutralizing antibodies with exceptional breadth and potency against currently circulating SARS-CoV-2 variants and sarbecoviruses.

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) has aroused concerns over their increased infectivity and transmissibility, as well as decreased sensitivity to SARS-CoV-2-neutralizing antibodies (NAbs) and the current coronavirus disease 2019 (COVID-19) vaccines. Such exigencies call for the development of pan-sarbecovirus vaccines or inhibitors to combat the circulating SARS-CoV-2 NAb-escape variants and other sarbecoviruses. In this study, we isolated a broadly NAb against sarbecoviruses named GW01 from a donor who recovered from COVID-19. Cryo-EM structure and competition assay revealed that GW01 targets a highly conserved epitope in a wide spectrum of different sarbecoviruses. However, we found that GW01, the well-known sarbecovirus NAb S309, and the potent SARS-CoV-2 NAbs CC12.1 and REGN10989 only neutralize about 90% of the 56 tested currently circulating variants of SARS-CoV-2 including Omicron. Therefore, to improve efficacy, we engineered an IgG-like bispecific antibody GW01-REGN10989 (G9) consisting of single-chain antibody fragments (scFv) of GW01 and REGN10989. We found that G9 could neutralize 100% of NAb-escape mutants (23 out of 23), including Omicron variant, with a geometric mean (GM) 50% inhibitory concentration of 8.8 ng/mL. G9 showed prophylactic and therapeutic effects against SARS-CoV-2 infection of both the lung and brain in hACE2-transgenic mice. Site-directed mutagenesis analyses revealed that GW01 and REGN10989 bind to the receptor-binding domain in different epitopes and from different directions. Since G9 targets the epitopes for both GW01 and REGN10989, it was effective against variants with resistance to GW01 or REGN10989 alone and other NAb-escape variants. Therefore, this novel bispecific antibody, G9, is a strong candidate for the treatment and prevention of infection by SARS-CoV-2, NAb-escape variants, and other sarbecoviruses that may cause future emerging or re-emerging coronavirus diseases.