Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability.

While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here, we describe an immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N terminus of the ebolavirus glycoproteins (GPs) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails.

Efficacy and immunogenicity of AS04-HPV-16/18 vaccine in females with existing cervical HR-HPV infection at first vaccination: A pooled analysis of four large clinical trials worldwide.

Females with existing high-risk HPV (HR-HPV) infections remain at risk of subsequent multiple or recurrent infections, on which benefit from HPV vaccines was under-reported. We pooled individual-level data from four large-scale, RCTs of AS04-HPV-16/18 vaccine to evaluate efficacy and immunogenicity in females DNA-positive to any HR-HPV types at first vaccination. Females receiving the AS04-HPV-16/18 vaccine in the original RCTs constituted the vaccine group in the present study, while those unvaccinated served as the control group. Vaccine efficacy (VE) against new infections and associated cervical intraepithelial neoplasia (CIN) 2+ in females DNA-negative to the considered HR-HPV type but positive to any other HR-HPV types, VE against reinfections in females DNA-positive to the considered HR-HPV type but cleared naturally during later follow-up, and levels of anti-HPV-16/18 IgG were assessed. Our final analyses included 5137 females (vaccine group = 2532, control group = 2605). The median follow-up time was 47.88 months (IQR: 45.72-50.04). For the prevention of precancerous lesions related to the non-infected HR-HPV types at baseline, VE against HPV-16/18 related CIN 2+ was 82.70% (95% CI: 63.70-93.00%). For the prevention of reinfections related to the infected HR-HPV types following natural clearance, VE against HPV-16/18 12MPI was non-significant (p > .05), albeit robust immunity persisted for at least 48 months. Females with existing HR-HPV infections at first vaccination still benefit from vaccination in preventing precancers related to the non-infected types at baseline. VE against reinfections related to the infected types following natural clearance remains to be further investigated.

Comparative efficacy of energy-restricted dietary interventions in overweight and obese populations: A systematic review and network meta-analysis.

This meta-analysis compared the effectiveness of different energy-restricted diets on body composition, glucose metabolism, and lipid metabolism in overweight and obese populations. Five databases were searched to identify relevant studies in English from inception until July 20, 2023, for randomized controlled trials of at least 2 weeks duration assessing the effects of continuous energy-restricted diets compared with any intermittent energy-restricted diet in obesity adults. The risk of bias was assessed using the Cochrane Risk of Bias Tool version 2.0, while the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system was used to assess the certainty of the evidence. A non-informative prior distribution Bayesian network meta-analysis was conducted. Thirty-eight studies (3039 participants) assessing four energy-restricted diets were included. Three RCTs were at high risk of bias with a very low to moderate certainty of evidence. Combined with pairwise comparisons and surface under the cumulative ranking curve, alternate-day fasting may be the best energy restriction regimen with the potential to have the most beneficial effects on various aspects of the obesity population. More rigorously designed and long-term follow-up studies are warranted.

Cost-effectiveness of the screen-and-treat strategies using HPV test linked to thermal ablation for cervical cancer prevention in China: a modeling study.

BACKGROUND: Self-sampling HPV test and thermal ablation are effective tools to increase screening coverage and treatment compliance for accelerating cervical cancer elimination. We assessed the cost-effectiveness of their combined strategies to inform accessible, affordable, and acceptable cervical cancer prevention strategies. METHODS: We developed a hybrid model to evaluate costs, health outcomes, and incremental cost-effectiveness ratios (ICER) of six screen-and-treat strategies combining HPV testing (self-sampling or physician-sampling), triage modalities (HPV genotyping, colposcopy or none) and thermal ablation, from a societal perspective. A designated initial cohort of 100,000 females born in 2015 was considered. Strategies with an ICER less than the Chinese gross domestic product (GDP) per capita ($10,350) were considered highly cost-effective. RESULTS: Compared with current strategies in China (physician-HPV with genotype or cytology triage), all screen-and-treat strategies are cost-effective and self-HPV without triage is optimal with the most incremental quality-adjusted life-years (QALYs) gained (220 to 440) in rural and urban China. Each screen-and-treat strategy based on self-collected samples is cost-saving compared with current strategies (-$818,430 to -$3540) whereas more costs are incurred using physician-collected samples compared with current physician-HPV with genotype triage (+$20,840 to +$182,840). For screen-and-treat strategies without triage, more costs (+$9404 to +$380,217) would be invested in the screening and treatment of precancerous lesions rather than the cancer treatment compared with the current screening strategies. Notably, however, more than 81.6% of HPV-positive women would be overtreated. If triaged with HPV 7 types or HPV16/18 genotypes, 79.1% or 67.2% (respectively) of HPV-positive women would be overtreated with fewer cancer cases avoided (19 cases or 69 cases). CONCLUSIONS: Screen-and-treat strategy using self-sampling HPV test linked to thermal ablation could be the most cost-effective for cervical cancer prevention in China. Additional triage with quality-assured performance could reduce overtreatment and remains highly cost-effective compared with current strategies.

Clinical performance of a newly developed domestic urine-based HPV test for cervical cancer screening in China.

Although urine-based human papillomavirus (HPV) detection is promising in cervical cancer screening, it has not yet been well-developed. Women aged 30-65 were invited to participate in the current study to provide one urine and two paired vaginal samples. Urine was detected by polymerase chain reaction (PCR)-based HPV test (urine-based HPV test). Two vaginal samples were tested by careHPV and GenPlex® HPV genotyping assay, respectively. Women with vaginal HPV positive were called back for colposcopy and biopsied if clinically indicated. The consistency was 79.0% (κ = 0.563) and 80.5% (κ = 0.605) between the urine-based HPV test, careHPV test, and GenPlex® HPV genotyping assay. Against CIN2 detection, the careHPV test showed 77.4% sensitivity, and 71.0% specificity, while the GenPlex® HPV genotyping assay had a sensitivity of 100% and a specificity of 58.7%. For urine-based HPV test, the corresponding rates were 96.8% and 58.7%. Moreover, no significant differences were observed between the urine-based HPV test and careHPV test (p = 0.3395) and GenPlex® HPV genotyping assay (p = 0.338). The newly developed urine-based HPV test demonstrated acceptable consistency and comparable clinical performance with referenced HPV tests for vaginal samples. Therefore, urine-based HPV detection could be a useful alternative for women with difficulties to access cervical cancer screening.

Association between dietary phosphorus intake and chronic constipation in adults: evidence from the National Health and Nutrition Examination Survey.

BACKGROUND: Several studies suggest a link between micronutrients and constipation. However, the relationship between constipation and phosphorus has rarely been examined. The main aim of this study was to investigate the association between changes in the prevalence of chronic constipation and dietary phosphorus intake among adult respondents of the National Health and Nutritional Examination Survey (NHANES). METHODS: Data were extracted from the NHANES database for the years 2005-2010. A total of 13,948 people were included in the analysis. Dietary information was collected using the respondents' 24-h dietary records. We conducted multiple logistic regression analyses to examine the correlation between phosphorus intake and poor bowel movement. The primary and secondary outcomes was constipation defined by stool consistency and stool frequency, respectively. RESULTS: Following multi-variate adjustment in model III, a significant association between chronic constipation and each additional 0.1-g intake of dietary phosphorus (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.95, 1.00; P = 0.034 for stool consistency vs. OR, 0.94; 95% CI, 0.90, 0.99; P = 0.027 for stool frequency) was observed. Following multi-variate adjustment in model III, OR values and 95% CI from the second to fourth quartiles compared to the first quartile (reference group) were 0.92 (0.66, 1.27), 0.73 (0.47, 1.13), and 0.39 (0.20, 0.76), respectively, using the stool frequency definition. CONCLUSIONS: This study revealed a negative correlation between phosphorus intake and chronic constipation. This may be due to the fact that dietary phosphorus intake is associated with softer stools and increased stool frequency. Further studies in different settings should be considered to verify these findings.

Study on the Protective Effect of Platelet-Rich Plasma Combined with Injection of Pain Points Around Knee Joint on Knee Osteoarthritis and its Molecular Mechanism.

Objective: Previous studies showed the PRP have the therapeutic effects for KOA, but the more detail roles remained unclear and therefore this study was carried on to explore the deeper mechanisms for PRP. Methods: NRS and WOMAC scores were used to evaluate the clinical efficacy before surgery, 1 month and 6 months after surgery, and the postoperative joint structure changes (n = 24). Examination of pathology of the femoral condyle plate in rats using HE staining (n = 6); Angiogenesis experiments were used to investigate the effect of different groups of cell culture supernatants on the tubular structure formation capacity of HUVECs (n = 3). Observe the proliferation of chondrocytes using clonal formation experiments (n = 3). Western blot was used to analyze the PI3K/AKT signaling pathway and the expression of exosome-secretion-related proteins (n = 3). Results: In clinical studies, PRP can reduce patients' NRS and WOMAC scores and alleviate the progression of knee arthritis; In rat experiments, PRP reduced damage from knee arthritis and lowered Mankin's score. PRP improves tubular formation of HUVECs and the proliferation capacity of chondrocytes. Compared with the blank control group, the protein expression levels of PI3K, AKT, mTOR, P27, and cyclinD1 in the PRP group were increased. Compared with the PRP group, the protein expression levels of PI3K, AKT, mTOR, P27, and cyclinD1 in the PRP+Axitinib group supplemented with VEGFRs inhibitor and PI3K inhibitor group were significantly decreased. The effect of the LY294002 +PRP group was better than that of the above groups. Macrophage-derived exosomes activate HIF-1a and COX-2 in endothelial cells to promote chondrocyte repair of KOA. Conclusion: PRP can promote chondrocytes proliferation and repair by activating the PI3K/AKT signaling pathway, thereby exerting anti-OA effects. It provides new targets and methods for the clinical treatment of OA.

Developing a visual model for predicting depression in patients with lung cancer.

AIMS AND OBJECTIVES: To investigate and analyse the prevalence of depression among patients with lung cancer, identify risk factors of depression, and develop a visual, non-invasive, and straightforward clinical prediction model that can be used to predict the risk probability of depression in patients with lung cancer quantitatively. BACKGROUND: Depression is one of the common concomitant symptoms of patients with lung cancer, which can increase the risk of suicide. However, the current assessment tools cannot combine multiple risk factors to predict the risk probability of depression in patients. DESIGN: A cross-sectional study. METHODS: The clinical data from 297 patients with lung cancer in China were collected and analysed in this cross-sectional study. The clinical prediction model was constructed according to the results of the Chi-square test and the logistic regression analysis, evaluated by discrimination, calibration, and decision curve analysis, and visualised by a nomogram. This study was reported using the TRIPOD checklist. RESULTS: 130 patients with lung cancer had depressive symptoms with a prevalence of 43.77%. A visual prediction model was constructed based on age, disease duration, exercise, stigma, and resilience. This model showed good discrimination at an AUC of 0.842. Calibration curve analysis indicated a good agreement between experimental and predicted values, and the decision curve analysis showed a high clinical utility. CONCLUSIONS: The visual prediction model developed in this study has excellent performance, which can accurately predict the occurrence of depression in patients with lung cancer at an early stage and assist the medical staff in taking targeted preventative measures. RELEVANCE TO CLINICAL PRACTICE: The visual, non-invasive, and simple nomogram can help clinical medical staff to calculate the risk probability of depression among patients with lung cancer, formulate personalised preventive care measures for high-risk groups as soon as possible, and improve the quality of life of patients.

Estimation of economic burden throughout course of cervical squamous intraepithelial lesion and cervical cancer in China: A nationwide multicenter cross-sectional study.

Objective: Cervical squamous intraepithelial lesion (SIL) and cervical cancer are major threats to females' health and life in China, and we aimed to estimate the economic burden associated with their diagnosis and treatment. Methods: A nationwide multicenter, cross-sectional, hospital-based survey was conducted in 26 qualified hospitals across seven administrative regions of China. We investigated females who had been pathologically diagnosed with SIL and cervical cancer, and included five disease courses ("diagnosis", "initial treatment", "chemoradiotherapy", "follow-up" and "recurrence/progression/metastasis") to estimate the total costs. The median and interquartile range (IQR) of total costs (including direct medical, direct non-medical, and indirect costs), reimbursement rate by medical insurance, and catastrophic health expenditures in every clinical stage were calculated. Results: A total of 3,471 patients in different clinical stages were analyzed, including low-grade SIL (LSIL) (n=549), high-grade SIL (HSIL) (n=803), cervical cancer stage IA (n=226), IB (n=610), IIA (n=487), IIB (n=282), III (n=452) and IV (n=62). In urban areas, the estimated total costs of LSIL and HSIL were [Formula: see text]1,637.7 (IQR: [Formula: see text]956.4-[Formula: see text]2,669.2) and [Formula: see text]2,467.1 (IQR: [Formula: see text]1,579.1-[Formula: see text]3,762.3), while in rural areas the costs were [Formula: see text]459.0 (IQR: [Formula: see text]167.7-[Formula: see text]1,330.3) and [Formula: see text]1,230.5 (IQR: [Formula: see text]560.6-[Formula: see text]2,104.5), respectively. For patients with cervical cancer stage IA, IB, IIA, IIB, and III-IV, the total costs were [Formula: see text]15,034.9 (IQR: [Formula: see text]11,083.4-[Formula: see text]21,632.4), [Formula: see text]19,438.6 (IQR: [Formula: see text]14,060.0-[Formula: see text]26,505.9), [Formula: see text]22,968.8 (IQR: [Formula: see text]16,068.8-[Formula: see text]34,615.9), [Formula: see text]26,936.0 (IQR: [Formula: see text]18,176.6-[Formula: see text]41,386.0) and [Formula: see text]27,332.6 (IQR: [Formula: see text]17,538.7-[Formula: see text]44,897.0), respectively. Medical insurance covered 43%-55% of direct medical costs for cervical cancer patients, while the coverage for SIL patients was 19%-43%. For most cervical cancer patients, the expense was catastrophic, and the extent of catastrophic health expenditure was about twice large for rural patients than that for urban patients in each stage. Conclusions: The economic burden of SIL and cervical cancer in China is substantial, with a significant proportion of the costs being avoidable for patients with LSIL. Even for those with medical insurance, catastrophic health expenditures are also a major concern for patients with cervical cancer, particularly for those living in rural areas.

Triage performance and predictive value of the human gene methylation panel among women positive on self-collected HPV test: Results from a prospective cohort study.

Triaging of women positive for high-risk human papillomavirus (hrHPV) on self-collected samples requires a molecular reflex test to avoid recall for cytology or visual tests. We assessed triage performance and predictive value of human gene methylation panel (ZNF671/ASTN1/ITGA4/RXFP3/SOX17/DLX1) alone and with combination of HPV16/18 genotyping in a longitudinal screening study. Out of 9526 women at baseline, 1758 women positive for hrHPV on self-collected samples followed up yearly were included in the current analysis. Satisfactory risk stratification to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was demonstrated by the methylation panel with an odds ratio (OR) of 11.3 among methylation-positive women compared to methylation-negative counterparts. Triaging with methylation panel reduced colposcopy referral rate by 67.2% with sensitivity and specificity of 83.0% and 69.9% to detect CIN2+. The corresponding values for the combining methylation and HPV 16/18 were 96.6% and 58.3%. The cumulative 3-year incident CIN2+ risk was 6.8% (95% CI: 4.9%-8.6%) for hrHPV positive women, which was reduced to 4.5% (95% CI: 2.7%-6.3%) and 2.9% (95% CI: 1.2%-4.5%) for women negative on methylation triaging alone and negative on the combined strategy. The corresponding risk for women positive for both methylation and HPV 16/18 reached 33.7% (95% CI: 19.0%-45.8%). Our study demonstrated the satisfactory triage performance and predictive value of the methylation panel, especially in combination with HPV 16/18 genotyping. The substantially lower risk of CIN2+ among the triage negative women over the next 3 years suggests that the interval for repeat HPV test can be safely extended to at least 2 years.

Prominent Neutralizing Antibody Response Targeting the Ebolavirus Glycoprotein Subunit Interface Elicited by Immunization.

The severe death toll caused by the recent outbreak of Ebola virus disease reinforces the importance of developing ebolavirus prevention and treatment strategies. Here, we have explored the immunogenicity of a novel immunization regimen priming with vesicular stomatitis virus particles bearing Sudan Ebola virus (SUDV) glycoprotein (GP) that consists of GP1 & GP2 subunits and boosting with soluble SUDV GP in macaques, which developed robust neutralizing antibody (nAb) responses following immunizations. Moreover, EB46, a protective nAb isolated from one of the immune macaques, is found to target the GP1/GP2 interface, with GP-binding mode and neutralization mechanism similar to a number of ebolavirus nAbs from human and mouse, indicating that the ebolavirus GP1/GP2 interface is a common immunological target in different species. Importantly, selected immune macaque polyclonal sera showed nAb specificity similar to EB46 at substantial titers, suggesting that the GP1/GP2 interface region is a viable target for ebolavirus vaccine.Importance: The elicitation of sustained neutralizing antibody (nAb) responses against diverse ebolavirus strains remains as a high priority for the vaccine field. The most clinically advanced rVSV-ZEBOV vaccine could elicit moderate nAb responses against only one ebolavirus strain, EBOV, among the five ebolavirus strains, which last less than 6 months. Boost immunization strategies are desirable to effectively recall the rVSV vector-primed nAb responses to prevent infections in prospective epidemics, while an in-depth understanding of the specificity of immunization-elicited nAb responses is essential for improving vaccine performance. Here, using non-human primate animal model, we demonstrated that booster immunization with a stabilized trimeric soluble form of recombinant glycoprotein derived from the ebolavirus Sudan strain following the priming rVSV vector immunization led to robust nAb responses that substantially map to the subunit interface of ebolavirus glycoprotein, a common B cell repertoire target of multiple species including primates and rodents.

Opioid-free anesthesia compared to opioid anesthesia for laparoscopic radical colectomy with pain threshold index monitoring: a randomized controlled study.

BACKGROUND: Few studies have investigated the depth of intraoperative analgesia with non-opioid anesthesia. This study evaluated whether opioid-free anesthesia can provide an effective analgesia-antinociception balance monitored by the / pain threshold index in laparoscopic radical colectomy. METHODS: We enrolled 102 patients undergoing laparoscopic radical colectomy with general anesthesia. Participants were randomly allocated into two groups to receive opioid-free anesthesia (group OFA) with dexmedetomidine (loading dose with 0.6 µg·kg-1 for 10 min and then 0.5 µg·kg-1·h-1 continuous infusion) and sevoflurane plus bilateral paravertebral blockade (0.2 µg·kg-1 dexmedetomidine and 0.5% ropivacaine 15 ml per side) or opioid-based anesthesia (group OA) with remifentanil, sevoflurane, and bilateral paravertebral blockade (0.5% ropivacaine 15 ml per side). The primary outcome variable was pain intensity during the operation, as assessed by the pain threshold index with the multifunction combination monitor HXD- I. Results were analyzed using repeated measures analysis of variance and Student's t-test. The secondary outcomes were wavelet index, lactic levels, and blood glucose concentration during the operation. The visual analog scale (VAS), rescue analgesic consumption, and side-effects of opioids after surgery were further assessed. RESULTS: One hundred and one patients were included in the analysis. Analysis revealed that the intraoperative pain threshold index readings were not significantly different between the groups from incision to the end of the operation (P = 0.06). Furthermore, similar changes in the brain wavelet index readings were observed in the OFA and OA groups. There was no statistical difference in VAS scores between the groups (P > 0.05); however, non-opioid anesthesia did reduce the rescue analgesic consumption after operation (P < 0.05). In the OFA group, the blood glucose levels increased by 20% compared to baseline and were significantly higher than those in the OA group (P < 0.001). The incidences of postoperative nausea and vomiting, urine retention, intestinal paralysis and pruritus were not significantly different from those in the OA group (P > 0.05). CONCLUSIONS: This study suggests that compared to the opioid anesthesia regimen, our opioid-free anesthesia regimen achieved an equally effective intraoperative pain threshold index in laparoscopic radical colectomy. The incidence of opioid-related adverse reactions was not different between regimens, and intraoperative blood glucose levels were higher with opioid-free anesthesia. TRIAL REGISTRATION: ChiCTR1900021223, 02/02/2019, Title: " Opioid-free anesthesia in laparoscopic surgery: a randomized controlled trial ". Website: hppts:// www.chictr.ogr.cn.

Detection of RAS gene mutation and its clinical significance in children with acute lymphoblastic leukemia. / å„¿ç«¥æ€¥æ€§æ·‹å·´ç»†èƒžç™½è¡€ç— ä¸­RASåŸºå› çªå˜çš„æ£€æµ‹åŠå ¶ä¸´åºŠæ„ä¹‰.

OBJECTIVES: To investigate the mutation rate of the RAS gene and its clinical significance in children with acute lymphoblastic leukemia. METHODS: A retrospective analysis was performed on the medical data of 120 children with newly diagnosed acute lymphoblastic leukemia, who were admitted to the Third Affiliated Hospital of Zhengzhou University from January 2015 to January 2020 and underwent next-generation sequencing. The clinical and molecular features were analyzed. The impact of RAS gene mutation on the overall survival rate was evaluated in these children. RESULTS: Among the 120 children, 35 (29.2%) had RAS gene mutation, 30 (25.0%) had KRAS gene mutation, and 5 (4.2%) had both NRAS and KRAS gene mutations. All NRAS mutations and 71% (25/35) of KRAS mutations were located at the 12th and 13th codons. RAS gene mutation was detected in 35 (33.3%) out of 105 children with B-lineage acute lymphoblastic leukemia, but it was not detected in those with acute T lymphocyte leukemia. Of all the children, 11 (9.2%) were lost to follow-up, and among the 109 children followed up, 16 (14.7%) died. The children with RAS gene mutation had a significantly lower 2-year overall survival rate than those without RAS gene mutation (P<0.05). The prognosis of children with RAS gene mutation combined with WT1 overexpression and WBC>50×109/L at diagnosis was worse (P<0.05). CONCLUSIONS: RAS gene mutation is commonly observed in children with B-lineage acute lymphoblastic leukemia and may have an adverse effect on prognosis.

Efficacy of point-of-care thermal ablation among high-risk human papillomavirus positive women in China.

Thermal ablation is a point-of-care ablative treatment technique for cervical intraepithelial neoplasia (CIN). However, limited information is available about its efficacy in low- and middle-income countries. We evaluated the efficacy of thermal ablation in treatment of CIN detected through high-risk human papillomavirus (HPV) screening in China. Women positive on high-risk HPV and having colposcopically suspected lesions eligible for ablation underwent colposcopy, biopsy and thermal ablation in one visit. Women ineligible were recalled for large loop excision of transformation zone (LLETZ) when histopathology results were high-grade CIN. Posttreatment follow-up at 6 months or more was with HPV test and cytology followed by colposcopy and biopsy for HPV and/or cytology-positive women. Cure was defined as either negative cytology and HPV test or absence of histopathology proved CIN in any positive women. Of total 218 HPV-positive women treated with thermal ablation (n = 170) or LLETZ (n = 48), 196 reported for follow-up evaluation. For women with histologically confirmed CIN at baseline (thermal ablation-104; LLETZ-38), cure rates were 84.6% for thermal ablation and 86.8% for LLETZ. Cure rates after thermal ablation were 90.3% for CIN grade one (CIN1) and 76.2% for CIN grade two or worse (CIN2+). HPV clearance rate was 80.4% in women undergoing thermal ablation, which was lower for HPV16/18 compared to other oncogenic types (67.6% vs 85.7%). HPV test had a negative predictive value (NPV) of 98.7% to detect CIN2+ at follow-up and the positive predictive value (PPV) was 40.4%. Thermal ablation is effective to treat CIN as well as to clear the high-risk HPV infection. HPV test has high PPV and NPV in following up patients posttreatment.

Effectiveness and cost-effectiveness of eliminating cervical cancer through a tailored optimal pathway: a modeling study.

BACKGROUND: The World Health Assembly has adopted a global strategy to eliminate cervical cancer. However, neither the optimal pathway nor the corresponding economic and health benefits have been evaluated. We take China as an example to assess the optimal pathway towards elimination and the cost-effectiveness of tailored actions. METHODS: A validated hybrid model was used to assess the costs and benefits of alternative strategies combining human papillomavirus vaccination, cervical screening, and treatment of pre-invasive lesions and invasive cancer for females with different immunization history. All Chinese females living or projected to be born during 2015-2100, under projected trends in aging, urbanization, and sexual activity, were considered. Optimal strategies were determined by cost-effectiveness efficiency frontiers. Primary outcomes were cervical cancer cases and deaths averted and incremental cost-effectiveness ratios (ICERs). We employed a lifetime horizon from a societal perspective. One-way and probabilistic sensitivity analyses evaluate model uncertainty. RESULTS: The optimal pathway represents an integration of multiple tailored strategies from females with different immunization history. If China adopts the optimal pathway, the age-standardized incidence of cervical cancer is predicted to decrease to fewer than four new cases per 100,000 women (i.e., elimination) by 2047 (95% confidence interval 2043 to 2050). Compared to the status quo, the optimal pathway would avert a total of 7,509,192 (6,922,744 to 8,359,074) cervical cancer cases and 2,529,873 (2,366,826 to 2,802,604) cervical cancer deaths in 2021-2100, with the discounted ICER being $- 339 (- 687 to - 79) per quality-adjusted life-year. CONCLUSIONS: By adopting an optimal pathway from 2021 (namely, the year of the first Chinese Centennial Goals) onwards, cervical cancer could be eliminated by the late 2040s (namely, ahead of the second Chinese Centennial Goals) while saving net economic costs in China.

One-pot synthesis and multiple MS/MS fragmentation studies of phospholysine peptides.

RATIONALE: Compared with phosphorylation of arginine and histidine, the study of phosphorylation of lysine lags far behind. The major challenges toward the current study of phosphorylation of lysine include synthesis and unambiguous phosphosite identification. This study provided a simple chemical synthesis method to construct phospholysine peptides (pLys peptides) and investigated their fragmentation under multiple activation types. METHODS: Herein, we developed a synthetic method for pLys peptides in aqueous solution within one pot. Two peptides were lysine-phosphorylated using this method. The purified pLys peptides were first characterized using NMR, then were subjected to nano-liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) analysis under multiple fragmentation method including collision-induced dissociation (CID), higher energy collisional dissociation (HCD), electron transfer dissociation (ETD), electron transfer/higher energy collisional dissociation (EThcD), and ultraviolet photodissociation (UVPD) fragmentation to investigate the relevant diagnostic ions. RESULTS: Two pLys peptides were synthesized with a moderate yield following an easily handled experimental protocol. NMR spectra showed the phosphorylation occurred on ε-NH2 of lysine but not other groups. As for the fragmentation, in general, pLys immonium ions and phosphate-related neutral losses were ubiquitous among spectra derived from these activation types except for ETD. Using these ions as diagnostic ions, the misassigned phosphosites by algorithm could be recorrected. UVPD-generated spectra owned good sequence-coverage and abundant fragment ions, with pLys immonium ions and neutral losses of weak intensity. CONCLUSIONS: A synthetic method was developed for pLys peptides in aqueous solution within one pot. The characteristic pLys immonium ions and phosphate-related neutral loss could serve as the diagnostic ions for unambiguous phosphosite identification of pLys peptides. In addition, UVPD was promising for the identification of pLys peptides.

Synthesis and biological evaluation of isatin derivatives containing 1,3,4-thiadiazole as potent a-glucosidase inhibitors.

A series of (Z)-3-(2-(1,3,4-thiadiazol-2-yl)hydrazono)-1-substituted indolin-2-ones derivatives (3a-3m) were designed and synthesized. All newly synthesized compounds were evaluated for their a-glucosidase inhibitory activity with resveratrol as positive control in vitro. Except for 3i and 3j, all of the compounds showed a potent inhibitory activity against a-glucosidase with IC50 values in the range of 3.12 ± 1.25 to 45.95 ± 1.26 µM and the purity of these compounds was greater than 95%. The IC50 values were being compared to the standard resveratrol (IC50 = 22.00 ± 1.15 µM) and it was found that compounds 3b, 3d-3h were found to be more active than resveratrol. Specifically, (Z)-3-(2-(1,3,4-thiadiazol-2-yl)hydrazono)-1-(4-chlorobenzyl)indolin-2-one (3d) exhibited the most potent a-glucosidase inhibitory activity with IC50 value of 3.12 ± 1.25 µM. The kinetic analysis revealed that compound (3d) is noncompetitive inhibitor. Structure activity relationship has been established for all compounds. Furthermore, the binding interactions of compound 3d with the active site of a-glucosidase were confirmed through molecular docking. This study has identified a new class of potent a-glucosidase inhibitors for further investigation.

Triage options to manage high-risk human papillomavirus-positive women: A population-based cross-sectional study from rural China.

Improvement in managing HPV-positive women is urgently needed. Based on a population-based study which included 2112 women aged 49 to 69 from Shanxi, China, we aimed to evaluate the clinical performance of multiple triage strategies based on liquid-based cytology (LBC), p16INK4a , viral load and partial genotyping, as a single or combined strategy for detecting cervical intraepithelial neoplasia grade 2/3 or higher (CIN2+/CIN3+) in women who tested positive by Hybrid Capture 2 (HC2). Among 452 HC2-positive women, the test positivity of LBC (ASC-US+), p16INK4a , HPV16/18 and HPV16/18/31/33/45 were 39.6%, 38.5%, 18.0% and 40.0%, respectively. Compared to LBC (ASC-US+) triage, a single triage strategies using p16INK4a or extended genotyping (SureX HPV16/18/31/33/45) achieved comparable sensitivity (relative sensitivity: 1.08, 95% confidence interval [CI]: 0.93-1.26 and 0.96, 95% CI: 0.76-1.22) and specificity (relative specificity: 1.05, 95% CI: 0.96-1.14 and 1.02, 95% CI: 0.92-1.14) for CIN3+. Viral load triage using a ≥50 RLU/CO cut-point also yielded similar results with LBC (ASC-US+). Among combined triage strategies, HPV16/18 genotyping with reflex p16INK4a showed higher sensitivity and slightly lower specificity than LBC (ASC-US+) for CIN3+ detection, however, the differences were not statistically significant. Of note, after a negative result by p16INK4a or LBC among HPV16/18 negative women, the posttest probability of CIN3+ was lower than 1%. Our study suggested that p16INK4a , extended genotyping and increased viral load cut-point could be promising alternatives to cytology triage. Combined triage algorithms of HPV16/18 with reflex p16INK4a or cytology, if negative, are associated with the substantial low posttest risk sufficient to release women to next screening round.

Comparative performance evaluation of different HPV tests and triaging strategies using self-samples and feasibility assessment of thermal ablation in 'colposcopy and treat' approach: A population-based study in rural China.

Human papillomavirus (HPV) test, self-sampling and thermal ablation for cervical intraepithelial neoplasia (CIN) have been developed separately to increase screening coverage and treatment compliance of cervical cancer screening programmes. A large-scale study in rural China screened 9,526 women with their combinations to explore the optimal cervical cancer-screening cascade in the real-world. Participants received careHPV and polymerase chain reaction (PCR) HPV tests on self-collected samples. Women positive on either HPV test underwent colposcopy, biopsy and thermal ablation in a single visit. Samples positive on either HPV test were retested for genotyping. Absolute and relative performance of HPV tests, triage strategies, 'colposcopy and thermal ablation' approach were statistically evaluated. PCR HPV test detected 33.3% more CIN grade two or worse (CIN2+) at a cost of 28.1% more colposcopies compared to careHPV. Sensitivities of PCR HPV and careHPV tests to detect CIN2+ were 96.7 and 72.5%. Specificities for the same disease outcome were 82.1 and 86.0%. Triaging HPV-positive women with HPV16/18 genotyping considerably improved the positive predictive value for CIN2+ (4.8-5.0 to 18.2-19.2%). Ninety-six women positive on HPV and having abnormal colposcopy were eligible for thermal ablation and all accepted same-day treatment, contributing to 64.6% being treated appropriately (CIN1+ on histopathology), which reached up to 84.8% among women positive on HPV 16/18 triage. No serious side-effects/complications were reported. The combination of PCR HPV test followed by HPV 16/18 triaging on self-collected samples and colposcopy of triage positive women followed by immediate thermal ablation might be the appropriate screening cascade for rural China.

Anti-Inflammatory Effects of Neochlorogenic Acid Extract from Mulberry Leaf (Morus alba L.) Against LPS-Stimulated Inflammatory Response through Mediating the AMPK/Nrf2 Signaling Pathway in A549 Cells.

Neochlorogenic acid (nCGA) is a phenolic compound isolated from mulberry leaf (Morus alba L.), which possesses multiple pharmacological activities containing antioxidant and anti-inflammatory effects. However, the role of nCGA in the treatment of acute pneumonia and the underlying molecular mechanism are still unclear. Hence, the aim of study is to investigate the anti-inflammatory properties of nCGA on LPS-stimulated inflammation in A549 cells. In the present study, results reported that nCGA without cytotoxicity significantly reduced the production of TNF-α, IL-6, and NO, and further suppressed the proteins of iNOS, COX2, TNF-α, IL-6 expression. Furthermore, nCGA also inhibited NF-κB activation and blocked MAPKs signaling pathway phosphorylation. In addition, we found nCGA significantly increased the expression of HO-1 via activating the AMPK/Nrf2 signaling pathway to attenuate the inflammatory response, whereas this protective effect of nCGA was reversed by pre-treatment with compound C (C.C, an AMPK inhibitor). Therefore, all these results indicated that nCGA might act as a natural anti-inflammatory agent for the treatment of acute pneumonia.