Summary Background A new test ( care HPV; QIAGEN, Gaithersburg, MD, USA) has been developed to detect 14 high-risk types of carcinogenic human papillomavirus (HPV) in about 2·5 h, to screen women in ...developing regions for cervical intraepithelial neoplasia (CIN). We did a cross-sectional study to assess the clinical accuracy of care HPV as a rapid screening test in two county hospitals in rural China. Methods From May 10 to June 15, 2007, the care HPV test was done locally by use of self-obtained vaginal and provider-obtained cervical specimens from a screening population-based set of 2530 women aged 30 to 54 years in Shanxi province, China. All women were assessed by visual inspection with acetic acid (VIA), Digene High-Risk HPV HC2 DNA Test (HC2), liquid-based cytology, and colposcopy with directed biopsy and endocervical curettage as necessary. In 2388 women with complete data, 441 women with negative colposcopy, but unsatisfactory or abnormal cytology or who were positive on HC2 or the new care HPV test, were recalled for a second colposcopy, four-quadrant cervical biopsies, and endocervical curettage. An absence of independence between the tests was not adjusted for and the Bonferroni correction was used for multiple comparisons. Findings Complete data were available for 2388 (94·4%) women. 70 women had CIN2+ (moderate or severe CIN or cancer), of whom 23 had CIN3+. By use of CIN2+ as the reference standard and area-under-the-curve analysis with a two-sided alpha error level of 0·0083, the sensitivities and specificities of the care HPV test for a cut-off ratio cut-point of 0·5 relative light units, were 90·0% (95% CI 83·0–97·0) and 84·2% (82·7–85·7), respectively, on cervical specimens, and 81·4% (72·3–90·5) and 82·4% (80·8–83·9), respectively, on vaginal specimens (areas under the curve not significantly different, p=0·0596), compared with 41·4% (29·9–53·0) and 94·5% (93·6–95·4) for VIA (areas under the curve significantly different, p=0·0001 and p=0·0031, for cervical and vaginal-specimen comparisons for the care HPV test, respectively). The sensitivity and specificity of HC2 for cervical specimens were 97·1% (93·2–100) and 85·6% (84·2–87·1), respectively (areas under the curve not significantly different from the care HPV test on cervical specimens, p=0·0163). Interpretation The care HPV test is promising as a primary screening method for cervical-cancer prevention in low-resource regions. Funding Bill & Melinda Gates Foundation.
Summary Background Controversy remains over whether high-risk human papillomavirus (HPV) DNA testing should be used as a primary screen for cervical cancer. The aims of our study were to assess ...whether HPV DNA testing could be applied to cervical-cancer screening programmes in China, as well as other similar developing countries. Methods We did a pooled analysis of population-based cervical cancer screening studies done in mainland China from 1999 to 2008 with concurrent HPV DNA testing (Hybrid Capture 2 assay; Qiagen, Gaithersburg, MD, USA), liquid-based cytology (LBC), and visual inspection with acetic acid (VIA). Eligible women were sexually active, not pregnant, had an intact uterus, and had no history of cervical intraepithelial neoplasia (CIN), cervical cancer, or pelvic irradiation. All women positive for any test were referred for colposcopy and biopsy. Cervical lesions were diagnosed by directed or random biopsy. We assessed the diagnostic accuracy of HPV DNA testing for the detection of CIN grade 3 or greater. Findings 30 371 women from 17 cross-sectional, population-based studies in various parts of China were screened. 1523 women were subsequently excluded because of inadequate HPV DNA specimens or they did not have a biopsy taken, which included women with atypical squamous cells of undetermined significance; low-grade squamous intraepithelial lesion or worse; positive HPV, negative cytology, and missing or positive colposcopy results; and unsatisfactory cytology results. HPV DNA testing had a higher sensitivity of 97·5% (95% CI 95·7–98·7) for detection of CIN grade 3 or worse, and a lower specificity of 85·1% (82·3–87·9), compared with cytology (sensitivity 87·9% 95% CI 84·7–90·7, specificity 94·7% 93·5–96·0) and VIA (54·6% 48·0–61·2, 89·9% 86·8–93·0). Sensitivity did not vary by study or age (<35 years, 35–49 years, ≥50 years); however, specificity did vary with age (p<0·0001) and was highest in women younger than 35 years (89·4%; 95% CI 86·1–91·5). An increase in the positive cutoff point from the manufacturer recommended 1 pg/mL to 2 pg/mL led to a decrease in the overall HPV DNA positivity from 16·3% to 13·9% (p<0·0001), which could result in a decrease in referral rates, although sensitivity was slightly lower (97·5% to 95·2%). An increase in the cutoff point to 10 pg/mL in women younger than 35 years maintained a high sensitivity 97·7% (95% CI 87·7–99·9) and increased specificity to 93·5% (95% CI 91·9–94·6). Interpretation HPV DNA testing is highly sensitive and moderately specific for CIN grade 3 or worse, with consistent results across study sites and age groups—including women younger than 35 years. A rise in the cutoff point might be beneficial for future screening programmes in China, especially when screening women younger than 35 years. Funding Fogarty International Clinical Research Scholars Program (Fogarty International Center, US National Institutes of Health, through the International Clinical Research Fellows Program at Vanderbilt University); Academic Capacity Development Program of the Beijing Municipal Commission of Education; and Cancer Institute and Hospital of the Chinese Academy of Medical Sciences.
Abstract Purpose The aim of this study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety of single and multiple doses of cinacalcet in Chinese healthy volunteers ...(HVs) for the purposes of a New Drug Application package for the Chinese Food and Drug Administration. Methods In this randomized, open-label, single ascending–dose and multiple-dose, parallel-group study, 42 Chinese HVs were randomized to receive a single oral dose of 25, 50, or 100 mg of cinacalcet and multiple doses of 50 mg of cinacalcet once daily for 7 days. Plasma cinacalcet concentrations were analyzed by HPLC-MS/MS. The PK parameters were assessed with noncompartmental analysis. Plasma intact parathyroid hormone, serum calcium, and phosphorus concentrations were measured for PD evaluation. The safety profile was also assessed. Adverse events (AEs) were noted during the study. Findings Of the 42 randomized HVs, 41 completed the study per protocol; 1 prematurely discontinued the study because of AEs. Cinacalcet has nonlinear PK properties over a dose range of 25 to 100 mg after a single dose. Mean (SD) Cmax values were 7.68 (4.25), 17 (6.33), and 31.3 (16.42) ng/mL with single doses of 25, 50, and 100 mg of cinacalcet, respectively. Mean (SD) AUC0– last values were 58.4 (25.38), 187 (70.7), and 367 (180.03) hr∙ng/mL with single doses of 25, 50, and 100 mg of cinacalcet, respectively. Steady state was attained within 7 doses of successive daily administration of 50 mg of cinacalcet. At steady state, the mean (SD) Cmax and AUC0–last values were 20.6 (9.63) ng/mL and 297 (146.15) ng∙h/mL. The accumulation ratios of Cmax and AUC (AUCτ /AUC0–24 ) were 1.21 and 1.32. Plasma intact parathyroid hormone and serum calcium concentrations had similar patterns, both decreased after administration of cinacalcet, whether after single dose or multiple doses. A total of 52 AEs were reported in 20 HVs (47.6%). The most frequently reported AEs after single-dose and multiple-dose cinacalcet administration were hypocalcemia, numbness, dizziness, and muscle soreness. No serious AEs were reported. Implications Cinacalcet was well tolerated and effective after administration of a single oral dose up to 100 mg and multiple doses of 50 mg of cinacalcet once daily for 7 days. Cinacalcet has nonlinear PK properties over a dose range of 25 to 100 mg after a single dose. PK profiles after multiple doses were similar to those after a single dose with no accumulation. Cinacalcet had similar PK and safety profiles between Chinese and Western HVs at the same dose levels.
Summary Background Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although ...Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. Methods We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. Findings Associations exceeding the genome-wide significance threshold (p<5 × 10−8 ) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1 ) having the strongest association with NKTCL susceptibility (p=4·21 × 10−19 , odds ratio OR 1·84 95% CI 1·61–2·11 in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10−14 ). This association is distinct from MHC associations with Epstein-Barr virus infection. Interpretation To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. Funding Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).
Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor with recurrent potential, most commonly occurring in the lung but rarely in the kidney with nonspecific clinical symptoms and ...radiographic features, thus may be misdiagnosed as primary malignant lesions. We described a 6-year-old boy with renal IMT misdiagnosed as Wilms' tumor and then treated with right nephrectomy. It should be emphasized that in addition to the most common renal tumors in children, IMT should also be taken as a differential diagnosis. It is therefore mandatory to carry out clinical interpretation, careful histologic examination, and immunohistochemical studies collectively to make solid diagnosis.
Summary Background Enterovirus 71 (EV71) outbreaks are a socioeconomic burden, especially in the western Pacific region. Results of phase 1 clinical trials suggest an EV71 vaccine has a clinically ...acceptable safety profile and immunogenicity. We aimed to assess the best possible dose and formulation, immunogenicity, and safety profile of this EV71 vaccine in healthy Chinese children. Methods This randomised, double-blind, placebo-controlled, phase 2 trial was undertaken at one site in Donghai County, Jiangsu Province, China. Eligible participants were healthy boys or girls aged 6–36 months. Participants were randomly assigned (1:1:1:1:1) to receive either 160 U, 320 U, or 640 U alum-adjuvant EV71 vaccine, 640 U adjuvant-free EV71 vaccine, or a placebo (containing alum adjuvant only), according to a blocked randomisation list generated by SAS 9.1. Participants and investigators were masked to the assignment. The primary endpoint was anti-EV71 neutralising antibody geometric mean titres (GMTs) at day 56, analysed according to protocol. The study is registered with ClinicalTrials.gov , number NCT01399853. Findings We randomly assigned 1200 participants, 240 (120 aged 6–11 months infants and 120 aged 12–36 months children) of whom were assigned to each dose. 1106 participants completed the study and were included in the according-to-protocol analysis. The main reasons for dropout were withdrawal of consent and refusal to donate a blood sample. Infants who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (742·2 95% CI 577·3–954·3), followed by those who received the 320 U formulation (497·9 383·1–647·0). For children, those who received the 320 U formulation had the highest GMTs on day 56 (1383·2 1037·3–1844·5). Participants who received the vaccine had significantly higher GMTs than did who received placebo (p<0·0001). For the subgroup of participants who were seronegative at baseline, both infants and children who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (522·8 403·9–676·6 in infants and 708·4 524·1–957·6 in children), followed by those who received the 320 U adjuvant vaccine (358·2 280·5–457·5 in infants and 498·0 383·4–646·9 in children). 549 (45·8%) of 1200 participants (95 CI 42·9–48·6%) reported at least one injection-site or systemic adverse reaction, but the incidence of adverse reactions did not differ significantly between groups (p=0·36). The 640 U alum-adjuvant vaccine group had a significantly higher incidence of induration than did the 640 U adjuvant-free group (p=0·001). Interpretation Taking immunogenicity, safety, and production capacity into account, the 320 U alum-adjuvant formulation of the EV71 vaccine is probably the best possible formulation for phase 3 trials. Funding The National Science and Technology Major Project (2011ZX10004-902) of the Chinese Ministry of Science and Technology, China's 12–5 National Major Infectious Disease Program (2012ZX10002-001), and Beijing Vigoo Biological.
Abstract Copper sulfide (CuS) has emerged as a promising photothermal agent. However, its potential toxic effects still remained poorly understood. Herein, CuS nanoplates were synthesized for ...toxicity assessment. The in vitro study indicated that the cell viability decreased when CuS nanoplate concentration was higher than 100 μg/mL. CuS nanoplates caused apparent toxicity to HUVEC and RAW 264.7 cells. For acute toxicity, maximum tolerated dose and lethal dose 50 were 8.66 and 54.5 mg/kg, respectively. Furthermore, the sub-chronic toxicity test results indicated that there was no obvious effect at tested doses during the test period. The biodistribution study showed that intravenously administrated CuS nanoplates were mainly present in the spleen, liver and lung. Taken together, our results shed light on the rational design of CuS nanomaterials to minimize toxicity, thus providing a useful guideline in selecting CuS as the photothermal agent for cancer therapy. From the Clinical Editor Photothermal ablation therapy is a promising new treatment modality for cancer. One of the potential photothermal agents is copper sulfide (CuS). In this article, the potential toxic effects of CuS nanoplates were studied. The authors showed that further modification on the design of CuS nanomaterials was needed to minimize toxicity.
Objective
Artificial intelligence (AI) prediction is increasingly used for decision making in health care, but its application for adverse outcomes in emergency department (ED) patients with acute ...pancreatitis (AP) is not well understood. This study aimed to clarify this aspect.
Methods
Data from 8274 ED patients with AP in three hospitals from 2009 to 2018 were analyzed. Demographic data, comorbidities, laboratory results, and adverse outcomes were included. Six algorithms were evaluated, and the one with the highest area under the curve (AUC) was implemented into the hospital information system (HIS) for real‐time prediction. Predictive accuracy was compared between the AI model and Bedside Index for Severity in Acute Pancreatitis (BISAP).
Results
The mean ± SD age was 56.1 ± 16.7 years, with 67.7% being male. The AI model was successfully implemented in the HIS, with Light Gradient Boosting Machine (LightGBM) showing the highest AUC for sepsis (AUC 0.961) and intensive care unit (ICU) admission (AUC 0.973), and eXtreme Gradient Boosting (XGBoost) showing the highest AUC for mortality (AUC 0.975). Compared to BISAP, the AI model had superior AUC for sepsis (BISAP 0.785), ICU admission (BISAP 0.778), and mortality (BISAP 0.817).
Conclusions
The first real‐time AI prediction model implemented in the HIS for predicting adverse outcomes in ED patients with AP shows favorable initial results. However, further external validation is needed to ensure its reliability and accuracy.
Summary Background Up to now, all tested Ebola virus vaccines have been based on the virus strain from the Zaire outbreak in 1976. We aimed to assess the safety and immunogenicity of a novel ...recombinant adenovirus type-5 vector-based Ebola vaccine expressing the glycoprotein of the 2014 epidemic strain. Methods We did this randomised, double-blind, placebo-controlled, phase 1 clinical trial at one site in Taizhou County, Jiangsu Province, China. Healthy adults (aged 18–60 years) were sequentially enrolled and randomly assigned (2:1), by computer-generated block randomisation (block size of six), to receive placebo, low-dose adenovirus type-5 vector-based Ebola vaccine, or high-dose vaccine. Randomisation was pre-stratified by dose group. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was occurrence of solicited adverse reactions within 7 days of vaccination. The primary immunogenicity endpoints were glycoprotein-specific antibody titres and T-cell responses at day 28 after the vaccination. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov , number NCT02326194. Findings Between Dec 28, 2014, and Jan 9, 2015, 120 participants were enrolled and randomly assigned to receive placebo (n=40), low-dose vaccine (n=40), or high-dose vaccine. Participants were followed up for 28 days. Overall, 82 (68%) participants reported at least one solicited adverse reaction within 7 days of vaccination (n=19 in the placebo group vs n=27 in the low-dose group vs n=36 in the high-dose group; p=0·0002). The most common reaction was mild pain at the injection site, which was reported in eight (20%) participants in the placebo group, 14 (35%) participants in the low-dose group, and 29 (73%) participants in the high-dose vaccine group (p<0·0001). We recorded no statistical differences in other adverse reactions and laboratory tests across groups. Glycoprotein-specific antibody titres were significantly increased in participants in the low-dose and high-dose vaccine groups at both day 14 (geometric mean titre 421·4 95% CI 249·7–711·3 and 820·5 598·9–1124·0, respectively; p<0·0001) and day 28 (682·7 424·3–1098·5 and 1305·7 970·1–1757·2, respectively; p<0·0001). T-cell responses peaked at day 14 at a median of 465·0 spot-forming cells (IQR 180·0–1202·5) in participants in the low-dose group and 765·0 cells (400·0–1460·0) in those in the high-dose group. 21 (18%) participants had mild fever (n=9 in the placebo group, n=6 in the low-dose group, and n=6 in the high-dose group). No serious adverse events were recorded. Interpretation Our findings show that the high-dose vaccine is safe and robustly immunogenic. One shot of the high-dose vaccine could mount glycoprotein-specific humoral and T-cell response against Ebola virus in 14 days. Funding China National Science and Technology, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology.
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