Assessment of Key Factors Impacting Variability in AAV Vector Genome Titration by Digital PCR.

Recombinant adeno-associated virus (rAAV) has emerged as a prominent vector for in vivo gene therapy, owing to its distinct advantages. Accurate determination of the rAAV genome titer is crucial for ensuring the safe and effective administration of clinical doses. The evolution of the rAAV genome titer assay from quantitative PCR (qPCR) to digital PCR (dPCR) has enhanced accuracy and precision, yet practical challenges persist. This study systematically investigated the impact of various operational factors on genome titration in a single-factor manner, aiming to address potential sources of variability in the quantitative determination process. Our findings revealed that a pretreatment procedure without genome extraction exhibits superior precision compared with titration with genome extraction. Additionally, notable variations in titration results across different brands of dPCR instruments were documented, with relative standard deviation (RSD) reaching 23.47% for AAV5 and 11.57% for AAV8. Notably, optimal operations about DNase I digestion were identified; we thought treatment time exceeding 30 min was necessary, and there was no need for thermal inactivation after digestion. And we highlighted that thermal capsid disruption before serial dilution substantially affected AAV genome titers, causing a greater than ten-fold decrease. Conversely, this study found that additive components of dilution buffer are not significant contributors to titration variations. Furthermore, we found that repeated freeze-thaw cycles significantly compromised AAV genome titers. In conclusion, a comprehensive dPCR titration protocol, incorporating insights from these impact factors, was proposed and successfully tested across multiple serotypes of AAV. The results demonstrate acceptable variations, with the RSD consistently below 5.00% for all tested AAV samples. This study provides valuable insights to reduce variability and improve the reproducibility of AAV genome titration using dPCR.

Assessment of effectiveness and impact of universal prophylaxis with nirsevimab for prevention of hospitalizations due to respiratory syncytial virus in infants. The NIRSE-GAL study protocol.

Nirsevimab has been recently licensed for universal RSV prophylaxis in infants. NIRSE-GAL is a three-year population-based study initiated in Galicia in September 2023. It aims to evaluate nirsevimab effectiveness against RSV-related hospitalizations lower respiratory tract infections (LRTI), severe RSV, all-cause LRTI, and all-cause hospitalization. NIRSE-GAL also aims to estimate nirsevimab impact on primary healthcare use in the short and mid-term, children's wheezing and asthma, and medical prescriptions for RSV. The immunization campaigns will be scheduled based on the expected start week for the RSV season and will last the whole season. Immunization will be offered to: i) infants born during the campaign (seasonal), ii) infants < 6 months at the start of the campaign (catch-up), and iii) infants with high-risk factors, aged 6-24 months at the start of the campaign (high-risk). The follow-up period will start: i) the immunization date for all immunized infants, ii) the start of the campaign, for the non-immunized catch-up or high-risk groups, or iii) the birthdate for the non-immunized seasonal group. Infants will be followed up until outcome occurrence, death, or end of study. Nirsevimab effectiveness will be estimated using Poisson and Cox regression models. Sensitivity and stratified analyses will be undertaken. The number of averted cases and the number needed to immunize will be estimated. Immunization failure and nirsevimab safety will be monitored. NIRSE-GAL was approved by the ethics committee of Galicia (CEIC 2023-377) and registered in ClinicalTrials.gov (ID: NCT06180993). Findings will be mainly shared via peer-reviewed publications and scientific conferences.

Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Occurrence and Risk Assessment of Pesticides, Phthalates, and Heavy Metal Residues in Vegetables from Hydroponic and Conventional Cultivation.

Hydroponic cultivation of fresh produce is gaining popularity worldwide, but few studies have provided a comparative assessment of hydroponic and conventional soil-based vegetables. In this study, we analyzed a series of hazardous chemicals, including 120 pesticides, 18 phthalates (PAEs), and 2 heavy metals (lead and cadmium) in four vegetable commodities (lettuces, celeries, tomatoes, and cucumbers) from hydroponic and conventional soil-based cultivation. Our study showed that at least one pesticide was present in 84% of the conventionally grown samples, whereas only 30% of the hydroponic samples contained detectable pesticide residues. Regarding the total PAE concentrations, there was no significant difference between conventional and hydroponic vegetables. The lead and cadmium residues in conventionally cultivated vegetables were significantly higher than in those produced from hydroponic cultivation. Lead is the primary heavy metal pollutant across all vegetable samples. The hazard index (HI) values of the hydroponic and conventional vegetables were 0.22 and 0.64, respectively. Since both values are below one, the exposure to these hazardous chemicals through consumption of the studied vegetables may not pose a significant health risk. The HI values also suggested that the health risks of eating hydroponic vegetables are lower than for conventional soil-based vegetables.

Disparities in mortality risk after diagnosis of hematological malignancies in 185 countries: A global data analysis.

This study was to report proxy measures for mortality risk in patients with hematological malignancies across 185 countries globally and explore its association with their socioeconomic status and treatment. The incidence, mortality, and 5-year prevalence data were extracted from the GLOBOCAN database. The data regarding the human development index (HDI), gross national income (GNI), vulnerability index, and concordance with cancer Essential Medicines List (EML) were obtained from open-source reports. The ratio of mortality to 5-year-prevalence (MPR) and that of mortality to incidence (MIR) were calculated and age-standardized using Segi's world standard population. Finally, the possible associations were assessed using Pearson correlation analyses. In 2020, the global incidence, mortality, and 5-year prevalence of HMs were 1,278,362, 711,840, and 3,616,685, respectively. Global age-standardized MPR and MIR were 0.15 and 0.44, respectively; they varied significantly among 6 regions, 185 countries, 4 HM types, and 4 HDI groups worldwide. Older populations always had higher ratios. The correlation of MPRs and MIRs with HDI, GNI, and concordance with cancer EML was negative, whereas it was positive with the vulnerability index (lower was better). Increasing access to cancer drugs in resource-limited regions with a focus on vulnerable children may aid in reducing HM-related mortality risk.

In vitro inhalation bioaccessibility and health risk assessment of difenoconazole in the atmosphere.

BACKGROUND: Assessment of the risk of pesticide inhalation in populations around farmland is necessary because inhalation is one of the ways in which pesticides can risk human health. This study aimed to identify the inhalation risk of difenoconazole on humans by using dose-response and exposure assessments. RESULTS: In the field simulation application, respiratory exposure in populations around farmland ranged from 71 to 430 ng/m3 . Using response surface methodology, the maximum bioaccessibility of difenoconazole in three simulated lung fluids was 35.33% in Gamble's solution (GS), 34.12% in artificial lysosomal fluid (ALF), and 42.06% in simulated interstitial lung fluid (SLF). Taking the proliferation activity of the A549 cell model as the endpoint, the benchmark dose limit and benchmark dose of difenoconazole on A549 cells were 16.36 and 5.60 mg/kg, respectively. The margin of exposure to difenoconazole in GS, ALF and SLF were, respectively, 8.66 × 105 to 5.28 × 106 , 8.97 × 105 to 5.47 × 106 and 7.28 × 105 to 4.44 × 106 . CONCLUSION: The risk assessment results indicate that under all circumstances, applying difenoconazole is safe for populations around farmland. However, a fan-shaped nozzle, suspension concentrate and greater inhalation height increase the risk of inhalation. © 2023 Society of Chemical Industry.

Preclinical safety assessment of an oncolytic herpes simplex virus type 2 expressed PD-L1/CD3 bispecific antibody.

Oncolytic virotherapy is an emerging and safe therapeutic approach based on the inherent cytotoxicity of oncolytic viruses and their ability to replicate and spread within tumors in a selective manner. We constructed a new type of oncolytic herpes simplex virus armed with Bispecific Antibody (BsAb) molecules targeting PD-L1/CD3 (oHSV2-PD-L1/CD3-BsAb) to treat human malignancies. We demonstrated the anti-tumor efficacy of oHSV2-PD-L1/CD3-BsAb. To move forward with clinical trials of oHSV2-PD-L1/CD3-BsAb, we conducted a comprehensive preclinical safety evaluation, including hemolysis test, anaphylaxis test, repeated dose toxicity test in cynomolgus monkeys, biodistribution in cynomolgus monkeys and tissue cross-reactivity of PD-L1/CD3-BsAb with human and cynomolgus monkey tissues in vitro. Our preclinical safety evaluation indicated that oHSV2-PD-L1/CD3-BsAb is safe and suitable for clinical trials. After undergoing a thorough evaluation by the United States Food and Drug Administration (FDA), oHSV2-PD-L1/CD3-BsAb has successfully obtained approval to initiate Phase I clinical trials in the United States (FDA IND: 28717).

The impact of antimicrobial management by clinical pharmacists in obstetrics and gynecology on antimicrobial indicators, bacterial resistance and drug costs from 2011 to 2021 in China.

Objectives: The goal of our study is to analyze the effectiveness and role of clinical pharmacists in antibiotic management through retrospective research from 2011 to 2021, depending on the current scenario of the antibiotic application in China. Methods: We formed a team of pharmacists to carry out multifaceted intervention measures, such as forming a working group, developing a plan, establishing management rules via the pre-trial system, prescription comments, collaborating with the administrative department, implementing training and publicity, and so on. Antibiotic use was studied, bacterial drug resistance was determined, and antibiotic costs were computed. Results: The pharmacist intervention and rectification of inappropriate antibacterial drug orders considerably enhanced the rational use rate of antibiotics and reduced the cost of antibiotics. Antibiotic use in clean surgery decreased from 90.22% to 11.14%, the use rate of antibiotics decreased from 63.82% to 30.26%, and antibiotic use intensity decreased from 42.75DDDs to 30.04DDDs. The types, timing, and course of antibacterials used in wards were all improved to varying degrees. Bacterial drug resistance improved noticeably, with resistance of Escherichia coli to cephalosporins, ciprofloxacin and carbapenems decreased in varying degrees. The use of antibacterial drugs has decreased significantly. Conclusions: It is feasible and effective for pharmacists in gynecology and obstetrics to control antibiotic use, which plays a positive role in promoting the safe, effective, and cost-effective use of antibiotics and serves as a valuable reference for the antibiotic management.

Organochlorine pesticides (OCPs) in freshwater resources of Pakistan: A review on occurrence, spatial distribution and associated human health and ecological risk assessment.

The extensive use of organochlorine pesticides (OCPs) has resulted in the widespread contamination of different environmental matrices in Pakistan. Freshwater bodies are also prone to OCPs contamination as they receive agricultural and industrial runoff from different sources. In the present study, the data regarding OCPs' fate and distribution in freshwater resources of Pakistan was reviewed and associated risks to human and ecological health were assessed. Among all the OCPs, DDTs were more prevalent with the highest mean concentration of 2290 ng/L observed in River Ravi (Lahore and Sahiwal District). Human health risk assessment showed a higher risk to the children with high Hazard Quotient (HQ) values ranging between 4.1 × 10-9- 295 for Aldrin. The River Ravi (Lahore and Sahiwal District), the River Sutlej (Kasur & Bahawalpur District), and the River Kabul (Nowshehra District) were categorized as high-risk water bodies based on Hazard Index (HI) and Non-Cancer Risk (CRI) index values > 10. Ecological risk assessment revealed a higher risk posed to invertebrate species from DDT exposure. In summary, this review highlights the occurrence and distribution of OCPs and their associated human health and ecological risks in freshwater bodies of Pakistan and also contributes to signifying the need for proper management and regulation of banned pesticides and future research perspectives.

Excavating the social representations and perceived barriers of organ donation in China over the past decade: A hybrid text analysis approach.

Background: Organ donation has been claimed as a prosocial behavior to prolong the recipient's life and deliver great love. However, the supply-demand ratio of organs in China is highly unbalanced. Being entangled with multiple factors derived from individual and supra-individual levels, organ donation in China is important but sensitive. Previous scholars usually depended on obtrusive approaches to explore the facilitators and hindrances of organ donation, which is hard to discover genuine perceptions toward organ donation. Besides, relatively limited scholarly attention has been paid to what hampers organ donation in China. Objective: We intended to excavate the diversified social representations and perceived barriers to organ donation in China over the past decade. Method: Two kinds of text analysis methods-semantic network analysis and conventional content analysis, were applied to 120,172 posts from ordinary users on the Sina Weibo platform to address the research questions. Results: Regarding social representations, the "hope, understanding, and acceptance" of organ donation was the most pronounced one (34% of the whole semantic network), followed by "family story" (26%), "the procedure of organ donation in NGOs" (15%), "the practical value of organ donation" (14%), and "organ donation in the medical context" (11%). Regarding perceived barriers, a four-layer framework was constructed, including (1) the individual level, mainly about the fear of death and postmortem autopsy; (2) the familial level, which refers to the opposition from family members; (3) the societal level, which alludes to distrust toward medical institutions and the general society; (4) the cultural level, which covers religious-cultural concerns about fatalism. Conclusion: In concordance with prior works on social representations regarding organ donation, the current study also uncovered the coexistence of antithetical representations about organ donation-the longing for survival and the fear of death. This representation pair serves as the foundation of Chinese people's ambivalence. Besides, family-related narratives were dispersed over various representations, demonstrating the critical position of family support in organ donation. Moreover, the four-layer framework concerning donation barriers affords a reference for future empirical studies. The practical implications of this work are further discussed.

[Determination of polychlorinated naphthalenes in soil using accelerated solvent extraction-molecular sieves solid-phase extraction coupled with gas chromatography-tandem mass spectrometry].

Emerging pollutants (EPs) are chemical substances that are commonly not regulated and can be detected at low or very low concentrations. However, EPs have triggered special concern because their long-term adverse effects on the environment and human health remain unknown. Most EPs show biological toxicity, environmental persistence, and bioaccumulation. Even at low concentrations in the environment, EPs may pose significant environmental and health risks. Therefore, their treatment has been explicitly included in the 14th Five Year Plan for National Economic and Social Development of the People's Republic of China and the Outline of the Long-term Goals for 2035. Soil is a source of pollutants, and its quality is directly related to economic development, ecological security, and people's livelihood. At present, China's soil environmental monitoring system is not perfect, and the ability to monitor these new organic pollutants is lagging. Therefore, to strengthen the supervision of construction and agricultural land soil environments, it is essential to strengthen the soil environment monitoring ability for these EPs and establish a reliable, steady, and economic analysis method, including their separation and analysis methods in soil. Polychlorinated naphthalenes (PCNs) have received considerable attention as emerging halogenated compounds. They were listed in Annexes A and C of the Stockholm Convention on persistent organic pollutants (POPs) in 2015 because of their persistence, multimedia fate, and toxicity. PCNs have now been detected in the surrounding soils. Owing to their trace levels in complex soil, high requirements have been put forward for the pretreatment and instrument analysis of PCNs. This study aims to develop a new method for the selective purification of PCNs in soil, which can not only effectively remove lipids and other interferences in soil but also effectively reduce time, labor, and material costs in the pre-treatment process. Based on the physicochemical properties of the 13X molecular sieve, it was explored to purify soil-extracts as solid-phase extraction (SPE) sorbents. With n-hexane as the loading and rinsing solvent, 10 mL of a dichloromethane/n-hexane mixture (2∶15, v/v) was used to elute the PCNs. Moreover, selective separation of target substances from lipid macromolecules and other interferences could be achieved simultaneously. For the selective separation of PCNs, the average recovery of the internal standard could reach 56.1% to 88.0%. 13X molecular sieves are superior to gel permeation chromatography (GPC) and Florisil SPE, and they exhibit good cleanup efficiency similar to a multilayer silica gel/alumina column (53.0%-117.0%). Although the obtained recoveries are not as high as those obtained with a multilayer silica gel/alumina column, 13X molecular sieves have advantages in terms of simple operation, environmental friendliness, and low cost. Based on these fundamental experiments, accelerated solvent extraction was used to extract targets in soil, molecular sieves were used as SPE sorbents for purification, and GC-MS/MS was employed for PCN analysis. This method was developed as a systematic analytical method for PCNs determination. The method detection limits (MDLs) for PCN homologs were in the range of 0.009-0.6 ng/g. The precision and accuracy of the method were evaluated using spiked matrices. At three spiked levels (4, 10, and 18 ng), the recoveries of PCNs (CN-3, 13, 42, 46, 52, 53, 73, and 75) were 70%-128%, 71%-115%, and 61%-114%, respectively, and the corresponding relative standard derivations were 4.2%-23%, 6.5%-31% and 4.7%-22%. Thus, this method meets the requirements of trace analysis and shows acceptable parallelism, sensitivity, accuracy, and precision, thus being feasible for the analysis of emerging pollutant. The method is expected to play an important role in sample pretreatment in the future, especially for the nationwide investigation of soil pollution.

Research on the Heterogeneity of Carbon Emissions under the Government's Promotion of Urban Agglomeration Development: Empirical Evidence from County-to-District Reforms.

County-to-district reform (CTDR) is an important policy path for the government to promote the cultivation and construction of urban agglomerations, and exploring its "carbon emission" effect is of great significance for the high-quality development of urban agglomerations and the realization of the "dual carbon" goal. Based on the panel data of 120 counties in the Yangtze River Delta urban agglomeration from 2000-2017, this paper empirically tests the effect of county-to-district reforms on per capita carbon emissions in the counties of the central and peripheral cities of the Yangtze River Delta urban agglomeration under the Kutznets curve (EKC) hypothesis and the integrated difference-in-difference (DID) model and STIRPAT model. The results show that: (1) The carbon emission effect of county-to-district reforms have significant regional heterogeneity. The reforms of the central city of the urban agglomeration significantly reduced the per capita carbon emission of the county by 4.27%, whereas the reforms of the periphery cities of the urban agglomeration significantly increased per capita carbon emission by 6.56%. (2) The impact of county-to-district reforms on county per capita carbon emissions began to appear in the fourth year of reform. (3) Mechanism analysis showed that county-to-district reforms promoted central cities population agglomeration and reduction of carbon emission intensity can help reduce the per capita carbon emission level in counties, whereas peripheral cities have a dual carbon-increasing effect of decreasing population density and increasing carbon emission intensity. Therefore, the approval of county-to-district reforms should be strictly controlled, and the reform of non-central cities would be especially prudent, so as to reduce the negative effect of reform on the high-quality development of cities.

Temporal Variations in Seroprevalence of Severe Acute Respiratory Syndrome Coronavirus 2 Infections by Race and Ethnicity in Arkansas.

Background: The aim of this study was to estimate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates in the small rural state of Arkansas, using SARS-CoV-2 antibody prevalence as an indicator of infection. Methods: We collected residual serum samples from adult outpatients seen at hospitals or clinics in Arkansas for non-coronavirus disease 2019 (COVID-19)-related reasons. A total of 5804 samples were identified over 3 time periods: 15 August-5 September 2020 (time period 1), 12 September-24 October 2020 (time period 2), and 7 November-19 December 2020 (time period 3). Results: The age-, sex-, race-, and ethnicity-standardized SARS-CoV-2 seroprevalence during each period, from 2.6% in time period 1 to 4.1% in time period 2 and 7.4% in time period 3. No statistically significant difference in seroprevalence was found based on age, sex, or residence (urban vs rural). However, we found higher seroprevalence rates in each time period for Hispanics (17.6%, 20.6%, and 23.4%, respectively) and non-Hispanic Blacks (4.8%, 5.4%, and 8.9%, respectively) relative to non-Hispanic Whites (1.1%, 2.6%, and 5.5%, respectively). Conclusions: Our data imply that the number of Arkansas residents infected with SARS-CoV-2 rose steadily from 2.6% in August to 7.4% in December 2020. There was no statistical difference in seroprevalence between rural and urban locales. Hispanics and Blacks had higher rates of SARS-CoV-2 antibodies than Whites, indicating that SARS-CoV-2 spread disproportionately in racial and ethnic minorities during the first year of the COVID-19 pandemic.

Assessment and validation of the internal gross tumour volume of gastroesophageal junction cancer during simultaneous integrated boost radiotherapy.

BACKGROUND: Respiratory motion may introduce errors during radiotherapy. This study aims to assess and validate internal gross tumour volume (IGTV) margins in proximal and distal borders of gastroesophageal junction (GEJ) tumours during simultaneous integrated boost radiotherapy. METHODS: We enrolled 10 patients in group A and 9 patients in group B. For all patients, two markers were placed at the upper and lower borders of the tumour before treatment. In group A, within the simulation and every 5 fractions of radiotherapy, we used 4-dimensional computed tomography (4DCT) to record the intrafractional displacement of the proximal and distal markers. By fusing the average image of each repeated 4DCT with the simulation image based on the lumbar vertebra, the interfractional displacement could be obtained. We calculated the IGTV margin in the proximal and distal borders of the GEJ tumour. In group B, by referring to the simulation images and cone-beam computed tomography (CBCT) images, the range of tumour displacement in proximal and distal borders of GEJ tumour was estimated. We calculated the proportion of marker displacement range in group B lay within the IGTV margin calculated based on the data obtained in group A to estimate the accuracy of the IGTV margin. RESULTS: The intrafractional displacement in the cranial-caudal (CC) direction was significantly larger than that in the anterior-posterior (AP) and left-right (LR) directions for both the proximal and distal markers of the tumour. The interfractional displacement in the AP and LR directions was larger than that in the CC direction (p = 0.001, p = 0.017) based on the distal marker. The IGTV margins in the LR, AP and CC directions were 9 mm, 8.5 mm and 12.1 mm for the proximal marker and 15.8 mm, 12.7 mm and 11.5 mm for the distal marker, respectively. In group B, the proportions of markers that located within the IGTV margin in the LR, AP and CC directions were 96.5%, 91.3% and 96.5% for the proximal marker and 100%, 96.5%, 93.1% for the distal marker, respectively. CONCLUSIONS: Our study proposed individualized IGTV margins for proximal and distal borders of GEJ tumours during neoadjuvant radiotherapy. The IGTV margin determined in this study was acceptable. This margin could be a reference in clinical practice.

Cost-effectiveness of postmastectomy hypofractionated radiation therapy vs conventional fractionated radiation therapy for high-risk breast cancer.

BACKGROUND: The phase 3 NCT00793962 trial demonstrated that postmastectomy hypofractionated radiation therapy (HFRT) was noninferior to conventional fractionated radiation therapy (CFRT) in patients with high-risk breast cancer. This study assessed the cost-effectiveness of postmastectomy HFRT vs CFRT based on the NCT00793962 trial. METHODS: A Markov model was adopted to synthesize the medical costs and health benefits of patients with high-risk breast cancer based on data from the NCT00793962 trial. Main outcomes were discounted lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). We employed a time-dependent horizon from Chinese, French and USA payer perspectives. Model robustness was evaluated with one-way and probabilistic sensitivity analyses. RESULTS: Patients receiving CFRT versus HFRT gained an incremental 0.0163 QALYs, 0.0118 QALYs and 0.0028 QALYs; meanwhile an incremental cost of $2351.92, $4978.34 and $8812.70 from Chinese, French and USA payer perspectives, respectively. Thus CFRT versus HFRT yielded an ICER of $144,281.47, $420,636.10 and $3,187,955.76 per QALY from Chinese, French and USA payer perspectives, respectively. HFRT could maintain a trend of >50% probabilities of cost-effectiveness below a willingness-to-pay (WTP) of $178,882.00 in China, while HFRT was dominant relative to CFRT, regardless of the WTP values in France and the USA. Sensitivity analyses indicated that the ICERs were most sensitive to the parameters of overall survival after radiotherapy. CONCLUSIONS: Postmastectomy HFRT could be used as a cost-effective substitute for CFRT in patients with high-risk breast cancer and should be considered in appropriately selected patients.

Safety and efficacy of preoperative chemoradiotherapy in fit older patients with intermediate or locally advanced rectal cancer evaluated by comprehensive geriatric assessment: A planned interim analysis of a multicenter, phase II trial.

BACKGROUND AND PURPOSE: Comprehensive geriatric assessment (CGA) is a diagnostic method to assess the physical and mental health status of older patients. The purpose of this study was to assess the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for intermediate or locally advanced rectal cancer in older people who were classified as "fit" by CGA. The interim analysis focusing on safety was reported here as the first part of this trial. METHODS AND MATERIALS: This is a single arm, multicenter, phase II trial. The eligible patients for this study were aged 70 years or above that fulfilled the standard of intermediate or locally advanced risk category, and met the standard of fit (SIOG1) evaluated by CGA. All patients received preCRT (50 Gy) with Raltitrexed (3 mg/m2 on d1 and d22). Qualitative and quantitative variables were described using descriptive statistics. The surgery adherence predicting was analyzed by multivariate logistic regression. RESULTS: Thirty-nine fit patients were enrolled. All patients except one finished radiotherapy without dose reduction. Thirty-two patients finished the prescribed Raltitrexed therapy as scheduled. A serious toxicity was observed in 12 patients (30.8%), and only six patients (15.4%) experienced non-hematological side effects. CONCLUSION: Overall, our results showed that preCRT was feasible and safe in older patients with rectal cancer who were evaluated as fit based on CGA, supporting the use of CGA to tailor oncological treatment and predict the tolerance of a specific therapy. Completing this trial as planned would provide further valuable insights.

MicroRNA-31-5p Exacerbates Lipopolysaccharide-Induced Acute Lung Injury via Inactivating Cab39/AMPKα Pathway.

Acute lung injury (ALI) and the subsequent acute respiratory distress syndrome remain devastating diseases with high mortality rates and poor prognoses among patients in intensive care units. The present study is aimed at investigating the role and underlying mechanisms of microRNA-31-5p (miR-31-5p) on lipopolysaccharide- (LPS-) induced ALI. Mice were pretreated with miR-31-5p agomir, antagomir, and their negative controls at indicated doses for 3 consecutive days, and then they received a single intratracheal injection of LPS (5 mg/kg) for 12 h to induce ALI. MH-S murine alveolar macrophage cell lines were cultured to further verify the role of miR-31-5p in vitro. For AMP-activated protein kinase α (AMPKα) and calcium-binding protein 39 (Cab39) inhibition, compound C or lentiviral vectors were used in vivo and in vitro. We observed an upregulation of miR-31-5p in lung tissue upon LPS injection. miR-31-5p antagomir alleviated, while miR-31-5p agomir exacerbated LPS-induced inflammation, oxidative damage, and pulmonary dysfunction in vivo and in vitro. Mechanistically, miR-31-5p antagomir activated AMPKα to exert the protective effects that were abrogated by AMPKα inhibition. Further studies revealed that Cab39 was required for AMPKα activation and pulmonary protection by miR-31-5p antagomir. We provide the evidence that endogenous miR-31-5p is a key pathogenic factor for inflammation and oxidative damage during LPS-induced ALI, which is related to Cab39-dependent inhibition of AMPKα.

Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections.

The clinical features and immune responses of asymptomatic individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been well described. We studied 37 asymptomatic individuals in the Wanzhou District who were diagnosed with RT-PCR-confirmed SARS-CoV-2 infections but without any relevant clinical symptoms in the preceding 14 d and during hospitalization. Asymptomatic individuals were admitted to the government-designated Wanzhou People's Hospital for centralized isolation in accordance with policy1. The median duration of viral shedding in the asymptomatic group was 19 d (interquartile range (IQR), 15-26 d). The asymptomatic group had a significantly longer duration of viral shedding than the symptomatic group (log-rank P = 0.028). The virus-specific IgG levels in the asymptomatic group (median S/CO, 3.4; IQR, 1.6-10.7) were significantly lower (P = 0.005) relative to the symptomatic group (median S/CO, 20.5; IQR, 5.8-38.2) in the acute phase. Of asymptomatic individuals, 93.3% (28/30) and 81.1% (30/37) had reduction in IgG and neutralizing antibody levels, respectively, during the early convalescent phase, as compared to 96.8% (30/31) and 62.2% (23/37) of symptomatic patients. Forty percent of asymptomatic individuals became seronegative and 12.9% of the symptomatic group became negative for IgG in the early convalescent phase. In addition, asymptomatic individuals exhibited lower levels of 18 pro- and anti-inflammatory cytokines. These data suggest that asymptomatic individuals had a weaker immune response to SARS-CoV-2 infection. The reduction in IgG and neutralizing antibody levels in the early convalescent phase might have implications for immunity strategy and serological surveys.

Magnetic Nanoparticle-Based Automatic Chemiluminescent Enzyme Immunoassay for Golgi Protein 73 and the Clinical Assessment.

Golgi protein 73 (GP73) is an independent diagnostic indicator of cirrhosis. However, it lacks automatic detection techniques to meet the large-scale clinical requirement in physical examination. In this paper, an automatic approach was established based on the ACL2800 automatic chemiluminescent analyzer, using magnetic nanoparticles (MNPs) and chemiluminescence. This method depended on sandwich strategy among biotin-labeled capture monoclonal antibody, target GP73 and acridinium ester (AE)-labeled reporter monoclonal antibody, conjugation of streptavidin-labeled MNPs to biotin-labeled capture monoclonal antibody, and chemiluminescent detection of AE-linked targets. Optimal conditions were investigated and clinical assessment was processed. Detection of GP73 demonstrated a high sensitivity of 1.19 ng/mL with a wide range from 1.34 ng/mL to 684.38 ng/mL. The quantitative detection was achieved with the repeatability of 2.69%, the coefficient of variation of 3.55% and the percent recovery of 93.46%-107.82%. Therefore, an automatic quantitative detection method was successfully developed, which was a potential screening method in physical examination.