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Data Availability
The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.
PMC10173559
Declarations
PMC10173559
Competing interests
The authors declare that they have no competing interests
PMC10173559
Ethics approval and consent to participate
This study was reviewed and approved by the Makerere University School of Public Health’s Research and Ethics Committee (Protocol #: 825) and cleared by the Uganda National Council for Science and Technology (UNCST). All participants provided written informed consent prior to participation in the study. All study proce...
PMC10173559
Consent for publication
Not applicable.
PMC10173559
References
PMC10173559
Subject terms
PD-L1-positive esophageal squamous cell carcinoma, ESCC
OESOPHAGEAL SQUAMOUS CELL CARCINOMA
First-line systemic therapeutic options for advanced esophageal squamous cell carcinoma (ESCC) are limited. In this multicenter, double-blind phase 3 trial, a total of 551 patients with previously untreated, locally advanced or metastatic ESCC and PD-L1 combined positive score of ≥1 were randomized (2:1) to receive ser...
PMC9941045
Main
esophageal cancer, death, ESCC
OESOPHAGEAL CANCER, ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer and accounts for approximately 84% of all esophageal cancer casesSystemic chemotherapy remains the backbone of treatment of unresectable or metastatic ESCC. Although 5-fluorouracil (5-FU) or paclitaxel plus cisplatin ...
PMC9941045
Results
PMC9941045
Patients and treatment
A total of 976 patients were screened between 19 June 2019 and 17 December 2021, and 551 of them were randomly assigned to serplulimab plus chemotherapy (
PMC9941045
Efficacy
DISEASE PROGRESSION
At the data cutoff date, 219 (60%) patients in the serplulimab plus chemotherapy group and 129 (70%) in the placebo plus chemotherapy group had disease progression or had died. At the time of this final PFS analysis, serplulimab plus chemotherapy met the criteria for superiority in prolonging PFS over placebo plus chem...
PMC9941045
Discussion
esophageal cancer, tumor, death, ESCC, treatment-related adverse
TUMOR, OESOPHAGEAL CANCER, ADVERSE EVENTS, SOLID TUMORS, MICROSATELLITE INSTABILITY, SECONDARY, LUNG METASTASES, CPS, METASTASES
In this double-blind, placebo-controlled, randomized phase 3 study, we evaluated the efficacy and safety of first-line serplulimab plus chemotherapy versus placebo plus chemotherapy in patients with locally advanced or metastatic, PD-L1-positive (CPS ≥ 1) ESCC. In our prespecified final analysis for PFS and interim ana...
PMC9941045
Methods
PMC9941045
Ethics statement
Cancer Center/Cancer
The study was performed in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The study protocol was approved by the institutional review boards or ethics committees of all participating centers (the ethics committee of the leading clinical c...
PMC9941045
Study design and participants
ASTRUM-007 was a randomized, placebo-controlled, double-blind, phase 3 clinical study conducted at 70 hospitals in China (Supplementary Table
PMC9941045
Randomization and masking
CPS, DISEASE
Eligible patients were randomly assigned (2:1) using an integrated web response system to receive serplulimab plus chemotherapy or placebo plus chemotherapy. Randomization was stratified by PD-L1 expression level (CPS ≥ 10 versus CPS < 10), age (≥65 years versus <65 years) and disease status (locally advanced versus di...
PMC9941045
Procedures
Cancer
ADVERSE EVENT, ADVERSE EVENT, CANCER
Patients received serplulimab or placebo (3 mg kgTumor imaging was scheduled once every 6 weeks for 48 weeks from randomization and every 12 weeks thereafter. Response was assessed according to RECIST v1.1 by the blinded IRRC and the investigators locally. During follow-up, patients were contacted every 12 weeks to ass...
PMC9941045
Outcomes
death
DISEASE PROGRESSION
The dual primary endpoints were PFS (time from randomization to first disease progression or death) assessed by the IRRC in accordance with RECIST v1.1 and OS (time from randomization to death due to any cause). Secondary endpoints included IRRC-assessed PFS using iRECIST
PMC9941045
Statistical analysis
REGRESSION, EVENTS
The planned sample size was 540 patients, with 339 PFS events and 388 OS events needed to achieve a power of 80% to show an HR of 0.68 for PFS at a one-sided α level of 0.005 and an HR of 0.73 for OS at a one-sided α level of 0.02 for comparison between the serplulimab plus chemotherapy group and the placebo plus chemo...
PMC9941045
Reporting summary
Further information on research design is available in the
PMC9941045
Online content
Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-022-02179-2.
PMC9941045
Supplementary information
Supplementary Table 1, study protocol and statistical analysis plan.Reporting Summary
PMC9941045
Extended data
PMC9941045
Extended data
is available for this paper at 10.1038/s41591-022-02179-2.
PMC9941045
Supplementary information
The online version contains supplementary material available at 10.1038/s41591-022-02179-2.
PMC9941045
Acknowledgements
This study was funded by Shanghai Henlius Biotech, Inc. We thank the patients, their families and the study personnel involved in this trial. We thank the clinical study team (clinical operations, Lu Luo, Guiyu Yang and Haoyu Yu; statistics, Xiao Qi and Jianchen Cheng) and Wenjie Zhang from Shanghai Henlius Biotech, In...
PMC9941045
Author contributions
J.H. and Q.W. contributed to the conception, design and planning of the study. All authors contributed to the acquisition of data. B.Z., J.H., Y.S. and Q.W. contributed to the writing of the manuscript, and all authors contributed to critical review and revision of the manuscript. J.H. had full access to all of the dat...
PMC9941045
Peer review
PMC9941045
Data availability
huangjingwg@163.com, Cancer
CANCER
All requests for data will be reviewed by the leading clinical site (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College) and the sponsor (Shanghai Henlius Biotech, Inc) to verify whether the request is subject to any ...
PMC9941045
Code availability
No custom code was used for statistical analysis in this study.
PMC9941045
Competing interests
ONCOLOGY
Y.K., J.L., Q.W. and J.Z. are employees of Shanghai Henlius Biotech, Inc. J.H. has served a consulting or advisory role for Merck Sharp & Dohme Oncology and Roche. All other authors declare no competing interests.
PMC9941045
References
PMC9941045
Introduction
Edited by: Mrinmoy Sanyal, Stanford University, United StatesReviewed by: Lei Li, Oracle, Australia; Larry Ellingsworth, Novavax, Inc., United States†These authors have contributed equally to this workThe SARS-CoV-2 Omicron variant has become the dominant SARS-CoV-2 variant and exhibits immune escape to current COVID-1...
PMC10585368
Methods
ADENOVIRUS
We have conducted a non-randomized, open-label and parallel-controlled phase 4 trial to evaluate the magnitude and longevity of immune responses to booster vaccination with intramuscular adenovirus vectored vaccine (Ad5-nCoV), aerosolized Ad5-nCoV, a recombinant protein subunit vaccine (ZF2001) or homologous inactivate...
PMC10585368
Results
SARS-CoV-2-specific mucosal IgA
The aerosolized Ad5-nCoV induced the most robust and long-lasting neutralizing activity against Omicron variant and IFNg T-cell response among all the boosters, with a distinct mucosal immune response. SARS-CoV-2-specific mucosal IgA response was substantially generated in subjects boosted with the aerosolized Ad5-nCoV...
PMC10585368
Discussion
Our findings suggest that aerosolized Ad5-nCoV may provide an efficient alternative in response to the spread of the Omicron BA.4/5 variant.
PMC10585368
Clinical trial registration
PMC10585368
Introduction
More than 6.8 million people have died from COVID-19 worldwide since the start of the pandemic (More than 100 countries worldwide have already issued recommendations on booster or additional vaccination (In China, seven COVID-19 vaccines have been authorized for use, including five inactivated vaccines, an adenovirus-v...
PMC10585368
Materials and methods
PMC10585368
Study design
This study was a non-randomized, open-label and parallel-controlled phase 4 trial (ChiCTR2200057278). 904 eligible participants were randomly assigned to four groups using computer-generated random numbers in SPSS, to receive one dose of Ad5-nCoV via intramuscular injection (Ad5-nCoV-IM, 5×10
PMC10585368
Vaccines
All COVID-19 vaccines in this study were developed based on the SARS-CoV-2 wild-type strain (Wuhan-Hu-1 strain) isolated in December 2019. Ad5-nCoV (Convidecia) is a replication-defective human type 5 adenovirus-vectored vaccine, encoding the full-length Spike gene of the Wuhan-Hu-1 strain (YP_009724390) (
PMC10585368
RBD-binding IgG assay
SECONDARY
RBD-binding IgG antibodies in the heat-inactivated human serum samples and the culture supernatant of PBMCs stimulated for 4 days with R848 + IL-2 were detected with an RBD-binding IgG ELISA kit (Beijing, Kewei). Briefly, diluted samples and a reference standard were added in duplicate to rSARS-CoV-2 RBD-precoated well...
PMC10585368
Coronavirus-specific saliva IgA assay
IgA
CORONAVIRUS
Saliva samples were collected by centrifugation after having each subject spit about 2 mL of saliva into a disposable saliva sample collector (HUAXIA Medical Equipment). Coronavirus-specific IgA was tested with a SARS-CoV-2 specific (COVID-19 Coronavirus Panel 2) Mesoscale Discovery (MSD) immunoassay. According to the ...
PMC10585368
Pseudotype-based neutralization assays
The generation of SARS-CoV-2 Pseudoviruses was performed using the human immunodeficiency virus (HIV) pseudotyped virus production system (Neutralizing activity in each sample was measured with a serial dilution approach as Nie et al. reported (
PMC10585368
RBD-ACE2 competitive binding assay
RBD
VIRUS
The RBD neutralizing antibody against the different SARS-CoV-2 variants was evaluated using a commercial ELISA kit (Vazyme) by a surrogate virus neutralization test (sVNT). Sera are serially diluted by 3-fold from 1:5 to 1:1215 or 1:10935 with horseradish peroxidase-labeled recombinant RBD (HRP-RBD) protein and incubat...
PMC10585368
Spike-specific IgG ELISpot assays
Spike-specific IgG ELISpot assays were performed on R848- and IL-2-activated PBMCs with a human IgG ELISpot Kit (Mabtech). Briefly, fresh PBMCs were activated with a mixture of R848 at 1 μg ml
PMC10585368
IFNγ ELISpot assays
STERILE
IFNγ ELISpot assays were performed with fresh PBMCs and a human IFNγ ELISpot Kit (Mabtech) following the manufacturer’s instructions. Tests were performed in duplicate. The precoated ELISpot plates were washed with sterile PBS and blocked with RPMI 1640 medium containing 10% fetal bovine serum and 1× penicillin–strepto...
PMC10585368
Statistical analysis
All analyses of participant samples were conducted using GraphPad Prism 8.0.2 or SAS 9.4. Levels of antibodies against SARS-CoV-2 are presented as the median concentration or median titer with IQR. Spike-specific IgG spots and IFNγ responses are depicted as the median with IQR. Categorical data were analyzed by the χ
PMC10585368
Results
PMC10585368
Baseline characteristics of the participants
In this study, 904 subjects who received two doses of inactivated vaccine 6 months prior were assigned to 4 groups for booster vaccination (Trial profile.Baseline characteristics of the participants.Data are n (%) or median. Seropositivity for neutralizing antibody against SARS-CoV-2 from a subset of participants in ea...
PMC10585368
SARS-CoV-2-specific serum IgG and mucosal IgA responses
Concentrations of anti-SARS-CoV-2 IgG and IgA antibodies were assessed before and after the boost. (Wild-type SARS-CoV-2 RBD-specific binding antibody responses. The level of saliva IgA at day 0 and 14 after boost was also measured to evaluate the mucosal immune response induced by different vaccines. An obvious increa...
PMC10585368
Pseudotyped SARS-CoV-2 neutralizing antibody responses
Before booster vaccination, only 6.3%~11.8% of participants had a weak wild-type pseudovirus neutralizing antibody (PNAb) titer. Generation of PNAb against wild-type SARS-CoV-2 was significantly increased after booster vaccination in all groups (Pseudotyped SARS-CoV-2 neutralizing antibody responses. Similar kinetics w...
PMC10585368
SARS-COV-2 surrogate virus neutralization antibody response
The breadth and magnitude of neutralizing antibody responses to various SARS-CoV-2 variants were investigated via an SARS-CoV-2 Surrogate Virus Neutralization Test (sVNT) based on the RBD-ACE2 competitive binding assay. In all the groups, the better antibody responses were against wild-type strain, Alpha and Delta vari...
PMC10585368
Spike-specific IgG B-cell responses
To further investigate the ability of the boosters to induce antigen-specific B-cell responses, spike-specific IgG spots were detected at baseline and at 28 days and 6 months after booster vaccination in R848-activated peripheral blood mononuclear cells (PBMCs) (Wild-type SARS-CoV-2 spike-specific IgG B-cell responses....
PMC10585368
Spike-specific IFNγ responses
Spike-specific IFNγ responses were detected at days 0, 14, 28 and month 6 after booster vaccination to determine the T-cell responses (SARS-CoV-2 spike-specific IFNγ ELISpot responses.
PMC10585368
Discussion
T-cell immunity, infection, dimer vaccine
INFECTION
In China, where more than 95% of individuals vaccinated against COVID-19 received inactivated vaccines, we evaluated the immunogenicity of homologous and heterologous boosters in adults who received prime vaccination with two doses of the inactivated COVID-19 vaccine approximately 6 months prior. Both homologous and he...
PMC10585368
Data availability statement
The original contributions presented in the study are included in the article/
PMC10585368
Ethics statement
The studies involving humans were approved by the Ethics Committee of 305 Hospital of PLA. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.
PMC10585368
Author contributions
MH, ZHZ
RECRUITMENT
YS is the principal investigator of this trial. WC, LH, YWL, and KL designed the trials and the study protocol. ZZ and SW drafted the manuscript. WC and LH contributed to critical review and revising of the report. ZZ, SW, YWL, and KL contributed to data interpretation and revising the manuscript. SW led laboratory ana...
PMC10585368
Conflict of interest
TZ is the employee of CanSino Biologics and has stock options in CanSino Biologics.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
PMC10585368
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or ...
PMC10585368
Supplementary material
REGRESSION
The Supplementary Material for this article can be found online at: RBD-specific IgG reverse cumulative distribution curves. Reverse cumulative distribution curves denote the percentage of participants in each group that reach a different level of antibody concentration at days 0, 7, 14, 28 and months 3 and 6 after the...
PMC10585368
References
PMC10585368
Background
SECONDARY, HOLIDAY
Emerging evidence suggests that children’s fatness increases and fitness declines at a greater rate during the summer holiday period, compared with the school year. The aim of this study was to compare rates of change in fitness and fatness over the in-term and summer holiday periods among Australian schoolchildren. A ...
PMC10601165
Methods
HOLIDAY
Children (n = 381) initially in Grade 4 (age 9) were recruited for this 2-year longitudinal study. Fatness (% body fat, BMI z-score, waist-to-height ratio) and fitness (20-m shuttle run and standing broad jump) were measured at the start and end of two consecutive years. Rates of change were calculated for the two in-s...
PMC10601165
Results
overweight
HOLIDAYS
During the holidays, percentage body fat increased at a greater rate (annualised rate of change [RoC]: +3.9 vs. Grade 4 and + 4.7 vs. Grade 5), and aerobic fitness declined at a greater rate (RoC − 4.7 vs. Grade 4 and − 4.4 vs. Grade 5), than during the in-school periods. There were no differences in rates of change fo...
PMC10601165
Conclusion
HOLIDAY
This study highlights that during the summer holiday period, children experience greater increases in fatness and declines in fitness, with children who live with low-SES families and are overweight being more affected. The findings suggest the need for targeted interventions during this period to address these negativ...
PMC10601165
Trial registration
Australia New Zealand Clinical Trials Registry, identifier ACTRN12618002008202. Retrospectively registered on 14 December 2018.
PMC10601165
Supplementary Information
The online version contains supplementary material available at 10.1186/s12889-023-17009-4.
PMC10601165
Keywords
PMC10601165
Background
HOLIDAYS, SECONDARY, HOLIDAY
Physical fitness and body composition play a crucial role in the overall health and wellbeing of children [Recent research suggests that increases in fatness and declines in aerobic fitness in children occur at a greater rate during the school summer holiday period compared to the school year [The “Structured Days Hypo...
PMC10601165
Materials and methods
PMC10601165
Participants
The participants in this study were drawn from the
PMC10601165
Measures
The dependent variables were measures of fatness (percentage body fat, Body Mass Index (BMI) z-score and waist-to-height ratio) and fitness (maximal aerobic power, standing broad jump). Each child’s height was measured using a Seca 213 stadiometer (Seca, Hamburg, Germany), and weight and percentage body fat (The Pubert...
PMC10601165
Bias
Numerous efforts were made to minimise study biases. In particular, a randomised stratified sampling methodology was used. Outcomes were gathered using high-quality tools and protocols with established reliability and validity. Research personnel were thoroughly trained, and participant retention was maximised through ...
PMC10601165
Sample size justification
Full details of the power calculation are provided in the study protocol [
PMC10601165
Analysis
HOLIDAY
Figure  Schematic of data treatment to extrapolate the rates of change in fatness and fitness across Grade 4, Grade 5 and the holiday period. Outcomes (here, estimated VOMulti-level models were carried out in R [
PMC10601165
Results
overweight
HOLIDAYS, HOLIDAY
Participant characteristics are shown in Table  Participant characteristicsData are shown for the outcome with the largest sample size (n = 156 for SBJ)BMI = Body Mass Index; SES = socio-economic statusTable  Observed rates of change (means, SDs) for fatness and fitness outcomes across the study timepoints.%BF = percen...
PMC10601165
Sex
Sex did not moderate differences in rates of change for any outcome.
PMC10601165
Socio-economic status
HOLIDAYS
SES moderated differences in the rate of change in %BF and zBMI. Overall, children from lower SES families showed greater increases in fatness over the holidays compared to children from higher SES families. Every 1 SD increase in SES was associated with a 7.5%BF/year greater difference in the rate of change during the...
PMC10601165
Pubertal status
HOLIDAYS, HOLIDAY
Pubertal status moderated differences in rates of change in all fatness measures. Children who were early pubertal in Grade 4 showed relatively lower increases in all fatness measures over the holidays compared to children who were mid-pubertal (p = 0.023–0.046). In Grade 5, these differences were similar but did not r...
PMC10601165
Weight status
overweight
OBESE, HOLIDAY
Weight status moderated differences in rates of change in %BF. Compared to children of normal-weight, children who were overweight (but not obese) increased %BF relatively faster in the holiday periods than in both in-school periods (p = 0.020–0.027). The corresponding rate of decline in aerobic fitness for children wh...
PMC10601165
Discussion
PMC10601165
Main findings
weight gain, overweight, adiposity
HOLIDAYS, HOLIDAY, ADIPOSITY
The focus of this study was to compare rates of change in children’s fitness and fatness between in-school and summer holiday periods, and to explore whether differences in rates of change in these outcomes were moderated by sex, SES, pubertal status, or weight status. During the holiday period, there was a significant...
PMC10601165
Strengths and limitations
HOLIDAYS, HOLIDAY
Key strengths of the current study are its longitudinal design spanning two school years. Furthermore, it used the highest quality measures of fatness and fitness possible for collection in a school setting. Relatively few studies of children’s summer holiday fatness and fitness have been conducted outside the US, and ...
PMC10601165
Implications
weight gain
HOLIDAYS, HOLIDAY
If the holiday environment leads to increases in fatness and decreases in aerobic fitness, there are potential policy implications. Interventions targeted at the holiday period (such as summer camps and programs which offer a mix of physical and learning activities), at the home environment, or at effectively extending...
PMC10601165
Conclusion
overweight
HOLIDAY
In summary, this study provides important insights into the differential rates of change in children’s fitness and fatness during in-school and summer holiday periods. Our findings suggest that during the holiday period, there is a significant increase in the rate of change of percentage body fat and a significant decl...
PMC10601165
Acknowledgements
Not applicable.
PMC10601165
Authors’ contributions
CM
HOLIDAYS
TO and CM developed the concept for this study. TO, CM, DD, FF, GT & RG obtained funding for the original Life on Holidays study. TO, CM, EE & AM drafted the manuscript. DD performed the analysis. All authors have read and approved the final version of the manuscript and agree with the order of presentation of the auth...
PMC10601165
Funding
CM
HOLIDAYS
The life on Holidays study was funded by the National Health and Medical Research Council [grant number APP1143379] (2018–2022). The funding body played no role in the design, collection, analysis and interpretation of data or in writing the manuscript. AW is supported by NHMRC Project Grant APP143379 (2018–2022). CM i...
PMC10601165
Data Availability
Data analysed during this study will be made available upon reasonable request to the corresponding author Carol Maher by emailing her at carol.maher@unisa.edu.au.
PMC10601165
Declarations
PMC10601165
Competing interests
The authors declare no competing interests.
PMC10601165
Ethics approval and consent to participate
Ethical approval was obtained from the University of South Australia Human Research Ethics Committee, Adelaide, Australia (200980), the South Australian Department of Education and Child Development (2008-0055) and the Adelaide Catholic Education Centre (201820). All methods were carried out in accordance with relevant...
PMC10601165
Consent for publication
Not applicable.
PMC10601165
References
PMC10601165
Keywords
ChiCTR2000039383, pain, fractures, diaphragmatic paralysis, hemidiaphragmatic paresis
The sensory innervation of the clavicle is complex, and the best regional block technology for clavicular surgery has yet to be determined. The purpose of this study was to compare the application of ultrasound-guided superficial cervical plexus block combined with clavipectoral fascial plane block verses interscalene ...
PMC10371927
Introduction
upper limb muscle strength, fracture, clavicular fracture, Clavicular fracture, clavicle fracture, nausea, vomiting
ADVERSE REACTIONS, LARYNGEAL SPASM, COMPLICATIONS
Clavicular fracture is the most common injury in the shoulder, particularly in young men. It mainly occurs due to sports or traffic accidents, especially in the middle of the clavicle. Better functional results can be obtained by surgical treatment. General anaesthesia can be used during surgery, but there is a risk of...
PMC10371927
Materials and methods
PMC10371927
Study design and participants
cardio-cerebrovascular diseases, abnormal blood coagulation, allergy, fractures, hypertension
RESPIRATORY INSUFFICIENCY, ALLERGY, CORONARY HEART DISEASE, HEART FAILURE, HYPERTENSION, OBSTRUCTIVE EMPHYSEMA, PUNCTURE SITE INFECTION
This is a single-centre double-blind, randomized controlled trial of 50 patients with American Society of Anaesthesiologists (ASA) I-II at our hospital (Teaching Hospital, Residency training Hospital). This study was performed in line with the principles of the Declaration of Helsinki. Hospital ethics committee approva...
PMC10371927