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CONFLICT OF INTEREST STATEMENT
The authors declare no actual or potential conflicts of interest that could influence this study.
PMC10519819
Ethics Statement
This study was approved (2023023H) by the Sports Science Experimental Ethics Committee of Beijing Sport University. Informed consent forms were provided and signed by all participants before participating in this study.
PMC10519819
Supporting information
Tables S1–S8. Click here for additional data file.
PMC10519819
ACKNOWLEDGEMENTS
We thank Xin Wang, Dong‐Mei Yu, Na Zhang, Shuo‐Yan Wang, and all the researchers who provided assistance and advice during our experiments.
PMC10519819
DATA AVAILABILITY STATEMENT
Data available on request from the authors.
PMC10519819
REFERENCES
PMC10519819
Subject terms
anaphylaxis, tumours, cancer, allergic toxicity, toxicity, urticaria
OVARIAN CANCER, ANAPHYLAXIS, TUMOURS, CANCER, URTICARIA
All antibodies approved for cancer therapy are monoclonal IgGs but the biology of IgE, supported by comparative preclinical data, offers the potential for enhanced effector cell potency. Here we report a Phase I dose escalation trial (NCT02546921) with the primary objective of exploring the safety and tolerability of M...
PMC10368744
Introduction
cancer
CANCER
All monoclonal antibodies in clinical use for the treatment of cancer belong to the IgG class, the most prevalent immunoglobulin in human blood
PMC10368744
Results
PMC10368744
Dose escalation
SOLID TUMOUR
Patients with any solid tumour expressing FRα using our immunohistochemical assay (Fig. 
PMC10368744
Safety
toxicities, pruritus, rash, urticaria
ADVERSE EVENTS, ADVERSE EVENT, EVENTS, URTICARIA
MOv18 IgE was generally well tolerated with the great majority of adverse events being low grade (≤2, NCI Common Terminology Criteria for Adverse Events version 4.0). The most common events were localised cutaneous toxicities including urticaria, pruritus and rash (Fig. 
PMC10368744
Pharmacodynamics
SKIN
Skin prick testing was routinely performed before each intravenous dose. In general, the reaction to MOv18 IgE in this test was indistinguishable from the negative diluent control, although a wheal reaction of up to 3 mm was also considered negative (Fig. Free FRα protein was detected at one or more time points (baseli...
PMC10368744
Anti-drug antibody responses
Samples for the ADA assay were collected from 26 patients. ADA detection was definitively confirmed, at 1 or 2 time points, in only 3 patients (Supplementary Fig. 
PMC10368744
Pharmacokinetics
Serum MOv18 IgE clearance profiles in each individual patient are shown in Fig. 
PMC10368744
Anti-tumour activity
Twenty of 24 patients, who had at least one on-treatment CT scan, were evaluable for efficacy (Fig. 
PMC10368744
Discussion
Urticaria, anaphylaxis, toxicity, cancer, rash, urticaria, pruritus
HYPERSENSITIVITY REACTIONS, OVARIAN CANCER, ANAPHYLAXIS, URTICARIA, ADVERSE EVENTS, CANCER, URTICARIA, SECONDARY
In this clinical trial of an IgE antibody for the treatment of cancer, a manageable safety profile, distinct from that of IgG drugs, was observed and preliminary evidence of efficacy demonstrated. Both anti-tumour activity and adverse events occurred at doses very much lower than typically observed for IgG antibodies. ...
PMC10368744
Methods
PMC10368744
Study design
toxicity, ovarian cancer, tumour, Cancer
DISEASE PROGRESSION, TUMOUR, OVARIAN CANCER, CANCER
This was an open-label, dose-escalating Phase I study of MOv18 IgE conducted at 4 sites in the United Kingdom. The study was undertaken under the sponsorship and management of the Cancer Research UK Centre for Drug Development, conducted in accordance with International Council for Harmonisation Good Clinical Practice ...
PMC10368744
Patients
tumour
RECRUITMENT, TUMOUR, SOLID TUMOUR
Recruitment and treatment took place between 23 February 2016 and 20 April 2021. Eligible patients had advanced or metastatic solid tumours not suitable for alternative standard treatment and were over 16 years of age. Immunohistochemical evidence of tumour FRα membrane expression was required (based on a criterion of ...
PMC10368744
Drug administration
Stock, Cancer
ADVERSE REACTIONS, DISEASE, CANCER
Drug was supplied (Cancer Research UK) and manufactured as single-use aseptic 1 mL fill in 2 mL glass vials containing a solution of MOv18 IgE at a concentration of 1 mg/mL at pH6.5 with 0.1 M sodium citrate, 30 g/L L-arginine, 50 g/L sucrose and 0.02% polysorbate 20 in water for injection. Stock was stored at 5 ± 3 °C...
PMC10368744
Dose escalation
The planned escalation in successive flat dosing cohorts was 70 μg, 250 μg, 500 μg, 700 μg, 1.5 mg, 3 mg, 6 mg and 12 mg total protein. An accelerated dose escalation scheme, starting with single-patient cohorts, was planned up to cohort 5 (1.5 mg)
PMC10368744
Cutaneous testing and basophil activation test
SKIN, POSITIVE
Skin prick testing (SPT) with a solution of MOv18 IgE antibody was undertaken in patients prior to each intravenous administration. Positive histamine and negative saline controls were included, and the presence of a wheal reaction in response to the positive control was required for a test to be considered valid (Fig....
PMC10368744
Other pharmacodynamic assays
allergic toxicity, anaphylaxis, anti-FRα
ADVERSE EVENTS, ANAPHYLAXIS, INFUSION REACTION
No features of anaphylaxis or other manifestation of allergic toxicity were observed in preclinical animal models, but in addition to the risk mitigation steps described above, serial measurements of serum tryptase were included in this trial. Tryptase is released by degranulation of activated effector cells, and eleva...
PMC10368744
Pharmacokinetic sampling and assays
Pharmacokinetic blood samples were drawn immediately pre-dose and at 0.5, 2, 4, 6, and 24 h, then 7 days, following the first dose, and 28 and 70 days after the final dose. Serum was separated from blood and stored at −70°C prior to analysis for MOv18 IgE concentrations by indirect ELISA, using a fully validated assay....
PMC10368744
Reporting summary
Further information on research design is available in the 
PMC10368744
Supplementary information
Supplementary InformationPeer Review FileReporting Summary
PMC10368744
Supplementary information
The online version contains supplementary material available at 10.1038/s41467-023-39679-9.
PMC10368744
Acknowledgements
Thomas’ NHS, Cancer
CANCER
The trial was funded and sponsored by Cancer Research UK, who collaborated with the academic authors in designing the trial, collated the clinical data, and reviewed the manuscript. The authors acknowledge additional financial support from the UK Department of Health and Cancer Research UK via Experimental Cancer Medic...
PMC10368744
Author contributions
allergy
ALLERGY
S.K., H.G., M.F., S.Can., D.J. and J.S. developed MOv18 IgE. J.S. (chief clinical investigator), S.K. (chief scientific investigator), C.C., C.B., P.J. and S.M. wrote the trial protocol. S.Car. and C.Sel. manufactured MOv18 IgE. J.S., S.K., H.B. and J.C. wrote a first draft of the manuscript, and all authors reviewed a...
PMC10368744
Peer review
PMC10368744
Data availability
The summary study data are available within this Article,
PMC10368744
Competing interests
J.S. and S.K. are co-founders of Epsilogen Ltd. H.B. is presently employed, and J.C. formerly employed, through a fund from Epsilogen Ltd. S.K., H.B., H.G., D.J, G.P. and J.S. hold patents on anti-tumour IgE antibodies. The remaining authors declare no competing interests.
PMC10368744
References
PMC10368744
Background
infection
INFECTION
The COVID-19 pandemic is characterized by rapid increases in infection burden owing to the emergence of new variants with higher transmissibility and immune escape. To date, monitoring the COVID-19 pandemic has mainly relied on passive surveillance, yielding biased epidemiological measures owing to the disproportionate...
PMC10437130
Objective
This study compared 4 different approaches of active SARS-CoV-2 surveillance focusing on feasibility and epidemiological outcomes.
PMC10437130
Methods
RECRUITMENT
A 2-factor factorial randomized controlled trial was conducted in 2020 in a German district with 700,000 inhabitants. The epidemiological outcome comprised SARS-CoV-2 prevalence and its precision. The 4 study arms combined 2 factors: individuals versus households and direct testing versus testing conditioned on symptom...
PMC10437130
Results
infections
RECRUITMENT, SARS-COV-2 INFECTION, INFECTIONS
Recruitment was conducted between November 18 and December 11, 2020. The response rates in the 4 arms varied between 34.31% (2340/6821) and 41.17% (2043/4962). The prescreening classified 16.61% (1207/7266) of the patients as COVID-19 symptomatic. Altogether, 4232 persons without prescreening and 7623 participating in ...
PMC10437130
Conclusions
This study showed that postal mailing of gargle sample kits and returning home-based self-collected liquid gargle samples followed by high-sensitivity RT-LAMP analysis is a feasible way to conduct active SARS-CoV-2 population surveillance without burdening routine diagnostic testing. Efforts to improve participation ra...
PMC10437130
Trial Registration
Deutsches Register Klinischer Studien (DRKS) DRKS00023271; https://tinyurl.com/3xenz68a
PMC10437130
International Registered Report Identifier (IRRID)
RR2-10.1186/s13063-021-05619-5
PMC10437130
Introduction
PMC10437130
Background
VIRUS, ASYMPTOMATIC SARS-COV-2, CONTAGIOUS DISEASE, INFLUENZA
Epidemiological surveillance of populations using serological or nucleic acid–based diagnostics is a well-known public health preparedness tool and is, for example, implemented in the global influenza surveillance network. Here, a system of World Health Organization collaborating centers acts mainly reactively to seaso...
PMC10437130
Objectives
active SARS-CoV-2 infection
The objective of this study was to compare 4 different approaches to population-level surveillance of active SARS-CoV-2 infection and to report the epidemiological outcomes and feasibility. The cost-effectiveness was reported separately [
PMC10437130
Methods
This study followed the principles of CONSORT (Consolidated Standards of Reporting Trials; extension for multiarm parallel-group randomized trials) statement (
PMC10437130
Ethics Approval
The trial was approved by the ethics committee at the University of Heidelberg on November 2, 2020 (amendment November 9, 2020; file number S790/2020).
PMC10437130
Participation and Informed Consent
DELETION
The study applied the Declaration of Helsinki ethical standards and adhered to the legal requirements for research on humans in Germany as stated in the guidelines for good clinical practice and the Medical Devices Act (Medizinproduktegesetz) issued by the Ministry of Health of Germany and implemented by the Federal In...
PMC10437130
Trial Registration
The trial was registered (November 30, 2020) on the German Clinical Trials Register (registration number DRKS00023271), and the study protocol has been published accordingly [
PMC10437130
Study Design
The study was designed as a 2-factor factorial, multiarm parallel randomized controlled trial. The 4 study arms represented all combinations of two factors: i) testing unconditional (A) versus testing under the condition of upstream COVID-19 symptom prescreening (B), and ii) testing individuals (1) versus households (2...
PMC10437130
Study Setting
The trial was conducted during the second SARS-CoV-2 wave in fall 2020 in Germany in Heidelberg and the Rhine-Neckar district, which is the location of Heidelberg University and the catchment area of the closely cooperating district health authority. The public health authority of the Rhine-Neckar district, also respon...
PMC10437130
Outcomes
SECONDARY
We considered effectiveness, feasibility, and costs to comprehensively inform policy makers as trade-offs are to be expected when the evidence is reviewed by an evidence-to-decision framework, for example, Grading of Recommendations, Assessment, Development, and Evaluations [The secondary outcomes were the participatio...
PMC10437130
Sample Size
infection
INFECTION
As high-quality test capacity is a limiting resource in active surveillance, we designed the study so that each arm would end up with the same number of laboratory tests, competing for feasibility, effectiveness, and cost-effectiveness. However, a composite end point was not possible, and a priori assumptions regarding...
PMC10437130
Randomization
infections
HOLIDAYS, RECRUITMENT, INFECTIONS
A stratified general population representative sample with 2 strata (Rhine-Neckar district plus Heidelberg city) and 2 different sampling approaches (Heidelberg—simple random sample and Rhine-Neckar—2 stage cluster sampling) were used to draw 3 weekly batches to avoid negative impacts on the response rate owing to unce...
PMC10437130
Recruitment and Study Materials
-11, RECRUITMENT
Study recruitment started on November 18, 2020, and ended on December 11, 2020, and one-time reminders were sent until December 16, 2020. The general implementation (including testing activities and hotlines) lasted until December 23, 2020.The study website displayed information in 5 languages (German, Turkish, English...
PMC10437130
Logistics
The study arms A1 and A2 immediately received gargle sample collection kits, whereas the study arms B1 and B2 had to complete the prescreening questionnaire first. The differences in logistics in are discussed in detail as follows:Study arm A1: Randomly selected individuals (hereinafter referred to as initially contact...
PMC10437130
Laboratory and Blinding
To enable scale-up of testing while maintaining sensitivity, an RT-LAMP was used for analyzing the liquid gargle samples. Weakly (<3 replicates positive) and clearly positive gargle samples (all replicates positive) were subsequently analyzed using RT-PCR as a confirmation test [Laboratory staff who conducted the RT-LA...
PMC10437130
Data Processing
Data cleaning was performed using SAS software (version 9.4 TS1M4; SAS Institute Inc). Statistical analyses were performed using R (version 4.1.1; R Foundation for Statistical Computing) and Stata (version 15.1; StataCorp).
PMC10437130
Statistical Methods
PMC10437130
Prescreening Questionnaire
SARS-CoV-2 infection
SARS-COV-2 INFECTION
We developed a symptom screening algorithm using machine learning. The underlying data sets were from various settings with and without SARS-CoV-2 infected patients, including samples from a general population screen and persons tested for SARS-CoV-2 infection because of symptoms or high-risk exposure (
PMC10437130
Descriptive Statistics
Differences in demographics, frequency of COVID-19 symptoms, and epidemiological variables between the trial arms were assessed using the chi-square test and ANOVA (no adjustment for multiple testing). The significance level α was set at 5%.
PMC10437130
Prevalence Estimation
The total number of SARS-CoV-2 cases was calculated using the Horvitz-Thomson estimator to account for unequal selection probabilities in the 2-stage sampling [
PMC10437130
Sensitivity Analysis
The trial was implemented in parallel to the existing passive surveillance system; hence, persons could have been captured by both systems. Some hotline callers refused to participate because they had already tested positive in the passive surveillance. Therefore, we conducted a sensitivity analysis and recalculated th...
PMC10437130
Results
PMC10437130
Recruitment
Altogether, 30,629 addresses were provided by 51 municipalities’ registration offices. After excluding duplicates, 27,908 (99.23%) addresses out of the planned sample size of 28,125 were randomly allocated to the arms (Study flowchart. A1: individuals without mandatory prescreening; A2: households without mandatory pre...
PMC10437130
Outcomes
SARS-COV-2 INFECTION, ASYMPTOMATIC SARS-COV-2
Although the prescreening was not compulsory in A1 and A2, approximately 92.71% (1894/2043) of the participants in A1 and 81.3% (730/898) of the initially contacted individuals in A2 completed the optional questionnaire. The random forest algorithm classified approximately 16.61% (1207/7266) of the initially contacted ...
PMC10437130
Prevalence Estimates
The weighted prevalence estimates (initial cases only) differed considerably between combined arms A with 0.36% (95% CI 0.14%-0.59%) and B with 0.05% (95% CI 0.00%-0.10%). However, we did not detect a significant difference between the single arms (household members in A2 and B2 included). In A1, the prevalence was 0.3...
PMC10437130
Discussion
PMC10437130
Principal Findings
INFECTION TOE
To the best of our knowledge, this is the only study to date that has simultaneously tested different approaches to active SARS-CoV-2 surveillance for the general public based on daily renewed random and population representative samples in a seamless chronology. In this paper, we focused on the feasibility and epidemi...
PMC10437130
Study Participation
throat
MAY
The overall participation rate of 36.57% (10,207/27,908) was lower than the envisaged 50%. First, the complexity of the information material necessary for a 4-arm trial might have been difficult to understand, thereby hindering a timely and appropriate participation [Complementary qualitative data from approximately 80...
PMC10437130
Acceptability of Self-Sampling
infections
INFECTIONS
In our study, mail-in gargle self-sampling proved to be feasible. The method was perceived as pleasant, allowed for high test accuracy in asymptomatic patients, and reduced the risk of spreading infections. Liquid gargle sampling was valued as more convenient than nasopharyngeal swabs, and although self-sampling was cu...
PMC10437130
Cost-Effectiveness
From an epidemiological perspective, we identified A2 as the most cost-effective strategy, closely followed by A1, based on evidence from a parallel economic evaluation [
PMC10437130
Limitations
infection
INFECTION, SARS-COV-2 INFECTION
This study had several limitations. First, the actual execution of the trial was limited to 3 weeks; time constraints limited adequate testing of the prescreening tool and impeded pilot studies. Second, random samples from most municipalities yielded a representative pool of potential participants; however, Heidelberg ...
PMC10437130
Active Versus Passive Surveillance
In Germany, the RKI’s COVID-19 figures stem from passive surveillance, aiming to capture all positive test results (tested symptomatic persons and positively tested contact persons) to monitor the pandemic’s progress. However, data are transmitted through multiple tiers from physicians and laboratories to the RKI via l...
PMC10437130
Conclusions
TB, low infection, HTN, infection, TJA
INFECTION, HTN
The pandemic developed in a highly dynamic manner in most countries, with scarcely comparable trends. The succession of gradually increasing bouts of infection has been interrupted by periods of low infection activity. There is no reason to believe that future pandemics with similar hazard potential will evolve in a le...
PMC10437130
Abbreviations
Consolidated Standards of Reporting TrialsRobert Koch Institutereverse transcription loop-mediated isothermal amplificationreal-time reverse transcription–polymerase chain reaction
PMC10437130
Data Availability
Anonymized data and a data dictionary will be made available in a public repository. Consent forms, invitation letters, and information material for the study are made available upon official request to the Network University Medicine for COVID-19 research in Germany. The study protocol has been published.
PMC10437130
Background
postoperative pulmonary complications
PULMONARY COMPLICATIONS
Neurosurgical patients represent a high-risk population for postoperative pulmonary complications (PPCs). A lower intraoperative driving pressure (DP) is related to a reduction in postoperative pulmonary complications. We hypothesized that driving pressure-guided ventilation during supratentorial craniotomy might lead ...
PMC10201743
Methods
This was a randomized trial conducted between June 2020 and July 2021 at Beijing Tiantan Hospital. Fifty-three patients undergoing supratentorial craniotomy were randomly divided into the titration group or control group at a ratio of 1 to 1. The control group received 5 cmH
PMC10201743
Results
Fifty-one patients were included in the analysis. The median (IQR [range]) DP in the titration group versus the control group was 10 (9–12 [7–13]) cmH
PMC10201743
Conclusions
Driving pressure-guided ventilation during supratentorial craniotomy did not contribute to postoperative homogeneous aeration, but it may lead to improved respiratory compliance and lower lung ultrasonography scores.
PMC10201743
Clinical trial registration
ClinicalTrials.gov NCT04421976.
PMC10201743
Supplementary Information
The online version contains supplementary material available at 10.1186/s12871-023-02144-7.
PMC10201743
Keywords
PMC10201743
Introduction
pulmonary infection
POSTOPERATIVE ATELECTASIS, PULMONARY INFECTION
In neurosurgery, due to the long-term use of general anesthesia and postoperative bed rest, the risk of postoperative atelectasis and pulmonary infection is increased [Optimization of the ventilation strategy can minimize iatrogenic injury in previously healthy lungs, reducing the incidence of PPCs [Electrical impedanc...
PMC10201743
Materials and methods
PMC10201743
Study design
This was a single-center, randomized, parallel group, patient and outcome assessor-blinded trial exploring a ventilation strategy targeting DP during supratentorial craniotomy conducted between June 21, 2020, and July 1, 2021, at Beijing Tiantan Hospital, Capital Medical University. The study adhered to the Consolidate...
PMC10201743
Study population
respiratory disease, dysphagia, pneumonia, Coma, cranial nerve damage, acute lung injury
RESPIRATORY DISEASE, DYSPHAGIA, PNEUMONIA, COMA, HEART DISEASE, ACUTE RESPIRATORY DISTRESS SYNDROME, CHRONIC LUNG DISEASE
Participants were recruited if they met the following criteria: Glasgow Coma Scale score of more than 8 points, age between 18 and 70 years, American Society of Anesthesiologists (ASA) level ≥ II, mechanical ventilation duration ≥ 2 h, and elective supratentorial craniotomy. Patients were excluded if they met at least ...
PMC10201743
Randomization and blinding
Randomization was conducted using computer-generated random numbers sealed in opaque envelopes. Patients were randomly allocated into two groups by the corresponding envelope. Knowing the group task, the anesthesiologist was responsible for the intervention, and the other researchers, blinded to the random allocation, ...
PMC10201743
Anesthesia
Smokers had quit smoking more than four weeks before surgery. For intravenous induction, sufentanil (0.2–0.3 µg ⋅ kg
PMC10201743
Ventilation protocol
Volume-controlled mechanical ventilation was provided (Datex Ohmeda S/5 Advance, General Electric Healthcare, Helsinki, Finland). All patients were preoxygenated with a 0.8 FiO
PMC10201743
Measurements
Pulmonary complications
PULMONARY COMPLICATIONS
The dynamic changes in aeration distribution can be visualized and evaluated by EIT [LUS can be used as a fast and easily available bedside test to evaluate lung areation. A-lines are a single line or multiple lines parallel to the pleural line and occur in normal lungs [To evaluate gas exchange, arterial blood gas was...
PMC10201743
Outcomes
SECONDARY
The primary outcome was the GI value immediately after extubation. The secondary outcomes were LUSs, respiratory system compliance, PaO
PMC10201743
Sample size calculation
The sample size was estimated for a previous study. A difference of 0.1 in GI between groups according to a previous study was detected [
PMC10201743
Statistical analysis
INTRAOPERATIVE BLEEDING
Categorical variables are reported as the number (proportion) of patients, normally distributed data are presented as the mean and standard deviation (SD), and nonnormally distributed data are presented as the median (IQR [range]). The Kolmogorov–Smirnov test was used to assess the normality of the distribution. For ba...
PMC10201743
Results
postoperative pulmonary complications
Of 57 patients assessed for eligibility, 4 patients did not meet the inclusion criteria, so 53 patients were randomized into two groups and received the intended interventions. One patient was excluded because he returned to the intensive care unit (ICU) with a tracheal tube after the operation in the titration group, ...
PMC10201743
Discussion
ADVERSE EFFECTS, COLLAPSED LUNG, RECRUITMENT
The main findings of this study included the following: (1) compared with a fixed 5 cmHDP is a significant mediator of PPCs. A DP of greater than 16 cmHThe GI directly represents global inhomogeneity in tidal ventilation [In this study, the LUSs were higher in the control group than in the titration group immediately a...
PMC10201743
Conclusions
Driving pressure-guided ventilation during supratentorial craniotomy did not contribute to postoperative homogeneous aeration, but it may lead to improved respiratory compliance and lower lung ultrasonography scores.
PMC10201743
Acknowledgements
We thank all the patients and the institutions for supporting this study.
PMC10201743
Authors’ contribution
RH: provided the conception, supervised the study implementation, and critical revision and reviewed the manuscript. FL: contributed to the study design, anesthesia implementation, data collection, and wrote the draft. WZ: provided the conception, performed the study, and analyzed the data. ZZ: participated in the stud...
PMC10201743
Funding
ZYLX201708
This study was supported by funding from Clinical Medicine Development of Special Funding Support (ZYLX201708; DFL20180502) and the Beijing Municipal Science & Technology Commission (Z19110700660000).
PMC10201743
Data Availability
The datasets used and analysed during the current study available from the corresponding author on reasonable request.
PMC10201743