N-protein vaccine Convacell(R) is effective against COVID-19: phase 3, randomized, double-blind, placebo-controlled clinical trial (preprint)

We have developed a Convacell(R), a COVID-19 vaccine based on the conservative viral nucleocapsid (N) protein. The N protein is evolutionary conservative and is abundantly expressed on the surface of infected cells, allowing anti-N immune response generated by Convacell(R) to rapidly clear infected cells and provide long-lasting protection against COVID-19. Convacell(R) has been demonstrated to be safe and highly immunogenic, creating immune responses lasting over a year, in phase I/II and IIb clinical trials. Phase IIb clinical trial has also demonstrated that a single dose vaccination regimen with Convacell(R) is sufficient to provide an immune response. Here we report the finding of the phase III clinical trial of Convacell(R). Two groups of volunteers from Russia have been either vaccinated with a single dose of Convacell(R) or injected with placebo, and then monitored for incidence of COVID-19 and adverse effects. Anti-N antibody titers at admission were also analyzed, to take into account for potential effects of previous virus encounters. Disease incidence over 6 months results indicate an overall vaccine efficacy of 85.2% (95% confidence interval: 67.4-93.3%). Additionally, Convacell(R) has shown a good safety profile. Overall, Convacell(R) demonstrated highly desirable qualities and good performance as a vaccine and can be considered as valuable COVID-19 preventative measure.

A Suicide Attempt Multicomponent Intervention Treatment (SAMIT Program): Study Protocol for a Multicentric Randomised Controlled Trial (preprint)

Background: Suicide has become a first-order public health concern, especially following the negative impact of COVID-19 on the mental health of the general population. Few studies have analyzed the effects of early psychotherapeutic interventions on subjects who have attempted suicide, and even fewer have focused on those hospitalized in non-psychiatric units after a medically serious suicide attempt (MSSA). The main aim of this study is to describe the protocol designed to evaluate the effectiveness of individual psychological treatment for patients hospitalized after an MSSA. The secondary objectives of the study are: 1) to evaluate the impact on quality of life and other psychosocial variables of patients with a recent MSSA who receive early psychological intervention; 2) to analyze the biological, psychological, and clinical impact of early psychotherapeutic treatment on subjects hospitalized after an MSSA. Methods: An experimental, controlled, and randomized trial will be conducted with patients over 16 years of age admitted to two general hospitals. The case intervention group will enroll for 8-sessions of individual psychotherapy, Suicide Attempts Multi-component Intervention Treatment (SAMIT), combining Dialectical Behaviour Therapy (DBT), Mentalization-Based Therapy (MBT), and Narrative approaches, while the control group will receive a treatment-as-usual intervention (TAU). Longitudinal assessment will be conducted at baseline (before treatment), post-treatment, and 3, 6, and 12 months after. The main outcome variable will be re-attempting suicide during follow-up. Discussion: Some psychotherapeutic interventions, usually implemented in outpatient, have proven to be effective in preventing suicidal behaviours. The combination of some of these may be a powerful treatment for preventing future SA in patients hospitalised after an MSSA, which is the most severely suicidal subgroup. Moreover, assessment of the biological, clinical and psychometric impact of this new intervention on patients during the first year after the attempt may help understand some of the multi-level factors associated with the effectiveness of psychotherapeutic interventions in MSSAs. The prevalence of high suicide rates requires the design of effective psychological interventions for their prevention, and also in order to design new pharmacological and psychological treatments.

Impact Of SARS-CoV-2 Pandemic On The Diagnosis Of Cervical Cancer And Precursor Lesions - A Single Center Retrospective Study (preprint)

Objective: The aim of our study was to perform a retrospective analysis of the volume of cervical screening tests, the number of patients treated with an excision method, and the incidence of invasive and non-invasive cervical during a pandemic and pre-pandemic period of 24 months. Results: There was a statistically significant age difference between the two study periods, both by the average age of patients and by age group. The mean difference was 32 years before the pan-demic and 35 years during the pandemic (p-value >0.05). The majority of patients presenting for investigations before and during the pandemic were in the 30-39-year-old age group (31.95%, respectively; 34.2% (p-value = 0.003). The biggest patient loss ratio identified by age group was in the 50–59 years: 14,53% in the pre-pandemic period and 9,1% in the pandemic period. In the pan-demic period, patients from rural areas presented in the clinical trial with a lower rate of 39.52% (83 patients) vs. 60.47% (127 patients) in urban areas. A higher percentage of patients experiencing cervicorrhagia as a clinical manifestation in the pandemic period vs. the prepandemic period, with an increase in more severe lesions in the pandemic period, has a statistical significance of 8% more newly diagnosed compared to the pre-pandemic period. Conclusion: The addressability of the patients during the COVID period was not affected in a drastic way in our study. We encountered a decrease in appointments in the age group 50–59 years and a decrease in patients with rural residence. In our study, we found an increase in cervicorrhagia as a reason for consultation in the pandemic period with a higher lesion degree, both on a pap smear and on a cervical biopsy.

Optimisation of SARS-CoV-2 culture from clinical samples for clinical trial applications (preprint)

Clinical trials of SARS-CoV-2 therapeutics often include virological secondary endpoints to compare viral clearance and viral load reduction between treatment and placebo arms. This is typically achieved using RT-qPCR, which cannot differentiate replicant competent virus from non-viable virus or free RNA, limiting its utility as an endpoint. Culture based methods for SARS-CoV-2 exist; however, these are often insensitive and poorly standardised for use as clinical trial endpoints. We report optimisation of a culture-based approach evaluating three cell lines, three detection methods, and key culture parameters. We show that Vero-ACE2-TMPRSS2 (VAT) cells in combination with RT-qPCR of culture supernatants from the first passage provides the greatest overall detection of Delta viral replication (22/32, 68.8%), being able to identify viable virus in 83.3% (20/24) of clinical samples with initial Ct values <30. Likewise, we demonstrate that RT-qPCR using culture supernatants from the first passage of Vero hSLAM cells provides the highest overall detection of Omicron viral replication (9/31, 29%), detecting live virus in 39.1% (9/23) of clinical samples with initial Ct values < 25. This assessment demonstrates that combining RT-qPCR with virological end point analysis has utility in clinical trials of therapeutics for SARS-CoV-2; however, techniques may require optimising based on dominant circulating strain.

Greater Role of Cognitive Impairment Over Fatigue in Post-COVID-19 Quality of Life: A Post-Hoc Analysis of a Randomized Controlled Trial (preprint)

BackgroundPost COVID-19 Condition (PCC) is a common and debilitating condition with significant reports of fatigue and psychosocial impairment globally. The extent to which cognitive symptoms and fatigue contribute to reduced quality of life in affected individuals remains clear. MethodsThis is a post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial that evaluated the effect of vortioxetine on cognitive function in adults with PCC. The post-hoc analysis herein aimed to determine the overall effect of baseline cognitive function [as measured by the Digit Symbol Substitution Test (DSST)] and baseline fatigue severity [as measured by the Fatigue Severity Scale (FSS)] on baseline health-related quality of life (HRQoL) [as measured by the 5-item World Health Organisation Well-Being Index (WHO-5)]. ResultsA total of 200 participants were enrolled in the primary trial. Due to missing baseline data, our statistical analysis included baseline measures of 147 individuals. Our generalized linear model analysis revealed a significant positive correlation between DSST-measured objective cognitive function and self-reported WHO-5-measured HRQoL ({beta} = 0.069, 95% CI [0.006, 0.131], p = 0.032). In contrast, our analysis revealed a significant negative correlation between FSS and WHO-5 scores ({beta} = -0.016, 95% CI [-0.021, -0.011], p < 0.001). The beta-coefficient ratio ({beta}DSST / {beta}FSS = 0.069 / 0.016) is calculated as 4.313. ConclusionsOverall, we observed that increased cognitive function was associated with increased HRQoL at baseline in adults with PCC. Moreover, we observed that increased severity of fatigue symptoms was associated with decreased HRQoL at baseline in adults with PCC. Furthermore, we observed that an improvement in cognitive function would have a four-fold greater impact on HRQoL than the effect generated by improvement in fatigue.

Subjective and Objective Measures of Cognitive Function are Correlated in Persons with Post-COVID-19 Condition: A Secondary Analysis of a Randomized Controlled Trial (preprint)

Background: It remains unclear whether subjective and objective measures of cognitive function in Post COVID-19 Condition (PCC) are correlated. The extent of correlation has mechanistic and clinical implications. Methods This post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial contains baseline data of subjective and objective measures of cognition in a rigorously characterized cohort living with PCC. Herein, we evaluated the association between subjective and objective condition function, as measured by the Perceived Deficits Questionnaire, 20-item (PDQ-20) and the Digit Symbol Substitution Test (DSST) and Trails Making Test (TMT)-A/B, respectively. Results A total of 152 participants comprised the baseline sample. Due to missing data, our statistical analyses included 150 for self-reported PDQ-20, 147 individuals for combined DSST-measured cognitive function (composite z-score of the Pen/Paper plus Online CogState Version, NcombinedDSST), 71 for in-person DSST-measured cognitive function (Pen/Paper Version), 70 for TMT-A-measured cognitive function, and 70 for TMT-B-measured cognitive function. After adjusting for age, sex, and education, PDQ-20 was significantly correlated with pen-and-paper DSST (β = -0.003, p = 0.002) and TMT-B (β = 0.003, p = 0.008) scores, but not with TMT-A scores (β = -0.001, p = 0.751). Conclusions Overall, a statistically significant correlation was observed between subjective and objective cognitive functions. Clinicians providing care for individuals with PCC who have subjective cognitive function complaints may consider taking a measurement-based approach to cognition at the point of care that focuses exclusively on patient-reported measures.

H2 inhalation therapy in patients with moderate Covid 19 (H2 COVID) : a prospective ascending-dose phase 1 clinical trial (preprint)

Introduction: The Covid-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has triggered a serious global health crisis, resulting in millions of reported deaths since its initial identification in China in November 2019. The global disparities in immunization access emphasize the urgent need for ongoing research into therapeutic interventions. This study focuses on the potential use of molecular dihydrogen (H2) inhalation as an adjunctive treatment for Covid-19. H2 therapy shows promise in inhibiting intracellular signaling pathways associated with inflammation, particularly when administered early in conjunction with nasal oxygen therapy. Methods: This Phase I study, characterized by an open-label, prospective, monocentric, and single ascending dose design, seeks to assess the safety and tolerability of the procedure in individuals with confirmed SARS-CoV-2 infection. Employing a 3+3 design, the study includes three exposure durations (target durations): 1 day (D1), 3 days (D2), and 6 days (D3). Results: We concluded that the Maximum Tolerated Duration is at least three days. Every patient showed clinical improvement and excellent tolerance to H2 therapy. Discussion/conclusion: To the best of our knowledge, this phase 1 clinical trial is the first to establish the safety of inhaling a mixture of H2 (3.6%) and N2 (96.4%) in hospitalized Covid-19 patients. The original device and method employed ensure the absence of explosion risk. The encouraging outcomes observed in the 12 patients included in the study justify further exploration through larger, controlled clinical trials.

VOLUME VERSUS PRESSURE TARGETED NON-INVASIVE VENTILATION IN AMYOTROPHIC LATERAL SCLEROSIS (VOP ALS): study protocol for a randomised controlled trial (preprint)

Introduction Amyotrophic lateral sclerosis (ALS) is a rare, idiopathic, progressive, neuromuscular disease. The prevalence in England and Wales is between 4 and 5 cases per 100,000. A significant proportion of ALS cases are complicated by respiratory and sleep impairment which can reduce health related quality of life (HRQOL) and survival. Non-invasive ventilation (NIV) is the standard of care to treat respiratory and sleep symptoms. Patients who are compliant with NIV have improved survival, HRQOL and reduced symptoms. Different modes of NIV are available and broadly fall into two categories: pressure support ventilation (PSV) and volume assured pressure support (VAPS) ventilation. A clinically enhanced version of VAPS in the form of intelligent volume assured pressure support with automatic EPAP (iVAPS-AE) is now widely available and although spontaneous timed (ST) mode is the preferred choice in ALS, to date no one mode has been shown to be superior. In this single-centre randomised controlled trial we will explore the differences in NIV compliance and effect on HRQOL, between ST and iVAPS-AE NIV modes in patients diagnosed with respiratory failure due to ALS. We also want to explore the optimal NIV mode for patients diagnosed with ALS. This trial is still in the data collection phase and has the potential to guide changes in clinical respiratory practice in ALS. Methods and Analysis VOP ALS is a single blinded, single centre, RCT exploring the impact of iVAPS-AE on patient outcomes compared to ST-mode in patients diagnosed with ALS related respiratory impairment. Primary outcome is mean NIV compliance and secondary outcome is health reported quality of life, both measured over 90 days. The study aimed to recruit 40 patients, but it was revised to 15 because of the COVID-19 pandemic. The analysis will be mainly descriptive by treatment arms and summarised with 95% confidence interval. Ethics and Dissemination VOP ALS is sponsored in the UK by University Hospitals Coventry and Warwickshire NHS Trust and has been granted ethical approval by Northwest - Haydock Research Ethics Committee Ethics Committee (REC ref: 21/NW/0326). Publication of results in a peer-reviewed journal and conference presentations are expected. Trial Registration Number: NCT05328492. Registered 4th April 2022 - Retrospectively registered, https://clinicaltrials.gov/study/NCT05328492

Publication status of 95 clinical trials of 3 COVID-19 vaccines developed by Chinese companies: An observational cohort study (preprint)

Transparency shortcomings can undermine confidence in the safety and efficacy of vaccines. This study assesses the publication status of 95 clinical trials of 3 COVID-19 vaccines developed by Chinese companies that received a World Health Organization Emergency Use Listing (EUL) and have been marketed globally. We searched trial registries and the scientific literature to assess current trial status and the public availability of results. After excluding 2 withdrawn trials, we found that at least 62/93 trials (67%) involving 307,933 patients had verifiably been completed or terminated. Only 44 of those 62 trials (71%) had published results in a peer-reviewed journal; none had tabular summary results available on a trial registry. The results of 18/62 (29%) verifiably completed or terminated trials remained unpublished. The trial status information stated in trial registries was often incorrect. Our findings reveal a substantial gap between the disclosure practices of the 3 Chinese companies and global best practice benchmarks. Transparency and global public trust in Chinese biopharmaceutical products could be improved by aligning Chinese legal disclosure requirements with those prevalent in more mature markets, or by the voluntary adoption of stronger transparency practices by Chinese companies.

Real-world Nuvaxovid COVID-19 vaccine safety profile after first 100,000 doses in Australia, 2022-2023 (preprint)

Introduction Nuvaxovid became available in Australia from February 2022, a year later than the first COVID-19 vaccines were released. It was a much-anticipated alternative vaccine for people that had either suffered an adverse event to and/or were hesitant to receive one of the mRNA or adenovirus based COVID-19 vaccines. Although safety from clinical trials was reassuring, small trial population size, relatively low administration rates worldwide and limited post-licensure intelligence meant potential rare adverse events were underinformed. Methods We conducted a retrospective observational analysis of adverse events following immunisation (AEFI) spontaneously reported to SAFEVAC, the integrated vaccine safety surveillance system used by Victoria and Western Australia, Australia. Reports received from 14 Feb 2022 to 30 June 2023 were analysed by vaccinee demographics, reported reactions and COVID-19 vaccine dose received and compared as reporting rates (RR) per 100,000 doses administered. Results 356 AEFI reports were received, following 102,946 Nuvaxovid doses administered. Rates were higher post dose 1 than dose 2 (rate ratio 1.5, p=0.0008); primary series than booster (rate ratio 2.4, p<0.0001); in females than males (rate ratio 1.4, p<0.01), especially those aged 30-49 years (RR=1.6, p=0.002). Serious AEFI included 76 chest pain (RR=73.8), two myocarditis (RR=1.9) and 20 pericarditis (RR=19.4). No cases of Guillain Barre or thrombosis with thrombocytopaenia syndromes were reported and no deaths attributable to vaccination. Conclusion The shared SAFEVAC platform enables pooling of clinically reviewed data across jurisdictions, increasing the safety profile evidence base of novel vaccines like Nuvaxovid and improving the odds for identification and description of rare events across all vaccines.

Leukopenia of Asymptomatic COVID-19 Infections under 18 Years Old in Recovery Stage (Running head: Leukopenia of Asymptomatic COVID-19 Infections) (preprint)

Objectives In December, 2019, a type of novel coronavirus which was designated novel coronavirus 2019 (2019-nCoV) by the World Health Organization (WHO) occurred in Wuhan, Hubei, China. There is limited information available on the epidemiological and clinical characteristics of patients under 18 years old in the recovery stage. To compare the difference of epidemiological and clinical characteristics of COVID-19 involving 25 patients under 18 years old in the recovery stage between confirmed and asymptomatic infections.Methods The retrospective, single-center cohort study of COVID-19 involving 25 patients under 18 years old in the recovery stage at Guizhou Provincial Staff Hospital in Guiyang, China, from January 29 to March 31, 2020; last date of follow-up was April 22. We collected and analyzed epidemiological, demographic, clinical, laboratory, radiological, and treatment data. The researchers compared the epidemiological and clinical characteristics of confirmed COVID-19 infections and asymptomatic infections.Results Among the 25 COVID infections under 18 years old, 16 (64%) were mild or moderate confirmed cases, and 9 (36%) were asymptomatic. The shortest treatment period was 6 days, the longest 26 days, and the average treatment period was 14 days. Four cases (44.4%) had visited Wuhan or had a living story in the city. There were 9 (100%) asymptomatic cases were familial cluster outbreak, with an average infection number was 6 cases among all families. The number of asymptomatic COVID-19 infections with leukopenia was significantly more than confirmed cases (p = 0.04).Conclusions Leukopenia mostly occurred in asymptomatic COVID-19 infections under 18 years old compared with the confirmed patients.Trial registration: The Chinese Clinical Trial Register (CCTR number: ChiCTR2000032458) registered this study retrospectively on 28 April 2020.

Interventions for the management of post COVID-19 condition (long COVID): Protocol for a living systematic review & network meta-analysis (preprint)

Background: Up to 15% of survivors of COVID-19 infection experience long-term health effects, including fatigue, myalgia, and impaired cognitive function, termed post COVID-19 condition or long COVID. Several trials that study the benefits and harms of various interventions to manage long COVID have been published and hundreds more are planned or are ongoing. Trustworthy systematic reviews that clarify the benefits and harms of interventions are critical to promote evidence-based practice. Objective To create and maintain a living systematic review and network meta-analysis addressing the benefits and harms of pharmacologic and non-pharmacologic interventions for the treatment and management of long COVID. Methods Eligible trials will randomize adults with long COVID, to pharmacologic or non-pharmacologic interventions, placebo, sham, or usual care. We will identify eligible studies by searches of MEDLINE, EMBASE, CINAHL, PsycInfo, AMED, and CENTRAL, from inception, without language restrictions. Reviewers will work independently and in duplicate to screen search records, collect data from eligible trials, including trial and patient characteristics and outcomes of interest, and assess risk of bias. Our outcomes of interest will include fatigue, pain, post-exertional malaise, changes in education or employment status, cognitive function, mental health, dyspnea, quality of life, patient-reported physical function, recovery, and serious adverse events. For each outcome, when possible, we will perform a frequentist random-effects network meta-analysis. When there are compelling reasons to suspect that certain interventions are only applicable or effective for a subtype of long COVID, we will perform separate network meta-analyses. The GRADE approach will guide our assessment of the certainty of evidence. We will update our living review biannually, upon the publication of a seminal trial, or when new evidence emerges that may change clinical practice. Conclusion This living systematic review and network meta-analysis will provide comprehensive, trustworthy, and up-to-date summaries of the evidence addressing the benefits and harms of interventions for the treatment and management of long COVID. We will make our findings available publicly and work with guideline producing organizations to inform their recommendations.

Identification of COVID-19 Infection from Features Extraction of Exhaled Breath Using Signal Processing Methods (preprint)

The goal of the exhaled breath waveform used in ventilation monitoring is to improve COVID-19 illness detection.  Using exhaled breath patterns to differentiate between COVID and non-COVID healthy individuals, an algorithm for valid exhaled breath waveform segmentation and feature computation is created to identify the COVID-19 infection. A two-minute exhaled breath pattern was recorded using a device and a nasal cannula sampling tube, resulting in the collection of exhaled breath waveforms from each subject. The developed algorithm is utilized to evaluate the valid exhaled breath waveforms and compute the features classified to distinguish between individuals who contracted COVID-19 infection and this who are healthy. Slope e2, activity e2 and intersection angle of expiration and inspiration phase showed p-value of 0.000, denoting the strong significance difference between COVID-19 patients and non-COVID healthy individuals. The statistical analyses revealed p-values of 0.039, 0.008, and 0.024 for area e2, mobility of e2 and complexity e3, indicating its significance in differentiating COVID-19 patients with non-COVID healthy individuals. The slope, area, and intersection angle as significant features showed good predictive power for compliance with p-value analysis with area under the receiver operating characteristic curve with 0.667, 0.693, and 0.775. Slope of e2, area of e2, intersection angle of expiration and inspiration phases are identified as the promising features to be chosen in discriminating COVID and non-COVID individuals.  Trial registration: Clinical trial approval by Medical Research and Ethics Committee (MREC), 53 Malaysia, NMRR-21-763-59692. Registered 9th June 2021 and valid till 8th June 2023.

Effectiveness of tele-exercise on muscle function and physical performance in older adults for preventing sarcopenia: A protocol for systematic review (preprint)

Introduction: Sarcopenia is characterized by the progressive weakening of muscle function that occurs with age. This condition frequently leads to frailty, disability, and even death. Research on sarcopenia prevention is growing. Tele-exercise intervention is increasingly gaining attention in this field, with the rapid advancement of the Internet and the influence of the COVID-19. However, there is a lack of empirical support for its effectiveness. Our study aims to assess the effect of tele-exercise on sarcopenia in older persons, specifically focusing on its ability to improve muscle strength, muscle mass and physical performance. Methods and analysis Searching will be performed in the following eleven databases (Medline, Embase, Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, WOS, Scopus, CBM, CNKI, WANFANG, VIP) for published trials and two trial registries (Clinicaltrials.gov and the WHO International Clinical Trials Registry Platform) for unpublished trials. Google Scholar will be utilized to find grey literatures. The criterion of inclusion will be clinical trials involving tele-exercise interventions in older adults diagnosed with sarcopenia (possible, confirmed, or severe sarcopenia). For data synthesis, we will utilize a summary table to show the major characteristics of selected trials and a summary graph to demonstrate the risk of bias using RoB 2 in each trial, which will be further discussed in a narrative synthesis. The possibility of meta-analysis for quantitative data will be assessed according to the homogeneity analysis of the trials, using the methods of fixed or random effects model. If meta-analysis is possible, subgroup analysis and sensitivity analysis will be performed as well. Publication bias will be assessed through the use of the funnel plot and Egger's linear regression test when an adequate number of trials are available. Finally, the GRADE approach will be used to classify the certainty of evidence body into four categories (high, moderate, low, and very low). Ethics and dissemination The findings of the systematic review will be shared through publishing in a peer-reviewed journal and presentation at appropriate conferences. Since we will not be utilizing specific patient data, ethical approval is unnecessary. PROSPERO registration number CRD42024516930

Application of Multidisciplinary Diagnosis and Treatment (MDT) Clinical Teaching Model in the Clinical Teaching of Some Undergraduates of Breast Diseases in Surgery (preprint)

Background Breast surgery, emerging as an independent discipline with a wealth of specialist cases and an extensive case resource library in medical history. Contemporary clinical teaching faces challenges with traditional methods unable to address students' theoretical strength and practical limitations. The COVID-19 pandemic further strained learning environments, limiting students' exposure to patient diagnosis and treatment. Conventional clinical teaching, organized by disciplines, often results in technical isolation and a narrow clinical perspective, impeding the development of well-rounded medical professionals. Multidisciplinary Comprehensive Diagnosis and Treatment (MDT) emerges as a patient-centric, collaborative approach involving various medical departments in clinical decision-making. Despite its success in clinical settings, the effectiveness of MDT in undergraduate medical education remains largely unexplored.Methods This study conducted at the Breast Department of the First Affiliated Hospital of Zhengzhou University, aimed to compare the learning outcomes of clinical interns under traditional and MDT teaching modes. In a randomized controlled trial with 140 participants, the MDT group received comprehensive training from diverse healthcare professionals, while the traditional group had standard teaching. Evaluation included pre-test and post-test assessments on knowledge acquisition, skill acquisition, and clinical decision-making. Longitudinal analysis and statistical tests, including t-tests and multiple regression, were employed.Results A total of 140 clinical medicine students participated, randomly assigned to MDT (n = 70) and Traditional Teaching Mode (n = 70) groups. Key baseline characteristics, such as age, gender, and completion rates, were comparable between groups. For each group’s pre- and post-test scores, MDT group means consistently surpassed Traditional Teaching Mode, with significant differences (p < 0.05).Correlation analysis showed that there were no significant variable correlations between individual performance characteristics and test scores. Post-training, significant score improvements were observed in both groups across all tests (p < 2.2e-16). Utilizing the Wilcoxon rank sum test, pre-test differences were not significant. However, post-test scores favored the MDT group significantly (p = 0.0016, 2.8e-09, 3.6e-07). For students pursuing a master's, no statistically significant differences in specialty choice were observed between groups, though a trend towards more MDT students choosing surgical specialties was noted.Conclusion This study pioneers the application of the MDT teaching method in breast cancer clinical education, comparing its efficacy against traditional teaching modes. Findings demonstrate that MDT-based breast cancer diagnosis and treatment education is more efficient and optimized, offering a transformative basis for clinical undergraduate education reform in China. The results advocate for the reconfiguration of multidisciplinary consultation clinical teaching and traditional methods, promising enhanced educational outcomes and heightened medical student knowledge.

Molecular hydrogen for outpatients with Covid-19 (Hydro-Covid): a phase 3, randomised, triple-blinded, adaptive, placebo-controlled, multicentre trial (preprint)

Background: Due to its antioxidative, anti-inflammatory, anti-apoptosis, and antifatigue properties, molecular hydrogen (H2) is potentially a novel therapeutic gas for acute coronavirus disease 2019 (COVID-19) patients. Aim To determine the efficacy and safety profile of hydrogen rich water (HRW) to reduce the risk of progression of COVID-19. Design and settings We conducted a phase 3, triple-blind, randomized, placebo-controlled trial to evaluate treatment with HRW started within 5 days after the onset of signs or symptoms in primary care patients with mild-to-moderate, laboratory-confirmed COVID-19 and at least one risk factor for severe COVID-19 illness. Method Participants were randomly assigned to receive HRW or placebo twice daily for 21 days. The composite primary endpoint was the incidence of clinical worsening (dyspnea, fatigue) associated with a need for oxygen therapy, hospitalization or death at day-14; the incidence of adverse events was the primary safety end point. Results A total of 675 participants were followed up until day-30. 337 in the HRW group and 338 in the placebo group. Baseline characteristics were similar in the two groups. HRW was not superior to placebo in preventing clinical worsening at day-14: in H2 group, 46.1% met a clinical deterioration, 43.5% in the placebo group, Hazard Ratio 1.09, 90% confidence interval [0.90-1.31]. One death was reported in the H2 group and 2 in the placebo group at day-30. Adverse events were reported in 91 (27%) and 89 (26.2%) participants respectively. Conclusion Twice-daily ingestion of HRW from the onset of COVID-19 symptoms for 21 days did not reduce clinical worsening. Keywords: COVID-19; Molecular Hydrogen; Administration, Oral; Primary health care; Outcome Assessment;

PFC/M1 activation and excitability: a longitudinal cohort study on fatigue symptoms in healthcare workers post-COVID-19 (preprint)

Background Fatigue is one of the most common neurological symptoms reported post coronavirus disease 2019 (COVID-19) infection. In order to establish effective early intervention strategies, more emphasis should be placed on the correlation between fatigue and cortical neurophysiological changes, especially in healthcare workers, who are at a heightened risk of COVID-19 infection.Methods A prospective cohort study was conducted involving 29 COVID-19 medical workers and 24 healthy controls. The assessment included fatigue, sleep and health quality, psychological status, and physical capacity. Functional near-infrared spectroscopy (fNIRS) was employed to detect activation of brain regions. Bilateral primary motor cortex (M1) excitabilities were measured using single- and paired-pulse transcranial magnetic stimulation. Outcomes were assessed at 1, 3, and 6 months into the disease course.Results At 1-month post-COVID-19 infection, 37.9% of patients experienced severe fatigue symptoms, dropping to 10.3% at 3 months. Interestingly, the remarkable decreased activation/excitability of bilateral prefrontal lobe (PFC) and M1 were closely linked to fatigue symptoms after COVID-19. Notably, greater increase in M1 region excitability correlated with more significant fatigue improvement. Re-infected patients exhibited lower levels of brain activation and excitability compared to single-infection patients.Conclusions Both single infection and reinfection of COVID-19 lead to decreased activation and excitability of the PFC and M1. The degree of excitability improvement in the M1 region correlates with a greater recovery in fatigue. Based on these findings, targeted interventions to enhance and regulate the excitability of M1 may represent a novel strategy for COVID-19 early rehabilitation.Trial registration The Ethics Review Committee of Xijing Hospital, No. KY20232051-F-1, registered February 3, 2023. The Chinese Clinical Trial Registry, ChiCTR2300068444, registered February 20, 2023. https://www.chictr.org.cn

Implementation and Adherence to Regular Asymptomatic Testing in a COVID-19 Vaccine Trial (preprint)

Background: For pathogens which cause infections that present asymptomatically, evaluating vaccine efficacy (VE) against asymptomatic infection is important for understanding a vaccine's potential epidemiological impact. Regular testing for subclinical infections is a potentially valuable strategy but its success hinges on participant adherence and minimising false positives. This paper describes the implementation and adherence to weekly testing in a COVID-19 vaccine trial. Methods: COV002 was a phase 2/3 trial assessing the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2. Asymptomatic infections were detected using weekly self-administered swabs for RT-PCR testing. We analysed adherence using mixed-effects regression models and estimated the probability of true and false positive asymptomatic infections using estimates of adherence and testing characteristics. Findings: 356,551 tests were self-administered by 10,811 participants during the 13-month follow-up. Median adherence was 75.0% (IQR 42.6-90.9), which translated to a 74.5% (IQR 50.9-78.8) probability of detecting a positive asymptomatic infection during the swabbing period, and between 21 and 96 false positives during VE evaluation. The odds of returning a swab declined by 8% per week and further after testing positive and unblinding. Adherence was higher in older age groups, females and non-healthcare workers. Interpretation The COV002 trial demonstrated the feasibility of running a long-term regular asymptomatic testing strategy. This information could be valuable for designing future phase III vaccine trials in which infection is an outcome. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, AstraZeneca.

Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial (preprint)

Background Tixagevimab and cilgavimab (AZD7442) are two monoclonal antibodies developed by AstraZeneca for the pre-exposure prophylaxis and treatment of patients infected by SARS-CoV-2. Its effectiveness and safety in patients hospitalized with COVID-19 was not known at the outset of this trial. Methods DisCoVeRy is a phase 3, adaptive, multicentre, randomized, controlled trial conducted in 63 sites in Europe. Participants were randomly assigned (1:1) to receive placebo or tixagevimab-cilgavimab in addition to standard of care. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale. Several clinical, virological, immunological and safety endpoints were also assessed. Findings Due to slow enrolment, recruitment was stopped on July 1st, 2022. The antigen positive modified intention-to-treat population (mITT) was composed of 173 participants randomized to tixagevimab-cilgavimab (n=91) or placebo (n=82), 91.9% (159/173) with supplementary oxygen, and 47.4% (82/173) previously vaccinated at inclusion. There was no significant difference in the distribution of the WHO ordinal scale at day 15 between the two groups (odds ratio (OR) 0.93, 95%CI [0.54-1.61]; p=0.81) nor in any clinical, virological or safety secondary endpoints. In the global mITT (n=226), neutralization antibody titers were significantly higher in the tixagevimab-cilgavimab group/patients compared to placebo at day 3 (Least-square mean differences (LSMD) 1.44, 95% Confidence interval (CI) [1.20-1.68]; p < 10-23) and day 8 (LSMD 0.91, 95%CI [0.64-1.18]; p < 10-8) and it was most important for patients infected with a pre-omicron variant, both at day 3 (LSMD 1.94, 95% CI [1.67-2.20], p < 10-25) and day 8 (LSMD 1.17, 95% CI [0.87-1.47], p < 10-9), with a significant interaction (p < 10-7 and p=0.01 at days 3 and 8, respectively). Interpretation There were no significant differences between tixagevimab-cilgavimab and placebo in clinical endpoints, however the trial lacked power compared to prespecified calculations. Tixagevimab-cilgavimab was well tolerated, with low rates of treatment related events.

COVID-19 Antibody Responses In Cystic Fibrosis