The preclinical and clinical progress of cell sheet engineering in regenerative medicine.

Cell therapy is an accessible method for curing damaged organs or tissues. Yet, this approach is limited by the delivery efficiency of cell suspension injection. Over recent years, biological scaffolds have emerged as carriers of delivering therapeutic cells to the target sites. Although they can be regarded as revolutionary research output and promote the development of tissue engineering, the defect of biological scaffolds in repairing cell-dense tissues is apparent. Cell sheet engineering (CSE) is a novel technique that supports enzyme-free cell detachment in the shape of a sheet-like structure. Compared with the traditional method of enzymatic digestion, products harvested by this technique retain extracellular matrix (ECM) secreted by cells as well as cell-matrix and intercellular junctions established during in vitro culture. Herein, we discussed the current status and recent progress of CSE in basic research and clinical application by reviewing relevant articles that have been published, hoping to provide a reference for the development of CSE in the field of stem cells and regenerative medicine.

Awake prone positioning in acute hypoxaemic respiratory failure.

Awake prone positioning (APP) of patients with acute hypoxaemic respiratory failure gained considerable attention during the early phases of the coronavirus disease 2019 (COVID-19) pandemic. Prior to the pandemic, reports of APP were limited to case series in patients with influenza and in immunocompromised patients, with encouraging results in terms of tolerance and oxygenation improvement. Prone positioning of awake patients with acute hypoxaemic respiratory failure appears to result in many of the same physiological changes improving oxygenation seen in invasively ventilated patients with moderate-severe acute respiratory distress syndrome. A number of randomised controlled studies published on patients with varying severity of COVID-19 have reported apparently contrasting outcomes. However, there is consistent evidence that more hypoxaemic patients requiring advanced respiratory support, who are managed in higher care environments and who can be prone for several hours, benefit most from APP use. We review the physiological basis by which prone positioning results in changes in lung mechanics and gas exchange and summarise the latest evidence base for APP primarily in COVID-19. We examine the key factors that influence the success of APP, the optimal target populations for APP and the key unknowns that will shape future research.

An ensemble prediction model for COVID-19 mortality risk.

Background: It's critical to identify COVID-19 patients with a higher death risk at early stage to give them better hospitalization or intensive care. However, thus far, none of the machine learning models has been shown to be successful in an independent cohort. We aim to develop a machine learning model which could accurately predict death risk of COVID-19 patients at an early stage in other independent cohorts. Methods: We used a cohort containing 4711 patients whose clinical features associated with patient physiological conditions or lab test data associated with inflammation, hepatorenal function, cardiovascular function, and so on to identify key features. To do so, we first developed a novel data preprocessing approach to clean up clinical features and then developed an ensemble machine learning method to identify key features. Results: Finally, we identified 14 key clinical features whose combination reached a good predictive performance of area under the receiver operating characteristic curve 0.907. Most importantly, we successfully validated these key features in a large independent cohort containing 15 790 patients. Conclusions: Our study shows that 14 key features are robust and useful in predicting the risk of death in patients confirmed SARS-CoV-2 infection at an early stage, and potentially useful in clinical settings to help in making clinical decisions.

Analysis of the prevalence and influencing factors of anxiety and depression in the Chinese population: A cross-sectional survey.

To explore the prevalence and influencing factors of anxiety and depression symptoms among Chinese people in 2021. Investigation teams were recruited in 120 cities across the country. Based on the data from "the Seventh National Population Census in 2021″, quota sampling was conducted on the residents of these cities to obtain samples that conformed to population characteristics. Next, baseline information on research objects was collected, and the questionnaire survey was conducted through the online questionnaire Wenjuanxing platform. The Patient Health Questionnaire-9 (PHQ-9) rating scale was used to evaluate the mental state of the subjects. The correlation between baseline information and different PHQ-9 risk intervals was analyzed using the Chi-square test and Logit model. The impact of relevant risk factors on PHQ-9 scores was analyzed using the decision tree. The Chi-square test results revealed that place of residence (p = 0.438) and obesity (p = 0.443) was not significantly correlated with PHQ-9 risk intervals. According to Logit model analysis, age (p = 0.001, 95%CI 0.84-0.96), marital status (p < 0.001, 95%CI 0.71-0.89), drinking (p < 0.001, 95%CI 1.07-1.18), diabetes or hypertension (p = 0.001, 95%CI 1.11-1.47), health care (p < 0.001, 95%CI 0.53-0.66), economic welfare (p = 0.022, 95%CI 0.85-0.99), COVID-19 vaccine (p < 0.001, 95%CI 1.28-1.72), and HPV vaccine (p < 0.001, 95%CI 0.46-0.57) were potential influencing factors of PHQ-9 risk intervals. Decision tree analysis results showed that the grouping strategy in the PHQ-9 two-side groups had a better classification effect on the questionnaire population according to the PHQ-9 score characteristics. The prevalence rate of moderate to severe depression among Chinese people was about 8.29%. Age, marital status, drinking, diabetes or hypertension, health care, economic well, COVID-19 vaccine, and HPV vaccine were potential influencing factors of anxiety and depression symptoms in Chinese people.

Awake Prone Positioning in Non-Intubated Patients With Acute Hypoxemic Respiratory Failure Due to COVID-19.

BACKGROUND: Awake prone positioning (APP) has been advocated to improve oxygenation and prevent intubation of patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19). This paper aims to synthesize the available evidence on the efficacy of APP. METHODS: We performed a systematic review of proportional outcomes from observational studies to compare intubation rate in patients treated with APP or with standard care. RESULTS: A total of 46 published and 4 unpublished observational studies that included 2,994 subjects were included, of which 921 were managed with APP and 870 were managed with usual care. APP was associated with significant improvement of oxygenation parameters in 381 cases of 19 studies that reported this outcome. Among the 41 studies assessing intubation rates (870 subjects treated with APP and 852 subjects treated with usual care), the intubation rate was 27% (95% CI 19-37%) as compared to 30% (95% CI 20-42%) (P = .71), even when duration of application, use of adjunctive respiratory assist device (high-flow nasal cannula or noninvasive ventilation), and severity of oxygenation deficit were taken into account. There appeared to be a trend toward improved mortality when APP was compared with usual care (11% vs 22%), which was not statistically significant. CONCLUSIONS: APP was associated with improvement of oxygenation but did not reduce the intubation rate in subjects with acute respiratory failure due to COVID-19. This finding is limited by the high heterogeneity and the observational nature of included studies. Randomized controlled clinical studies are needed to definitively assess whether APP could improve key outcome such as intubation rate and mortality in these patients.

Lung RecruitmEnt Assessed by EleCtRical Impedance Tomography (RECRUIT): A Multicenter Study of COVID-19 ARDS.

RATIONALE: Defining lung recruitability is needed for safe positive end-expiratory pressure (PEEP) selection in mechanically ventilated patients. However, there is no simple bedside method including both assessment of recruitability and risks of overdistension as well as personalized PEEP titration. OBJECTIVES: To describe the range of recruitability using electrical impedance tomography (EIT), effects of PEEP on recruitability, respiratory mechanics and gas exchange, and a method to select optimal EIT-based PEEP . METHODS: This is the analysis of COVID-19 patients , from an ongoing multicenter prospective physiological study including patients with moderate-severe ARDS of different causes. EIT, ventilator data, hemodynamics and arterial blood gases were obtained during PEEP titration maneuvers. EIT-based optimal PEEP was defined as the crossing point of the overdistension and collapse curves during a decremental PEEP trial. Recruitability was defined as the amount of modifiable collapse when increasing PEEP from 6 to 24 cmH2O (=ΔCollapse24-6). Patients were classified as low, medium or high recruiters based on the tertiles of ΔCollapse24-6. MEASUREMENTS AND MAIN RESULTS: In 108 COVID-19 patients, recruitability varied from 0.3% to 66.9% and was unrelated to ARDS severity. EIT-based PEEP differed between groups: 10 vs. 13.5 vs. 15.5 cmH2O for low vs. medium vs. high recruitability (p<0.05). This approach assigned a different PEEP level than the highest compliance approach in 81% of patients. The protocol was well tolerated; in 4 patients the PEEP level did not reach 24 cmH2O due to hemodynamic instability. CONCLUSIONS: Recruitability varies widely among COVID-19 patients. EIT allows personalizing PEEP setting as a compromise between recruitability and overdistension. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Plasma cell-free DNA promise monitoring and tissue injury assessment of COVID-19.

Coronavirus 2019 (COVID-19) is a complex disease that affects billions of people worldwide. Currently, effective etiological treatment of COVID-19 is still lacking; COVID-19 also causes damages to various organs that affects therapeutics and mortality of the patients. Surveillance of the treatment responses and organ injury assessment of COVID-19 patients are of high clinical value. In this study, we investigated the characteristic fragmentation patterns and explored the potential in tissue injury assessment of plasma cell-free DNA in COVID-19 patients. Through recruitment of 37 COVID-19 patients, 32 controls and analysis of 208 blood samples upon diagnosis and during treatment, we report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA fragmentation characteristics reflect patient-specific physiological changes during treatment. Further analysis on cfDNA tissue-of-origin tracing reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, our work demonstrates and extends the translational merit of cfDNA fragmentation pattern as valuable analyte for effective treatment monitoring, as well as tissue injury assessment in COVID-19.

Stress load and volunteer motivation of patient volunteers in Fangcang shelter hospitals in Shanghai, China during the COVID-19 pandemic: a cross-sectional survey.

OBJECTIVES: This study aims to assess the volunteer motivation and stress load of patient volunteers in the Fangcang shelter hospitals (FSHs), examine their associations, and explore the potential influence factors of volunteer motivation. DESIGN: Cross-sectional online survey conducted from 21 April to 20 May 2022. SETTING: Questionnaires were collected from patient volunteers selected by random cluster sampling in the FSHs in Shanghai, China. PARTICIPANTS: 197 participants who met the inclusion criteria as patients who were asymptomatic or presenting with mild symptoms in the FSHs and who volunteered to assist with routine work under quarantined settings. OUTCOME MEASURES: We investigated sociodemographic information, stress load and volunteer motivation through an online survey using the Volunteer Function Inventory and the Stress Overload Scale. Comparisons between groups were conducted by applying t-tests or analysis of variance. The correlation between volunteer motivation and stress was analysed by Pearson correlation. Influencing factors of volunteer motivation were determined by multivariable linear regression models. A value of p<0.05 was used to declare statistical significance. RESULTS: The mean score of volunteer motivation of patient volunteers was 73.24 (SD 12.00), while that of stress load was 46.08 (SD 21.28). The mean scores of the personal vulnerability (PV) and event load (EL), two dimensions of stress load, were 26.99 (SD 12.46) and 19.09 (SD 9.63), respectively. The majority of the participants (136, 69.04%) were grouped in the low (PV)-low (EL) stress category. Participants' volunteer motivation was negatively correlated with stress load (r=-0.238, p<0.001), as well as PV (r=-0.188, p<0.01) and EL (r=-0.283, p<0.001). Multivariable linear regression analysis identified that the potential influencing factors of volunteer motivation were occupation (B=1.100, 95% CI 0.037 to 2.164, p=0.043), health condition (B=-3.302, 95% CI -5.287 to -1.317, p<0.001) and EL (B=-0.434, 95% CI -0.756 to -0.111, p=0.009). Participants who worked in the public sector, had better health conditions and had lower EL were more likely to have higher volunteer motivation. CONCLUSIONS: Our study suggested that reducing stress load might be a possible pathway to encourage and maintain volunteerism in the FSH context. Implications and suggestions for future research on patient volunteer recruitment and management could be drawn from our findings.

Digital Therapeutics: Emerging New Therapy for Nonalcoholic Fatty Liver Disease.

The increased prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide is particularly worrisome, as no medication has been approved to treat the disease. Lifestyle modifications aimed at promoting weight loss and weight maintenance remain the current first-line treatment for NAFLD. However, due to the lack of standard and scientific guidance and out-of-hospital supervision, long-term outcomes of lifestyle interventions for patients with NAFLD are often unsatisfactory. In addition, the COVID-19 pandemic aggravated this dilemma. At the same time, digital therapeutics (DTx) are expected to be a new method for the convenient management and treatment of patients with NAFLD and are attracting a great deal of attention. DTx, which provide evidence-based medicine through software programs for remote intervention in preventing, treating, or managing diseases, overcome the drawbacks of traditional treatment. The efficacy of the approach has already been demonstrated for some chronic diseases, but DTx have not been fully developed for NAFLD. This study reviews the concepts, clinical value, and practical applications related to DTx, with an emphasis on recommendations based on unmet needs for NAFLD. A better understanding of the current state will help clinicians and researchers develop high-quality, standardized, and efficient DTx products, with the aim of optimizing the prognosis of patients with NAFLD.

Longitudinal proteomic investigation of COVID-19 vaccination.

Although the development of COVID-19 vaccines has been a remarkable success, the heterogeneous individual antibody generation and decline over time are unknown and still hard to predict. In this study, blood samples were collected from 163 participants who next received two doses of an inactivated COVID-19 vaccine (CoronaVac®) at a 28-day interval. Using TMT-based proteomics, we identified 1,715 serum and 7,342 peripheral blood mononuclear cells (PBMCs) proteins. We proposed two sets of potential biomarkers (seven from serum, five from PBMCs) at baseline using machine learning, and predicted the individual seropositivity 57 days after vaccination (AUC = 0.87). Based on the four PBMC's potential biomarkers, we predicted the antibody persistence until 180 days after vaccination (AUC = 0.79). Our data highlighted characteristic hematological host responses, including altered lymphocyte migration regulation, neutrophil degranulation, and humoral immune response. This study proposed potential blood-derived protein biomarkers before vaccination for predicting heterogeneous antibody generation and decline after COVID-19 vaccination, shedding light on immunization mechanisms and individual booster shot planning.

Community-Level Social Support to Mitigate the Impact of Combined Frailty and Multimorbidity on Psychological Distress Among Rural Chinese Older Adults During the COVID-19 Pandemic: Multilevel Modeling Study.

BACKGROUND: Accumulating research provides evidence that the psychological health of older people deteriorated from before to during the COVID-19 pandemic. Unlike robust individuals, coexisting frailty and multimorbidity expose older adults to more complicated and wide-ranging stressors. Community-level social support (CSS) is also an important impetus for age-friendly interventions, and it is 1 of the components of social capital that is seen as an ecological-level property. To date, we have not found research that examines whether CSS buffered the adverse impacts of combined frailty and multimorbidity on psychological distress in a rural setting during COVID-19 in China. OBJECTIVE: This study explores the combined effect of frailty and multimorbidity on psychological distress in rural Chinese older adults during the COVID-19 pandemic and examines whether CSS would buffer the aforementioned association. METHODS: Data used in this study were extracted from 2 waves of the Shandong Rural Elderly Health Cohort (SREHC), and the final analytic sample included 2785 respondents who participated in both baseline and follow-up surveys. Multilevel linear mixed effects models were used to quantify the strength of the longitudinal association between frailty and multimorbidity combinations and psychological distress using 2 waves of data for each participant, and then, cross-level interactions between CSS and combined frailty and multimorbidity were included to test whether CSS would buffer the adverse impact of coexisting frailty and multimorbidity on psychological distress. RESULTS: Frail older adults with multimorbidity reported the most psychological distress compared to individuals with only 1 or none of the conditions (ß=.68, 95% CI 0.60-0.77, P<.001), and baseline coexisting frailty and multimorbidity predicted the most psychological distress during the COVID-19 pandemic (ß=.32, 95% CI 0.22-0.43, P<.001). Further, CSS moderated the aforementioned association (ß=-.16, 95% CI -0.23 to -0.09, P<.001), and increased CSS buffered the adverse effect of coexisting frailty and multimorbidity on psychological distress during the COVID-19 pandemic (ß=-.11, 95% CI -0.22 to -0.01, P=.035). CONCLUSIONS: Our findings suggest that more public health and clinical attention should be paid to psychological distress among multimorbid older adults with frailty when facing public health emergencies. This research also suggests that community-level interventions prioritizing social support mechanisms, specifically improving the average levels of social support within communities, may be an effective approach to alleviate psychological distress for rural older adults who concurrently manifest frailty and multimorbidity.

COVID-19 Vaccination as a Trigger of IgA Vasculitis: Truth or Illusion?

We read with great interest the recent article by Ramdani and colleagues in The Journal of Rheumatology on a nationwide multicenter, retrospective study conducted in France describing the status of the occurrence of IgA vasculitis (IgAV) after coronavirus disease 2019 (COVID-19) vaccination.1 We support and appreciate the authors' work and agree with their conclusions that IgA vasculitis following COVID-19 vaccination is usually benign and that a fortuitous link cannot be ruled out and now requires a worldwide pharmacovigilance study, but there are some concerns about some of the details in the article.

The functional views on response of host rabbit post coronavirus vaccination via ACE2 PET.

Molecular imaging can dynamically and quantitatively record the biochemical changes in a systemic view. In this research, SARS-CoV-2 pseudovirus was intramuscularly injected to simulate the vaccination with inactivated virus. New Zealand white rabbits were evaluated with 18F-FDG PET for inflammation and 68Ga-cyc-DX600 PET for ACE2 fluctuation, which were performed before and at 3, 7 and 14 days post injection (d P.I.); furthermore, one rabbit was vaccinated with two cycles with interval of 14 days for a longer period evaluation. Different with the vaccination-induced inflammatory response that was random and individual, ACE2 regulation was systemic and organ-specific: the liver and spleen were of a moderate decrease post injection but rebound at 14 d P.I., while there were a downward trend in heart, testis and bone marrow; besides, similar pattern of ACE2 regulation were recorded after the second injection with a relatively greater volatility. In conclusion, ACE2 PET gave a more comprehensive view on host response post vaccination, hold substantial promise in continuous monitoring of coronavirus vaccine administration and effectiveness.

Assessment of microbiota in the gut and upper respiratory tract associated with SARS-CoV-2 infection.

BACKGROUND: The human microbiome plays an important role in modulating the host metabolism and immune system. Connections and interactions have been found between the microbiome of the gut and oral pharynx in the context of SARS-CoV-2 and other viral infections; hence, to broaden our understanding of host-viral responses in general and to deepen our knowledge of COVID-19, we performed a large-scale, systematic evaluation of the effect of SARS-CoV-2 infection on human microbiota in patients with varying disease severity. RESULTS: We processed 521 samples from 203 COVID-19 patients with varying disease severity and 94 samples from 31 healthy donors, consisting of 213 pharyngeal swabs, 250 sputa, and 152 fecal samples, and obtained meta-transcriptomes as well as SARS-CoV-2 sequences from each sample. Detailed assessment of these samples revealed altered microbial composition and function in the upper respiratory tract (URT) and gut of COVID-19 patients, and these changes are significantly associated with disease severity. Moreover, URT and gut microbiota show different patterns of alteration, where gut microbiome seems to be more variable and in direct correlation with viral load; and microbial community in the upper respiratory tract renders a high risk of antibiotic resistance. Longitudinally, the microbial composition remains relatively stable during the study period. CONCLUSIONS: Our study has revealed different trends and the relative sensitivity of microbiome in different body sites to SARS-CoV-2 infection. Furthermore, while the use of antibiotics is often essential for the prevention and treatment of secondary infections, our results indicate a need to evaluate potential antibiotic resistance in the management of COVID-19 patients in the ongoing pandemic. Moreover, a longitudinal follow-up to monitor the restoration of the microbiome could enhance our understanding of the long-term effects of COVID-19. Video Abstract.